Role of dopamine receptors in the dual effect of naloxone on quinpirole-induced yawning in morphine pretreated rats

Summary The present study was undertaken to determine the state of sensitivity of dopamine D2/133 receptors involved in the mediation of yawning behaviour at various times following acute morphine administration to rats. Morphine (3.0 mg/kg, s.c.) induced a biphasic effect on locomotor activity: an initial inhibitory phase lasting for about 30 min was after about an hour followed by a phase of locomotor activation lasting for about 60 min. Dopamine D2/D3 receptor agonist quinpirole (0.01–0.1 mg/kg, s.c.) induced yawning behaviour in rats. Morphine given at 15 or 60 min before (inhibitory phase) inhibited the yawning response to quinpirole (0.1 mg/kg) but not when given at 90 or 120 min before (stimulatory phase). Naloxone (1.0 mg/kg) given 10 min before quinpirole restored yawning inhibited by morphine pretreatment during the inhibitory phase (15–60 min after morphine). However, during the morphine-induced stimulatory phase naloxone strongly inhibited the yawning response to quinpirole. D 1 receptor antagonist SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hemimaleate] at 0.01 mg/ kg did not affect quinpirole-induced yawning or its inhibition by morphine. However, in rats which received morphine 90 min prior to testing yawning, SCH 23390 enhanced quinpirole-induced yawning behaviour as compared with morphine- or saline-pretreated animals. The data obtained in the present study indicate that morphine pretreatment initially induces a lack of responsiveness of the D2/D3 receptors mediating yawning behaviour and subsequently increases their sensitivity. However, the behavioural expression of hypersensitivity of these receptors seems to be attenuated by the concomitant activation of D1 receptors after morphine pretreatment, and thus the enhanced response to quinpirole is first seen after blockade of D1 receptors. Correspondence to L. Ahtee at the above address     

D-2 but not D-1 dopamine agonists produce augmented behavioral response in rats after subchronic treatment with methamphetamine or cocaine

A study was performed to examine behavioral response to a challenge of selective dopamine D-1 and D-2 agonists in rats previously sensitized by subchronic administration of methamphetamine or cocaine. Rats in three groups received repeated injections (IP) of saline, methamphetamine (4 mg/kg/day) or cocaine (20 mg/kg/day), respectively, for 14 days. After an abstinence period of 7–13 days, all groups were challenged with either a selective D-1 agonist (SKF 38393) or D-2 agonists (quinpirole or RU 24213). The ability of SKF 38393 (6 mg/kg or 18 mg/kg) to produce grooming behavior did not differ significantly among the saline-, methamphetamine-and cocaine-treated groups. In contrast, quinpirole (1 mg/kg) and RU 24213 (3 mg/kg) produced more intense stereotypy consisting of rearing, sniffing and repetitive head movement in the two psychostimulant-treated groups than in the saline-treated group. Such augmented response to selective D-2 agonists was observed even after a 1-month abstinence period. These results suggest that the enduring behavioral sensitization induced by two pharmacologically distinct psychostimulant agents, methamphetamine and cocaine, occurs through a common neurobiological mechanism of lasting supersensitivity in postsynaptic D-2, but not D-1 dopamine receptors.     

Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists andd-amphetamine

The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 µg/side of the dopamine receptor agonists SKF 38393 (D₁) and quinpirole (D₂) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonistd-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.     

Production of climbing behaviour in mice requires both D1 and D2 receptor activation

The ability of SKF38393 (a D1 agonist), quinpirole (a D2 agonist), and apomorphine (a mixed D1/D2 agonist) to induce stereotyped climbing behaviour in mice was investigated. Apomorphine produced a dose-related increase in stereotyped cage climbing which lasted for up to 60 min. SKF38393 and quinpirole failed to produce climbing when administered alone. When given in combination intense apomorphine-like cage climbing was observed which lasted for up to 2 h. Apomorphine or the combination of SKF38393 and quinpirole also produced biting of the cage. The climbing behaviour produced by either apomorphine or SKF38393/quinpirole combinations was antagonised by either the D1 antagonist, SCH23390 or the D2 antagonist clebopride. These results demonstrate that both D1 and D2 receptor activation is necessary to produce apomorphine-like cage climbing in mice. Offprint requests to: N.A. Moore     

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 (1.25 mg/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.     

Comparative effects of scopolamine and quinpirole on the striatal fos expression induced by stimulation of D1 dopamine receptors in the rat

Treatment of intact rats with the full D₁ dopamine agonist A-77636 induced Fos-like immunoreactivity in the medial and, to a lesser extent, the lateral portions of the striatum. Pretreatment with the muscarinic antagonist scopolamine hydrobromide (1.5–6 mg/kg) potentiated the response to A-77636 and eliminated the mediolateral staining gradient seen after A-77636 alone. Similar effects were not produced by scopolamine methylbromide, which fails to cross the blood–brain barrier, demonstrating that the actions of scopolamine were centrally mediated. The effects of scopolamine were further compared to those of the D₂-like dopamine agonist quinpirole using a factorial design in which subjects were pretreated with either scopolamine, quinpirole, or a combination of the two drugs before receiving A-77636. Pretreatment with either scopolamine or quinpirole increased staining in the lateral striatum, but the combination of the two drugs was no more effective than was quinpirole alone. Pretreatment with quinpirole, but not scopolamine, resulted in a markedly ‘patchy’ pattern of staining and actually suppressed staining in the region between patches in the medial striatum. These findings demonstrate that there are both differences and similarities between the effects of scopolamine and quinpirole on D₁ agonist-induced Fos expression and suggest that although inhibition of cholinergic neurons may be one of the mechanisms through which the effects of quinpirole are produced, other factors must also contribute.     

边缘叶脑白质切开术对QNP处理大鼠中枢多巴胺含量的影响

目的探讨边缘叶脑白质切开术(尾状核下束和扣带回前部)对喹吡罗(Quinpirole,QNP)处理大鼠中枢系统多巴胺含量的影响,为临床手术治疗强迫症提供实验依据。方法40只SD大鼠随机分为正常对照组、模型组、模型手术组及模型假手术组。模型组大鼠颈部皮下注射QNP建立强迫检查行为动物模型,应用立体定向进行大鼠边缘叶脑白质切开术,观察大鼠脑组织中多巴胺含量的变化。结果边缘叶脑白质切开术能明显减弱QNP诱发的大鼠强迫检查行为,与假手术组之间的差别具有非常显著性意义(P<0.001)。模型手术组左侧前额皮质多巴胺含量比模型假手术组降低(P<0.05),右侧无显著变化(P>0.05)。皮质下结构隔核、纹状体和杏仁核多巴胺含量比对照组和模型假手术组显著增加(P<0.05)。结论边缘叶脑切开术能降低左侧前额皮质多巴胺含量,增加皮质下结构多巴胺含量,改善QNP处理诱发的大鼠强迫检查行为。     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

Sensitization to cocaine and dopamine autoreceptor subsensitivity in the nucleus accumbens

It has been suggested that dopamine autoreceptor subsensitivity may play a role in cocaine-induced behavioral sensitization. In order to evaluate this hypothesis, we administered cocaine to rats daily (15 mg/kg ip × 2 days, 30 mg/kg ip × 5 days) and then monitored nucleus accumbens dopamine during the local administration (through the dialysis probe) of the D₂/D₃ agonist, quinpirole (0, 0.1, 1, and 10 μM). Our results indicate that, relative to saline-pretreated control animals, repeated cocaine administration impaired the ability of quinpirole to decrease extracellular dopamine 1–2 days after the last drug injection. However, quinpirole was equipotent at reducing accumbal dopamine in cocaine- and saline-treated animals following a 21–22 day withdrawal period. These results demonstrate that repeated cocaine produces a short duration functional tolerance in the capacity of autoreceptor stimulation to inhibit accumbal dopamine release. © 1995 Wiley-Liss, Inc.     

Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT_1A receptor agonist and 5-HT₂ receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D₂/D₃ receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D₂/D₃ receptor-mediated transmission.