Preferential Dopamine D3 Receptor Agonist Research Articles

Dopamine D1 or D3 receptor modulators prevent morphine tolerance and reduce opioid withdrawal symptoms

The long-term treatment of chronic pain by opioids is limited by tolerance and risk of addiction/dependence. Previously, we have shown that combination treatment of morphine with a dopamine D1 or D3 receptor modulator restored morphine analgesia in morphine-resistant neuropathic pain and decreased morphine's reward potential in an acute setting. Here, we investigated whether such adjunct therapy with a dopamine D1 receptor preferring antagonist (SCH 39166) or a dopamine D3 receptor preferring agonist (pramipexole) could prevent morphine tolerance and reduce withdrawal symptoms. Initially, tolerance to the combination of morphine + pramipexole was assessed in mice. Mice receiving intraperitoneal injections of morphine showed reduced thermal thresholds on Day 7 whereas those receiving morphine + pramipexole maintained analgesia at Day 7. Next, tolerance and withdrawal to both combinations were tested over 14 days in rats. Rats were assigned one of four drug conditions, (1) saline, 2) morphine, 3) morphine + SCH 39166, 4) morphine + pramipexole), for chronic administration via osmotic pumps. Chronic administration of morphine over 14 days resulted in a significant reduction of morphine analgesia. However, analgesia was maintained when morphine was administered with either the dopamine D1 receptor preferring antagonist or the D3 receptor preferring agonist. Withdrawal symptoms peaked at 48 h and were decreased in rats receiving either combination compared to morphine alone. The data suggests that adjunct therapy with dopamine D1 or D3 receptor preferring modulators prevents morphine tolerance and reduces the duration of morphine withdrawal symptoms, and thus this combination has potential for long-term pain management therapy.

PET Imaging of Pancreatic Dopamine D2 and D3 Receptor Density with 11C-(+)-PHNO in Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D2 and D3 receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (11C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R2 = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) (R2 = 0.57, P = 0.05), nor did mean baseline proinsulin (R2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D3 receptor and dopamine D2 receptor in HCs. No colocalization of the dopamine D3 receptor or dopamine D2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D3 receptor, dopamine D2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D3 receptor and dopamine D2 receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for 11C-(+)-PHNO, a dopamine D3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

The atypical antipsychotic blonanserin reverses (+)-PD-128907- and ketamine-induced deficit in executive function in common marmosets

Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+)-PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia.

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine’s reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine.

Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats

The preferential dopamine D3 receptor agonist pramipexole (PRA) disrupts prepulse inhibition (PPI) of acoustic startle, an operational measure of sensorimotor gating, in rats. Drug effects on PPI are sensitive to numerous experimental variables; proceeding with in-depth analyses of drug effects without a clear understanding of these variables is inefficient. The present studies characterized the impact on PRA-induced PPI deficits by a range of experimental parameters. As shown previously, PRA reduced both PPI and startle magnitude beginning 5–15 min post-injection; PRA effects on PPI were statistically significant through 35 min post-injection, while those on startle magnitude were still significant 65 min post-injection. PRA-induced PPI deficits were evident under conditions that matched startle magnitude in vehicle and PRA conditions and were independent of PRA-induced changes in prepulse-elicited motor activity. Additionally, PRA-induced PPI deficits did not differ significantly between uni- vs. cross-modal stimuli or between male vs. female rats, with no robust effect of estrous phase in females. These findings demonstrate that PRA effects on PPI are observed across several different experimental conditions and are dissociable from changes in startle magnitude or prepulse-elicited responses. Recommendations are made regarding “optimal” experimental conditions for studying the neurobiology of PRA-induced changes in PPI in rats.

Role of the Neurokinin-1 Receptors in Ejaculation in Anesthetized Rats

Several lines of evidence indicate a role for substance P in the control of ejaculation, although its mode of action needs to be clarified. The effects and sites of action of a selective antagonist for the substance P-preferred receptor (neurokinin-1 receptor subtype; NK1) were investigated in a pharmacological model of ejaculation. Ejaculation was induced in anesthetized rats by intracerebroventricular (i.c.v.) delivery of the dopamine D3 receptor preferring agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT). The effects of the selective NK1 antagonist RP67580 on 7-OH-DPAT-induced ejaculation were measured following intraperitoneal (i.p.), i.c.v., or intrathecal (i.t.) (third lumbar spinal segment; L3) administration. Intraseminal vesicle pressure (SVP) and electromyogram of the bulbospongiosus muscle (BS) were recorded as physiological markers of emission and expulsion phases of ejaculation, respectively. Upon i.p., i.c.v., or i.t. administration, RP67580 significantly reduced the occurrence of ejaculation elicited by 7-OH-DPAT. A mild decrease in the occurrence of SVP and BS responses was observed in rats treated ip with RP67580, whereas only SVP responses were moderately affected following i.c.v. or i.t. administration. These results show the multilevel regulation of 7-OH-DPAT-induced ejaculation by NK1 receptors.

Blockade by the cannabinoid CB1 receptor antagonist, rimonabant (SR141716), of the potentiation by quinelorane of food-primed reinstatement of food-seeking behavior.

It has been shown previously that the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716), reduced the intake of palatable food as well as the self-administration of several drugs of abuse, suggesting that endocannabinoid systems play a role in brain reward function. The present study investigated whether a cannabinoid step was involved in food-seeking behavior induced by explicit stimuli, using an operant reinstatement procedure in rats. Experimental sessions consisted of a 15-min food rewarded period, followed by a 45-min extinction period. Rimonabant did not affect the response reinstatement induced by noncontingent delivery of food pellets, but prevented (0.03-0.3 mg/kg) the potentiation by quinelorane, a dopamine D3 receptor-preferring agonist, of food-seeking behavior. A possible link between cannabinoid processes and D3- and/or D2-mediated dopaminergic transmission was further investigated by studying Fos protein expression in cortico-limbic structures in D3 (D3-/-) and D2 (D2-/-) knockout mice. Rimonabant (10 mg/kg) increased Fos immunoreactivity in the prefrontal cortex (pFCortex) and in the shell but not the core of the nucleus accumbens (NAcc). Fos induction by this dose of rimonabant was not seen in mice lacking CB1 receptors, providing clear evidence for the involvement of CB1 receptors. In the NAcc shell, the effect of rimonabant was suppressed in D3-/-, but remained unchanged in D2-/- mice. In contrast, Fos expression by rimonabant in the pFCortex was impervious to D2 or D3 receptor deletion. In conclusion, these data indicate first that rimonabant prevented the enhancement by quinelorane of the appetitive value of food pellets unexpectedly delivered during extinction and second that rimonabant effects might involve D3 receptor-mediated processes. Overall, these results are consistent with the notion that endocannabinoid functions control brain reward processes and in particular the capacity of explicit stimuli to precipitate food-seeking behavior.

Fused Azaindole Derivatives: Molecular Design, Synthesis and in vitro Pharmacology Leading to the Preferential Dopamine D3 Receptor Agonist FAUC 725.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Fused Azaindole Derivatives: Molecular Design, Synthesis and In Vitro Pharmacology Leading to the Preferential Dopamine D3 Receptor Agonist FAUC 725

Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2 long, D2 short, D3 and D4 showed that the azaindole 1 revealed D3 affinity ( K i=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of ( S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.

Tyrosine-induced release of dopamine is under inhibitory control of presynaptic dopamine D2 and, probably, D3 receptors in the dorsal striatum, but not in the nucleus accumbens

Stimulation of dopamine D2-like receptors decreases extracellular dopamine in the dorsal striatum and the nucleus accumbens. It is unknown whether the role of these receptors differs from that of dopamine D3 receptors. It is also unknown to what extent the role of these two types of receptors varies across both structures. Using microdialysis, we therefore investigated whether intracerebrally administered quinpirole, a dopamine D2-like receptor agonist, and PD 128907, ( S(+)−(4 aR,10 bR)−3,4,4 a,10 b−tetrahydro−4−propyl−2 H,5 H−[1]−benzopyrano[4,3− b]−1,4−oxazin−9−ol, a dopamine D3 receptor preferring agonist, differentially alter the tyrosine-induced increase of extracellular dopamine in the dorsal striatum and the nucleus accumbens, respectively. Perfusion of tyrosine (100 μM) into the dorsal striatum and the nucleus accumbens enhanced extracellular dopamine in a physiological manner in both areas. Infusion of the Na + channel blocker tetrodotoxin (2 μM) suppressed the enhanced level of dopamine derived from exogenous tyrosine in both brain areas. Infusion of the dopamine D2-like receptor agonist quinpirole at a concentration (1 nM), which alone did not affect basal extracellular dopamine, reduced tyrosine-enhanced extracellular dopamine when infused into the dorsal striatum, but not into the nucleus accumbens; the preferential dopamine D3 receptor agonist, PD 128907, had similar effects. Haloperidol, a dopamine D2-like receptor antagonist, given systemically at a dose, which alone did not significantly affect basal dopamine levels (10 nmol/kg i.p.), enhanced extracellular dopamine derived from exogenous tyrosine. This haloperidol treatment antagonized only the quinpirole-induced, but not the PD 128907-induced reduction in dopamine levels seen in tyrosine-treated rats. The results show that extracellular dopamine derived from exogenous tyrosine is under inhibitory control of presynaptic dopamine D2-like receptors in the dorsal striatum, but not in the nucleus accumbens; to what extent the same holds for dopamine D3 receptors remains to be proven. Future studies are required to elucidate whether the noted difference is absolute or not.

7-Hydroxy-N,N’-di-n-propyl-2-aminotetraline, a Preferential Dopamine D3 Agonist, Induces c-fos mRNA Expression in the Rat Cerebellum

The effects of a preferential dopamine D3 receptor agonist 7-hydroxy-N,N’-di-n-propyl-2-aminotetralin (7-OH-DPAT) on c-fos mRNA expression in the rat cerebellum were studied by Northern blot analysis. 7-OH-DPAT (0.003- 10 mg /kg, s.c.) markedly increased c-fos mRNA expression in the cerebellum, while its effects in the striatum, nucleus accumbens, and frontal cortex were negligible. The effect of 7-OH-DPAT on cerebellar c-fos mRNA expression was dose-dependent and statistically significant at doses of 0.3 mg /kg or more. A preferential dopamine D2 agonist, bromocriptine (0.01 -3 mg /kg, s.c.), failed to increase c-fos mRNA expression in the cerebellum. The effect of 7-OH-DPAT was blocked by two dopamine D2-type-receptor antagonists, haloperidol and perospirone, but not the Di-type-receptor antagonist SCH23390. Furthermore, dopaminergic denervation by 6-hydroxydopamine did not inhibit but rather potentiated the 7-OH-DPAT-induced c-fos mRNA expression in the cerebellum. These findings suggest that 7-OH-DPAT increases c-fos mRNA expression in the rat cerebellum, probably through postsynaptic dopamine D3 receptor activation.

Dopaminergic 7-aminotetrahydroindolizines: ex-chiral pool synthesis and preferential D3 receptor binding

Starting from both isomers of enantiopure asparagine, heterocyclic bioisosteres of the preferential dopamine D3 receptor agonist ( R)-7-OH-DPAT were investigated when SAR studies led to the 3-formyl substituted aminoindolizine ( S ) -1e (FAUC 54) displaying a K i value of 6.0 nM for the high affinity D3 binding site. In contrast, D3 affinity of the enantiomer ( R ) -1e was 300 fold lower.

The effects of dopamine D2 receptor ligands on novelty‐induced behavior in the rat open field test

To determine the potential role of dopamine D2 receptor in mechanisms of anxiety, the effects of the preferential dopamine D2 receptor agonist, quinpirole, and antagonists, haloperidol and (–) sulpiride, were examined, in comparison to the action of the preferential dopamine D3 receptor agonist, (±)7-OH-DPAT and d-amphetamine, in the rat open field test. The effects of dopamine D2 receptor ligands in active doses were additionally verified in the Vogel conflict procedure. Quinpirole at the lower dose of 1.0 mg/kg produced a selective anti-thigmotactic effect, and increased the number of entries into the central part of the open field, without any influence on animals motility. At this dose the drug also increased punished but not free drinking. Both haloperidol and (–) sulpiride reduced the number of entries into the central sector of the open field without changing rat motor activity. (–) Sulpiride in a dose-dependent manner decreased also the time spent in the central part of the open field. No effect of the antipsychotics was observed in the Vogel conflict test. (±)7-OH-DPAT failed to exert any action in the open field test, except the general inhibitory effect at the highest dose examined. d-Amphetamine increased rats ambulation without any effect on exploratory behavior. The data are discussed in relation to the role of changes in dopaminergic activity in modulation of anxiety, and relative importance of dopamine D2 receptor mechanisms.

The effects of dopamine D2 receptor ligands on novelty-induced behavior in the rat open field test

To determine the potential role of dopamine D2 receptor in mechanisms of anxiety, the effects of the preferential dopamine D2 receptor agonist, quinpirole, and antagonists, haloperidol and (–) sulpiride, were examined, in comparison to the action of the preferential dopamine D3 receptor agonist, (±)7-OH-DPAT and d-amphetamine, in the rat open field test. The effects of dopamine D2 receptor ligands in active doses were additionally verified in the Vogel conflict procedure. Quinpirole at the lower dose of 1.0 mg/kg produced a selective anti-thigmotactic effect, and increased the number of entries into the central part of the open field, without any influence on animals motility. At this dose the drug also increased punished but not free drinking. Both haloperidol and (–) sulpiride reduced the number of entries into the central sector of the open field without changing rat motor activity. (–) Sulpiride in a dose-dependent manner decreased also the time spent in the central part of the open field. No effect of the antipsychotics was observed in the Vogel conflict test. (±)7-OH-DPAT failed to exert any action in the open field test, except the general inhibitory effect at the highest dose examined. d-Amphetamine increased rats ambulation without any effect on exploratory behavior. The data are discussed in relation to the role of changes in dopaminergic activity in modulation of anxiety, and relative importance of dopamine D2 receptor mechanisms.

Effects of intra-amygdala R(+) 7-OH-DPAT on intra-accumbens d-amphetamine-associated learning. II. Instrumental conditioning.

Rats were trained to associate an initially neutral conditioned stimulus (CS) with a response-independent, intra-accumbens infusion of d-amphetamine (the unconditioned stimulus; US). Elsewhere, we have reported that as a result of this training, presentations of the CS alone elicited a conditioned response consisting of increased locomotor activity and that acquisition of this conditioned response was enhanced by post-session, intra-amygdala infusion of the dopamine D3 receptor preferring agonist, R(+) 7-OH-DPAT. Here, in this same group of animals, we have examined the conditioned rewarding properties of the drug-associated CS by determining its ability to support the acquisition of a novel instrumental response in the absence of drug reward. Thus, rats were presented with two novel levers. Presentation of the drug-associated CS was made contingent upon depression of one of the levers (CR lever), while responding upon the other lever (NCR lever) had no programmed consequences. Preferential responding upon the lever delivering the drug-associated CS was observed despite a 6-week interval between CS-US training and the conditioned reward test. Intra-accumbens administration of d-amphetamine (0-20 microg) increased the control over behaviour exerted by the CS, increasing CR. but not NCR lever responding. In contrast, rats that received three pairings of an intra-accumbens infusion of d-amphetamine in combination with intra-amygdala infusion of R(+) 7-OH-DPAT, 3 weeks prior to testing, displayed similar rates of response upon both levers and were insensitive to the potentiation of responding for conditioned reward following intra-accumbens d-amphetamine. However, intra-accumbens d-amphetamine stimulated locomotor activity in a similar, dose-related manner in both groups. In this way, rats that had received intra-accumbens infusion of d-amphetamine in combination with intra-amygdala infusion of R(+) 7-OH-DPAT appeared exactly like control group rats, for which the CS had been paired with intra-accumbens d-amphetamine on a negative basis only. A locomotor activity test indicated that one behavioural consequence of intra-amygdala administration of R(+) 7-OH-DPAT was the reduction of the unconditioned locomotor response resulting from intra-accumbens administration of d-amphetamine. Hence, the present data demonstrate that the conditioned rewarding properties of a drug-associated CS are specific to the CS-US association and are relatively insensitive to decay over time. However, the rewarding properties of a drug-associated CS were selectively abolished following activation of amygdala D3 receptors during presentation of the drug reward. Potential explanations for this effect are discussed, including the possibility that intra-amygdala R(+) 7-OH-DPAT reduced the incentive value of the US.