Effects Of Quinpirole Research Articles

Characterization of dopamine D1, D2, and D3 receptor function in adult rhesus monkeys exposed to cocaine in utero

In fetal rhesus monkeys, prenatal cocaine exposure has been shown to increase dopamine (DA) D1 and D2 receptor densities within the striatum (Fang et al., 1997), but little is known about the long‐term effects of prenatal cocaine exposure on the DA system. In the present study, D2 receptor availability in the striatum, as measured by positron emission tomography (PET), was not different in adult rhesus monkeys that had been exposed to cocaine (n=10) in utero (Morris et al., 1996) compared to controls (n=8). The ability of a high‐efficacy D1 agonist, SKF 81297 (0.03–0.3 mg/kg), to elicit blinking was then characterized. Preliminary data (n=3) indicates that there is a dose‐dependent increase in blinking, with cocaine‐exposed monkeys appearing slightly more sensitive than control monkeys. To study the D3 receptor system, quinpirole‐induced yawning was examined. The prenatally cocaine exposed male monkeys exhibited increased sensitivity to the stimulating effects of quinpirole compared to controls. The prenatally cocaine exposed female monkeys did not differ from controls. These preliminary data suggests that gestational cocaine alters DA receptor function in adult male monkeys. This is particularly striking when one considers the prenatal exposure was over 13 years ago. Whether these neurochemical changes influence the behavioral vulnerability to self‐administer cocaine remains to be studied. DA 10584

The influence of cost manipulation on water contrafreeloading induced by repeated exposure to quinpirole in the rat

Quinpirole (QNP), a D2/D3 dopaminergic receptor agonist, was found to elicit an apparently antieconomical drinking behavior called contrafreeloading (CFL). The perseverative operant responding observed may represent a compulsive-like behavior prompted by sensitization to the effects of QNP. In the present study, we investigated the effect of different response costs on instrumental behavior and CFL in rats repeatedly treated with QNP (0.5 mg/kg i.p.). Moreover, we studied the consummatory components of ingestive behavior in no-choice paradigms and the role of learned operant conditioning in free drinking. In experiment 1, rats were trained to perform under three different fixed ratio schedules of reinforcement (FR1, FR3, and FR10) and were given a choice between operant and free access to water. In experiment 2, rats were divided into four groups, each one resembling experiment 1 in one or more features, with no choice available and water consumption measured at an interval of 0-60 min. (a) Increasing FR significantly reduced CFL % in saline -- but not in QNP-injected groups; (b) under free-drinking conditions, QNP caused a progressive hypodipsic effect which was, however, contrasted by maintaining cues formerly contingent on operant access to water; and (c) under CFL conditions QNP-treated rats drank more than under free access conditions. QNP confers rigidity in responding for water, impeding adaptation to different contingencies for access to the resource. In QNP-treated rats, CFL behavior appears adaptive as far as it allows animals to partially circumvent the hypodipsic effect of the drug.

Drug and Reinforcement History as Determinants of the Response-Maintaining Effects of Quinpirole in the Rat

The present study examined the effect of drug and reinforcement history on quinpirole-maintained responding in rats. Quinpirole (0.01, 0.032, or 0.1 mg/kg per injection) was assessed as a reinforcer in experimentally naive rats, as well as in rats trained to self-administer cocaine, remifentanil, ketamine, or food under a fixed ratio 1 schedule of reinforcement. Quinpirole failed to maintain responding in experimentally naive rats, or in ketamine- or food-trained rats. However, robust responding was maintained in rats with a history of cocaine reinforcement, and modest levels of responding were observed in rats with a history of responding for remifentanil. In a second set of studies, the effects of protracted drug histories on quinpirole-maintained responding in food-trained rats were assessed. Rats were maintained with food reinforcement, and different groups of rats were then allowed to respond for saline, quinpirole, and response-contingent cocaine or were administered noncontingent cocaine; all rats were subsequently allowed to respond for quinpirole. Only rats that previously responded for cocaine showed quinpirole-maintained responding; all other conditions failed to establish quinpirole-maintained responding. Although the high levels of quinpirole-maintained responding observed when quinpirole was substituted for cocaine are suggestive of positive reinforcing effects, these response-maintaining effects were highly dependent upon both drug and reinforcement history, suggesting that quinpirole may only function as a reinforcer under very specific conditions. The behavioral effects of quinpirole under these situations represent a novel constellation of actions relative to other drug reinforcers, and they suggest that the direct effects of self-administered quinpirole may be important in establishing the response-maintaining effects.

D2-like receptors in nucleus accumbens negatively modulate acetylcholine release in prefrontal cortex

Glutamatergic and dopaminergic inputs converge on medium spiny neurons in nucleus accumbens and regulate the excitability of these projections to target areas including the cholinergic basal forebrain. NMDA receptors situated on these projections are locally modulated by D1- and D2-like receptors. We previously reported that the D1-like positive modulation of NMDA receptor activity is expressed trans-synaptically in the control of basal forebrain cholinergic projections to prefrontal cortex. The present experiments tested the hypothesis that D2-like receptors in accumbens negatively modulate cortical ACh release. Perfusion of NMDA (150 μM) into the shell region of the accumbens produced a sustained increase (150–200%) in ACh release in prefrontal cortex. This increase was completely blocked by co-perfusion with the D2-like agonist quinpirole (100 μM). Perfusion of quinpirole also reduced basal ACh release (∼50%) in prefrontal cortex. The contribution of D2 receptors to the quinpirole effect was assessed in two additional studies. The first study revealed that co-perfusion of the D2 antagonist haloperidol (100 μM) blocked the quinpirole-induced attenuation of NMDA mediated ACh release. The second experiment demonstrated that intra-accumbens perfusion of quinelorane (100 μM), a more selective D2 agonist than quinpirole, also attenuated the NMDA mediated ACh release. Collectively, these studies demonstrate that D2 receptors in accumbens negatively modulate basal and NMDA mediated increases in ACh release in prefrontal cortex. This negative modulation may contribute to the integration of normal attentional processing and goal directed behavior and to the therapeutic effects of antipsychotic medication on cognition in psychopathologies such as schizophrenia.

Prenatal Exposure to Cocaine Increases the Rewarding Potency of Cocaine and Selective Dopaminergic Agonists in Adult Mice

Substance abuse during pregnancy results in persistent affective and behavioral deficits in drug-exposed children, and increased rates of substance abuse have been observed in young adults prenatally exposed to drugs of abuse. Animal models of prenatal cocaine exposure have yielded differing results depending on the behavioral method used to assess drug potency. The effects of cocaine, the dopamine D1 agonists SKF-81297 and SKF-82958, and the D2 agonist quinpirole on intracranial self-stimulation were measured in adult Swiss-Webster mice exposed to cocaine in utero (40 mg/kg/day) and vehicle controls with the curve-shift method of brain stimulation-reward (BSR) threshold determination. The reward-potentiating effects of cocaine (0.3-30 mg/kg IP) and SKF-82958 but not SKF-81297 on BSR were increased in adult male but not female mice after prenatal cocaine exposure. Quinpirole exerted biphasic effects on BSR, both elevating (0.1-0.3 mg/kg IP) and lowering (1.0-10 mg/kg IP) reward thresholds. Both effects of quinpirole were also enhanced in adult male mice after prenatal cocaine exposure. Prenatal cocaine exposure results in increased reward-potentiating potency of cocaine on BSR in adult mice in a sexually-dimorphic manner. This augmented rewarding effect of cocaine is also associated with increased sensitivity to both D1- and D2-selective agonists.

Effect of quinpirole on timing behaviour in the free-operant psychophysical procedure: evidence for the involvement of D2 dopamine receptors

Operant timing behaviour is sensitive to dopaminergic manipulations. It has been proposed that this effect is mediated principally by D(2)-like dopamine receptors. However, we recently found that the effect of d-amphetamine on timing in the free-operant psychophysical procedure was mediated by D(1)-like dopamine receptors. It has not been established whether stimulation of D(2)-like receptors affects timing in this schedule. To examine the effects of a D(2)-like receptor agonist quinpirole on second-range timing and the ability of dopamine receptor antagonists to reverse quinpirole's effects. Rats responded on two levers (A and B) under a free-operant psychophysical schedule in which reinforcement was provided intermittently for responding on A during the first half, and B during the second half, of 50-s trials. Logistic functions were fitted to the relative response rates [percent responding on B (%B) vs time (t)] under each treatment; quantitative timing indices [T (50) (value of t when %B = 50) and Weber fraction] were compared among treatments. Quinpirole (0.04, 0.08 mg kg(-1)) reduced T (50). This effect was attenuated by D(2)-like receptor antagonists haloperidol (0.05, 0.1 mg kg(-1)), eticlopride (0.04, 0.08 mg kg(-1)) and sulpiride (30, 60 mg kg(-1)), but not by the D(3) receptor-preferring antagonist nafadotride (0.5, 1 mg kg(-1)), the D(4) receptor antagonist L-745870 (1, 3 mg kg(-1)) or the D(1)-like receptor antagonist SKF-83566 (0.015 mg kg(-1)). Results suggest that quinpirole reduced T (50) via an action at D(2) receptors. D(1)-like and D(2)-like receptors may mediate behaviourally similar but pharmacologically distinct effects on timing behaviour.

Nigrostriatal lesion induces D2‐modulated phase‐locked activity in the basal ganglia of rats

There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves ('direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. 'Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism.

Tolerance to the effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) on free-operant timing behaviour: interaction between behavioural and pharmacological mechanisms

The psychostimulant d-amphetamine, the D(2/3) dopamine receptor agonist quinpirole and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behaviour. There is evidence that tolerance develops to the effects of psychostimulants on timing performance during chronic treatment; this tolerance is generally attributed to behavioural adaptation rather than to pharmacological desensitisation. There have been no previous investigations of tolerance to the effect of DOI on free-operant timing behaviour. To demonstrate tolerance to DOI's effect on timing performance and to examine the nature of this tolerance. Rats were trained under the free-operant psychophysical procedure to press two levers (A and B) in 80-s trials in which reinforcement was provided intermittently for responding on A in the first half and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 8-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices (T (50) [time corresponding to %B = 50]; Weber fraction). In experiment 1, DOI (0.25 mg kg(-1)) reduced T (50) compared to vehicle; tolerance to this effect was seen after repeated daily treatments with DOI if the rats were exposed to behavioural training during the period of treatment but not if the repeated treatments took place during a 'holiday' from behavioural training. In experiment 2, repeated treatment with DOI resulted in tolerance to the effect of DOI on T (50) and cross-tolerance to the effect of d-amphetamine (0.4 mg kg(-1)), but no cross-tolerance was seen to the effect of quinpirole (0.08 mg kg(-1)). The results indicate that behavioural adaptation is involved in the development of tolerance to DOI's effect on timing. The finding of cross-tolerance to d-amphetamine but not to quinpirole suggests that the reduction of T (50) in the free-operant psychophysical procedure may be brought about by two distinct pharmacological mechanisms, one activated by DOI and d-amphetamine, and the other by quinpirole.

Histamine H 3 and dopamine D 2 receptor-mediated [ 35S]GTPγ[S] binding in rat striatum: Evidence for additive effects but lack of interactions

The interactions in the rat striatum between H 3 receptors (H 3Rs) and D 2 receptors (D 2Rs) were investigated with the [ 35S]GTPγ[S] binding assay. The H 3R agonist ( R)α-methylhistamine increased [ 35S]GTPγ[S] binding to striatal membranes with an EC 50 = 14 ± 5 nM and a maximal effect of +19 ± 1%. This effect was inhibited by the H 3R antagonist ciproxifan with a K i = 1.0 ± 0.3 nM. The D 2R agonist quinpirole increased [ 35S]GTPγ[S] binding to the same membranes with an EC 50 = 1.5 ± 0.5 μM and a maximal effect of +28 ± 2%. Its effect was blocked by haloperidol with a K i = 0.3 ± 0.1 nM. The maximal effects of the H 3R and D 2R agonists were additive (+46 ± 3%). However, D 2R ligands did not modify the effects of H 3R ligands and vice versa. Ciproxifan behaved as an H 3R inverse agonist and decreased [ 35S]GTPγ[S] binding. Haloperidol had no effect and did not change the inverse agonist effect of ciproxifan. Administrations for 10 days of ciproxifan (1.5 mg/kg/day) or haloperidol (0.5 mg/kg/day) did not change the effects of quinpirole and ( R)α-methylhistamine, respectively. These data suggest that striatal H 3Rs and D 2Rs do not interact through their coupling to G-proteins. However, a hyperactivity of histaminergic and dopaminergic neurons being observed in schizophrenia, the additive activations of H 3Rs and D 2Rs suggest that they cooperate to generate some schizophrenic symptoms. Such a postsynaptic mechanism may underlie the antipsychotic-like effects of H 3R inverse agonists and supports their therapeutic interest, alone or as adjunctive treatment with neuroleptics.

Reinforcement history determines the reinforcing effects of quinpirole in the rat

These experiments were aimed at extending the finding that the D3-peferring agonist, 7-OH-DPAT, maintained responding in rhesus monkeys with a history of cocaine-reinforced responding, but not in all monkeys with a history of food-reinforced responding (Psychopharmacol. 125:13–22). In the present experiments, the effect of reinforcement history on responding for quinpirole (QPRL) was examined in rats. In one set of studies rats were trained to self-administer cocaine, remifentanil, ketamine, or liquid-food (LF) under an FR1 schedule of reinforcement, and QPRL (0.01, 0.032, or 0.1 mg/kg/inj) was assessed as a substitute reinforcer during 1.5 hour sessions over 7 days. When cocaine history was provided, QPRL maintained robust responding with the highest rates at 0.032 QPRL. However, QPRL was generally no different than saline when responding was previously maintained by LF, remifentanil, or ketamine. A second set of studies assessed the type of cocaine history necessary to establish QPRL-reinforced responding in rats initially trained to respond for LF. Two substitutions were used with rats returned to LF between substitutions. In the first substitution, either saline, 0.032 QPRL, response-contingent, or non-contingent cocaine were delivered. Following interpolated LF, a second substitution was carried out with only QPRL. Rats previously maintained with response-contingent cocaine were now maintained by QPRL; all other rats failed to be maintained by QPRL. Thus, a response-contingent cocaine history was necessary to establish the reinforcing effect of QPRL. Research supported by grants DA20669 and F013771 through NIDA

Insulin Replacement Restores the Behavioral Effects of Quinpirole and Raclopride in Streptozotocin-Treated Rats

Streptozotocin (STZ)-induced diabetes can modulate dopamine (DA) neurotransmission and thereby modify the behavioral effects of drugs acting on DA systems. Insulin replacement, and in some conditions repeated treatment with amphetamine, can partially restore sensitivity of STZ-treated rats to dopaminergic drugs. The present study sought to characterize the role of insulin and amphetamine in modulating the behavioral effects of drugs that selectively act on D2/D3 receptors. In control rats, quinpirole and quinelorane produced yawning, whereas raclopride and gamma-hydroxybutyric acid (GHB) produced catalepsy. Raclopride antagonized quinpirole- and quinelorane-induced yawning with similar potency. STZ treatment increased blood glucose concentration, decreased body weight, and markedly reduced sensitivity to quinpirole-induced yawning, quinelorane-induced yawning as well as to raclopride-induced catalepsy, while enhancing sensitivity to GHB-induced catalepsy. Repeated treatment with amphetamine partially restored sensitivity of STZ-treated rats to amphetamine-stimulated locomotion and also produced conditioned place preference, without affecting blood glucose and body weight changes. However, amphetamine treatment did not restore sensitivity to the behavioral effects of quinpirole, raclopride, or GHB, suggesting differential regulation of dopamine transporter activity and sensitivity of D2 receptors in hypoinsulinemic rats. Insulin replacement in STZ-treated rats normalized blood glucose and body weight changes and fully restored sensitivity to quinpirole-induced yawning, as well as to raclopride-induced catalepsy, while reducing sensitivity to GHB-induced catalepsy. Overall, these data indicate that changes in insulin status markedly affect sensitivity to the behavioral effects of dopaminergic drugs. The results underscore the importance of insulin in modulating DA neurotransmission; these effects might be especially relevant to understanding the co-morbidity of eating disorders and substance abuse.

Compulsive-like effects of quinpirole on drinking behavior in rats are inhibited by substituting ethanol for water

We have previously reported that in rats given the choice between operant and free access to water (contrafreeloading: CFL), repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, shifted the animals towards the operant access and inhibited water intake. The purpose of the present study was to investigate the influence of substituting different concentrations of ethanol (2, 4, 6%) for water on the effects of repeated daily administrations of vehicle or quinpirole (0.5 mg/kg i.p.) in rats that for 6 days were given access to the fluid according to an FR3 schedule of reinforcement and for the following 9 days were given the choice between operant and free access to the fluid. On the first day quinpirole completely suppressed operant behavior, which however progressively increased in the subsequent sessions, approaching control levels by day 6. Ethanol presentation did not alter these effects of quinpirole. When the resource was also freely available, quinpirole produced the expected shift from free to operant access to water (CFL). Substituting ethanol for water resulted in a concentration-related reduction of the over-responding and, consequently, of CFL induced by quinpirole. In vehicle-injected subjects ethanol did not affect responding and only marginally reduced fluid intake. Thus, ethanol appears to prevent perseveration in performing needless instrumental behavior induced by repeated activation of D2/D3 receptors.

Sensorimotor Gating and Dopamine Function in Postpartum Rats

There is much speculation regarding the effects of estrogen withdrawal at the end of pregnancy on forebrain dopamine, however, few studies have directly examine changes in this system postpartum. The present work sought to determine what changes in forebrain dopamine function occur in the postpartum rat. Specifically, prepulse inhibition of the acoustic startle response (PPI) was measured in primiparous female rats on postpartum day 2 (PPD2) or 14 (PPD14) following treatment with saline or the dopamine D2 agonist, quinpirole. Diestrus (DI) females served as controls. Dopamine content and turnover as well as cyclic AMP (cAMP) accumulation were determined within the nucleus accumbens and dorsal striatum in these same females. In addition, circulating levels of plasma corticosterone, estradiol and progesterone were measured. PPI was significantly disrupted in both postpartum groups. This effect was associated with decreased cAMP content within the nucleus accumbens. Quinpirole treatment (0.1 and 0.5 mg/kg) dose-dependently disrupted PPI in DI controls while PPD2 and PPD14 animals demonstrated reduced sensitivity to the D2 agonist. PPD14 animals demonstrated increased startle amplitude, an effect that was attenuated by quinpirole treatment. PPD14 females were also less sensitive to quinpirole-mediated reductions in DA turnover within the nucleus accumbens and both PPD2 and PPD14 females had an attenuated response to the stimulatory effects of quinpirole on corticosterone secretion. Collectively these findings suggest that the postpartum period is associated with reduced sensorimotor gating and altered forebrain DA systems, which may be related to shifts in circulating hormones.

D2‐class dopamine receptor inhibition of NMDA currents in prefrontal cortical neurons is platelet‐derived growth factor receptor‐dependent

NMDA receptor function is modulated by both G-protein-coupled receptors and receptor tyrosine kinases. In acutely isolated rat hippocampal neurons, direct activation of the platelet-derived growth factor (PDGF) receptor or transactivation of the PDGF receptor by D4 dopamine receptors inhibits NMDA-evoked currents in a phospholipase C (PLC)-dependent manner. We have investigated further the ability of D2-class dopamine receptors to modulate NMDA-evoked currents in isolated rat prefrontal cortex (PFC). We have demonstrated that, similar to isolated hippocampal neurons, the application of PDGF-BB or quinpirole to isolated PFC neurons induces a slow-onset and long-lasting inhibition of NMDA-evoked currents. However, in contrast to hippocampal neurons, the inhibition of NMDA-evoked currents by quinpirole in PFC neurons is dependent upon D2/3, rather than D4, dopamine receptors. In PFC slices, application of both PDGF-BB and quinpirole induced a phosphorylation of the PDGF receptor at the PLCgamma binding and activation site, Tyr1021. The PDGF receptor kinase inhibitor, tyrphostin A9, and the D2/3 dopamine receptor antagonist, raclopride, inhibited quinpirole-induced Tyr1021 phosphorylation. These finding suggest that quinpirole treatment inhibits NMDAR signaling via PDGF receptor transactivation in both the hippocampus and the PFC, and that the effects of quinpirole in these regions are mediated by D4 and D2/3 dopamine receptors, respectively.

Reduced basal and ethanol stimulation of striatal extracellular dopamine concentrations in dopamine D2 receptor knockout mice

The present study was undertaken to examine the role of the dopamine (DA) D2 receptor in the ethanol-evoked DA response in the ventral striatum. We performed microdialysis experiments using the D2 null mutant and wild-type controls and measured the effect of an intraperitoneal (i.p.) injection of either saline or ethanol (2 g/kg) on dialysate DA concentrations in the ventral striatum. Dialysate ethanol concentrations were also determined in the samples from the ventral striatum. In addition, the effects of quinpirole, a D2/D3 agonist, were examined in both the ventral and dorsal striatum. Basal dialysate concentrations of DA were significantly reduced in both the ventral and dorsal striatum of the D2 knockouts compared with wild-type controls. Ethanol administration significantly enhanced ventral striatal DA in both groups, but the increase in dialysate DA concentration was 3.5-fold higher in the wild-type controls. The time course of dialysate ethanol concentrations was similar in the two groups. Saline injection did not alter DA concentrations in either the ventral or dorsal striatum. However, quinpirole (0.3 mg/kg) administration significantly depressed striatal dialysate DA concentrations in the wild-type mice, but not in the D2 knockouts. The results suggest that the D2 receptor is necessary for normal development and regulation of striatal extracellular DA concentrations, but the mechanism for this alteration is unclear. In addition, the blunted ethanol-evoked DA response in the D2 knockouts may contribute, in part, to some of the behavioral deficits previously observed in response to ethanol.

Inhibition of jaw opening reflex and single neurons in the trigeminal subnucleus caudalis by activation of striatal D2 dopamine receptors

The influence of striatal dopaminergic receptors on the inhibitory action of the striatum on the jaw opening reflex (JOR) was studied in anesthetized rats. Single unit activity was recorded at the subnucleus caudalis of the trigeminal nerve. Dopamine agonists and antagonists were microinjectd into the striatum. The striatal administration of apomorphine inhibits the JOR evoked by dental pulp stimulation. Similar results were observed by microinjections of quinpirole, an agonist of D 2 receptors, but not by microinjection of SKF 38393, a D 1 agonist. The effect of quinpirole was only inhibited by intrastriatal microinjection of haloperidol, a blocker of D 2 receptors and reversed by systemic administration of 1 mg/kg of naloxone. The evoked neuronal responses in subnucleus caudalis, by tooth pulp stimulation, were also suppressed by microinjection of quinpirole into the striatum and reversed by naloxone (1 mg/kg, i.v.). Based on the above results, we conclude that the activation of striatal D 2 dopamine receptors is responsible for the inhibition of the JOR possibly by action on the subnucleus caudalis of the trigeminal nerve.

Compulsive-like effects of repeated administration of quinpirole on drinking behavior in rats

We have previously reported that repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, facilitate instrumental behavior in rats given the choice between operant and free access to water (contrafreeloading: CFL). The goal of the present study was to investigate the effects of repeated daily administrations of quinpirole (0.5 mg/kg i.p.) on the appetitive versus the consummatory component of water-reinforced behavior, under two experimental conditions. Under one condition, the rats were given access to tap water according to an FR3 schedule of reinforcement. Under the second condition, the rats were given the choice between operant and free access to water. Five major findings were obtained. First, acutely quinpirole suppressed operant behavior and, therefore, water intake for at least 1 h. Second, upon repeated administrations tolerance developed to the suppressant effect of quinpirole on instrumental behavior but only to a lesser extent to the antidipsic effect, dissociating the appetitive from the consummatory components of water-reinforced behavior. Third, in CFL conditions quinpirole induced a progressively larger preference for the operant access. Fourth, even when the rats were given the choice between free access to highly palatable saccharine (0.05 or 0.01%) solutions and operant access to tap water, quinpirole shifted the animals towards the operant access. Fifth, repeated quinpirole produced lasting consequences on drinking behavior, since after rehydration and under drug-free conditions quinpirole-pretreated rats ingested larger amounts of water than control rats. In conclusion, the repeated activation of D2/D3 receptors appears to induce the rats to perseverate in performing needless instrumental behavior.

Effect of quinpirole on striatal dopamine release and locomotor activity in nicotine-treated mice

The effect of chronic oral nicotine treatment which in its intermittent delivery resembles human smoking was studied on the sensitivity of dopamine autoreceptors in mice. On the 50th day of nicotine administration in the drinking water or after 23–25 h withdrawal quinpirole (D 2/D 3 agonist, 0.01–0.1 mg/kg s.c.) was given, and accumbal and dorsal striatal dopamine outflow, locomotor activity and body temperature were measured. Dorsal striatal extracellular dopamine concentration and locomotor activity were found to be elevated during nicotine administration. Chronic nicotine did not alter the effects of small, autoreceptor preferring doses of quinpirole on accumbal or dorsal striatal dopamine, locomotor activity or body temperature. However, quinpirole's locomotor activity reducing effect was slightly diminished in mice treated repeatedly with nicotine (0.4 mg/kg twice daily for 10 days s.c.). Thus, although repeated nicotine treatment for 5–14 days decreases dopamine autoreceptor sensitivity, after long-term oral nicotine treatment such a decrease is not seen. Thus, the changes occurring in the sensitivity of D 2-like dopamine receptors probably play a minor role in regulating the dopaminergic transmission during long-term nicotine administration.

In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): A novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.

Control of the Subthalamic Innervation of Substantia Nigra Pars Reticulata by D1 and D2 Dopamine Receptors

The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed.