Selective Dopamine D2 Research Articles

SKF82958, a dopamine D1 receptor agonist, disrupts prepulse inhibition in the medial prefrontal cortex and nucleus accumbens in C57BL/6J mice.

Prepulse inhibition (PPI) is a crucial indicator of sensorimotor gating that is often impaired in neuropsychiatric diseases. Although dopamine D1 receptor agonists have been found to disrupt PPI in mice, the underlying mechanisms are not fully understood. In this study, we aimed to identify the brain regions responsible for the PPI-disruptive effect of the D1 agonist in mice. Results demonstrated that intraperitoneal administration of the selective dopamine D1 receptor agonist SKF82958 dramatically inhibited PPI, while the dopamine D1 receptor antagonist SCH23390 enhanced PPI. Additionally, local infusion of SKF82958 into the nucleus accumbens and medial prefrontal cortex disrupted PPI, but not in the ventral hippocampus. Infusion of SCH23390 into these brain regions also failed to enhance PPI. Overall, the study suggests that the nucleus accumbens and medial prefrontal cortex are responsible for the PPI-disruptive effect of dopamine D1 receptor agonists. These findings provide essential insights into the cellular and neural circuit mechanisms underlying the disruptive effects of dopamine D1 receptor agonists on PPI and may contribute to the development of novel treatments for neuropsychiatric diseases.

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats.

JOURNAL/nrgr/04.03/01300535-202504000-00031/figure1/v/2024-07-06T104127Z/r/image-tiff Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia. Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia. Currently, studies have reported increased oscillation power in cases of levodopa-induced dyskinesia. However, little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia. Furthermore, the role of the dopamine D3 receptor, which is implicated in levodopa-induced dyskinesia, in movement disorder-related changes in neural oscillations is unclear. We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson's disease. Furthermore, levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components, as well as bidirectional primary motor cortex (M1) ↔ dorsolateral striatum gamma flow. Administration of PD128907 (a selective dopamine D3 receptor agonist) induced dyskinesia and excessive gamma oscillations with a bidirectional M1 ↔ dorsolateral striatum flow. However, administration of PG01037 (a selective dopamine D3 receptor antagonist) attenuated dyskinesia, suppressed gamma oscillations and cortical gamma aperiodic components, and decreased gamma causality in the M1 → dorsolateral striatum direction. These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity, and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

6-Nitrodopamine is an endogenous mediator of the rabbit corpus cavernosum relaxation.

6-Nitrodopamine (6-ND) is a novel endogenous catecholamine that has a potent relaxant action on vascular smooth muscle in vitro. To evaluate the basal release of 6-ND and noradrenaline from rabbit-isolated corpus cavernosum (RbCC) and its relaxing action on this tissue. Rabbit corpus cavernosa were dissected and suspended in a 5-mL organ bath containing oxygenated Krebs-Henseleit's solution. 6-ND and noradrenaline release was quantified by liquid chromatography coupled to tandem mass spectrometry. The relaxant activity of 6-ND was assessed in RbCC strips pre-contracted with endothelin-1 (10nM). Rabbit corpus cavernosum presented basal release of both 6-ND (2.9±0.8ng/mL, n=12) and noradrenaline (1.7±1.3ng/mL, n=12). The 6-ND release was reduced by pre-treatment with Nω-nitro-l-arginine methyl ester (l-NAME) (100 µM), whereas that of noradrenaline was unaffected. Tetrodotoxin (TTX, 1 µM) abolished the noradrenaline release but had no effect on 6-ND release, indicating a non-neurogenic origin for 6-ND. 6-ND and the selective dopamine D2-agonist L-741,626 caused concentration-dependent RbCC relaxations (pEC50 of 11±0.15 and 11.15±0.28, respectively). Pre-treatment with either l-NAME or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-on (ODQ) (100 µM) caused a rightward shift of the concentration-response curve to 6-ND, without affecting the L-741,626 responses. In TTX (100nM)-pre-treated preparations, neither l-NAME nor ODQ shifted the 6-ND concentration-response curve. Dopamine, noradrenaline, and adrenaline caused concentration-dependent RbCC contractions. Pre-incubation with 6-ND concentration-dependently inhibited the dopamine-induced contractions, without affecting those induced by either noradrenaline or adrenaline. 6-Nitrodopamine is the most potent endogenous relaxant agent in RbCC ever described and represents a novel mechanism by which NO causes corpus cavernosum smooth muscle relaxation. The finding that 6-ND acts as a truly selective dopamine D2-receptor antagonist indicates that the balance of dopamine and 6-ND release/synthesis may be the main mechanism that modulates corpus cavernosum smooth muscle tonus in vivo.

Comment on: Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.

Comment on: Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.

The dopamine D1 receptor antagonist SCH-23390 blocks the acquisition, but not expression of mitragynine-induced conditioned place preference in rats

Mitragynine (MG) is the primary active constituent of Mitragyna speciosa Korth (kratom), a psychoactive Southeast Asian plant with potential therapeutic use. Numerous studies support roles of dopaminergic system in drug reward. However, the involvement of the dopaminergic system in mediating MG reward and drug-seeking is poorly understood. Using conditioned place preference (CPP) paradigm, the present study aims to evaluate the roles of the dopamine (DA) D1 receptor in the acquisition and expression of MG-induced CPP in rats. The effects of SCH-23390, a selective DA D1 receptor antagonist, on the acquisition of MG-induced CPP were first investigated. Rats were pre-treated systemically with SCH-23390 (0, 0.1 and 0.3 mg/kg, i.p.) prior to MG (10 mg/kg) conditioning sessions. Next, we tested the effects of the DA D1 receptor antagonist on the expression of MG-induced CPP. Furthermore, the effects of a MG-priming dose (5 mg/kg) on the reinstatement of extinguished CPP were tested. The results showed that SCH-23390 dose-dependently suppressed the acquisition of a MG-induced CPP. In contrast, SCH-23390 had no effect on the expression of a MG-induced CPP. The findings of this study suggested a crucial role of the DA D1 receptor in the acquisition, but not the expression of the rewarding effects of MG in a CPP test. Furthermore, blockade of the D1-like receptor during conditioning did not prevent MG priming effects on CPP reinstatement test, suggesting no role for the DA D1 receptor in reinstatement sensitivity.

Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3Rpartial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003-0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01-0.1 mg/kg), (±)VK4-116 (1.0-10 mg/kg), and (±)VK4-40 (1.0-10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

RationaleThe dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive.ObjectivesThe investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms.MethodsMale C57BL/6 J mice and Sprague–Dawley rats were examined in five independent experiments. We assessed APH199 (0.1–5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light–dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats.ResultsAPH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats.ConclusionsOur data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.

Dopamine D3/D2 Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders.

Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14-50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.

Behavioural effects of a selective dopamine D4 receptor agonist, APH199, in animal models

Behavioural effects of a selective dopamine D4 receptor agonist, APH199, in animal models

Fenoldopam Mesylate Enhances the Survival of Mesenchymal Stem Cells Under Oxidative Stress and Increases the Therapeutic Function in Acute Kidney Injury

Mesenchymal stem cells (MSCs) have gained interest as an alternative therapeutic option for renal diseases, including acute kidney injury (AKI). However, their use is often limited owing to low survival rates in vivo. Fenoldopam mesylate (FD) is a selective dopamine D1 receptor agonist with antioxidative and anti-apoptotic roles. Herein, we investigated whether FD can enhance the survival of MSCs undergoing oxidative stress in vitro. In addition, the therapeutic effect of MSCs and FD-treated MSCs (FD-MSCs) was compared in a mouse model of AKI induced by cisplatin. The survival of MSCs under oxidative stress was augmented by FD treatment. FD induced the phosphorylation of cAMP response element–binding protein and AKT, contributing to enhanced growth compared with untreated MSCs. The expression of nuclear factor erythroid-2-related factor 2 (NRF2) and heme oxygenase-1 was increased by FD treatment, and nuclear translocation of NRF2 was found exclusively in FD-MSCs. FD downregulated BAX expression, increased the mitochondrial membrane potential, reduced reactive oxygen species generation, and decreased the apoptotic death of MSCs induced by oxidative stress. Moreover, renal function and tubular injury were improved in FD-MSCs compared with non-treated MSCs. Furthermore, tubular injury, apoptosis, and macrophage infiltration, as well as the serum level of tumor necrosis factor-α were reduced, while tubular cell proliferation was markedly increased in FD-MSCs compared with MSCs. Our study demonstrated that FD increases the survivability of MSCs in an oxidative environment, and its use may be effective in preparing robust therapeutic MSCs.

Involvement of dopamine D2 -like receptors in the antiepileptogenic effects of deep brain stimulation during kindling in rats.

Deep brain electrical stimulation (DBS), as a potential therapy for drug resistive epileptic patients, has inhibitory action on epileptogenesis. In the present investigation, the role of dopamine D2 -like receptors in the antiepileptogenic action of DBS was studied. Seizures were induced in adult rats by stimulating the perforant path in a semi-rapid kindling method. Five minutes after the last kindling stimulation, daily DBS was applied to the perforant path at the pattern of low frequency stimulation (LFS; 1Hz; pulse duration: 0.1ms; intensity: 50-150 μA; 4 trains of 200 pulses at 5min intervals). Sulpiride (10μg/1μl, i.c.v.), a selective dopamine D2 -like receptor antagonist, was administered prior to the daily LFS application. Kindling stimulations increased cumulative daily behavioral seizure stages, daily afterdischarge duration (dADD), and population spike amplitude (PS) in dentate gyrus following perforant path stimulation, while applying LFS decreased the kindled seizures' parameters. In addition, kindling potentiated the early (at 10-50 ms inter-pulse interval) and late (at 150-1000 ms inter-pulse interval) paired-pulse inhibition and decreased the paired-pulse facilitation (at 70-100 ms inter-pulse interval). These effects were also inhibited by applying LFS. All inhibitory effects of LFS on kindling procedure were prevented by sulpiride administration. These data may suggest that LFS exerts its preventive effect on kindling development, at least partly, through the receptors on which sulpiride acts which are mainly dopamine D2 -like (including D2 , D3 , and D4 ) receptors.

Contrasting effects of DOI and lisuride on impulsive decision-making in delay discounting task.

The 5-HT2A receptor is the major target of classic hallucinogens. Both DOI (2,5-dimethoxy-4-iodoamphetamine) and lisuride act at 5-HT2A receptors, and lisuride shares comparable affinity with DOI and acts as a partial agonist at 5-HT2A receptors. However, not like DOI, lisuride lacks hallucinogenic properties. Impulsive decision-making refers to the preference for an immediate small reinforcer (SR) over a delayed large reinforcer (LR). The current study aims to compare the effects of DOI and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs. Impulsive decision-making was evaluated in male Sprague-Dawley rats by the percentage of choice for the LR in delay discounting task (DDT). Delay to the LR changed in an ascending order (0, 4, 8, 16, and 32s) across one session. DOI (0.5 and 1.0mg/kg) increased impulsive decision-making, and the effects of DOI (1.0mg/kg) were blocked by the 5-HT2A receptor antagonist ketanserin (1.0mg/kg) rather than the 5-HT2C receptor antagonist SB-242084 (1.0mg/kg). Contrarily, lisuride (0.1, 0.3, and 0.5mg/kg) decreased impulsive decision-making. The effects of lisuride (0.3mg/kg) were not antagonized by ketanserin (1.0mg/kg), selective 5-HT1A antagonist WAY-100635 (1.0mg/kg), or selective dopamine D4 receptor antagonist L-745870 (1.0mg/kg) but were attenuated by the selective dopamine D2/D3 receptor antagonist tiapride (40mg/kg). DOI and lisuride have contrasting effects on impulsive decision-making via distinct receptors. DOI-induced increase of impulsivity is mediated by the 5-HT2A receptor, while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor.

Effect of selective dopamine D3 and D4 receptor agonists on trunk pulmonary artery vascular reactivity from control and monocrotaline-treated rats.

Dopamine D1-like and D2-like receptors are expressed in the pulmonary arteries, however there is a little information about their effect on vascular tone in pulmonary circulation, even the vascular effect of activation of the dopamine D3 and D4 subtypes in physiological and pathological conditions such as pulmonary hypertension is unknown. The objective of this study was to evaluate the vascular response of trunk pulmonary artery rings from saline and monocrotaline-treated rats in the presence of selective dopamine receptor agonists. In trunk pulmonary artery rings with intact and denuded endothelium, cumulative concentration-response curves were performed for phenylephrine, acetylcholine, and dopamine receptor agonists (apomorphine-D2-like, SKF38393-D1, quinpirole-D2/D3, 7-OH-DPATD3, and PD168077-D4) alone and in the presence of corresponding selective dopamine receptor antagonists (SCH23390-D1, raclopride-D2/D3, U99194 maleate-D3, and L-745,870-D4). Contractile and relaxant effects generated during the activation with phenylephrine and acetylcholine, respectively, were significantly reduced in intact and denuded endothelium trunk pulmonary artery rings from monocrotaline rats in comparison with control rats. All dopamine receptor agonists, except the 7-OH-DPAT, produced significant vascular relaxation in intact trunk pulmonary artery rings precontracted with phenylephrine in both experimental groups. Also, the vascular relaxation of SKF38393, and particularly apomorphine and PD168077 was significant in denuded endothelium trunk pulmonary artery rings from control and monocrotaline groups. Furthermore, the vasorelaxation induced by these dopamine agonists was significantly reduced in pulmonary preparations from monocrotaline-treated rats in comparison to that recorded in preparations from control rats. The effect of dopamine receptor agonists decreased significantly in the presence of the corresponding antagonist in both experimental groups. The results support that dopamine D4 receptor agonist induces significant vascular relaxation, whereas dopamine D3 receptor agonist induces vasoconstriction in intact and denuded endothelium trunk pulmonary artery rings in control and monocrotaline-induced pulmonary arterial hypertension rats.

Dopaminergic signaling regulates zebrafish larvae's response to electricity.

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.

Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-quinolinyl-pentanamides as selective dopamine D3 receptor ligands

Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-quinolinyl-pentanamides as selective dopamine D3 receptor ligands

The selective dopamine D1 receptor agonist SKF81297 modulates NMDA receptor currents independently of D1 receptors

Dopamine D1 receptor (D1R) agonists are frequently used to study the role of D1Rs in neurotransmission and behaviour. They have been repeatedly shown to modulate glutamatergic NMDAR currents in the prefrontal cortex (PFC), giving rise to the idea that D1R activation tunes glutamatergic networks by regulating NMDAR activity. We report that the widely used D1R agonist SKF81297 potentiates NMDAR currents in a dose-dependent manner, independently of D1R activation in mPFC slices, cortical neuron cultures and NMDAR-expressing recombinant HEK293 cells. SKF81297 potentiated NMDAR currents through both GluN2A and GluN2B subtypes in the absence of D1R expression, while inhibiting NMDAR currents through GluN2C and GluN2D subtypes. In contrast, the D1R ligands SKF38393, dopamine and SCH23390 inhibited GluN2A- and GluN2B-containing NMDAR currents. SKF81297 also inhibited GluN2A- and GluN2B-containing NMDAR currents at higher concentrations and when glutamate/glycine levels were high, exhibiting bidirectional modulation. To our knowledge, these findings are the first report of a D1R-independent positive modulatory effect of a D1R ligand on NMDA receptors. Importantly, our results further emphasize the possibility of off-target effects of many D1R ligands, which has significant implications for interpreting the large body of research relying on these compounds to examine dopamine functions.

Preferential Effects of Cariprazine on Counteracting the Disruption of Social Interaction and Decrease in Extracellular Dopamine Levels Induced by the Dopamine D3 Receptor Agonist, PD-128907 in Rats: Implications for the Treatment of Negative and Depressive Symptoms of Psychiatric Disorders.

The negative and cognitive symptoms of schizophrenia and related disorders may be due to reduced dopaminergic tone in cortical brain areas. Alteration in the function of dopamine (DA) D3 receptors may play a role in this cortical hypofunctionality and underlie the deficits in social behaviors and cognitive functions in schizophrenia. Cariprazine is a potent DA D3-preferring D3/D2 receptor partial agonist that is approved for the treatment of schizophrenia and bipolar disorder. The objective of the study was to compare the abilities of cariprazine, aripiprazole (another DA receptor partial agonist with more D2 receptor preference), and ABT-925 (a selective DA D3 antagonist) to counteract the social deficit and neurochemical alterations induced by the D3 receptor-preferring agonist (+)-PD 128907 (PD) in rats. Administration of PD (0.16 mg/kg; s.c.) induced a marked (−72%) but short-lasting disruption of the defensive social aggregation behavior (huddling) in the first 10-min period. Cariprazine at all doses (0.1, 0.3, 1 mg/kg; p.o.) almost completely abolished the PD-induced disruption of huddling. Likewise, ABT-925 (3 mg/kg; p.o.) and to a lesser extent aripiprazole (20 mg/kg; p.o.) were effective in blocking the PD-induced disruption of huddling. As measured by microdialysis, the highest dose of cariprazine prevented a PD-induced decrease in DA levels (40–80 min post PD dose) in the medial prefrontal cortex (mPFC), whereas aripiprazole did not have a significant effect. ABT-925 significantly counteracted the effect of PD at 80 min post-dose. In the nucleus accumbens (nAcc) shell, the highest dose of cariprazine, as well as ABT-925 and aripiprazole, significantly reversed the PD-induced decrease in DA levels. Taken together, these data provide behavioral and in vivo neurochemical evidence for the preferential DA D3 receptor action of cariprazine in the rat. This property of cariprazine may offer therapeutic benefits against the cognitive deficits and negative/depressive symptoms of schizophrenia and related disorders.

Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders.

Over three decades of evidence indicate that dopamine (DA) D3 receptors (D3R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective D3R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D3R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D3R system. Third, the synthesis and characterization of highly potent and selective D3R antagonists/partial agonists have further strengthened the role of the D3R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D3R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D3R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D3R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.

Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D3 receptor ligands

Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D3 receptor ligands

Effects of the selective dopamine D3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0–10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6–56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.