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Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable by therapeutic approaches. However, evidence for AE-related recovery of striatal dopamine (DA) signaling or tyrosine hydroxylase (TH) loss has been inconsistent in rodent studies. This ambiguity may be related to the timing of AE intervention in relation to the status of nigrostriatal neuron loss. Here, we replicated human PD at diagnosis by establishing motor impairment with >80% striatal DA and TH loss prior to initiating AE, and assessed its potential to alleviate motor decline and restore DA and TH loss. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), biomarkers of human PD severity, changed in response to AE. 6-hydroxydopamine (6-OHDA) was infused unilaterally into rat medial forebrain bundle to induce progressive nigrostriatal neuron loss over 28 days. Moderate intensity AE (3× per week, 40 min/session), began 8-10 days post-lesion following establishment of impaired forelimb use. Striatal tissue DA, TH protein and mRNA, and serum levels of NfL/GFAP were determined 3-wks after AE began. Despite severe striatal DA depletion at AE initiation, forelimb use deficits and hypokinesia onset were alleviated by AE, without recovery of striatal DA or TH protein loss, but reduced NfL and GFAP serum levels. This proof-of-concept study shows AE alleviates motor impairment when initiated with >80% striatal DA loss without obligate recovery of striatal DA or TH protein. Moreover, the AE-related reduction of NfL and GFAP serum levels may serve as objective blood-based biomarkers of AE efficacy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Resveratrol (3,4',5-trihydroxy-trans-stilbene) has been investigated for its potential as a prophylactic against degenerative diseases. It is a sirtulin activator that has recently been shown to regulate dopaminergic systems that contribute to the behavioral effects of methamphetamine and cocaine. The present study examined the impact of resveratrol on stimulant neuropsychopharmacology in rodents. Acute resveratrol treatment (20-40mg/kg) was ineffective to alter methamphetamine (0.5mg/kg)-induced hyperactivity in mice. Rodents received resveratrol once-daily for seven days to determine the effect of repeated polyphenolic treatment. Repeated resveratrol treatment (1-20mg/kg) decreased methamphetamine (0.5mg/kg)-induced hyperactivity in mice. Methamphetamine's (0.1-60μM) efficacy to evoke [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was also attenuated by repeated resveratrol (1mg/kg) treatment. Repeated resveratrol treatment (10-20mg/kg) did not affect cocaine-induced hyperactivity in mice. Overall, these data suggest that resveratrol appears to have metaplastic and prophylactic activity to minimize the effects of methamphetamine to increase locomotor activity and evoke dopamine release. These data encourage future research to further investigate the relationship between polyphenolics and psychostimulant abuse and dependence., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-center oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na+/K+ ATPase pump (I Pump) and hyperpolarization-activated currents (I h ) playing key roles. Modulation of either I Pump or I h produced transitions between episodic and continuous rhythms and silence. As maximal activity of I Pump decreased, the interepisode interval and period increased along with a reduction in episode duration. Decreasing maximal conductance of I h decreased episode duration and increased interepisode interval. Pharmacological manipulations of I h with ivabradine, and I Pump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modeling and experimental results highlight key roles of I h and I Pump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity. [ABSTRACT FROM AUTHOR]

Microalgae of Dunaliella salina possesses multiple biological properties which are mainly attributed to the active compounds such as polyphenol, chlorophyll and β-carotene. However, the utilization of D. salina as a neuroprotective agent in the management of Parkinson's disease is still questionable. Presently, we observed the potential neuromodulatory effects of D. salina extract against the toxicity exposed to paraquat in fruit fly (Drosophila melanogaster). Male wild-type fruit flies were concomitantly induced by paraquat (3.5mM) and methanolic extract of D. salina (200μg/mL) in their diet during 4 days of observation. Paraquat-fed fruit flies exhibited a higher incidence mortality and severe influence on locomotor phenotypes (i.e. negative geotaxis) compared to the control. D. salina extract treatment that showed protection ability against these deleterious effects of paraquat. However, paraquat exposure caused a marked increase in malondialdehide (MDA) levels as indicating increase lipid peroxidation process in brains of fruit flies. Meanwhile, paraquat toxicity was also related to a significant decrease on dopamine levels in head of fruit flies, which were attenuated by D. salina extract treatment. Results revealed that D. salina extract significantly reduced the toxicity of paraquat compounds exposed to fruit flies and proved the usefulness of this model as a potential therapeutic strategy for symptoms that appear in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Parabens can potentially disrupt the hormonal regulation of energy metabolism, leading to issues related to obesity, metabolic health, and the cardiovascular and nervous systems. However, the health effects of parabens have yielded conflicting research results. The impact of these substances on aquatic organisms, specifically their neuro- and cardio-toxic effects, has been insufficiently investigated. Hence, the primary goal of our research was to investigate and comprehensively assess the neuro- and cardio-toxic effects of four distinct parabens using the Daphnia magna model. After 48 h of exposure to various concentrations (0.1, 1, and 10 mg/L) of four parabens (methyl-, ethyl-, propyl-, and butyl-paraben), along with a solvent control, we conducted a series of physiological tests, behavioral observations, and gene transcription analyses, focusing on cardiomyopathy, serotonin, glutamate, dopamine, GABA, acetylcholine receptors, and ion flux. From a physiological perspective, the heart rate and thoracic limb activity of the exposed daphnids showed substantial time- and dose-dependent inhibitions. Notably, among the parabens tested, butylparaben exhibited the most potent inhibition, with significant alterations in cardiomyopathy-related gene transcription. In the context of neurotoxicity, all the parabens had a significant impact on gene expression, with methylparaben having the most pronounced effect. Additionally, significant changes were observed in parameters such as distance moved, the distance between individuals, and the extent of body contact among the daphnids. In summary, our findings indicate that each paraben has the capacity to induce neurobehavioral and cardiotoxic disorders in Daphnia magna. The effects of butylparaben on the cardiovascular and nervous systems were found to be the most pronounced. These discoveries showed the potential ecological implications of paraben exposure in aquatic ecosystems, particularly regarding the predator avoidance abilities of Daphnia magna. • The neuro- and cardio-toxicity of parabens in Daphnia magna were assessed. • Parabens inhibited heart rate and limb activity of D. magna. • Butyl- and methylparaben were the most cardiotoxic and neurotoxic, respectively. • All parabens altered neurotoxicity-related genes in D. magna. • Parabens affected the behavior and distance moved in D. magna. [ABSTRACT FROM AUTHOR]

Drug addiction is a chronic brain disorder characterized by the compulsive repeated use of drugs. The reinforcing effect of repeated use of drugs on reward plays an important role in morphine-induced addictive behaviors. The nucleus accumbens (NAc) is an important site where morphine treatment produces its reinforcing effect on reward. However, how morphine treatment produces its reinforcing effect on reward in the NAc remains to be clarified. In the present study, we studied the influence of morphine treatment on the effects of DA and observed whether morphine treatment could directly change glutamatergic synaptic transmission in the NAc. We also explored the functional significance of morphine-induced potentiation of glutamatergic synaptic transmission in the NAc at behavioral level. Our results show that (1) morphine treatment removes the inhibitory effect of DA on glutamatergic input onto NAc neurons; (2) morphine treatment potentiates glutamatergic input onto NAc neurons, especially the one from the basolateral amygdala (BLA) to the NAc; (3) blockade of glutamatergic synaptic transmission in the NAc or ablation of projection neurons from BLA to NAc significantly decreases morphine treatment-induced increase in locomotor activity. These results suggest that morphine treatment enhances glutamatergic input onto neurons of the NAc via both disinhibitory and stimulating effect and therefore increases locomotor activity. [ABSTRACT FROM AUTHOR]

Probiotics, defined as live bacteria or bacterial products, confer a significant health benefit to the host, including amelioration of anxiety-like behavior and psychiatric illnesses. Here we administered Lactobacillus plantarum PS128 (PS128) to a germ-free (GF) mouse model to investigate the impact of the gut–brain axis on emotional behaviors. First, we demonstrated that chronic administration of live PS128 showed no adverse effects on physical health. Then, we found that administration of live PS128 significantly increased the total distance traveled in the open field test and decreased the time spent in the closed arm in the elevated plus maze test, whereas the administration of PS128 had no significant effects in the depression-like behaviors of GF mice. Also, chronic live PS128 ingestion significantly increased the levels of both serotonin and dopamine in the striatum, but not in the prefrontal cortex or hippocampus. These results suggest that the chronic administration of PS128 is safe and could induce changes in emotional behaviors. The behavioral changes are correlated with the increase in the monoamine neurotransmitters in the striatum. These findings suggest that daily intake of the L. plantarum strain PS128 could improve anxiety-like behaviors and may be helpful in ameliorating neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) acts through nicotinic and muscarinic ACh receptors in the ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson’s disease, and schizophrenia. α6-Containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. Here, we used genetic, pharmacological, behavioral, and biophysical approaches to study this nAChR subtype. For many experiments, we used mice expressing mutant α6 nAChRs (“α6L9S” mice) that increase the sensitivity of these receptors to agonists such as ACh and nicotine. Taking advantage of a simple behavioral phenotype exhibited by α6L9S mice, we compared the ability of full versus partial α6 ∗ nAChR agonists to activate α6 ∗ nAChRs in vivo . Using local infusions of both agonists and antagonists into the brain, we demonstrate that neurons and nAChRs in the midbrain are sufficient to account for this behavioral response. To complement these behavioral studies, we studied the ability of in vivo α6 ∗ nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch-clamp electrophysiology, we show that activating α6 ∗ nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in ventral tegmental area (VTA) DA neurons. Together, these results from in vivo studies strongly suggest that α6 ∗ nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine. [ABSTRACT FROM AUTHOR]

LMTK3 belongs to the LMTK family of protein kinases that are predominantly expressed in the brain. Physiological functions of LMTK3 and other members of the LMTK family in the CNS remain unknown. In this study, we performed a battery of behavioral analyses using Lmtk3-/-mice and showed that these mice exhibit abnormal behaviors, including pronounced locomotor hyperactivity, reduced anxiety behavior, and decreased depression-like behavior. Concurrently, the dopamine metabolite levels and dopamine turnover rate are increased in the striata of Lmtk3-/-mice compared with wild-type controls. In addition, using cultured primary neurons from Lmtk3-/-mice, we found that LMTK3 is involved in the endocytic trafficking of N-methyl-d-aspartate receptors, a type of ionotropic glutamate receptor. Altered membrane traffic of the receptor in Lmtk3-/-neurons may underlie behavioral abnormalities in the mutant animals. Together, our data suggest that LMTK3 plays an important role in regulating locomotor behavior in mice. [ABSTRACT FROM AUTHOR]

Abstract: Serotonin (5-HT) plays a role in several psychiatric disorders including drug addiction. The 5-HT system modulates the activity of midbrain dopamine (DA) systems, and the behavioural effects of psychostimulants mediated by these systems. The direction of this modulation depends upon the 5-HT receptor subtypes involved, with 5-HT2A and 5-HT2C receptors having opposing effects. For example the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor agonist Ro60-0175 both attenuate several cocaine-induced behavioural and neurochemical effects. To investigate the possible brain regions involved in the interactions between 5-HT2A or 5-HT2C receptor ligands and cocaine-induced behaviour, we examined the effects of M100907 or Ro60-0175 on cocaine-induced locomotion and mRNA expression of the immediate early gene zif268. Sprague-Dawley rats were pre-treated with M100907 (0.5mg/kg), Ro60-0175 (1.0mg/kg) or vehicle, and then injected with cocaine (15mg/kg) or vehicle. Locomotor activity was monitored for 60min before rats were sacrificed for zif268 mRNA in situ hybridization mapping. Cocaine increased locomotor activity and zif268 mRNA expression consistently in the nucleus accumbens core, the orbitofrontal cortex and the caudate. M100907 attenuated cocaine-induced locomotion and zif268 mRNA expression in these brain regions in a defined subset of rats but failed to alter any effects of cocaine in another defined subset of rats. Ro60-0175 blocked cocaine-induced locomotion and zif268 mRNA expression in similar brain regions. Our results suggest that despite the opposing actions of 5-HT at 5-HT2A and 5-HT2C receptors, ligands acting on these receptors likely modulate cocaine-induced locomotion via a common mechanism to influence DA-dependent circuitry. [Copyright &y& Elsevier]

Abstract: Abuse of a dangerous street drug called mephedrone (4-methylmethcathinone) has become commonplace in the United States. Mephedrone is hypothesized to possess abuse liability, share pharmacological properties with psychostimulants, and display toxicity that has been linked to fatalities and non-fatal overdoses. Knowledge about the pharmacology of mephedrone has been obtained primarily from surveys of drug abusers and emergency room visits rather than experimental studies. The present study used motor activity and conditioned place preference (CPP) assays to investigate behavioral effects of mephedrone. Acute mephedrone (3, 5, 10, 30mg/kg, ip) administration increased ambulatory activity in rats. Mephedrone (5mg/kg, ip)-induced ambulation was inhibited by pretreatment with a dopamine D1 receptor antagonist (SCH 23390) (0.5, 1, 2mg/kg, ip) and enhanced by pretreatment with a dopamine D2 receptor antagonist (sulpiride) (2mg/kg, ip). Rats injected for 5 days with low dose mephedrone (0.5mg/kg, ip) and then challenged with mephedrone (0.5mg/kg, ip) following 10 days of abstinence displayed sensitization of ambulatory activity. In CPP experiments, mephedrone (30mg/kg, ip) conditioning elicited a preference shift in both rats and mice. The CPP and dopamine-sensitive motor activation produced by mephedrone is suggestive of abuse liability and indicates commonalities between the neuropharmacological profiles of mephedrone and established drugs of abuse. [Copyright &y& Elsevier]

Abstract: Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse. Low and high dose administration of METH leads to locomotor stimulation, and dopaminergic and serotonergic neurotoxicity, respectively. The behavioral stimulant and neurotoxic effects of METH can contribute to addiction and other neuropsychiatric disorders, thus necessitating the identification of potential pharmacotherapeutics against these effects produced by METH. METH binds to σ receptors at physiologically relevant concentrations. Also, σ receptors are present on and can modulate dopaminergic and serotonergic neurons. Therefore, σ receptors provide a viable target for the development of pharmacotherapeutics against the adverse effects of METH. In the present study, CM156, a σ receptor ligand with high affinity and selectivity for σ receptors over 80 other non-σ binding sites, was evaluated against METH-induced stimulant, hyperthermic, and neurotoxic effects. Pretreatment of male, Swiss Webster mice with CM156 dose dependently attenuated the locomotor stimulation, hyperthermia, striatal dopamine and serotonin depletions, and striatal dopamine and serotonin transporter reductions produced by METH, without significant effects of CM156 on its own. These results demonstrate the ability of a highly selective σ ligand to mitigate the effects of METH. [Copyright &y& Elsevier]

Caffeine is widely consumed throughout the world, but little is known about the mechanisms underlying its rewarding and aversive properties. We show that pharmacological antagonism of dopamine not only blocks conditioned place aversion to caffeine, but also reveals dopamine blockade-induced conditioned place preferences. These aversive effects are mediated by the dopamine D2 receptor, as knockout mice showed conditioned place preferences in response to doses of caffeine that C57Bl/6 mice found aversive. Furthermore, these aversive responses appear to be centrally mediated, as a quaternary analog of caffeine failed to produce conditioned place aversion. Although the adenosine A2A receptor is important for caffeine’s physiological effects, this receptor seems only to modulate the appetitive and aversive effects of caffeine. A2A receptor knockout mice showed stronger dopamine-dependent aversive responses to caffeine than did C57Bl/6 mice, which partially obscured the dopamine-independent and A2A receptor-independent preferences. Additionally, the A1 receptor, alone or in combination with the A2A receptor, does not seem to be important for caffeine’s rewarding or aversive effects. Finally, excitotoxic lesions of the tegmental pedunculopontine nucleus revealed that this brain region is not involved in dopamine blockade-induced caffeine reward. These data provide surprising new information on the mechanism of action of caffeine, indicating that adenosine receptors do not mediate caffeine’s appetitive and aversive effects. We show that caffeine has an atypical reward mechanism, independent of the dopaminergic system and the tegmental pedunculopontine nucleus, and provide additional evidence in support of a role for the dopaminergic system in aversive learning. [ABSTRACT FROM AUTHOR]

The abuse of anabolic androgenic steroids (AASs) is not only a problem in the world of sports but is associated with the polydrug use of nonathletes. Investigations of the neurochemical effects of AAS have focused in part on the monoaminergic systems, involving, among other things, the development of dependence. We have previously shown that pretreatment with nandrolone decanoate attenuates dose-dependently the increase in extracellular dopamine (DA) concentration evoked by amphetamine and 3,4-methylenedioyxymethamphetamine in the nucleus accumbens (NAc). The aim of this study was to investigate whether the nandrolone pre-exposure modulates the acute neurochemical and behavioral effects of cocaine in rats and whether the effects are long lasting. DA, 5-hydroxytryptamine (5-HT), and their metabolites were measured from samples collected from the NAc by microdialysis. The behavior of the animals was recorded. The present study demonstrates that five injections of nandrolone (5 and 20 mg/kg) inhibited cocaine-evoked DA and 5-HT outflow in the NAc, locomotor activity (LMA), and stereotyped behavior in experimental animals, and that these effects are seen even after elimination of nandrolone from bloodstream. Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior, is related to gratification of stimulant drugs, this study suggests that nandrolone, at the doses tested, has a significant effect on the pleasurable properties of cocaine. Furthermore, because neurochemical and behavioral responses were still attenuated after a fairly long recovery period, it seems that nandrolone may induce long-lasting changes in the brains of rat. [ABSTRACT FROM AUTHOR]

Abstract: Dextro-amphetamine enhances memory and other cognitive functions in animals and humans. The use of d-amphetamine as a memory enhancer, however, is limited by a robust stimulatory side-effect profile caused by release of dopamine. The levo enantiomer of amphetamine has been shown to be considerably less effective as a dopamine releaser and less potent in producing the stimulatory effects characteristic of d-amphetamine. In order to determine whether l-amphetamine and the structurally related compound, l-methamphetamine, retain cognitive-enhancing effects despite their lack of stimulatory activity, we administered the compounds to rats prior to activity monitoring experiments, and in different animals, immediately after training on inhibitory avoidance and object recognition tasks. Results demonstrated that l-amphetamine and l-methamphetamine did not increase locomotion and stereotypies beyond control levels, but did produce significant memory enhancement. In addition, l-amphetamine and l-methamphetamine alleviated scopolamine-induced amnesia in the inhibitory avoidance task. In all cases, these compounds produced an effect comparable to that of d-amphetamine, but required only one quarter of the d-amphetamine dose to produce the same effect size. We also found that l-amphetamine modulates learning-induced changes in hippocampal Arc/Arg3.1 protein synthesis that correlate with memory consolidation. These results suggest that l-amphetamine and l-methamphetamine are potent memory enhancers in rats and may ultimately be useful for treating memory disorders in humans. [Copyright &y& Elsevier]

SK3 K+ channels influence neuronal excitability and are present in 5-hydroxytryptamine (5-HT) and dopamine (DA) nuclei in the brain stem. We therefore hypothesized that SK3 channels affect 5-HT and DA neurotransmission and associated behaviors. To explore this, we used doxycycline-induced conditional SK3-deficient (T/T) mice. In microdialysis, T/T mice had elevated baseline levels of striatal extracellular DA and the metabolites dihydroxyphenylacetic acid and homovanillic acid. While baseline hippocampal extracellular 5-HT was unchanged in T/T mice, the 5-HT response to the 5-HT transporter inhibitor citalopram was enhanced. Furthermore, baseline levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were elevated in T/T mice. T/T mice performed equally to wild type (WT) in most sensory and motor tests, indicating that SK3 deficiency does not lead to gross impairments. In the forced swim and tail suspension tests, the T/T mice displayed reduced immobility compared with WT, indicative of an antidepressant-like phenotype. Female T/T mice were more anxious in the zero maze. In contrast, anxiety-like behaviors in the open-field and four-plate tests were unchanged in T/T mice of both sexes. Home cage diurnal activity was also unchanged in T/T mice. However, SK3 deficiency had a complex effect on activity responses to novelty: T/T mice showed decreased, increased or unchanged activity responses to novelty, depending on sex and context. In summary, we report that SK3 deficiency leads to enhanced DA and 5-HT neurotransmission accompanied by distinct alterations in emotional behaviors. [ABSTRACT FROM AUTHOR]

There is compelling support for the contribution of dopamine and the D1R-like (D1R, D5R) receptor subfamily to the behavioral and neural effects of psychostimulant drugs of abuse. The relative roles of D1R and D5R subtypes in mediating these effects are not clear. The objectives of this study are to directly compare (C57BL/6J congenic) D1R knockout (KO) and D5R KO mice for baseline locomotor exploration, acute locomotor responses to cocaine, and locomotor sensitization to repeated cocaine administration, and to examine cocaine conditioned place preference (CPP) in D5R KO. D1R KO, D5R KO, and wild-type (WT) were assessed for baseline open field exploration, locomotor-stimulating effects of 15 mg/kg acute cocaine and sensitized locomotor responses to cocaine after repeated home cage treatment with 20 or 30 mg/kg cocaine. D5R KO and WT were tested for CPP to 15 mg/kg cocaine. D1R KO showed modest basal hyperactivity and increased center exploration relative to WT. Acute locomotor responses to cocaine were consistently absent in D1R KO, but intact in D5R KO. D5R KO showed normal locomotor sensitization to cocaine and normal cocaine CPP. D1R KO failed to show a sensitized locomotor response to 30 mg/kg cocaine. Failure to sensitize in D1R KO was not because of excessive stereotypies. Surprisingly, D1R KO showed a strong trend for sensitization to 20 mg/kg cocaine. D5R KO does not alter acute or sensitized locomotor responses to cocaine or cocaine CPP. D1R KO abolishes acute locomotor response to cocaine, but does not fully prevent locomotor sensitization to cocaine at all doses. [ABSTRACT FROM AUTHOR]

Previous research has shown that individual differences in response to novelty predict self-administration and the locomotor response to psychostimulant drugs of abuse. The aim of the present study was to determine if individual differences in response to novelty based on inescapable or free-choice novelty tests predict dopamine transporter (DAT) function and trafficking as well as nicotine-induced modulation of DAT. Results show that the maximal velocity ( Vmax) of [3H]dopamine uptake into prefrontal cortex (PFC) synaptosomes correlated negatively with the locomotor response to inescapable novelty. In contrast, Vmax correlated positively with novelty place preference in the free-choice novelty test. The divergent correlations between DAT and the two behavioral phenotypes suggest a differential contribution of DAT in these phenotypes, which are known not to be isomorphic. Furthermore, rats categorized as high responders to inescapable novelty had lower Vmax values, which were accompanied by less DAT expression at the cell surface in PFC compared with low responders, suggesting that inherent individual differences in DAT cellular localization may underlie the differential response to novelty. Compared with the saline control, nicotine increased Vmax and cell surface DAT immunoreactivity in PFC from high responders but not from low responders. Similarly, nicotine increased Vmax and cell surface DAT in PFC in rats classified as low in novelty place preference but not in rats classified as high in novelty place preference. Thus, despite the different behavioral phenotypes, the pharmacological effect of nicotine to increase DAT function and cell surface expression was apparent, such that rats with inherently lower DAT function show a greater sensitivity to the neurochemical effect of nicotine. [ABSTRACT FROM AUTHOR]

We reported heritable differences between Sprague–Dawley (SD) and Long Evans (LE) rats in their sensitivity to the disruption of prepulse inhibition of startle (PPI) by dopamine (DA) agonists, and in their basal levels and turnover of forebrain DA. In an effort to better understand these differences, we assessed strain patterns in the efficacy of D2-like receptor-G-protein coupling using [35S]GTPγS binding in brain regions that contribute to the dopaminergic regulation of PPI. Sensitivity to the PPI-disruptive effects of apomorphine (APO) was examined in SD, LE, and F1 (SD × LE) rats. Basal and DA-stimulated [35S]GTPγS binding were then assessed in these rats using conditions that preferentially exclude Gs proteins to favor visualization of D2-like receptors. To explore the behavioral specificity of these strain differences, locomotor responses to APO and amphetamine (AMPH) were also assessed in SD, LE, and F1 rats. Strain differences were evident in the PPI-disruptive effects of APO (SD>F1>LE), and in the locomotor responses to AMPH (LE>F1>SD) and APO (SD exhibited motor suppression, LE exhibited motor activation). Compared to SD rats, LE rats exhibited greater DA-stimulated [35S]GTPγS binding in nucleus accumbens and caudatoputamen, while F1 progeny had intermediate levels. In conclusion, SD and LE rats exhibit heritable differences in D2-mediated behavioral and biochemical measures. Conceivably, genes that regulate heritable differences in forebrain D2 function may contribute to heritable differences in PPI in patients with specific neuropsychiatric disorders, including schizophrenia and Tourette Syndrome.Neuropsychopharmacology (2006) 31, 721–729. doi:10.1038/sj.npp.1300877; published online 17 August 2005 [ABSTRACT FROM AUTHOR]

Disruption of dopaminergic (DA) systems is thought to play a central role in the addictive process and in the pathophysiology of schizophrenia. Although inheritance plays an important role in the predisposition to these disorders, the genetic basis of this is not well understood. To provide additional insight, we have performed a modifier screen in mice designed to identify mutations that perturb DA homeostasis. With a genetic background sensitized by a mutation in the dopamine transporter (DAT), we used random chemical mutagenesis and screened for mutant mice with locomotor abnormalities. Four mutant lines were identified with quantitatively elevated levels of locomotor activity. Mapping of mutations in these lines identified two loci that alter activity only when dopamine levels are elevated by a DAT mutation and thus would only have been uncovered by this type of approach. One of these quantitative trait loci behaves as an enhancer of DA neurotransmission, whereas the other may act as a suppressor. In addition, we also identified three loci which are not dependent on the sensitized background but which also contribute to the overall locomotor phenotype. [ABSTRACT FROM AUTHOR]

Abstract: Several lines of research have implicated glutathione (GSH) in schizophrenia. For instance, GSH deficiency has been reported in the prefrontal cortex of schizophrenics in vivo. Further, in rats postnatal GSH-deficiency combined with hyperdopaminergia led to cognitive impairments in the adult. In the present report we studied the effects of 2-day GSH-deficiency with l-buthionine-(S,R)-sulfoximine on monoaminergic function in mice. The effect of GSH-deficiency per se and when combined with the amphetamine and phencyclidine (PCP) models of schizophrenia was investigated. GSH-deficiency significantly altered tissue levels of dopamine (DA), 5-hydroxytryptamine (5-HT) and their respective metabolites homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in a region-specific fashion. The effects of GSH-deficiency on tissue monoamines were distinct from and, generally, did not interact with the effects of amphetamine (5 #x00A0;mg/kg; i.p.) on tissue monoamines. Microdialysis studies showed that extracellular DA-release after amphetamine (5 #x00A0;mg/kg, i.p.) was two-fold increased in the nucleus accumbens of GSH-deficient mice as compared with control mice. Basal DA was unaltered. Further, extracellular levels of HVA in the frontal cortex and hippocampus and 5-HIAA in the nucleus accumbens were elevated by GSH-deficiency per se. Spontaneous locomotor activity in the open field was unchanged in GSH-deficient mice. In contrast, GSH-deficiency modulated the locomotor responses to mid-range doses of amphetamine (1.5 and 5 #x00A0;mg/kg, i.p.). Further, GSH-deficient mice displayed an increased locomotor response to low (2 and 3 #x00A0;mg/kg, i.p.) doses of phencyclidine (PCP). In conclusion, the data presented here show that even short-term GSH-deficiency has consequences for DA and 5-HT function. This was confirmed on both neurochemical and behavioral levels. How GSH and the monoamines interact needs further scrutiny. Moreover, the open field findings suggest reduced or altered N-methyl-d-aspartate (NMDA) receptor function in GSH-deficient mice. Thus, GSH-deficiency can lead to disturbances in DA, 5-HT and NMDA function, a finding that may have relevance for schizophrenia. [Copyright &y& Elsevier]

The effects of a deletion for the brain derived neurotrophic factor (BDNF) allele (± BDNF) upon age-related changes in nigrostriatal dopaminergic (NSDA) function were assessed. Behavioral (beam crossing and spontaneous activity) and neurochemical (potassium-stimulated dopamine release from superfused striatum) measures were compared among Young (4–5 month), Middle (11–13 month) and Aged (19–21 month) ± BDNF and their wild type littermate control (+/+ BDNF) mice. No statistically significant differences were obtained between +/+ and ± BDNF mice at the Young age sampling period for any of the behavioral or neurochemical measures. Behavioral and neurochemical responses indices of NSDA function begin to diverge between +/+ and ± Middle age BDNF mice and maximal differences were observed at the Aged period. For both movement and stereotypy times, scores obtained from +/+ mice were significantly decreased compared with ± BDNF mice at the Aged period and center time scores of +/+ mice were decreased at both the Middle and Aged periods compared with ± BDNF mice. Neurochemically, potassium-stimulated DA release of +/+ mice was significantly greater than ± BDNF mice with maximal differences obtained at the Aged period. These results demonstrate marked differences in age-related changes of NSDA function between +/+ and ± BDNF mice and suggest that the deletion of one allele for BDNF may make these mice more susceptible to age-related declines in NSDA function. [Copyright &y& Elsevier]

The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1–1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801''s effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade. [Copyright &y& Elsevier]

The N-methyl-d-aspartate (NMDA) receptor, an ionotropic glutamate receptor, is implicated in motor activity that is regulated in the striatum and nucleus accumbens of the brain. A Src family kinase Lyn is highly expressed in striatum, cortex, thalamus, and cerebellum in the brain. Here we show that spontaneous motor activity is suppressed in lyn−/− mice. S.c. injection of methylphenidate, which causes accumulation of dopamine in synapses, reveals that dopaminergic pathway is normal in lyn−/− mice. After blocking the NMDA receptor, motor activity of lyn−/− mice increased to the same level as that of wild type mice. Therefore, the NMDA receptor-mediated signaling is enhanced in lyn−/− mice, indicating that Lyn regulates the NMDA receptor pathway negatively. Intriguingly, the activity of protein kinase C (PKC), an enzyme regulated downstream of NMDA receptors, is increased in lyn−/− mice. The present data suggest that the NMDA receptor signal that is enhanced in the absence of Lyn suppresses the motor activity, probably through inhibition of dopaminergic pathway at striatum.We conclude that Lyn contributes to coordination of motor activity through regulation of the NMDA pathway. It appears that this negative regulation involves suppression of downstream signaling of NMDA receptor such as those mediated by PKC. [Copyright &y& Elsevier]

The diverse physiological effects of dopamine are mediated by multiple receptor systems. The dDA1 represents one of the Drosophila dopamine receptors that activate the cAMP cascade. To gain insight into the role of dDA1, we generated a polyclonal antibody against the unique sequence in dDA1 and investigated dDA1 distribution in the central nervous system (CNS) of Drosophila melanogaster. In both larval and adult CNS pronounced dDA1 immunoreactivity was present in the neuropil of the mushroom bodies, a brain structure crucial for learning and memory in insects, and four unpaired neurons in each thoracic segment. In addition, the larval abdominal ganglion contained two dDA1 cells in each segment. This expression pattern appeared to be maintained in the condensed adult abdominal ganglion although the precise number and the intensity of staining were somewhat variable. The adult CNS also exhibited intense dDA1 immunoreactivity in the central complex, a structure controlling higher-order motor function, moderate expression in several neurosecretory cells, and weak staining in two unpaired neurons in the mesothoracic neuromere. The dDA1 expression in these areas was only detected in adult, but not in third instar larval CNS. [Copyright &y& Elsevier]

In rats, a distinct environment repeatedly paired with nicotine (0.421 mg/kg base, s.c.) comes to evoke an increase in activity in the absence of any drug. This hyperactivity indicates a Pavlovian-conditioned association between the environment and nicotine. We investigated whether a dopamine D[sub 1] receptor antagonist (SCH-23390), a D[sub 2] /D[sub 3] antagonist (eticlopride) or a GABA[sub B] agonist (baclofen) would prevent the acquisition of nicotine-conditioned hyperactivity. In saline-pretreated rats, acute nicotine suppressed activity during the conditioning phase (i.e. environment-nicotine pairings); chronic nicotine stimulated activity. Pretreatment with SCH-23390 (0.01 mg/kg, i.p.) attenuated the activating effects of nicotine without affecting controls. Eticlopride (0.03–0.07 mg/kg, i.p.) and baclofen (0.625 and 1.25 mg/kg, i.p.) did not affect nicotine-induced activity in a selective manner. Regardless of the pretreatment drug, rats acquired the environment-nicotine association as indexed in a drug-free test. The inability of SCH-23390 to block the acquisition of nicotine-conditioned locomotor activity is notable because in past research SCH-23390 blocked expression of the learned association.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]