Effects Of Quinpirole Research Articles

Dopamine Receptors Modulate Cytotoxicity of Natural Killer Cells via cAMP-PKA-CREB Signaling Pathway

Dopamine (DA), a neurotransmitter in the nervous system, has been shown to modulate immune function. We have previously reported that five subtypes of DA receptors, including D1R, D2R, D3R, D4R and D5R, are expressed in T lymphocytes and they are involved in regulation of T cells. However, roles of these DA receptor subtypes and their coupled signal-transduction pathway in modulation of natural killer (NK) cells still remain to be clarified. The spleen of mice was harvested and NK cells were isolated and purified by negative selection using magnetic activated cell sorting. After NK cells were incubated with various drugs for 4 h, flow cytometry measured cytotoxicity of NK cells against YAC-1 lymphoma cells. NK cells expressed the five subtypes of DA receptors at mRNA and protein levels. Activation of D1-like receptors (including D1R and D5R) with agonist SKF38393 enhanced NK cell cytotoxicity, but activation of D2-like receptors (including D2R, D3R and D4R) with agonist quinpirole attenuated NK cells. Simultaneously, SKF38393 elevated D1R and D5R expression, cAMP content, and phosphorylated cAMP-response element-binding (CREB) level in NK cells, while quinpirole reduced D3R and D4R expression, cAMP content, and phosphorylated CREB level in NK cells. These effects of SKF38393 were blocked by SCH23390, an antagonist of D1-like receptors, and quinpirole effects were abolished by haloperidol, an antagonist of D2-like receptors. In support these results, H89, an inhibitor of phosphokinase A (PKA), prevented the SKF38393-dependent enhancement of NK cells and forskolin, an activator of adenylyl cyclase (AC), counteracted the quinpirole-dependent suppression of NK cells. These findings show that DA receptor subtypes are involved in modulation of NK cells and suggest that D1-like receptors facilitate NK cells by stimulating D1R/D5R-cAMP-PKA-CREB signaling pathway and D2-like receptors suppress NK cells by inhibiting D3R/D4R-cAMP-PKA-CREB signaling pathway. The results may provide more targets of therapeutic strategy for neuroimmune diseases.

Anxiolytic-like effect of quinpirole in combination with a low dose of 17β-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 17β-estradiol (17β-E2) to ovariectomized (OVX) rats. Two weeks after surgery, OVX rats began 14 days of treatment with the vehicle, a low dose of 17β-E2 (5.0 μg/rat, s.c.), quinpirole (0.1 mg/kg, i.p.), sulpiride (10.0 mg/kg, i.p.), quinpirole plus 17β-E2 or sulpiride plus 17β-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 17β-E2 (5.0 μg/rat, s.c.) resulted in anxiolytic-like effect in OVX rats in the BWM. Repeated treatment of quinpirole and 17β-E2 profoundly increased anxiolytic-like effect of the single substances they exert per se. Co-administration of quinpirole with 17β-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 17β-E2 in OVX rats. Application of neither sulpiride nor sulpiride plus 17β-E2 led to any changes of rearing and grooming behavior in OVX rats in the OFT. The results of the present study suggest that 17β-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 17β-E2 exert synergistic effect on anxiety-related behavior.

Behavioral effects of quinpirole on schedule‐controlled responding in radiation sensitive and insensitive rats

A previous report noted that rats receiving head‐only exposure to iron ions (56Fe, a form of ionizing radiation) displayed neurobehavioral deficits on the rodent psychomotor vigilance task (rPVT), including changes in accuracy and premature responding, that were only apparent in a subset of exposed rats; i.e., radiation‐sensitive and insensitive groups emerged. Group‐specific changes in dopamine (DA) protein levels were also evident.To better understand DA system differences in radiation sensitivity, these radiation‐sensitive and insensitive groups and a sham‐irradiated control group were subsequently trained to press a lever for food pellets on a fixed‐ratio 30 schedule of reinforcement. The D2 receptor agonist quinpirole (0.01–1.0 mg/kg) dose‐dependently decreased response rates in all groups; irradiated groups were more sensitive than controls (i.e., showed greater decreases). The D2 receptor antagonist amisulpride (0.1–2.0 mg/kg) alone had no effect on performance, but did antagonize quinpirole's effects. The results show that the DA system is sensitive to radiation‐induced changes that alter behavior as exemplified by the DA system's response to drug administration, which could impact treatment of radiation‐induced cognitive deficits. This work was funded by NSBRI through NASA NCC 9–58‐PF02602 and 9–58‐NBPF02802.

Discriminative stimulus effects of direct‐ and indirect‐ acting dopamine receptor agonists in free‐feeding and food‐restricted mice.

In rats, the discriminative stimulus effects of direct‐ (e.g., quinpirole) and indirect‐ (e.g., cocaine) acting dopamine receptor agonists are mediated by multiple dopamine receptor subtypes and the relative contribution of D2 and D3 receptors to these effects can be altered by manipulating feeding conditions (e.g., food restriction). In these studies two‐lever discriminations were trained with either 10.0 mg/kg cocaine or 0.032 mg/kg quinpirole in free‐fed and food‐restricted mice using a fixed ratio 10 schedule of reinforcement for 50% sweetened condensed milk. Although free‐fed mice responded at lower rates under training conditions and were more sensitive to the rate suppressant effects of their respective training drugs, feeding condition did not affect the acquisition of either discrimination and did not alter the potencies of cocaine or quinpirole to increase cocaine‐ and quinpirole‐appropriate responding, respectively. These novel discriminations will allow for the identification of the specific receptors that mediate the interoceptive effects of cocaine and quinpirole and will serve as the basis for future studies of the influence of diet on drug effects in mice. CPF is supported by a NIDA Senior Scientist Award (K05 DA017918).

The role of dopamine D3 receptors in the discriminative stimulus effects of quinpirole, cocaine, and methamphetamine in rhesus monkeys

Dopamine (DA) D3 receptors may be a promising therapeutic target for stimulant abuse. Compounds deemed partial agonists in vitro do not typically show D3 agonist effects in vivo. It was recently reported that the D3 partial agonist PG619 elicited yawning in monkeys with an extensive cocaine history to a similar degree as the D3 agonist quinpirole (QUIN). The current experiments investigated the role of DA D3 receptors in three groups of monkeys trained to discriminate QUIN (0.03 mg/kg), cocaine (COC) or methamphetamine (MA), both at 0.1 mg/kg, in a two‐key saline versus drug discrimination (SD) paradigm. PG619 (0.3–10.0 mg/kg) did not substitute for QUIN, but enhanced QUIN‐appropriate responding when given as a pretreatment (3.0 mg/kg), indicating D3 agonist effects. Buspirone (0.03–0.3 mg/kg), a D3 antagonist, substituted for QUIN in 2 of 3 monkeys without decreasing response rates. In COC‐ and MA‐trained monkeys, QUIN did not substitute for the training dose. In preliminary studies, buspirone blocked the SD effects of COC and MA. Taken together, these findings using D3 partial agonists and antagonists suggest a unique pharmacology related to D3 receptor function and support the hypothesis that COC and MA exposure modifies these effects. These studies support the continued exploration of novel D3 receptor compounds for the treatment of stimulant abuse. DA12460, NIDA‐IRP

Effects of dopamine D2 agonist quinpirole on neuronal activity of anterior cingulate cortex and striatum in rats

The influence of acute D2 agonist quinpirole on locomotor activity has been effectively characterized. However, few studies have addressed the dynamic changes in neuronal activity of the anterior cingulate cortex (ACC) and striatum (STR), two crucial regions for cognitive and motor functions, after quinpirole administration. This study was conducted in order to acquire detailed information on the evoked activity of the neurons in the ACC and STR after acute quinpirole administration. Multichannel electrophysiological recording was used for tracking neuronal activity in the ACC and STR of urethane-anesthetized rats after administration of saline or 0.05 or 0.5mg/kg quinpirole. In contrast to the responses to saline, quinpirole dose-dependently increased the ratio of neurons, the activity of which was inhibited in the ACC and STR. By examining the ensemble neuronal activities of inhibition-responded neurons, there was no significant activity difference among the "treatments" (saline and low- and high-dose quinpirole), the "periods" (the duration of 0-15 and 16-45min after i.v. injection), and the interaction between "treatments" and "periods." Regarding activation-responded neurons, however, there was a significant "periods" difference in both ACC and STR, and the activity of 16-45min was significantly higher than the activity of 0-15min after high-dose quinpirole administration in ACC (p < 0.05) and STR (p < 0.001). Dose-dependent ACC and STR neuronal responses to quinpirole may offer a possible mechanism for understanding the locomotor responses to quinpirole in behaving rats. The late excitatory effect of high-dose quinpirole in the STR further suggests that this region would be critical for the activation of locomotor activity.

Activation of D1 Dopamine Receptors Induces Emergence from Isoflurane General Anesthesia

A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia. In adult rats, we tested the effects of chloro-APB (D1 agonist) and quinpirole (D2 agonist) on time to emergence from isoflurane general anesthesia. We then performed a dose-response study to test for chloro-APB-induced restoration of righting during continuous isoflurane anesthesia. SCH-23390 (D1 antagonist) was used to confirm that the effects induced by chloro-APB are specifically mediated by D1 receptors. In a separate group of animals, spectral analysis was performed on surface electroencephalogram recordings to assess neurophysiologic changes induced by chloro-APB and quinpirole during isoflurane general anesthesia. Chloro-APB decreased median time to emergence from 330 to 50 s. The median difference in time to emergence between the saline control group (n = 6) and the chloro-APB group (n = 6) was 222 s (95% CI: 77-534 s, Mann-Whitney test). This difference was statistically significant (P = 0.0082). During continuous isoflurane anesthesia, chloro-APB dose-dependently restored righting (n = 6) and decreased electroencephalogram δ power (n = 4). These effects were inhibited by pretreatment with SCH-23390. Quinpirole did not restore righting (n = 6) and had no significant effect on the electroencephalogram (n = 4) during continuous isoflurane anesthesia. Activation of D1 receptors by chloro-APB decreases time to emergence from isoflurane anesthesia and produces behavioral and neurophysiologic evidence of arousal during continuous isoflurane anesthesia. These findings suggest that selective activation of a D1 receptor-mediated arousal mechanism is sufficient to induce emergence from isoflurane general anesthesia.

Aberrant Dopamine D2-Like Receptor Function in a Rodent Model of Schizophrenia

Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAM-treated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcription-polymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinson's disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM. 5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (ADX88178) enhances glutamate-mediated activation of human and rat mGluR4 with EC(50) values of 4 and 9 nM, respectively. The compound is highly selective for mGluR4 with minimal activities at other mGluRs. Oral administration of ADX88178 in rats is associated with high bioavailability and results in cerebrospinal fluid exposure of >50-fold the in vitro EC(50) value. ADX88178 reverses haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. It is noteworthy that this compound alone has no impact on forelimb akinesia resulting from a bilateral 6-hydroxydopamine lesion in rats. However, coadministration of a low dose of L-DOPA (6 mg/kg) enabled a robust, dose-dependent reversal of the forelimb akinesia deficit. ADX88178 also increased the effects of quinpirole in lesioned rats and enhanced the effects of L-DOPA in MitoPark mice. It is noteworthy that the enhancement of the actions of L-DOPA was not associated with an exacerbation of L-DOPA-induced dyskinesias in rats. ADX88178 is a novel, potent, and selective mGluR4 PAM that is a valuable tool for exploring the therapeutic potential of mGluR4 modulation. The use of this novel tool molecule supports the proposal that activation of mGluR4 may be therapeutically useful in Parkinson's disease.

Increased drinking after intra-striatal injection of the dopamine D2/D3 receptor agonist quinpirole in the rat

Dopamine D2 receptor hyperactivity has been implicated in the development of psychogenic polydipsia in schizophrenic patients. Repeated treatment with dopamine agonists, including the D2/D3 agonist quinpirole, has been shown to induce hyperdipsia in a number of animal models. Despite these observations, obtained with systemic administrations, little attempt has been made to investigate where in the brain dopamine agonists act to induce hyperdipsia. The present study investigates the effects of repeated intra-caudate infusions of quinpirole on the intake of water by rats tested under free-drinking conditions. Rats with bilateral cannulae placed into the anterior, central or posterior caudate received quinpirole microinfusions (1 μg/side) for five consecutive days in their home cage. Water intake was measured 15 and 60 min after the treatment. When injected in the central caudate, quinpirole increased water intake, and this effect progressively increased over sessions, indicating the development of sensitization. When injected in the posterior caudate, the dipsogenic effect of quinpirole was less intense and did not undergo sensitization. The infusion of quinpirole in the anterior caudate did not affect drinking. The present study shows that caudate D2/3 receptors play an important role in the development of quinpirole-induced hyperdipsia, an animal model of psychotic polydipsia.

A comparison of the effects of the dopamine partial agonists aripiprazole and (−)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro

The effects of aripiprazole, (−)-(3-hydroxyphenyl)-N-n-propylpiperidine ((−)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (−)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration–response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (−)-3-PPP shifted the concentration–response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D2 ligands remains controversial.

Effects of Stimulation and Blockade of Receptor on Depression-Like Behavior in Ovariectomized Female Rats

The aim of the present study was to explore the hedonic effects of D2 receptor agonist, quinpirole and D2 receptor antagonist, and sulpiride alone or in combination with a low dose of 17β-E2-estradiol (17β-E2) in the adult ovariectomized female rats (OVX). OVX rats of Wistar strain were used in all experiments. Two weeks after surgery rats were chronically treated with vehicle, a low dose of 17β-E2 (5.0 μg/rat), quinpirole (0.1 mg/kg), sulpiride (10.0 mg/kg), quinpirole plus 17β-E2, or sulpiride plus 17β-E2 for 14 days before the forced swimming test. We found that sulpiride significantly decreased immobility time in the OVX females. A combination of sulpiride with a low dose of 17β-E2 induced more profound decrease of immobility time in the OVX rats compared to the rats treated with sulpiride alone. On the contrary, quinpirole failed to modify depression-like behavior in the OVX rats. In addition, quinpirole significantly blocked the antidepressant-like effect of 17β-E2 in OVX rats. Thus, the D2 receptor antagonist sulpiride alone or in combination with a low dose of 17β-E2 exerted antidepressant-like effect in OVX female rats, while the D2 receptor agonist quinpirole produced depressant-like profile on OVX rats.

Sensitivity to apomorphine-induced yawning and hypothermia in rats eating standard or high-fat chow

Feeding conditions modify sensitivity to indirect- and direct-acting dopamine receptor agonists as well as the development of sensitization to these drugs. This study examined whether feeding condition affects acute sensitivity to apomorphine-induced yawning or changes in sensitivity that occur over repeated drug administration. Quinpirole-induced yawning was also evaluated to see whether sensitization to apomorphine confers cross-sensitization to quinpirole. Drug-induced yawning was measured in different groups of male Sprague Dawley rats (n = 6/group) eating high (34.3%) fat or standard (5.7% fat) chow. Five weeks of eating high-fat chow rendered otherwise drug-naïve rats more sensitive to apomorphine- (0.01-1.0mg/kg, i.p.) and quinpirole- (0.0032-0.32mg/kg, i.p.) induced yawning, compared with rats eating standard chow. In other rats, tested weekly with apomorphine, sensitivity to apomorphine-induced yawning increased (sensitization) similarly in rats with free access to standard or high-fat chow; conditioning to the testing environment appeared to contribute to increased yawning in both groups of rats. Food restriction decreased sensitivity to apomorphine-induced yawning across five weekly tests. Rats with free access to standard or high-fat chow and sensitized to apomorphine were cross-sensitized to quinpirole-induced yawning. The hypothermic effects of apomorphine and quinpirole were not different regardless of drug history or feeding condition. Eating high-fat chow or restricting access to food alters sensitivity to direct-acting dopamine receptor agonists (apomorphine, quinpirole), although the relative contribution of drug history and dietary conditions to sensitivity changes appears to vary among agonists.

Drinking sucrose enhances quinpirole-induced yawning in rats

Food and drugs can activate brain dopamine systems and sensitivity to the effects of drugs acting on those systems is influenced by amount and content of food consumed. This study examined the effects of drinking sucrose on behavioral effects of the direct-acting dopamine receptor agonist quinpirole. Male Sprague-Dawley rats (n=6/group) had free access to water or 10% sucrose and quinpirole dose-response curves (yawning and hypothermia) were generated weekly for 8 weeks. Subsequently, all rats drank water for 8 weeks with quinpirole dose-response curves determined on weeks 9, 10, and 16. In rats drinking sucrose, the ascending (D3 receptor-mediated), but not descending (D2 receptor-mediated), limb of the yawning dose-response curve shifted leftward. The D3 receptor-selective antagonist PG01037 shifted the ascending limb of the dose-response curve to the right in all rats. When rats that previously drank sucrose drank water, their sensitivity to quinpirole did not return to normal. Quinpirole-induced hypothermia was not different between groups. These data show that drinking sucrose increases sensitivity to a dopamine D3, but not D2, receptor-mediated effect and that this change is long lasting. Dopamine receptors mediate the effects of many drugs and the actions of those drugs are likely impacted by dietary factors.

D2-like dopamine receptors differentially regulate unitary IPSCs depending on presynaptic GABAergic neuron subtypes in rat nucleus accumbens shell

In the nucleus accumbens (NAc), a medium spiny (MS) neuron receives GABAergic inputs from two major sources: fast-spiking (FS) neurons and other, adjacent MS neurons. These two types of inhibitory synapses are considered to play different roles in output activities, i.e., FS→MS connections suppress output from the NAc whereas MS→MS connections contribute to lateral inhibition. In the present study, we focused on the electrophysiological properties of unitary inhibitory postsynaptic currents (uIPSCs) obtained from MS→MS connections and FS→MS connections and examined the effects of quinpirole, a dopamine D(2)-like receptor agonist, on uIPSCs with multiple whole cell patch-clamp recording. Application of quinpirole (1 μM) reliably suppressed the amplitude of uIPSCs by 29.6% in MS→MS connections, with increases in paired-pulse ratio and failure rate. The suppressive effects of quinpirole on uIPSCs were mimicked by 1 μM PD128907, a D(2/3) receptor agonist, whereas quinpirole-induced suppression of uISPCs was blocked by preapplication of 1 μM sulpiride or 10 μM nafadotride, both D(2/3) receptor antagonists. On the other hand, quinpirole (1 μM) had divergent effects on FS→MS connections, i.e., quinpirole increased uIPSC amplitude in 38.1% of FS→MS connections and 23.8% of FS→MS connections were suppressed by quinpirole. Analysis of coefficient of variation in uIPSC amplitude implied the involvement of presynaptic mechanisms in quinpirole-induced effects on uIPSCs. These results suggest that activation of D(2)-like receptors facilitates outputs from MS neurons in the NAc by reducing lateral inhibition during a dormant period of FS neuron activities.

Quinpirole-induced 50 kHz ultrasonic vocalization in the rat: Role of D2 and D3 dopamine receptors

The goal of the present investigation was to study a full dose-response of quinpirole in production of species-specific 50 kHz ultrasonic vocalizations in rats, and to study involvement of D2 and D3 dopamine receptors in this response. Quinpirole, a D2/D3 dopamine agonist with high selectivity for D2 dopamine receptors, was injected into the shell of the nucleus accumbens. Quinpirole induced species-specific 50 kHz ultrasonic vocalizations at a wide range of doses as compared to saline. The dose-response study showed a triphasic effect of quinpirole and reached two comparable peak responses in the number of emitted vocalizations at 0.25 μg and 6 μg, respectively (a 24-fold dose difference). These two peaks were separated by a decreased phase. A medium dose range (0.5–1.0 μg) of quinpirole consistently depressed production of calls to the control level. Application of antagonists of D2 dopamine receptors (raclopride) and D3 dopamine receptors (U-99194A) before quinpirole revealed that quinpirole activates differentially the D2 and D3 dopamine receptors at different doses. The vocalization response induced by the low dose of quinpirole (0.25 μg) was antagonized by local pretreatment with the D3 receptor antagonist but not by the D2 receptor antagonist. On the other hand, the response induced by the high dose of quinpirole (6 μg) was antagonized by a similar local pretreatment with the D2 receptor antagonist but not by the D3 receptor antagonist. In conclusion, the results indicated that quinpirole can induce 50 kHz vocalizations after its direct intra-accumbens application in rats, and both D2 and D3 dopamine receptors are involved in the response. They play, however, different functional roles, as revealed by the triphasic effect of increasing doses of quinpirole.

Shingosine-1-phosphate regulates PKA/DARPP-32 signaling in striatal medium spiny neurons via GPR6-independent mechanisms

The vast majority of striatal neurons are GABAergic medium-sized spiny neurons. These cells receive glutamatergic input from the cortex, thalamus and limbic areas and dopaminergic input from the mesencephalon. Most relevant evidence indicates that dopamine D1 receptors are located on striatonigral projection neurons,5, 7 and that adenosine A2A receptors4, 12, 14 and most dopamine D2 receptors5, 7, 14 are located on striatopallidal projection neurons (see, however, 1, 13). Here we have utilized regulation of the phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000 (DARPP-32) to study the possible interactions among nigrostriatal dopaminergic neurons and the two classes of dopaminoceptive target neurons. We show that, in striatal slices, the D2 receptor agonist, quinpirole, strongly inhibits the phosphorylation of DARPP-32 induced by either the D1 receptor agonist, SKF 81297, or the A2A receptor agonist, CGS 21680. Tetrodotoxin abolished the effect of quinpirole on the D1 agonist-induced but not the A2A agonist-induced phosphorylation of DARPP-32. These data indicate that: (i) adenosine A2A and dopamine D2 receptors interact within the same striatopallidal neurons, and (ii) D2 receptors present on the striatopallidal neurons modulate the effects of D1 receptors on the striatonigral neurons. Thus, a single neurotransmitter is capable of activating distinct classes of receptors on distinct populations of target neurons, which, in turn, interact with each other through intercellular communication.

Same-sex cohabitation under the effects of quinpirole induces a conditioned socio-sexual partner preference in males, but not in female rats

The effects of the dopamine D2-type receptor agonist quinpirole (QNP) were examined on the development of conditioned same-sex partner preference induced by cohabitation in rats. In Experiment 1, males received either saline or QNP (1.25mg/kg) and cohabited during three trials with almond-scented stimulus males that were sexually naïve. In Experiment 2, males received six trials, and in Experiment 3 received three trials with sexually expert stimulus males. During a final drug-free preference test, males chose between the familiar or a novel male partner. In Experiments 1, 2 and 3 only QNP-treated males displayed a social preference for the familiar male, observed with more time spent together. In Experiment 3 males also displayed a sexual preference observed with more non-contact erections when were exposed to their male partner. In Experiment 4 we tested the effects on OVX, E+P primed females that received 1 systemic injection of either saline or QNP during three conditioning trials. In Experiment 5, females received 2 injections 12-h apart during each trial. Results indicated that both saline and QNP-treated females failed to develop partner preference. These data demonstrate that enhanced D2-type receptor activity during cohabitation facilitates the development of conditioned same-sex partner preference in males, but not in female rats. We discuss the implications for same-sex partner preferences.

D1 and D2 dopaminergic systems in the rat basolateral amygdala are involved in anxiogenic-like effects induced by histamine

Involvement of the dopamine receptors in the basolateral amygdala (BLA) in the effects of histamine on anxiety-like behaviors of the elevated plus maze in male Wistar rats was investigated. The results showed that bilateral intra-BLA injections of histamine (2.5, 5 and 7.5 µg/rat) induced an anxiogenic-like effect, revealed by decreases in percentage of open arm time (%OAT) and open arm entries (%OAE). Intra-BLA administration of dopamine D1 receptor agonist, SKF38393 (0.25 µg/rat), and dopamine D2 receptor agonist, quinpirole (0.03 and 0.05 µg/rat), decreased %OAT but not %OAE. Conversely, intra-BLA administration of dopamine D1 receptor antagonist, SCH23390 (0.5 and 1 µg/rat), and dopamine D2 receptor antagonist, sulpiride (0.3 and 0.5 µg/rat), increased %OAT and %OAE, suggesting an anxiolytic-like effect for both drugs. Interestingly, co-administration of a silent dose of SCH23390 or sulpiride prevented anxiogenic-like effects of SKF38393 and quinpirole, respectively. Conjoint administration of a sub-effective dose of SKF38393 (0.125 µg/rat) or quinpirole (0.01 µg/rat) along with lower doses of histamine (1 and 2.5 µg/rat) induced anxiolytic-like effects. On the other hand, intra-BLA pretreatment with a silent dose of SCH23390 (0.25 µg/rat) or sulpiride (0.1 µg/rat) prevented the anxiogenic-like effect of higher doses of histamine (5 and 7.5 µg/rat). No significant change was observed in total closed arm entries, as an index for motor activity of the animals. It can be concluded that the dopamine D1 and D2 receptors in the BLA may be involved in the anxiogenic-like effects induced by histamine.

NK3 receptors mediate an increase in firing rate of midbrain dopamine neurons of the rat and the guinea pig

This in vitro study investigates and compares the effects of NK3 receptor ligands on the firing rate of rat and guinea pig midbrain dopamine neurons. The findings are discussed in the light of choosing suitable animal models for investigating pharmacological properties of NK3 receptor antagonists, which have been proposed to possess therapeutic activity in neuropsychiatric diseases like e.g. schizophrenia. In vitro midbrain slice preparations of both species were used to record (extracellularly) the firing rates of dopamine neurons located in the substantia nigra (SN) and ventral tegmental area (VTA). Furthermore, the effect of the D2 receptor agonist quinpirole on guinea pig SN and VTA dopamine neurons was investigated. The efficacy of quinpirole in inhibiting guinea pig dopamine neuron firing activity was much less as compared to that of rat dopamine neurons, suggesting a lower dopamine D2 autoreceptor density on the guinea pig neurons. The NK3 receptor agonist senktide induced in subpopulations of rat SN (55%) and VTA (79%) and guinea pig SN (50%) and VTA (21%) dopamine neurons an increase in firing rate. In responsive neurons this effect was concentration-dependent with EC₅₀ values of 3-5 nM (for both species). The selective NK3 receptor antagonist osanetant (100 nM) was able to partly block the senktide-induced increase in firing rates of dopamine neurons and shifted the concentration-response relation curves for senktide to the right (pA₂ values were ~7.5). The fractional block of the senktide responses by osanetant appeared to be larger in guinea pig dopamine neurons, indicating that osanetant is a more potent blocker of NK3 receptor-mediated responses with noncompetitive properties in the guinea pig.