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Background: The metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential target for the treatment of psychosis that is suggested to have greater efficacy than antipsychotic medications that are currently utilized., Aims: This study sought to elucidate mechanisms of therapeutic action associated with the modulation of the mGlu5 receptor in a disordered system marked by dopamine dysfunction. We further explored epigenetic mechanisms contributing to heritable transmission of a psychosis-like phenotype in a novel heritable model of drug abuse vulnerability in psychosis., Methods: F1 generation male and female Sprague-Dawley rats that were the offspring of two neonatal quinpirole-treated (QQ) or two saline-treated (SS) animals were tested on nicotine-conditioned place preference (CPP). Regulators of G protein signaling 9 (RGS9) and β-arrestin 2 (βA2), which mediate dopamine (DA) D 2 signaling, were measured in the nucleus accumbens shell, prelimbic and infralimbic cortices. Reduced Representation Bisulfite Sequencing (RRBS) was used to analyze the cytosine methylation in these brain regions., Results: Pretreatment with the mGlu5-positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) 20 min prior to conditioning trials blocked enhanced nicotine CPP and mitigated aberrant G protein-dependent and -independent signaling in QQ animals. RRBS analysis revealed region-specific changes in several pathways, including nicotine addiction, dopamine synapses, and neural connectivity., Conclusions: These results reveal an important region-specific mechanism of action for CDPPB in a system marked by enhanced DAD 2 receptor signaling. Results additionally reveal DNA methylation as an epigenetic mechanism of heritability, further validating the current model as a useful tool for the study of psychosis and comorbid nicotine use., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to that of D1-type dopamine receptor (D1)-expressing direct pathway neurons, altered corticostriatal synaptic function precedes degeneration. D2-mediated signaling on iMSNs reduces their excitability and promotes endocannabinoid (eCB) synthesis, suppressing glutamate release from cortical afferents. D2 receptors are also expressed on glutamatergic cortical terminals, cholinergic interneurons, and dopaminergic terminals from substantia nigra where they suppress release of glutamate, acetylcholine and dopamine, respectively, and these cell types may contribute to early striatal dysfunction in HD. Thus, we used corticostriatal brain slices and optogenetic probes to directly investigate neuromodulatory signaling in the transgenic YAC128 HD mouse model., Results: Low-dose D2 agonist quinpirole reduced cortically-evoked glutamate release in dorsal striatum of premanifest YAC128 slices but not WT, and blocking type 1 cannabinoid receptors mitigated this effect. YAC128 corticostriatal brain slices also showed increased evoked dopamine and reduced evoked eCB release compared to WT, while acetylcholine signaling patterns remained relatively intact., Conclusions: These findings suggest that YAC128 corticostriatal slices show increased D2 sensitivity that is eCB-dependent, and that dopamine and eCB release are altered at an early disease stage. We provide evidence for impaired neuromodulatory signaling in early HD, guiding therapeutic efforts prior to the onset of overt motor symptoms later on., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague-Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis.

Background: Recent studies suggest that the anterior limb of the internal capsule may be an area of convergence for multiple compulsion loops. In this study, the role of different dopaminergic compulsion loops in the mechanism of obsessive-compulsive disorder (OCD) was investigated by selectively damaging dopaminergic neurons or fibers in the corresponding targets with 6-hydroxydopamine (6-OHDA) and depicting the anatomical map of various compulsion loops located in the anterior limb of the internal capsule., Methods: A total of 52 male Sprague Dawley (SD) rats were exposed to either saline (1 mL/kg, NS group, n = 6) or quinpirole (QNP, dopamine D2-agonist, 0.5 mg/kg, n = 46) twice weekly for 5 weeks. After each injection, the rats were placed on an open field to analyze aspects of their behaviour, including the number of home base visits (NOH), average time between each home base visit (ATBO), and total distance travelled (TDM). After model setup, 46 QNP rats were divided randomly into five groups: 6-OHDA anterior limb of internal capsule (AC) stereotactic injection group (QNP+AC group, n = 10), 6-OHDA mediodorsal thalamic nucleus (MD) stereotactic injection group (QNP+MD group, n = 10), 6-OHDA nucleus accumbens (NAC) stereotactic injection group (QNP+NAC group, n = 10), saline stereotactic injection group (QNP+NS-S group, n = 10), and non-surgical group (QNP+Non-S group, n = 6). In the NS group, rats simultaneously received a 6-OHDA stereotactic injection (NS+6-OHDA-S group, n = 6: AC2, MD2, NAC2). All QNP-treated rats were then continued to be given QNP twice a week for 4 weeks, and their behaviour was observed after each infusion. After 4 weeks, immunofluorescence staining was used to monitor the distribution of dopamine neurons and nerve fibers in different areas of the intervention nerve loops, and quantitative analysis was performed., Results: Compulsive behaviour declined gradually in the QNP+AC and QNP+NAC groups 3 and 4 weeks after surgery, with the QNP+AC group decreasing more rapidly. The QNP+MD group had decreased by 3 weeks after surgery but increased to almost the same level as pre-surgery at 4 weeks post-surgery. Postoperative fluorescence staining and quantitative analysis suggested the number of dopamine (DA) neurons or nerve fibers in the corresponding target area of the 6-OHDA injection were significantly reduced compared with the QNP+Non-S group., Conclusions: 6-OHDA selectively damages the targets of dopaminergic neurons or nerve fibers within the OCD loop, which somewhat alleviates compulsive behaviours. The results suggest that the AC might be the best target for therapeutic interventions for OCD., (© 2025 The Author(s). Published by IMR Press.)

Pain is a morbidity or comorbidity with a high incidence that significantly impacts the well-being of patients. In this study, we evaluated the effects of systemic administration of tramadol, a weak mu-opioid receptor (MOR) agonist, plus quinpirole (a D2-like receptor agonist). The study was performed in naïve rats and in rats with induced inflammatory and neuropathic pain. To measure the antinociceptive effect of the drugs, thermonociceptive and mechanonociceptive stimuli were applied and the emotional aspects of pain were evaluated using conditional place preference (CPP) experiments. Systemic quinpirole produced an antinociceptive effect only in naïve male rats. In naïve female animals, a small but significant pronociceptive effect was observed following quinpirole application. Tramadol plus quinpirole in male animals reversed allodynia and hyperalgesia induced by inflammatory and neuropathic insults, which were not alleviated by either drug alone. CPP experiments revealed that systemic quinpirole plus tramadol treatment was effective only in an inflammatory pain model. To evaluate whether tolerance to the antinociceptive effect was prevented by the combination of the drugs, a repeated administration five-day trial of tramadol plus quinpirole was evaluated under inflammatory pain conditions; quinpirole only slightly prevented the antinociceptive tolerance of MOR agonists. D2-like agonists are effective adjuvants for treating painful conditions in combination with a low dose of MOR agonists. Our results could lead to an investigation of whether these dopaminergic drugs in combination with opioids might reduce the MOR agonist dose while obtaining a higher analgesic effect with fewer side effects in humans., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Risky decision making involves the ability to weigh risks and rewards associated with different options to make adaptive choices. Previous work has established a necessary role for the basolateral amygdala (BLA) in mediating effective decision making under risk of punishment, but the mechanisms by which the BLA mediates this process are less clear. Because this form of decision making is profoundly sensitive to dopaminergic (DA) manipulations, we hypothesized that DA receptors in the BLA may be involved in risk-taking behavior. To test this hypothesis, male and female Long-Evans rats were trained in a decision-making task in which rats chose between a small, safe food reward and a larger food reward that was associated with a variable risk of footshock punishment. Once behavioral stability emerged, rats received intra-BLA infusions of ligands targeting distinct dopamine receptor subtypes prior to behavioral testing. Intra-BLA infusions of the dopamine D2 receptor (D2R) agonist quinpirole decreased risk taking in females at all doses, and this reduction in risk taking was accompanied by an increase in sensitivity to punishment. In males, decreased risk taking was only observed at the highest dose of quinpirole. In contrast, intra-BLA manipulations of dopamine D1 or D3 receptors (D1R and D3R, respectively) had no effect on risk taking. Considered together, these data suggest that differential D2R sensitivity in the BLA may contribute to the well-established sex differences in risk taking. Neither D1Rs nor D3Rs, however, appear to contribute to risky decision making in either sex., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Obsessive-compulsive disorder (OCD) is a mental affliction characterized by compulsive behaviors often manifested in intrusive thoughts and repetitive actions. The quinpirole model has been used with rats to replicate compulsive behaviors and study the neurophysiological processes associated with this pathology. Several changes in the dendritic spines of the medial prefrontal cortex (mPFC) and dorsolateral striatum (DLS) have been related to the occurrence of compulsive behaviors. Dendritic spines regulate excitatory synaptic contacts, and their morphology is associated with various brain pathologies. The present study was designed to correlate the occurrence of compulsive behaviors (generated by administering the drug quinpirole) with the morphology of the different types of dendritic spines in the mPFC and DLS. A total of 18 male rats were used. Half were assigned to the experimental group, the other half to the control group. The former received injections of quinpirole, while the latter rats were injected with physiological saline solution, for 10 days in both cases. After the experimental treatment, the quinpirole rats exhibited all the parameters indicative of compulsive behavior and a significant correlation with the density of stubby and wide neckless spines in both the mPFC and DLS. Dendritic spines from both mPFC and DLS neurons showed plastic changes correlatively with the expression of compulsive behavior induced by quinpirole. Further studies are suggested to evaluate the involvement of glutamatergic neurotransmission in the neurobiology of OCD., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dopamine (DA) D2 receptors (D2Rs) have 2 isoforms, a long form (D2L) and a short form (D2S). D2L is predominantly postsynaptic in the striatal medium spiny neurons and cholinergic interneurons. D2S is principally presynaptic autoreceptors in the nigrostriatal DA neurons. Recently, we demonstrated that L-3,4-dihydroxyphenylalanine (L-DOPA) augments D2L function through the coupling between D2L and GPR143, a receptor of L-DOPA that was originally identified as the gene product of ocular albinism 1. Here we show that GPR143 modifies the functions of D2L and D2S in an opposite manner. Haloperidol-induced catalepsy was attenuated in DA neuron-specific Gpr143 gene-deficient (Dat-cre;Gpr143 flox/y ) mice, compared with wild-type (Wt) mice. Haloperidol increased in vivo DA release from the dorsolateral striatum, and this increase was augmented in Gpr143 -/y mice compared with Wt mice. A D2R agonist quinpirole-induced increase in the phosphorylation of GSK3β(pGSK3β(S9)) was enhanced in Chinese hamster ovary (CHO) cells coexpressing D2L and GPR143 compared with cells expressing D2L alone, while it was suppressed in cells coexpressing D2S and GPR143 compared with D2S alone, suggesting that GPR143 differentially modifies D2R functions depending on its isoforms of D2L and D2S., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2 Bird and Mecp2 R168X mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2-like receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2-like receptor positive allosteric modulator, and quinpirole, a dopamine D2-like receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2-like receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2 Bird/+ and Mecp2 R168X/+ mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7 % CO 2 ). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2 R168X/+ and Mecp2 Bird/+ mice, while also reducing respiratory rate. These results suggest that D2-like receptors could contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of D2-like receptors alone was not sufficient to evoke these effects., (Copyright © 2024 Elsevier B.V. All rights reserved.)

An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D 1 /D 2 receptor agonist, apomorphine, and the D 2 /D 3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0 mg/kg) or vehicle from postnatal day 14-42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3 mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D 2 receptors at postnatal day 62 revealed a modest increase in D 2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D 2 R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D 2 R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D 2 Rs in the regulation of limbic information flow., Competing Interests: Declaration of competing interest Anthony A. Grace has received funds from Lundbeck, Pfizer, Lilly, Roche, Janssen, Alkermes, Newron, Takeda and Merck. The other author declares no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear., Aims: The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice., Methods: In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline ( n  = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride ( n  = 12). One day later, freezing during the CS+ and CS- was assessed., Results: We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment ( N  = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test., Conclusion: In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rationale: Antipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D 2 heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia., Objective: The current study sought to explore the use of the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) as a treatment to reduce symptoms related to psychosis and comorbid nicotine use., Methods: Neonatal treatment of animals with the dopamine D 2 -like receptor agonist quinpirole (NQ) from postnatal day (P)1-21 produces a lifelong increase in D 2 receptor sensitivity, showing relevance to psychosis and comorbid tobacco use disorder. Following an 8-day conditioning paradigm, brain tissue in the mesolimbic pathway was analyzed for several plasticity markers, including brain derived neurotrophic factor (BDNF), phosphorylated p70 ribosomal S6 kinase (phospho-p70S6K), and cadherin-13 (Cdh13)., Results: Pretreatment with CDPPB was effective to block enhanced nicotine conditioned place preference observed in NQ-treated animals. Pretreatment was additionally effective to block the nicotine-induced increase in BDNF and sex-dependent increases in cadherin-13 in the ventral tegmental area (VTA), as well as increased phospho-p70S6K in the nucleus accumbens (NAcc) shell found in NQ-treated animals., Conclusion: In conjunction with prior work, the current study suggests positive allosteric modulation of the mGlu5 receptor, an emerging target for schizophrenia therapeutics, may be effective for the treatment of comorbid nicotine abuse in psychosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Perinatal testosterone, or its metabolite estradiol, organize the brain toward a male phenotype. Male rodents with insufficient testosterone during this period fail to display sexual behavior and partner preference for receptive females in adulthood. However, cohabitation with non-reproductive conspecifics under the influence of a D2 agonist facilitates the expression of conditioned partner preference via Pavlovian learning in gonadally intact male rats. In the present experiment, three groups of neonatal PD1 males (N = 12/group) were either gonadectomized (GDX), sham-GDX, or left intact and evaluated for social preferences and sexual behaviors as adults. We then examined whether the effects of GDX could be reversed by conditioning the males via cohabitation with receptive females under the effects of the D2 agonist quinpirole (QNP) or saline, along with the size of some brain regions, such as the sexually dimorphic nucleus of the preoptic area (SDN-POA), suprachiasmatic nucleus (SCN), posterior dorsal medial amygdala (MeApd) and ventromedial hypothalamus (VMH). Results indicated that neonatal GDX resulted in the elimination of male-typical sexual behavior, an increase in same-sex social preference, and a reduction of the area of the SDN-POA. However, GDX-QNP males that underwent exposure to receptive females in adulthood increased their social preference for females and recovered the size in the SDN-POA. Although neonatal GDX impairs sexual behavior and disrupts partner preference and brain dimorphism in adult male rats, Pavlovian conditioning under enhanced D2 agonism ameliorates the effects on social preference and restores brain dimorphism in the SDN-POA without testosterone., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Early and progressive dysfunctions of the dopaminergic system from the Ventral Tegmental Area (VTA) have been described in Alzheimer's Disease (AD). During the long pre-symptomatic phase, alterations in the function of Parvalbumin interneurons (PV-INs) are also observed, resulting in cortical hyperexcitability represented by subclinical epilepsy and aberrant gamma-oscillations. However, it is unknown whether the dopaminergic deficits contribute to brain hyperexcitability in AD. Here, using the Tg2576 mouse model of AD, we prove that reduced hippocampal dopaminergic innervation, due to VTA dopamine neuron degeneration, impairs PV-IN firing and gamma-waves, weakens the inhibition of pyramidal neurons and induces hippocampal hyperexcitability via lower D2-receptor-mediated activation of the CREB-pathway. These alterations coincide with reduced PV-IN numbers and Perineuronal Net density. Importantly, L-DOPA and the selective D2-receptor agonist quinpirole rescue p-CREB levels and improve the PV-IN-mediated inhibition, thus reducing hyperexcitability. Moreover, similarly to quinpirole, sumanirole - another D2-receptor agonist and a known anticonvulsant - not only increases p-CREB levels in PV-INs but also restores gamma-oscillations in Tg2576 mice. Conversely, blocking the dopaminergic transmission with sulpiride (a D2-like receptor antagonist) in WT mice reduces p-CREB levels in PV-INs, mimicking what occurs in Tg2576. Overall, these findings support the hypothesis that the VTA dopaminergic system integrity plays a key role in hippocampal PV-IN function and survival, disclosing a relevant contribution of the reduced dopaminergic tone to aberrant gamma-waves, hippocampal hyperexcitability and epileptiform activity in early AD., (© 2024. The Author(s).)

Effective decision-making involves careful consideration of all rewarding and aversive outcomes. Importantly, negative outcomes often occur later in time, leading to underestimation, or "discounting," of these consequences. Despite the frequent occurrence of delayed outcomes, little is known about the neurobiology underlying sensitivity to delayed punishment during decision-making. The Delayed Punishment Decision-making Task (DPDT) addresses this by assessing sensitivity to delayed versus immediate punishment in rats. Rats initially avoid punished reinforcers, then select this option more frequently when delay precedes punishment. We used DPDT to examine effects of acute systemic administration of catecholaminergic drugs on sensitivity to delayed punishment in male and female adult rats. Cocaine did not affect choice of rewards with immediate punishment but caused a dose-dependent reduction in choice of delayed punishment. Neither activation nor blockade of D1-like dopamine receptor affected decision-making, but activation of D2-like dopamine receptors reduced choice of delayed punishment. D2 blockade did not attenuate cocaine's effects on decision-making, suggesting that cocaine's effects are not dependent on D2 receptor activation. Increasing synaptic norepinephrine via atomoxetine also reduced choice of delayed (but not immediate) punishment. Notably, when DPDT was modified from ascending to descending pre-punishment delays, these drugs did not affect choice of delayed or immediate punishment, although high-dose quinpirole impaired behavioral flexibility. In summary, sensitivity to delayed punishment is regulated by both dopamine and norepinephrine transmission in task-specific fashion. Understanding the neurochemical modulation of decision-making with delayed punishment is a critical step toward treating disorders characterized by aberrant sensitivity to negative consequences., (© 2023. The Psychonomic Society, Inc.)

Dopamine D2 receptor (D 2 R) is expressed in striatopallidal neurons and decreases forskolin-stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma-aminobutyric acid (GABA) release. Dopamine D3 receptor (D 3 R) mRNA is expressed in a population of striatal D 2 R-expressing neurons. Also, D 3 R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D 2 R and D 3 R colocalize in striatopallidal terminals and whether D 3 R modulates the D 2 R effect on forskolin-stimulated [ 3 H]cAMP accumulation in pallidal synaptosomes and high K + stimulated-[ 3 H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D 2 R and D 3 R functions; thus, we study whether this system regulates its functional interaction. D 2 R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K + decreases it. Both treatments increase the D 2 R inhibition of forskolin-stimulated [ 3 H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D 2 R function. Quinpirole also activates D 3 R, potentiating D 2 R inhibition of cAMP accumulation in the ophiobolin A-treated synaptosomes. D 2 R and D 3 R immunoprecipitate in pallidal synaptosomes and decrease after the kainic acid striatal lesion, indicating the striatal origin of the presynaptic receptors. CaM-kinase II alfa (CaMKIIα) immunoprecipitates with D 3 R and increases after high K + depolarization. In the presence of KN62, a CaMKIIα blocker, D 3 R potentiates D 2 R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D 3 R function regulation by CaMKIIα. Our data indicate that D 3 R potentiates the D 2 R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM-CaMKIIα system., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adolescence is a phase of substantial changes in the brain, characterized by maturational remodeling of many systems. This remodeling allows functional plasticity to adapt to a changing environment. The dopaminergic system is under morphological and physiological changes during this phase. In the present study, we investigated if changes in the dopaminergic tone alter mice behavior in a receptor and sex-specific manner, specifically at the beginning of the puberty period. We administered L-Dopa, SKF-38393 (D1 dopamine receptor agonist), and Quinpirole (D2 dopamine receptor agonist) and tested male and female mice's motor, anxiety- and depressive-like behavior. While females displayed an impaired exploratory drive, males presented an intense depressive-like response. Our results provide insights into the function of dopaminergic development in adolescent behavior and highlight the importance of studies in this time window with male and female subjects., Competing Interests: Declaration of Competing Interest The authors declare no conflicting financial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Amisulpride is an atypical benzamide antipsychotic/antidepressant, whose mechanism of action is thought to depend mainly on dopamine D2/3 receptor activity, but also with some serotonin 5-HT2B/7 effects. The present study examined the role of D2/3 receptors and 5-HT2B/7 receptors in amisulpride's discriminative stimulus. Selective agonists and antagonists of the above receptors were tested in adult, male C57BL/6 mice trained to discriminate 10 mg/kg amisulpride from vehicle in a two-lever drug discrimination assay. After acquisition of the two-lever discrimination, the amisulpride generalization curve yielded an ED50 = 0.56 mg/kg (95% CI = 0.42-0.76 mg/kg). Substitution tests found that the D2/3 antagonist raclopride (62.7% Drug Lever Responding), D2/3 agonist quinpirole (56.6% DLR), 5-HT7 agonist LP-44 (50.1% DLR) and 5-HT7 antagonist SB-269970 (36.7% DLR) produced various degrees of partial substitution for the amisulpride stimulus, whereas the 5-HT2B agonist BW 723C86 (17.9% DLR) and 5-HT2B antagonist SB-204741 (21.1% DLR) yielded negligible amisulpride-like effects. In combination tests with amisulpride, quinpirole decreased percent responding from 98.3% to 57.0% DLR, LP-44 decreased percent responding from 97.6% to 76.7% DLR, and BW 723C86 reduced percent responding from 95.66% to 74.11% DLR. Taken together, the results from stimulus generalization and antagonism studies suggest that amisulpride has a complex discriminative cue that involves mainly mixed D2/3 receptor antagonist/agonist effects and, to a lesser degree, mixed 5-HT7 receptor agonist/antagonist and perhaps 5-HT2B receptor antagonist effects., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by neuropsychiatric disturbance, cognitive impairment, and locomotor dysfunction. In the early stage (chorea) of HD, expression of dopamine D 2 receptors (D 2 R) is reduced, whereas dopamine (DA) levels are increased. Contrary, in the late stage (bradykinesia), DA levels and the expression of D 2 R and dopamine D 1 receptors (D 1 R) are reduced. 3-Nitropropionic acid (3-NPA) is a toxin that may replicate HD behavioral phenotypes and biochemical aspects. This study assessed the neurotransmitter levels, dopamine receptor gene expression, and the effect of acute exposure to quinpirole (D 2 R agonist) and eticlopride (D 2 R antagonist) in an HD model induced by 3-NPA in adult zebrafish. Quinpirole and eticlopride were acutely applied by i.p. injection in adult zebrafish after chronic treatment of 3-NPA (60 mg/kg). 3-NPA treatment caused a reduction in DA, glutamate, and serotonin levels. Quinpirole reversed the bradykinesia and memory loss induced by 3-NPA. Together, these data showed that 3-NPA acts on the dopaminergic system and causes biochemical alterations similar to late-stage HD. These data reinforce the hypothesis that DA levels are linked with locomotor and memory deficits. Thus, these findings may suggest that the use of DA agonists could be a pharmacological strategy to improve the bradykinesia and memory deficits in the late-stage HD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D 2 receptor (D 2 R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D 2 R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD., (© 2024. The Author(s).)

Obsessive-compulsive disorder (OCD) is a disabling mental condition that poses recurring bothersome intrusive thoughts, obsessions, and compulsions. Considering the positive impact of probiotics on neuropsychiatric disorders, herein, we investigated the effect of multistrain probiotic (Bifidobacterium lactis UBBLa-70, Bacillus coagulans Unique IS-2, Lactobacillus rhamnosus UBLR-58, Lactobacillus plantarum UBLP-40, Bifidobacterium infantis UBBI-01, Bifidobacterium breve UBBr-01, and glutamine) in the management of OCD-like phenotype in rats. Rats injected with quinpirole for 5 weeks showed an increased number of marble burying and self-grooming episodes. Quinpirole-injected animals also did less head dipping in the hole board test and avoided exploration of open spaces in the elevated-plus maze. These repetitive, compulsive, self-directed, and anxiety-like phenotypes were abolished after 8-week of multistrain probiotic treatment. The probiotic formulation also prevented the elevated mRNA expression of interleukin-6, tumor-necrosis factor-α, and C-reactive protein in the amygdala and dysregulated levels of 5-hydroxytryptamine, dopamine, and noradrenaline in the frontal cortex of quinpirole-injected rats. The level of brain-derived neurotrophic factor in the frontal cortex remained unaffected across the groups. The altered levels of goblet cells and crypt-to-villi ratio in quinpirole rats were prevented by multistrain probiotic treatment. The results of 16S-rRNA gene-sequencing of gut microbiota from feces contents revealed an elevation in the abundance of Allobaculum and Bifidobacterium species (specifically Bifidobacterium animalis), while the presence of Lactobacillus species (including Lactobacillus reuteri and Lactobacillus vaginalis) exhibited a decline in quinpirole-induced rats. These results imply that modifying the gut-brain axis may be a possible mechanism by which selective multistrain probiotic therapy prevents OCD-like behaviors., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Dopamine depletion associated with parkinsonism induces plastic changes in striatal medium spiny neurons (MSN) that are maladaptive and associated with the emergence of the negative side-effect of standard treatment: the abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Prevention of MSN dendritic spine loss is hypothesized to diminish liability for LID in Parkinson's disease. Blockade of striatal CaV1.3 calcium channels can prevent spine loss and significantly diminish LID in parkinsonian rats. While pharmacological antagonism with FDA approved CaV1 L-type channel antagonist dihydropyridine (DHP) drugs (e.g, isradipine) are potentially antidyskinetic, pharmacologic limitations of current drugs may result in suboptimal efficacy. To provide optimal CaV1.3 antagonism, we investigated the ability of a dual pharmacological approach to more potently antagonize these channels. Specifically, quinpirole, a D2/D3-type dopamine receptor (D2/3R) agonist, has been demonstrated to significantly reduce calcium current activity at CaV1.3 channels in MSNs of rats by a mechanism distinct from DHPs. We hypothesized that dual inhibition of striatal CaV1.3 channels using the DHP drug isradipine combined with the D2/D3 dopamine receptor agonist quinpirole prior to, and in conjunction with, levodopa would be more effective at preventing structural modifications of dendritic spines and providing more stable LID prevention. For these proof-of-principle studies, rats with unilateral nigrostriatal lesions received daily administration of vehicle, isradipine, quinpirole, or isradipine + quinpirole prior to, and concurrent with, levodopa. Development of LID and morphological analysis of dendritic spines were assessed. Contrary to our hypothesis, quinpirole monotherapy was the most effective at reducing dyskinesia severity and preventing abnormal mushroom spine formation on MSNs, a structural phenomenon previously associated with LID. Notably, the antidyskinetic efficacy of quinpirole monotherapy was lost in the presence of isradipine co-treatment. These findings suggest that D2/D3 dopamine receptor agonists when given in combination with levodopa and initiated in early-stage Parkinson's disease may provide long-term protection against LID. The negative interaction of isradipine with quinpirole suggests a potential cautionary note for co-administration of these drugs in a clinical setting., Competing Interests: Declaration of Competing Interest The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucose metabolism is reported to be regulated by the central nervous system, but it is unclear whether this regulation is altered in diabetes. We investigated whether regulation of glucose metabolism by central dopamine D 2 receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D 2 receptor agonist quinpirole and the antagonist l-sulpiride induced hyperglycemia in control mice, but not in streptozotocin (STZ)-induced diabetic mice, a type 1 diabetic model. Hyperglycemia induced by quinpirole or l-sulpiride was diminished following fasting and these drugs did not affect hyperglycemia in the pyruvate tolerance test. In addition, both quinpirole and l-sulpiride increased hepatic glucose-6-phosphatase (G6Pase) mRNA. In STZ-induced diabetic mice, dopamine and dopamine D 2 receptor mRNA in the hypothalamus, which regulates glucose homeostasis, were decreased. Hepatic glycogen and G6Pase mRNA were also decreased in STZ-induced diabetic mice. Neither quinpirole nor l-sulpiride increased hepatic G6Pase mRNA in STZ-induced diabetic mice. In diet-induced obesity mice, a type 2 diabetic model, both quinpirole and l-sulpiride induced hyperglycemia, and hypothalamic dopamine and dopamine D 2 receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D 2 receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D 2 receptors does not affect glucose levels in type 1 but does so in type 2 diabetic models. Moreover, hypothalamic dopaminergic function and hepatic glycogenolysis are decreased in the type 1 diabetic model, which reduces hyperglycemia induced by stimulation or blockade of dopamine D 2 receptors., Competing Interests: Declaration of competing interest The authors of the manuscript have no conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in an attenuation of the startle response. PPI is conserved across species and the underlying circuitry mediating this effect has been widely studied in rodents. However, recent work from our laboratories has shown an unexpected divergence between the circuitry controlling PPI in rodents as compared to macaques. The nucleus accumbens, a component of the basal ganglia, has been identified as a key modulatory node for PPI in rodents. The role of the nucleus accumbens in modulating PPI in primates has yet to be investigated. We measured whole-body PPI of the ASR in six rhesus macaques following (1) pharmacological inhibition of the nucleus accumbens using the GABA A agonist muscimol, and (2) focal application of the dopamine D2/3 agonist quinpirole (at 3 doses). We found that quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition in monkeys. These results differ from those observed in rodents, where both muscimol and quinpirole disrupt prepulse inhibition., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D 2 R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D 2 R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D 2 R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP + or MPTP treatment. Application of QNP (10 μM) alone significantly increased the viability of MPP + -treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D 2 R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D 2 R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin., (© 2023. The Author(s).)

The dopaminergic neurotransmitter system is implicated in several brain functions and behavioral processes. Alterations in it are associated with the pathogenesis of several human neurological disorders. Pharmacological agents that interact with the dopaminergic system allow the investigation of dopamine-mediated cellular and molecular responses and may elucidate the biological bases of such disorders. Zebrafish, a translationally relevant biomedical research organism, has been successfully employed in prior psychopharmacology studies. Here, we evaluated the effects of quinpirole (dopamine D2/D3 receptor agonist) in adult zebrafish on behavioral parameters, brain-derived neurotrophic factor (BDNF) and neurotransmitter levels. Zebrafish received intraperitoneal injections of 0.5, 1.0, or 2.0 mg/kg quinpirole or saline (control group) twice with an inter-injection interval of 48 h. All tests were performed 24 h after the second injection. After this acute quinpirole administration, zebrafish exhibited decreased locomotor activity, increased anxiety-like behaviors and memory impairment. However, quinpirole did not affect social and aggressive behavior. Quinpirole-treated fish exhibited stereotypic swimming, characterized by repetitive behavior followed by immobile episodes. Moreover, quinpirole treatment also decreased the number of BDNF-immunoreactive cells in the zebrafish brain. Analysis of neurotransmitter levels demonstrated a significant increase in glutamate and a decrease in serotonin, while no alterations were observed in dopamine. These findings demonstrate that dopaminergic signaling altered by quinpirole administration results in significant behavioral and neuroplastic changes in the central nervous system of zebrafish. Thus, we conclude that the use of quinpirole administration in adult zebrafish may be an appropriate tool for the analysis of mechanisms underlying neurological disorders related to the dopaminergic system., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Zebrafish are frequently used as a vertebrate model to elucidate toxicological and pharmacological mechanisms of action in the central nervous system. Pharmacological studies demonstrate that dopamine, signaling via several receptor subtypes, regulates zebrafish larval behavior. Quinpirole is a selective dopamine receptor agonist for D2 and D3 subtypes while ropinirole exhibits selectivity toward D2, D3, and D4 receptors. The main objective of this study was to determine the short-term actions of quinpirole and ropinirole on the locomotor activity and anxiolytic/anti-anxiolytic behaviors of zebrafish. Furthermore, dopamine signaling can cross talk with other neurotransmitter systems, including the GABAergic and glutamatergic system. As such, we measured transcriptional responses in these systems to determine whether dopamine receptor activation modulated GABAergic and glutaminergic systems. Ropinirole reduced locomotor activity of larval fish at concentrations of 1 μM and greater but quinpirole did not affect locomotor activity at all concentrations tested. Anxiolytic-related behaviors were also compared between the two pharmaceuticals. Noteworthy was that both dopamine receptor agonists at 1 μM increased the activity of zebrafish in the light phase of a light-dark preference test, which may be related to the activation of D2 and/or D3 receptors. In terms of interactions with other neurotransmitter systems, ropinirole up-regulated transcripts in larvae zebrafish related to both the GABAergic and glutamatergic systems (abat, gabra1, gabrb1, gad1b, gabra5, gabrg3, and grin1b). Conversely, quinpirole did not alter the abundance of any transcript measured, suggesting that dopamine-GABA interaction may involve D4-receptors, which has been noted in mammalian models. This study demonstrates pleiotropic actions of dopamine agonism on the GABA and glutamate system in larval zebrafish. This study has relevance for characterizing toxicants that act via dopamine receptors and for elucidating mechanisms of neurological disorders that involve motor circuits and multiple neurotransmitter systems, like Parkinson's disease., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

There is evidence about the importance of sex in pain. The purpose of this study was to investigate the effect of sex in the antiallodynic activity of spinal dopamine D 1 -and D 2 -like receptors in a model of fibromyalgia-type pain in rats. Reserpine induced the same extent of tactile allodynia in female and male rats. Intrathecal injection of SCH-23390 (3-30 nmol, D 1 -like receptor antagonist), pramipexole (0.15-15 nmol) or quinpirole (1-10 nmol D 2 -like receptor agonists) increased withdrawal threshold in reserpine-treated female rats. Those drugs induced a greater antiallodynic effect in female rats. Sex-difference was also observed in a nerve injury model. Ovariectomy abated the antiallodynic effect of SCH-23390 (30 nmol) in reserpine-treated rats, while systemic reconstitution of 17β-estradiol levels or intrathecal injection of estrogen receptor-α agonist protopanaxatriol in ovariectomized reserpine-treated females restored the antiallodynic effect of SCH-23390. Intrathecal administration of ICI-182,780 (estrogen receptor-α/β antagonist) or methyl-piperidino-pyrazole hydrate (estrogen receptor-α antagonist) abated 17β-estradiol-restored antiallodynic effect of SCH-23390 in rats. In contrast, ovariectomy slightly reduced the effect of pramipexole (15 nmol) or quinpirole (10 nmol) in reserpine-treated rats, whereas systemic reconstitution of 17β-estradiol levels did not modify the antiallodynic effect of both drugs. Combination 17β-estradiol/progesterone, but not 17β-estradiol nor progesterone alone, restored the antiallodynic effect of pramipexole and quinpirole in the rats. Mifepristone (progesterone receptor antagonist) abated 17β-estradiol + progesterone restoration of the antiallodynic effect of pramipexole and quinpirole. These data suggest that the antiallodynic effect of dopamine D 1 -and D 2 -like receptors in fibromyalgia-type pain depends on spinal 17β-estradiol/estrogen receptor-α and progesterone receptors, respectively., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [ 11 C]raclopride PET imaging and dopamine D 3 receptor (D 3 R) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED 50 of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between D 3 R sensitivity, represented by the ED 50 of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of D 3 R sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Dopamine (DA) is involved in neurological and physiological functions such as motor control. L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of DA, is conventionally believed to be an inert amino acid precursor of DA, and its major therapeutic effects in Parkinson's disease (PD) are mediated through its conversion to DA. On the contrary, accumulating evidence suggests that L-DOPA itself is a neurotransmitter. We here show that L-DOPA potentiates DA D2 receptor (DRD2) signaling through GPR143, the gene product of X-linked ocular albinism 1, a G-protein-coupled receptor for L-DOPA. In Gpr143-gene-deficient (Gpr143 -/y ) mice, quinpirole, a DRD2/DRD3 agonist, -induced hypolocomotion was attenuated compared to wild-type (WT) mice. Administration of non-effective dose of L-DOPA methyl ester augmented the quinpirole-induced hypolocomotion in WT mice but not in Gpr143 -/y mice. In cells co-expressing GPR143 and DRD2, L-DOPA enhanced the interaction between GPR143 and DRD2 and augmented quinpirole-induced decrease in cAMP levels. This augmentation by L-DOPA was not observed in cells co-expressing GPR143 and DRD1 or DRD3. Chimeric analysis in which the domain of GPR143 was replaced with GPR37 revealed that GPR143 interacted with DRD2 at the fifth transmembrane domain. Intracerebroventricular administration of a peptide that disrupted the interaction mitigated quinpirole-induced behavioral changes in WT mice but not in Gpr143 -/y mice. These findings provide evidence that coupling between GPR143 and DRD2 is required for selective DRD2 modulation by L-DOPA in the dorsal striatum., (© 2023 International Society for Neurochemistry.)

Impulsive behaviour on the five-choice serial reaction time task (5CSRTT), a task measuring attention and impulsivity in rodents, is known to depend on dopamine (DA) neurotransmission in the mesolimbic DA pathway. Previous research in our lab reported that systemic administration of the D2/3 agonist quinpirole, which decreases DA release in the striatum, reduced premature responses in rats performing the 5CSRTT. It is unclear, however, whether this effect is mediated by the activation of inhibitory somatodendritic receptors in the ventral tegmental area (VTA), which in turn leads to a reduction in DA release in the nucleus accumbens, a major terminal region of the mesolimbic DA pathway. In the present study, we investigated this possibility by infusing quinpirole directly into the VTA of rats during performance on the 5CSRTT. We found that quinpirole, at the highest dose, significantly reduced the frequency of premature responses on the 5CSRTT. Thus, the effects of quinpirole and other D2/3 receptor agonists to reduce this form of impulsive behaviour appear to depend on the activation of somatodendritic D2/3 receptors in the VTA., (© 2023. The Author(s).)

Background: Imaging migraine premonitory studies show increased midbrain activation consistent with the ventral tegmental area, an area involved in pain modulation and hedonic feeding. We investigated ventral tegmental area pharmacological modulation effects on trigeminovascular processing and consequent glycemic levels, which could be involved in appetite changes in susceptible migraine patients., Methods: Serotonin and pituitary adenylate cyclase-activating polypeptide receptors immunohistochemistry was performed in ventral tegmental area parabrachial pigmented nucleus of male Sprague Dawley rats. In vivo trigeminocervical complex neuronal responses to dura mater nociceptive electrical stimulation, and facial mechanical stimulation of the ophthalmic dermatome were recorded. Changes in trigeminocervical complex responses following ventral tegmental area parabrachial pigmented nucleus microinjection of glutamate, bicuculline, naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole were measured, and blood glucose levels assessed pre- and post-microinjection., Results: Glutamatergic stimulation of ventral tegmental area parabrachial pigmented nucleus neurons reduced nociceptive and spontaneous trigeminocervical complex neuronal firing. Naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole inhibited trigeminovascular spontaneous activity, and trigeminocervical complex neuronal responses to dural-evoked electrical and mechanical noxious stimulation. Trigeminovascular sensory processing through modulation of the ventral tegmental area parabrachial pigmented nucleus resulted in reduced circulating glucose levels., Conclusion: Pharmacological modulation of ventral tegmental area parabrachial pigmented nucleus neurons elicits changes in trigeminovascular sensory processing. The interplay between ventral tegmental area parabrachial pigmented nucleus activity and the sensory processing by the trigeminovascular system may be relevant to understand associated sensory and homeostatic symptoms in susceptible migraine patients.

Research characterizing the neuronal substrate of anxiety has implicated different brain areas, including the medial septal nucleus (m-SEPT). Previous reports indicated a role of dopamine and nitric oxide (NO) in anxiety-related behaviors. In this study, the extracellular single-unit recording was performed from the m-SEPT in adult male albino Wistar rats. Baseline activity was recorded for 5 min, and the post-injection recording was performed for another 5 min after the microinjection of each drug. The results showed that (1) both D1- and D2-like receptor agonists (SKF-38393 and quinpirole) enhanced the firing rate of m-SEPT neurons; (2) both D1- and D2-like antagonists (SCH-23390 and sulpiride) attenuated the firing rate of m-SEPT neurons; (3) L-arginine (NO precursor) increased the firing rate of m-SEPT neurons, but a non-specific NOS inhibitor, L-NAME, elicited no significant alterations; (4) the non-specific NOS inhibitor reversed the enhanced firing rate produced by SKF-38393 and quinpirole; (5) neither of the dopaminergic antagonists changed the enhanced activity resulted from the application of the NO precursor. These results contribute to our understanding of the complex neurotransmitter interactions in the m-SEPT and showed that both dopaminergic and NO neurotransmission are involved in the modulation of the firing rate of neurons in the m-SEPT., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Diabetes mellitus is associated with abnormalities in peripheral/central catecholaminergic systems, including changes in catecholamine levels and receptor expression., Objective: Since quinpirole-induced cardiac sympathetic inhibition is greater in diabetic than in normoglycemic rats, this study pharmacologically investigated the dopamine D 2 -like receptor subtypes that mediate cardiac sympathetic inhibition in diabetic (streptozotocin [STZ]-pretreated) pithed rats., Methods: Fifty male Wistar rats were pretreated with STZ, pithed and conditioned for spinal stimulation (C 7 -T 1 ) of the tachycardic sympathetic tone. The resulting increases in heart rate were evaluated following i.v. blocking doses of antagonists at D 2 , D 3 and D 4 receptors during a continuous i.v. infusion of quinpirole (an agonist at D 2 -like receptors) or saline (vehicle)., Results: With this experimental approach, the cardiac sympathetic inhibition produced by quinpirole in diabetic rats was: (i) unchanged after administration of vehicles and; (ii) abolished by the antagonists L-741,626 (D 2 ), SB-277011-A (D 3 ) or L-745,870 (D 4 )., Conclusion: These findings in diabetic pithed rats imply that: (i) the cardiac sympathetic inhibition by quinpirole involves activation of D 2/3/4 dopamine receptors; and (ii) there is a differential stimulation of these receptors compared to normoglycemic rats. These D 2/3/4 receptor subtypes could be a novel drug target for the therapy of typical cardiac complications of diabetes., (© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background: The pathogenesis of chronic migraine remains unresolved. Recent studies have affirmed the contribution of GLUA1-containing AMPA receptors to chronic migraine. The dopamine D2 receptor, a member of G protein-coupled receptor superfamily, has been proven to have an analgesic effect on pathological headaches. The present work investigated the exact role of the dopamine D2 receptor in chronic migraine and its effect on GLUA1-containing AMPA receptor trafficking., Methods: A chronic migraine model was established by repeated inflammatory soup stimulation. Mechanical, periorbital, and thermal pain thresholds were assessed by the application of von Frey filaments and radiant heat. The mRNA and protein expression levels of the dopamine D2 receptor were analyzed by qRT‒PCR and western blotting. Colocalization of the dopamine D2 receptor and the GLUA1-containing AMPAR was observed by immunofluorescence. A dopamine D2 receptor agonist (quinpirole) and antagonist (sulpiride), a PI3K inhibitor (LY294002), a PI3K pathway agonist (740YP), and a GLUA1-containing AMPAR antagonist (NASPM) were administered to confirm the effects of the dopamine D2 receptor, the PI3K pathway and GULA1 on central sensitization and the GLUA1-containing AMPAR trafficking. Transmission electron microscopy and Golgi-Cox staining were applied to assess the impact of the dopamine D2 receptor and PI3K pathway on synaptic morphology. Fluo-4-AM was used to clarify the role of the dopamine D2 receptor and PI3K signaling on neuronal calcium influx. The Src family kinase (SFK) inhibitor PP2 was used to explore the effect of Src kinase on GLUA1-containing AMPAR trafficking and the PI3K signaling pathway., Results: Inflammatory soup stimulation significantly reduced pain thresholds in rats, accompanied by an increase in PI3K-P110β subunit expression, loss of dopamine receptor D2 expression, and enhanced GLUA1-containing AMPA receptor trafficking in the trigeminal nucleus caudalis (TNC). The dopamine D2 receptor colocalized with the GLUA1-containing AMPA receptor in the TNC; quinpirole, LY294002, and NASPM alleviated pain hypersensitivity and reduced GLUA1-containing AMPA receptor trafficking in chronic migraine rats. Sulpiride aggravated pain hypersensitivity and enhanced GLUA1 trafficking in CM rats. Importantly, the anti-injury and central sensitization-mitigating effects of quinpirole were reversed by 740YP. Both quinpirole and LY294002 inhibited calcium influx to neurons and modulated the synaptic morphology in the TNC. Additional results suggested that DRD2 may regulate PI3K signaling through Src family kinases., Conclusion: Modulation of GLUA1-containing AMPA receptor trafficking and central sensitization by the dopamine D2 receptor via the PI3K signaling pathway may contribute to the pathogenesis of chronic migraine in rats, and the dopamine D2 receptor could be a valuable candidate for chronic migraine treatment., (© 2022. The Author(s).)

Background: The ventral pallidum (VP) is a dopaminoceptive forebrain structure regulating the ventral tegmental area (VTA) dopaminergic population activity. We have recently demonstrated that in the VP, the D2-like dopamine (DA) receptor agonist quinpirole dose dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. According to our hypothesis, quinpirole microinjected into the VP can modulate the VTA DAergic activity and influence motivation and learning processes of rats., Methods: Quinpirole was microinjected at 3 different doses into the VP of male rats, and controls received vehicle. Single unit recordings were employed to assess VTA DAergic activity. To investigate the possible reinforcing or aversive effect of quinpirole in the VP, the conditioned place preference paradigm was used., Results: Our results showed that intra-VP quinpirole microinjection regulates VTA DAergic neurons according to an inverted U-shaped dose-response curve. The largest dose of quinpirole decreased the population activity and strongly reduced burst activity of the DAergic neurons in the first hour after its application. In contrast, the 2 smaller doses increased DA population activity, but their effect started with a delay 1 hour after their microinjection. The CPP experiments revealed that the largest dose of quinpirole in the VP induced place aversion in the rats. Furthermore, the largest dose of quinpirole induced an acute locomotor activity reduction, while the medium dose led to a long-duration increase in locomotion., Conclusions: In summary, quinpirole dose dependently regulates VTA DAergic activity as well as the motivation and motor behavior of the rats at the level of the VP., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Rationale: Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment., Objective: Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure and function in an adolescent rat model of compulsivity., Methods: Juvenile Sprague-Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8)., Results: Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections., Conclusions: The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI., (© 2022. The Author(s).)

Anhedonia is characteristically preceded by chronic stress, likely involving downstream effects of glucocorticoid alterations on dopamine (DA) function. To elucidate the neural underpinnings of this interaction, we examined whether acute pharmacological modulation of DA alters reward learning after chronic mild stress (CMS). Forty-eight male Wistar rats were exposed to a 21-day CMS regime (n = 48 no stress controls) before completing the probabilistic reward task (PRT), a well-validated cross-species test of reward learning. We first examined whether stress-induced reward dysfunction could be restored by systemic injections of low-dose amisulpride (AMI), which increases DA transmission via D2-like autoreceptor blockade. Then, we investigated region-specific effects through bilateral infusions of quinpirole (QUIN), a D2-like receptor agonist, into either the nucleus accumbens core (NAcc) or medial prefrontal cortex (mPFC). Blunted reward learning in CMS animals was reversed by acute AMI administration, but this treatment did not alter reward learning in the no stress group. Elevated adrenal gland weight, a proxy for stress reactivity, predicted lower reward learning in the untreated CMS group. This effect was extinguished following AMI treatment. These findings might be attributed to significantly higher D2 receptor density in the NAcc of high stress reactive animals. To this end, NAcc QUIN infusions potentiated reward learning relative to mPFC QUIN infusions in CMS rats, but there was no effect in no stress control rats. Collectively, these findings suggest that DA modulation reverses stress-induced reward dysfunction, even among the most stress-reactive animals. The effect might depend on D2-like receptor activation in the mesolimbic system., (© 2022. The Psychonomic Society, Inc.)

Recent evidence indicates that 5-HT 1A receptors play a significant role in mediating maternal behavior in rats. Given that they also modulate the mesocortical dopamine system, we hypothesized that 5-HT 1A receptors may mediate maternal behavior, possibly by interacting with the D 2 receptor. To address this issue, we used a combination of 5-HT 1A agonist (8-OH-DPAT, 0.5 mg/kg) and two D 2 drugs (an agonist quinpirole, QUIN, 1.0 mg/kg; a potent D 2 antagonist haloperidol, HAL, 0.1 mg/kg) on rat maternal behavior in the home-cage maternal behavior and pup preference tests. We replicated the findings that acute QUIN, HAL, and 8-OH-DPAT disrupted home-cage maternal behavior. When administered in combination, pretreatment with HAL and QUIN worsened 8-OH-DPAT-induced maternal disruption and induced a decrease in the pup preference ratio. Accordingly, 8-OH-DPAT enhanced QUIN' and HAL's disruption of pup retrieval and pup preference, reversed the increase in hovering over pups induced by HAL. These findings suggest that activation of 5-HT 1A receptors enhances D 2 -mediated maternal disruption. Furthermore, given that the combination of D 2 drugs and 5-HT 1A agonists only produced an additive effect on maternal disruption, 5-HT 1A receptors may have a direct effect on maternal behavior independent of their interaction with D 2 receptors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Electrical stimulation of brain or muscle activities has gained attention for studying the molecular and cellular mechanisms involved in electric-induced responses. We recently showed zebrafish's response to electricity. Here, we hypothesized that this response is affected by the dopaminergic signaling pathways. The effects of multiple dopamine agonists and antagonists on the electric response of 6 days-postfertilization zebrafish larvae were investigated using a microfluidic device with enhanced control of experimentation and throughput. All dopamine antagonists decreased locomotor activities, while dopamine agonists did not induce similar behaviors. The D2-selective dopamine agonist quinpirole enhanced the movement. Exposure to nonselective and D1-selective dopamine agonists apomorphine and SKF-81297 caused no significant change in the electric response. Exposing larvae that were pretreated with nonselective and D2-selective dopamine antagonists butaclamol and haloperidol to apomorphine and quinpirole, respectively, restored the electric locomotion. These results reveal a correlation between electric response and dopamine signaling pathway. Furthermore, they demonstrate that electric-induced zebrafish larvae locomotion can be conditioned by modulating dopamine receptor functions. Our electrofluidic assay has profound application potential for fundamental electric-induced response research and brain disorder studies especially those related to the dopamine imbalance and as a chemical screening method when investigating biological pathways and behaviors., (© 2022 Wiley-VCH GmbH.)

Circadian genes, including Per1, in the medial shell region of nucleus accumbens (mNAcSh), regulate binge alcohol consumption. However, the upstream mechanism regulating circadian genes-induced alcohol consumption is not known. Since activation of dopamine D2 receptors (D2R) increases Per1 gene expression, we hypothesised that local infusion of quinpirole, a D2R agonist, by increasing Per1 gene expression in the mNAcSh, will increase binge alcohol consumption in mice. We performed two experiments on male C57BL/6J mice, instrumented with bilateral guide cannulas above the mNAcSh, and exposed to a 4-day drinking-in-dark (DID) paradigm. The first experiment determined the effects of bilateral infusion of quinpirole (100 ng/300 nl/site) or DMSO (Vehicle group) in the mNAcSh on Per1 gene expression and alcohol consumption. The second experiment determined the effect of antisense-induced downregulation of Per1 in the mNAcSh on the quinpirole-induced increase in alcohol consumption. Control experiments were performed by exposing the animals to sucrose (10% w/v). After the experiment, animals were euthanised, brains removed and processed for localisation of injection sites and analysis of Per1 gene expression in the mNAcSh. As compared with the DMSO, local bilateral infusion of quinpirole significantly increased the expression of Per1 in the mNAcSh along with an increase in the amount of alcohol consumed in mice exposed to DID paradigm. In addition, local antisense-induced downregulation of Per1 significantly attenuated the effects of intro-accumbal infusion of quinpirole on alcohol consumption. Our results suggest that Per1 in the mNAcSh mediates D2R activation-induced increase in alcohol consumption., (© 2022 Society for the Study of Addiction.)

In vivo administration of dopamine (DA) receptor (DR)-related drugs modulate gastric pepsinogen secretion. However, DRs on gastric pepsinogen-secreting chief cells and DA D 2 receptor (D 2 R) on somatostatin-secreting D cells were subsequently acquired. In this study, we aimed to further investigate the local effect of DA on gastric pepsinogen secretion through DRs expressed on chief cells or potential D 2 Rs expressed on D cells. To elucidate the modulation of DRs in gastric pepsinogen secretion, immunofluorescence staining, ex vivo incubation of gastric mucosa isolated from normal and D 2 R -/- mice were conducted, accompanied by measurements of pepsinogen or somatostatin levels using biochemical assays or enzyme-linked immunosorbent assays. D 1 R, D 2 R, and D 5 R-immunoreactivity (IR) were observed on chief cells in mouse gastric mucosa. D 2 R-IR was widely distributed on D cells from the corpus to the antrum. Ex vivo incubation results showed that DA and the D1-like receptor agonist SKF38393 increased pepsinogen secretion, which was blocked by the D1-like receptor antagonist SCH23390. However, D2-like receptor agonist quinpirole also significantly increased pepsinogen secretion, and D2-like receptor antagonist sulpiride blocked the promotion of DA. Besides, D2-like receptors exerted an inhibitory effect on somatostatin secretion, in contrast to their effect on pepsinogen secretion. Furthermore, D 2 R - / - mice showed much lower basal pepsinogen secretion but significantly increased somatostatin release and an increased number of D cells in gastric mucosa. Only SKF38393, not quinpirole, increased pepsinogen secretion in D 2 R - / - mice. DA promotes gastric pepsinogen secretion directly through D1-like receptors on chief cells and indirectly through D 2 R-mediated suppression of somatostatin release.

Dysfunction of the central dopamine D 2 -receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D 2 -receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D 2 -receptor-containing MSN (D 2 -MSN) may be synchronized with the activity of dopamine D 1 -receptor-containing MSN (D 1 -MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D 2 -receptor agonist quinpirole to further investigate the "D 1/ D 2 -MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D 2 -receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A 2A -receptor antagonist istradefylline, both of which may act on D 2 -MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D 1 -receptor antagonist SCH23390 and the GABA B -receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D 2 -receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D 1 -receptors and agonistic modulation of GABA B -receptors may share the discriminative stimulus effect via the activation of central dopamine D 2 -receptors., (Copyright © 2021. Published by Elsevier Inc.)

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D 2 receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D 2 agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 μM) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception., (Copyright © 2021. Published by Elsevier B.V.)

This study analyzed whether the positive allosteric modulator of metabotropic glutamate receptor type 5 (mGlu5) 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) would alleviate deficits in prepulse inhibition (PPI) and affect dopamine (DA) D 2 signaling in the dorsal striatum and prefrontal cortex (PFC) in the neonatal quinpirole (NQ) model of schizophrenia (SZ). Male and female Sprague-Dawley rats were neonatally treated with either saline (NS) or quinpirole HCL (1 mg/kg; NQ), a DAD 2 receptor agonist, from postnatal days (P) 1-21. Rats were raised to P44 and behaviorally tested on PPI from P44-P48. Before each trial, rats were subcutaneous (sc) administered saline or CDPPB (10 mg/kg or 30 mg/kg). On P50, rats were given a spontaneous locomotor activity test after CDPPB or saline administration. On P51, the dorsal striatum and PFC were evaluated for both arrestin-2 (βA-2) and phospho-AKT protein levels. NQ-treated rats demonstrated a significant deficit in PPI, which was alleviated to control levels by the 30 mg/kg dose of CDPPB. There were no significant effects of CDPPB on locomotor activity. NQ treatment increased βA-2 and decreased phospho-AKT in both the dorsal striatum and PFC, consistent with an increase DAD 2 signaling. The 30 mg/kg dose of CDPPB significantly reversed changes in βA-2 in the dorsal striatum and PFC and phospho-AKT in the PFC equivalent to controls. Both doses of CDPPB produced a decrease of phospho-AKT in the PFC compared to controls. This study revealed that a mGlu5 positive allosteric modulator was effective to alleviate PPI deficits and striatal DAD 2 signaling in the NQ model of SZ., (Copyright © 2021. Published by Elsevier Inc.)

We evaluated interactions between dopamine D2 receptor and nitric oxide (NO) actions on the regulation of anxiety and memory in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). A unilateral guide cannula was stereotaxically implanted over the right striatum. Elevated plus-maze test (EPM) test-retest protocol was employed to evaluate anxiety and memory in mice. The results revealed that injection of L-NAME (9 mg/kg) induced anxiolytic and amnesic effects, while L-arginine (9 mg/kg) produced anxiogenic and memory-improvement effects in the 6-OHDA mouse model of PD. Administration of sulpiride (20 mg/kg) induced anxiogenic and memory-improvement effects, whereas quinpirole (20 mg/kg) caused anxiolytic and amnesic effects in PD mice. Co-injection of sulpiride (5, 10, and 20 mg/kg) plus L-NAME (3 mg/kg) induced anxiolytic and amnesic effects. Co-injection of sulpiride (20 mg/kg) plus L-arginine (3 mg/kg) induced anxiogenic and memory-improvement effects. Co-administrations of quinpirole (20 mg/kg) and L-NAME (3 mg/kg) induced anxiolytic effect, but co-administration of quinpirole (20 mg/kg) plus L-arginine (3 mg/kg) caused anxiogenic and memory-improvement effects. The isobologram analysis revealed that there is a synergistic effect between sulpiride and L-arginine as well as quinpirole and L-NAME upon induction of anxiogenic and anxiolytic effects, respectively in PD mice. Our results suggested: (1) NO and dopamine D2 receptor mechanisms affect anxiety and memory in PD mice; (2) L-NAME reversed anxiogenic and memory-improvement effect induced by sulpiride; (3) Anxiolytic and amnesic effects induced by quinpirole reversed by L-arginine; (4) There is a synergistic effect between dopamine D2 receptor and NO systems on the modulation of anxiety and memory., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The development of myopia in guinea pigs can be inhibited by attenuating scleral hypoxia by increasing choroidal blood perfusion (ChBP). In this study, we reduced ChBP through surgical and pharmacological methods to determine the effect on myopia development. We also determined whether ChBP was reduced by quinpirole, a drug that enhances form-deprivation myopia (FDM)., Methods: ChBP was reduced in the right eyes of guinea pigs via transection of the temporal ciliary arteries or daily injections of phenylephrine into the inferior peribulbar space for one week during normal ocular growth. Other guinea pigs were subjected to two weeks of monocular FDM-with facemasks, along with daily injections of quinpirole, a dopamine D2 receptor agonist, to enhance the FDM. Changes in refraction, axial length, ChBP, and choroidal thickness (ChT) were measured in both treated and fellow eyes of the treatment and control groups. Scleral hypoxia labeling with pimonidazole adducts and α-smooth muscle actin (α-SMA) protein were also measured., Results: Surgical and pharmacological reduction of ChBP induced myopia development in the treated eyes. These treatments rendered the scleral hypoxia and increased scleral α-SMA expression. Furthermore, quinpirole injections, which increased the magnitude of myopia, augmented the FDM-associated reductions in ChBP and ChT and increased the levels of scleral hypoxia and α-SMA protein., Conclusions: Decreased ChBP in guinea pigs leads to scleral hypoxia and scleral myofibroblast transdifferentiation with increased α-SMA expression, ultimately resulting in myopia development. In future clinical trials, ChBP reduction can serve as a potential biomarker for early detection of myopia development.