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Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system. [ABSTRACT FROM AUTHOR]

Rationale: Nucleus accumbens (NAc) dopamine (DA) plays an integral role in overcoming effort costs, as blockade of D1 and D2 receptors reduces the choice of larger, more-costly rewards. Similarly, the stress neuropeptide corticotropin-releasing factor (CRF) modulates DA transmission and mediates stress-induced alterations in effort-related choice. Objectives: The current study explored how excessive stimulation of different DA receptors within the NAc core and shell alters effort-related decision-making and compared these effects to those induced by CRF stimulation. Methods: Male Long Evans rats were well-trained on an effort-discounting task wherein they choose between a low-effort/low-reward and a high-effort/high-reward lever where the effort requirement increased over blocks (2–20 presses). Dopamine D1 (SKF 81297, 0.2–2 μg), D2/3 (quinpirole, 1–10 μg), or D3 (PD 128,907, 1.5–3 μg) receptor agonists, or CRF (0.5 μg), were infused into the NAc core or shell prior to testing. Results: Stimulation of D2/3 receptors with quinpirole in the NAc core or shell markedly reduced the choice of high-effort option and increase choice latencies, without altering preference for larger vs smaller rewards. Stimulation of D1 or D3 receptors did not alter choice, although SKF 81297 infusions into the shell reduced response vigor. In comparison, core infusions of CRF flattened the discounting curve, reducing effortful choice when costs were low and increasing it when costs were high. Conclusions: Excessive stimulation of NAc D2 receptors has detrimental effects on effort-related decision-making. Furthermore, CRF stimulation induces dissociable effects on decision-making compared with those induced the effects of stimulation of different DA receptors. [ABSTRACT FROM AUTHOR]

Cognitive deficits in depression can be modelled using the novel object recognition (NOR) test, performance in which is impaired by chronic mild stress (CMS). We aimed to examine the involvement of mesocorticolimbic DA terminal regions, and to establish the substrate for CMS-induced impairment of NOR and its reversal by chronic antidepressant treatment. In experiments 1 and 2, we examined the effect of infusions into medial PFC, dorsal hippocampus (HPC), and nucleus accumbens (NAc) shell of D1 and D2 antagonists and D3 agonist, which were predicted to impair NOR with a short (1 h) delay, and of D1 and D2 agonists and D3 antagonist, which were predicted to facilitate NOR with a long (24 h) delay. Using optimal doses identified in experiment 2, in experiments 3 and 4, we examined effects on drug-stimulated NOR of CMS and chronic treatment with venlafaxine (VFX) or risperidone (RSP). We found a wide involvement of DA systems in memory for NOR: D1 receptors in PFC, HPC, and NAc; D3 receptors in PFC and HPC; and D2 receptors in PFC. CMS impaired D2- and D3-mediated effects in PFC and HPC; antidepressants rescued those effects in PFC but not HPC. The involvement of DA in NOR is multifaceted, but the effects of CMS and antidepressants are more discrete, involving D2 and D3 receptors in PFC specifically. While raising many difficult questions, these results suggest that the D2 and D3 receptors in the medial PFC may be an important substrate for cognitive deficits in depression and their remediation. [ABSTRACT FROM AUTHOR]

Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease. [ABSTRACT FROM AUTHOR]

The inbred Roman high- (RHA-I) and low-avoidance (RLA-I) rats, differing in dopaminergic activity and novelty/substance-seeking profiles, may be a suitable model to study the implication of the dopaminergic system in vulnerability to drug abuse. Differences in D3 receptor binding recently described between the two strains (Guitart-Masip M, Johansson B, Fernández-Teruel A, Cañete T, Tobeña A, Terenius L, Giménez-Llort L, Neuroscience 142:1231–1243, 2006b) may be important in shaping the aforementioned differences in novelty seeking. The aim of the present work was to study the effect of D3 receptor activation on novelty-induced locomotor activity in these two strains of rats. We administered saline and PD-128,907 (0.01 and 0.1 mg/kg), a putative D3 receptor agonist, to the Roman rats and studied the locomotor activity when animals were placed in a novel environment. Thereafter, by means of in situ hybridization, nerve growth factor inducible clone A (NGFI-A) mRNA was measured in the striatum and the Calleja islands of these animals. We found that RLA-I rats showed stronger locomotor inhibition than RHA-I rats after PD-128,907 administration. Moreover, RLA-I rats showed stronger reduction of NGFI-A mRNA in the Calleja islands than RHA-I rats. These results, together with previous findings, suggest that differences in D3 receptor expression in the Calleja islands may contribute to the divergent behavioral effect of PD-128,907 administration in the two strains of Roman rats. [ABSTRACT FROM AUTHOR]

Emerging evidence from agonist–antagonist studies suggests a role for the dopamine D3 receptor subtype in the regulation of PPI in animals, but such evidence is lacking for human subjects. This study examines the effect of the preferential D3 agonist ropinirole on PPI in humans. PPI was tested in 12 healthy men in three sessions associated with ropinirole 0.25 mg, ropinirole 0.5 mg, or placebo according to a balanced, crossover, double-blind design. Two prepulses (75- and 85-dB white noise bursts) and two lead intervals (50 and 80 ms) were employed. Ropinirole 0.5 mg significantly reduced prepulse inhibition (PPI) with both prepulses at the 80-ms lead intervals. There was no effect of treatment on startle amplitude and habituation. These results suggest a role for the dopamine D3 receptor in the mediation of human PPI, although a contribution from ropinirole’s agonistic activity at the D2 receptor cannot be entirely excluded. Firm conclusions on the role of the D3 receptor in the modulation of human PPI can only be drawn with the use of genetic approaches or more selective ligands for this receptor. [ABSTRACT FROM AUTHOR]

Maternal deprivation and handling can lead to a vulnerability to opiate dependence. However, the involvement of the dopamine D3 receptors has not been investigated. This study analysed the effects of a selective partial D3 receptor agonist, BP 897, on morphine-conditioned place preference (CPP) in deprived and handled rats. The effects of BP 897 were studied on the expression and the extinction of morphine CPP. Quantitative autoradiography of D2, D3 receptors and immunoautoradiography of dopamine transporter were performed in some saline- and morphine-treated rats 24 h after the place preference test. Morphine (5 mg/kg) induced a more prolonged morphine CPP in deprived and handled rats than in control animals. BP 897 (0.5 or 2 mg/kg) enhanced the expression of morphine conditioning in control rats. Same doses did not change morphine conditioning in deprived rats. BP 897 (2 mg/kg) suppressed morphine CPP in handled rats. An increase in basal D2 receptor density in the mesencephalon of handled rats, which was suppressed after morphine CPP, was observed. A decrease in D2 receptor levels in morphine-treated deprived rats occurred in the nucleus accumbens. This study shows that maternal deprivation and handling induced a prolonged morphine CPP, and different changes of D2/D3 receptor functioning revealed after morphine CPP. Early manipulations of infant–mother relationships may have different consequences on the balance of opioidergic and dopaminergic neurotransmission and may be of interest to reveal pharmacological properties of dopamine receptor partial agonists or antagonists potentially useful for therapeutic applications. [ABSTRACT FROM AUTHOR]

Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases. These studies were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia. The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-selective and D2-selective antagonists to inhibit the induction of yawning and hypothermia were assessed and a series of D2/D3 antagonists were characterized with respect to their ability to alter yawning induced by a low and high dose of PD-128,907 and sumanirole-induced hypothermia. D3-preferring agonists induced yawning at lower doses than those required to induce hypothermia and the D2-preferring agonist, sumanirole, induced hypothermia at lower doses than were necessary to induce yawning. The rank order of D3 selectivity was pramipexole > PD-128,907 = 7-OH-DPAT = quinpirole = quinelorane > apomorphine = U91356A. Sumanirole had only D2 agonist effects. PG01037, SB-277011A, and U99194 were all D3-selective antagonists, whereas haloperidol and L-741,626 were D2-selective antagonists and nafadotride’s profile of action was more similar to the D2 antagonists than to the D3 antagonists. D3 and D2 receptors have specific roles in the mediation of yawning and hypothermia, respectively, and the analysis of these effects allow inferences to be made regarding the selectivity of D2/D3 agonists and antagonists with respect to their actions at D2 and D3 receptors. [ABSTRACT FROM AUTHOR]

Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D3 and (less potently) D2 receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther 309:936–950, ; Millan et al., J Pharmacol Exp Ther 309:903–920, ; Millan et al., J Pharmacol Exp Ther 309:921–935, ). To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents. Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline. S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (±) S31411, and to its inactive (−) distomer, S32601. Apomorphine, and the selective D3/D2 receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D4 and D1/D5 receptor agonists were ineffective. The selective D3 vs D2 receptor partial agonist, BP897, did not substitute for S32504 and the selective D3 receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504 lever selection was blocked by the preferential D2 vs D3 receptor antagonists, L741,626 and S23199, and by the D2/D3 antagonists, raclopride and haloperidol. The D2/D3 receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties. The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D2 receptors Antipsychotics known to act as partial agonists at D2/D3 receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites. [ABSTRACT FROM AUTHOR]

The novel, selective dopamine D3 receptor antagonist, S33084 [(3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide], was tritium-labelled to 59 Ci/mmol specific activity. Determination of association and dissociation rate constants at recombinant, human (h) D3 receptors stably expressed in Chinese hamster ovary (CHO) cells yielded a Kd value (0.16 nM) comparable to that observed in saturation binding experiments (0.17 nM). The competition binding profile of [3H]S33084 with diverse D3 receptor agonists and antagonists correlated highly (0.99) with that of [3H]spiperone. In conclusion, [3H]S33084 is a highly potent and selective radioligand at dopamine D3 receptors, which should be of considerable use for their characterisation. [ABSTRACT FROM AUTHOR]

The paper examined the effect of 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin), a dopamine D3 receptors-prefering agonist, on the catalepsy evoked by reserpine, haloperidol and fluphenazine in rats (male Wistar), as well as the influence of nafadotride, a dopamine D3 receptors-prefering antagonist, on that effect. The obtained results show that 7-OH-DPAT, as well as L-DOPA, a drug of choice in the therapy of Parkinson's disease, used for comparison, antagonize the catalepsy induced by reserpine, haloperidol and fluphenazine. Nafadotride, used in a dose (0.2 mg/kg) which inhibits the 7-OH-DPAT-evoked locomotor hyperactivity but does not affect the hypermotility induced by amphetamine and quinpirole, antagonizes the anticataleptic effect of 7-OH-DPAT or L-DOPA. It is therefore assumed that dopamine D3 receptors are involved in the anticataleptic effect of both 7-OH-DPAT and L-DOPA. [ABSTRACT FROM AUTHOR]