Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of parkinson's disease.

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

Neuroprotective effects of dopamine D2 receptor agonist on neuroinflammatory injury in olfactory bulb neurons in vitro and in vivo in a mouse model of allergic rhinitis.

Available evidence indicates that dopamine D2 receptor modulates the neurotoxic effects induced by glutamate. However, neurotoxicity mediated by AMPA-subtype glutamate receptor has rarely been studied in the olfactory bulb. This study mainly explores the neuroprotective effects of dopamine D2 receptor agonist on AMPA receptor-mediated neurotoxicity in the olfactory bulb in a mouse model of allergic rhinitis (AR) with olfactory dysfunction (OD). In our study, we found that AR with OD was closely associated with increased surface expression of the AMPA receptor GluR1, reduced surface expression of GluR2, and apoptosis damage in the olfactory bulb in vivo. Quinpirole (a dopamine D2 receptor agonist) improved olfactory function in mice, ameliorated apoptosis injury in the olfactory bulb but not in the olfactory mucosa, and inhibited the internalization of GluR2-containing AMPA receptor in vitro and in vivo. In addition, phosphorylation plays a crucial role in the regulation of AMPA receptor trafficking. Our results showed that quinpirole reduced the phosphorylation of GluR1 S845 and GluR2 S880 in olfactory bulb neurons in vitro, but it had no obvious effect on GluR1 S831. Therefore, dopamine D2 receptor agonist may inhibit the phosphorylation of GluR1 S845 and GluR2 S880, thereby reducing AMPA receptor-mediated neurotoxicity and alleviating neurotoxic injury to the olfactory bulb caused by AR.

Feeding status alters exploratory and anxiety-like behaviors in zebrafish larvae exposed to quinpirole.

The dysfunction of dopaminergic signaling is associated with several neurological disorders. The use of pharmacological agents that interact with this signaling system may be employed to understand mechanisms underlying such disorders. Nutritional status can impact dopamine reuptake, receptor affinity, transporter activity, and the effects of drugs that bind to dopamine receptors or interact with dopaminergic system. Here we evaluated the effects of quinpirole (a dopamine D2/D3 receptor agonist) exposure on fed and non-fed zebrafish larvae. Zebrafish larvae (6 days post-fertilization, dpf) were exposed to quinpirole (5.5, 16.7, and 50.0 µM) or water (control group) for one hour. To evaluate the effect of feeding status on quinpirole exposure, the experiments were performed on fed and non-fed animals, a between subject experimental design. Both fed and non-fed quinpirole treated larvae exhibited increased erratic movements compared to controls in an open tank exploration task. No alterations were observed on the main parameters of exploratory behavior and swim activity for non-fed larvae treated with quinpirole compared to controls. However, fed animals exposed to quinpirole exhibited increased locomotor activity, anxiety-like behavior, and repetitive circular movements when compared to controls and non-fed exposed animals. In addition, we observed quinpirole exposure to have no effects on morphological parameters and heartbeat, but to impair optomotor responses in both fed and non-fed larvae compared to control. We also found quinpirole effects to interact with feeding status, as quinpirole-treated fed larvae improved while quinpirole treated non-fed larvae impaired their avoidance reaction towards an aversive stimulus. These results indicate that the behavioral effects of quinpirole exposure depended upon feeding status. They showed that consumption of food, a naturally rewarding stimulus known to engage the dopaminergic system, made this neurotransmitter system more susceptible to quinpirole's effects.

Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease.

Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice. In G2019S Lrrk2 KI mice, basal spontaneous glutamatergic transmission, synaptic facilitation, and NMDA/AMPA ratios were unchanged, whereas the stimulation of dopamine (DA) D2 receptor by quinpirole reduced the spontaneous and evoked excitatory postsynaptic currents (EPSC). Quinpirole reduced the EPSC amplitude of SPNs in KI but not in KD, KO and WT mice, suggesting that the enhanced LRRK2 kinase activity induced by the G2019S mutation is associated with the observed functional alteration of SPNs synaptic transmission. The effect of quinpirole was mediated by a phospholipase C (PLC)-dependent release of endocannabinoid, with subsequent activation of presynaptic cannabinoid receptor 1 and reduced release of glutamate. The key role of DA D2 receptor in reducing glutamatergic output in our LRRK2 genetic model of PD further supports the use of DA agonists in the treatment of early PD patients with LRRK2 mutations to counteract the disease progression.

Dopaminergic modulation of neuropathic pain: analgesia in rats by a D2-type receptor agonist.

Experimental studies have shown that dopaminergic mechanisms can modulate both nociception and chronic pain perception, but such property is not exploited pharmacologically at the clinical level. We have previously shown that levodopa produces D2-receptor-mediated antiallodynic effects in rats with peripheral mononeuropathy. Here, we test the effects of a D2-type receptor (D2R) agonist, quinpirole, on neuropathic pain in rats. Allodynic responses to cooling and light touch were measured in the hind limbs of rats with chronic constriction injury of one sciatic nerve. Single intraperitoneal injection of quinpirole (1 mg/kg) totally inhibited cold and tactile allodynic responses for over 3 and 48 h, respectively. At that dose, quinpirole had no effect on nocifensive responses to heat. Lumbar intrathecal injection of quinpirole produced short-term inhibition of the responses to cold and tactile stimuli, suggesting that spinal mechanisms may contribute to the antiallodynic activity of quinpirole. Chronic subcutaneous infusion of quinpirole by implanted Alzet pumps (0.025 mg/kg·day) provided a slowly progressing inhibition of cold and tactile allodynic responses, which re-emerged after the pumps were removed. These experiments show the involvement of dopaminergic systems in the modulation of chronic allodynias and provide experimental support for proposing the use of D2R agonists for neuropathic pain relief.

D1 receptor agonist improves sleep-wake parameters in experimental parkinsonism.

Both excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque monkey. Continuous sleep and wake electroencephalographic monitoring revealed no effect of the selective dopamine D2 receptor agonist quinpirole on EDS, whereas the selective dopamine D1 receptor agonist SKF38393 efficiently alleviated EDS and restored REM sleep to baseline values. The present results question the relevance of abandoning D1 receptor agonist treatment in PD as it might actually improve sleep-related disorders.

Anxiolytic-like effect of quinpirole in combination with a low dose of 17ß-estradiol in ovariectomized rats.

The aim of this study was to explore effects on anxiety-like behavior of the D2 dopamine receptor agonist, quinpirole and of the D2 dopamine receptor antagonist, sulpiride given alone or in combination with a low dose of 17ß-estradiol (17ß-E2) to ovariectomized (OVX) rats. Two weeks after surgery, OVX rats began 14 days of treatment with the vehicle, a low dose of 17ß-E2 (5.0 µg/rat, s.c.), quinpirole (0.1 mg/kg, i.p.), sulpiride (10.0 mg/kg, i.p.), quinpirole plus 17ß-E2 or sulpiride plus 17ß-E2. The animals were then tested in the black and white model (BWM) and the open field test (OFT). Quinpirole (0.1 mg/kg, i.p.) administered alone or in a combination with a low dose of 17ß-E2 (5.0 µg/rat, s.c.) resulted in anxiolytic-like effect in OVX rats in the BWM. Repeated treatment of quinpirole and 17ß-E2 profoundly increased anxiolytic-like effect of the single substances they exert per se. Co-administration of quinpirole with 17ß-E2 increased frequency of rearing and grooming in OVX rats in the OFT. Sulpiride (10.0 mg/kg, i.p.) treatment failed to alter anxiety-like behavior in OVX rats in the BWM. In addition, sulpiride blocked the anxiolytic-like effect of 17ß-E2 in OVX rats. Application of neither sulpiride nor sulpiride plus 17ß-E2 led to any changes of rearing and grooming behavior in OVX rats in the OFT. The results of the present study suggest that 17ß-E2 and quinpirole interact to exert anxiolytic-like action and that each of these drugs can potentiate effects of each other. Further research is needed to elucidate detailed mechanisms by which quinpirole and 17ß-E2 exert synergistic effect on anxiety-related behavior.

Morphine alters the locomotor responses to a D2/D3 dopamine receptor agonist differentially in adolescent and adult mice.

The D2-like dopamine receptors mediate the emotional/aversive state during morphine withdrawal. Given age-dependent differences in the affective responses to withdrawal, this study examined whether the response to dopamine receptor agonists is altered differentially across ages following morphine administration. Adolescent and adult mice were injected with morphine (twice daily, 10-40 mg/kg, s.c.) or saline for 6 days. Subsequently, they were examined for their locomotor response to quinpirole, a D2/D3 receptor agonist, and SKF 38393, a D1 receptor agonist. Quinpirole dose-dependently reduced locomotion in drug-naïve animals. Initial suppression was also observed in morphine-treated animals, but was followed by enhanced locomotion. Notably, this enhanced locomotion was markedly greater in adolescents than adults. Quinpirole-induced hypo-locomotion is thought to be mediated by the presynaptic D2Short receptors, whereas its activating effect is mediated by postsynaptic D2Long/D3 receptors. This suggests that following morphine administration, the postsynaptic, but not the presynaptic, dopaminergic signaling is differentially modulated across ages. This locomotor supersensitivity was not observed for SKF 38393, a D1 dopamine receptor agonist. The D2/D3 receptors are involved in the pathophysiology of many mental illnesses. Thus, this study offers a potential explanation for the increased psychiatric disorder co-morbidities when drug use begins during adolescence.

Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists.

RATIONALE: Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear. OBJECTIVE: The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT). METHODS: We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive 'HI' and low impulsive 'LI', respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner. RESULTS: Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats. CONCLUSIONS: These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.

Animal models of obsessive-compulsive disorder: exploring pharmacology and neural substrates.

During the last 30 years there have been many attempts to develop animal models of obsessive-compulsive disorder (OCD). Most models have not been studied further following the original publication, and in the past few years, most papers present studies employing a few established animal models, exploring the neural basis of compulsive behavior and developing new treatment strategies. Here we summarize findings from the five most studied animal models of OCD: 8-OHDPAT (8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide) induced decreased alternation, quinpirole-induced compulsive checking, marble burying, signal attenuation and spontaneous stereotypy in deer mice. We evaluate each model's face validity, derived from similarity between the behavior in the model and the specific symptoms of the human condition, predictive validity, derived from similarity in response to treatment (pharmacological or other), and construct validity, derived from similarity in the mechanism (physiological or psychological) that induces behavioral symptoms and in the neural systems involved. We present ideas regarding future clinical research based on each model's findings, and on this basis, also emphasize possible new approaches for the treatment of OCD.

Stereotypic behaviour in the deer mouse: pharmacological validation and relevance for obsessive compulsive disorder.

Stereotypy is an important manifestation of obsessive compulsive disorder (OCD). OCD involves disturbed serotonin and dopamine pathways, and demonstrates a selective response to serotonin reuptake inhibitors (SRI), with limited to no response to noradrenaline reuptake inhibitors (NRI). Deer mice (Peromyscus maniculatus bairdii) engage in various spontaneous stereotypic behaviours, including somersaulting, jumping and pattern running, and has to date not been explored for possible relevance for OCD. We studied the population diversity of spontaneous stereotypy in these animals, followed by assessing behavioural response to chronic high and low dose SRI (viz. fluoxetine) and NRI (viz. desipramine) treatment (both 10 mg/kg; 20 mg/kg x 21 days). We also studied behavioural responses to the 5-HT(2A/C) agonist, meta-chlorophenylpiperazine (mCPP) and the D2 agonist, quinpirole (2 mg/kg and 5 mg/kg respectively x 4 days). Deer mice showed a distinct separation into high and low stereotypic behaviour populations, with high and low dose fluoxetine, but not desipramine, significantly reducing stereotypic behaviour in both populations. A significant attenuation of stereotypy was also observed in both groups following quinpirole or mCPP challenge. In its response to drug treatment, spontaneous stereotypic behaviour in deer mice demonstrates predictive validity for OCD. States of spontaneous stereotypy are attenuated by 5-HT(2A/C) and dopamine D2 receptor agonists.

Experimental studies and theoretical aspects on A2A/D2 receptor interactions in a model of Parkinson's disease. Relevance for L-dopa induced dyskinesias.

Dual probe microdialysis was used to study A2A/D2 receptor interactions in the striato-pallidal GABA pathway in a model of Parkinson's Disease. The A2A agonist CGS21680 and/or the D2-like agonist quinpirole were perfused via reverse microdialysis into the DA denervated striatum and the effects on globus pallidus (GP) extracellular GABA levels were evaluated. CGS21680 alone produced in the DA denervated striatum a transient rise of GP GABA levels. Quinpirole perfused alone into the DA denervated striatum reduced GP GABA levels, which was not only counteracted by coperfused CGS21680, but led to an enhancement of the GABA levels, which was larger than that seen with CGS21680 alone. These results may reflect existence not only of antagonistic A2A/D2 interactions but also of the appearance of D2/A2A interactions increasing the A2A signaling at the level of the adenylate cyclase. Such actions diminish the therapeutic efficacy of L-dopa and D2 agonists. L-dopa induced dyskinesias could be caused by changes in the balance of A2A/D2 heteromers vs A2A homomers expressed at the surface membrane, where A2A homomers dominate with abnormal increases in A2A signaling. This may lead to stabilization of abnormal receptor mosaics (high order hetero-oligomers) leading to formation of abnormal motor programs contributing to dyskinesia development.

Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists.

1. Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. 2. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. 3. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. 4. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0-6 h in both groups of rats. 5. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. 6. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration.

Infralimbic D2 receptor influences on anxiety-like behavior and active memory/attention in CD-1 mice.

Ventromedial prefrontal cortical (vmPFC) dopamine (DA) influences attentional aspects of cognition and anxiety-like behavioral responding in rodents. The present study investigated the role of D2 receptors on spontaneous alternation in the Y-maze and anxiety-like behavior in a two-trial elevated plus-maze (EPM) procedure in CD-1 mice following vmPFC infusions of the D2 antagonist, sulpiride, and the D2 agonist, quinpirole. Pretrial 1 quinpirole infusions did not influence any anxiety measure (with the exception that the lowest dose increased protected stretch attends), but reduced protected exploration activity (closed-arm entry/time ratios and wall rearing). In Trial 2 24 h later (no injection), quinpirole exerted an anxiolytic behavioral profile relative to Trial 2 control mice (enhanced open-arm entry/time ratios, unprotected head dips), with no effects on protected exploration or risk assessment activity. Pretrial 1 sulpiride infusions enhanced unprotected exploration (open-arm entry/time ratios, unprotected stretch attend, and head dips), but did not influence protected exploration or risk assessment in the EPM. In Trial 2, 24 h later (no injection), sulpiride extended this anxiolytic profile to reduced protected exploration and risk assessment activity (closed-time ratio, protected stretch attend, and head dips). In the Y-maze, whereas quinpirole disrupted alternation performance (5- and 10-nmol dose) concomitant with marked repetitive same-arm returns (SAR) at the highest dose, sulpiride disrupted alternation performance concomitant with marked repetitive SAR behavior at the lowest dose only. These data indicate that although infralimbic (IL) quinpirole and sulpiride infusions similarly disrupted alternation performance in the Y-maze and reduced Trial 2 anxiety-like responding in the EPM, these drugs differentially produced these effects.

Dinapsoline: characterization of a D1 dopamine receptor agonist in a rat model of Parkinson's disease.

Dinapsoline is a new potent, full agonist at D1 dopamine receptors with limited selectivity relative to D2 receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of Parkinson's disease. Dinapsoline produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D1 receptor antagonist SCH-23390, but not by the D2 receptor antagonist raclopride. During a chronic 14-day treatment period in which rats received dinapsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D1:D2 selectivity in vitro than other D1 agonists, the contribution of D2 activity to tolerance was assessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In contrast, when dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D1 and D2 receptors to tolerance, experiments were performed with the selective D1 agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D2 agonist quinpirole plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D1 receptor agonists is influenced by the pattern of drug exposure but not by the D1:D2 selectivity of the agonist.

Cardiovascular responses to intrathecal dopamine receptor agonists in conscious DOCA-salt hypertensive rats.

Previous studies have demonstrated that in conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats, the hypotensive action of intravenous (i.v.) bromocriptine, a selective dopamine D2 receptor agonist, was mediated partly by peripheral and partly by spinal dopamine D2 receptor stimulation, and that this effect was greater and longer-lasting than that in uninephrectomized control rats. To determine whether this amplification results partly from a putative spinal hypersensitivity phenomenon, cardiovascular responses to intrathecal (i.t.) administration of apomorphine and quinpirole were studied in conscious, 4-week DOCA-salt hypertensive rats and compared with those in uninephrectomized control rats. In both groups, upper thoracic (T2-T4) i.t. injections of apomorphine (9.1, 45.5 and 91.1 microg/rat) induced immediate and dose-dependent decreases in mean aortic pressure (MAP) and heart rate (HR), while i.t. quinpirole (38.4 microg/rat) induced only bradycardia. Neither magnitude nor duration of these responses was enhanced in DOCA-salt hypertensive rats when compared to control rats. In DOCA-salt hypertensive rats, apomorphine-induced hypotension and bradycardia remained unaffected by i.v. (500 microg/kg) pretreatment with domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. However, i.t. (40 microg/rat at T2-T4) pretreatment with domperidone significantly reduced apomorphine-induced hypotension, but fully suppressed bradycardia elicited by either apomorphine or quinpirole. These results demonstrated that in conscious DOCA-salt hypertensive rats, intrathecally-injected apomorphine or quinpirole decreased MAP and/or HR through a spinal D2 dopaminergic mechanism, as previously demonstrated in normotensive intact rats. Since both magnitude and duration of these responses were unchanged with respect to uninephrectomized control rats, enhancement of the hypotensive effect of intravenously-administered bromocriptine in DOCA-salt hypertensive rats does not appear to involve spinal dopamine D2 receptors.

The validity of the pretreated, unilaterally MPTP-treated monkeys as a model of Parkinson's disease: a detailed behavioural analysis of the therapeutic and undesired effects of the D2 agonist quinpirole and the D1 agonist SKF 81297.

The goal of this study was to evaluate the validity of the pretreated, unilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD). For that purpose, a detailed ethogram was developed and assessed in four male rhesus monkeys that had received MPTP (2.5 mg) in the carotid artery contralateral to the dominant limb. Subsequently, the behavioural effects of the dopamine D2 agonist quinpirole and the dopamine D1 agonist SKF 81297 were studied. The ethogram was found to allow a clear-cut and objective separation of drug-induced behaviours into therapeutic and undesired effects in the MPTP-treated monkeys. Saline-treated monkeys predominantly displayed ipsilateral goal-directed fore-limb movements, and distinct types of ipsilaterally directed rotations. Although quinpirole and SKF 81297 increased motor behaviours, such as body displacement, contralateral fore-limb movements and contralateral rotational behaviours, assessment of the new detailed ethogram revealed that this increase was completely due to the activation of abnormal, non-goal-directed behaviours, such as dyskinetic fore-limb movements, pivoting and shuffling. Moreover, the new ethogram made clear that the drug treatments induced not only dyskinesia and dystonia, but also epileptoid behaviour, which was confirmed by EEG analysis. In summary, the detailed behavioural analysis showed that this model does not adequately predict the clinical effects of the D2 agonist. It is concluded that the pretreated, unilaterally MPTP-treated monkey is not a valid model to predict the therapeutic and undesired effects of dopaminergic drugs in humans.

The cannabinoid receptor agonist WIN 55,212-2 reduces D2, but not D1, dopamine receptor-mediated alleviation of akinesia in the reserpine-treated rat model of Parkinson's disease.

The effects of the synthetic cannabinoid receptor agonist WIN 55,212-2 on dopamine receptor-mediated alleviation of akinesia were evaluated in the reserpine-treated rat model of parkinsonism. The dopamine D2 receptor agonist quinpirole (0.1 mg/kg, ip) caused a significant alleviation of the akinesia. This effect was significantly reduced by coinjection with the cannabinoid receptor agonist WIN 55,212-2 (0.1 and 0.3 mg/kg). The simultaneous administration of the cannabinoid receptor antagonist SR 141716A (3 mg/kg, ip) with quinpirole and WIN 55,212-2 blocked the effect of WIN 55,212-2 on quinpirole-induced alleviation of akinesia. The selective dopamine D1 receptor agonist chloro-APB (SKF82958, 0.1 mg/kg) alleviated akinesia in a significant manner. WIN 55,212-2 (0.1-1 mg/kg, ip) did not affect the antiakinetic effect of chloro-APB. Combined injection of both D1 and D2 dopamine receptor agonists (both at either 0.1 or 0.02 mg/kg) resulted in a marked synergism of the antiakinetic effect. WIN 55,212-2 (0.1-1 mg/kg) significantly reduced the antiakinetic effect of combined injections of quinpirole and chloro-APB at both 0.1 and 0.02 mg/kg. The effect of 0.3 mg/kg WIN 55,212-2 on combined D1 and D2 agonist-induced locomotion (0.02 mg/kg) was blocked by SR 141761A (3 mg/kg). Neither WIN 55,212-2 alone (0.1 and 0.3 mg/kg) nor SR 141716A (3 and 30 mg/kg) alone had an antiparkinsonian effect. These results suggest that cannabinoids may modulate neurotransmission in the pathway linking the striatum indirectly to basal ganglia outputs via the lateral globus pallidus and the subthalamic nucleus.

Potential therapeutic use of the selective dopamine D1 receptor agonist, A-86929: an acute study in parkinsonian levodopa-primed monkeys.

The clinical utility of dopamine (DA) D1 receptor agonists in the treatment of Parkinson's disease (PD) is still unclear. The therapeutic use of selective DA D1 receptor agonists such as SKF-82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine hydrobromide) and A-77636 ([1R, 3S] 3-[1'-admantyl]-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzo pyran hydrochloride) seems limited because of their duration of action, which is too short for SKF-82958 (< 1 hr) and too long for A-77636 (> 20 hr, leading to behavioral tolerance). We therefore conducted the present acute dose-response study in four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed cynomolgus monkeys primed to exhibit levodopa-induced dyskinesias to evaluate the locomotor and dyskinetic effects on challenge with four doses (from 0.03 to 1.0 mg/kg) of A-86929 ([-]-[5aR,11bS]-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-+ ++azacyclopent-1- ena[c]phenathrene-9-10-diol), a selective and full DA D1-like receptor agonist with an intermediate duration of action. Levodopa and the DA D2-like receptor agonist, LY-171555 ([4aR-trans]-4,4a,5,6,7,8,8a,9-o-dihydro-5n-propyl-2H-pyrazo lo-3-4-quinoline hydrochloride) were also used for comparison. Acute administration of A-86929 was as efficacious in alleviating MPTP-induced parkinsonism as levodopa and LY-171555, but was less likely to reproduce the levodopa-induced dyskinesias in these animals than with either LY-171555 or subsequent challenge of levodopa. Selective stimulation of the DA D1 receptor may provide better integration of neural inputs transmitted to the internal segment of the globus pallidus (referred to as the basal ganglia output) compared with levodopa and selective DA D2 receptor agonist. Potent DA D1 receptor agents with an intermediate duration of efficacy such as A-86929 (approximately 4 hr at higher doses tested) are potential therapeutic tools in PD and merit further attention.