Sensitivity to ethanol-induced motor incoordination in FAST and SLOW selectively bred mice

Earlier studies using the grid test have indicated a negative genetic correlation between sensitivity to ethanol-induced locomotor stimulation and ethanol-induced motor incoordination in FAST and SLOW mice, lines selectively bred for differential sensitivity to ethanol's stimulant effects. Because different tests of motor coordination may not measure the same behavioral competencies or physiological substrates, the present experiments tested adult ethanol- or saline-exposed FAST and SLOW mice of two replicates (FAST-1, FAST-2, SLOW-1, and SLOW-2) using three additional tests of coordination: a stationary dowel, fixed-speed rotarod, and accelerating rotarod. After ethanol treatment, FAST-1 mice fell from the stationary dowel at shorter latencies than SLOW-1 mice, suggesting that they had relatively greater sensitivity to ethanol. However, brain ethanol concentrations (BrECs) were similar at time of fall, and no differences were found between replicate-2 lines. SLOW-1 mice fell from the fixed-speed rotarod at lower BrECs than FAST-1 mice, suggesting possibly greater sensitivity of the SLOW-1 line. Again, no replicate-2 line differences were found. No significant differences were detected for the accelerating rotarod. These results provide little support for a negative genetic relationship between sensitivity to the stimulant and ataxic effects of ethanol using these measures of motor coordination.     

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA_B receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA_B receptor agonist baclofen in FAST mice. We hypothesized that GABA_B receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA_B receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA_B receptor activation may instead enhance some of the behavioral effects of morphine.     

Ethanol-induced sensitization depends preferentially on D1 rather than D2 dopamine receptors

Behavioral sensitization, defined as a progressive increase in the locomotor stimulant effects elicited by repeated exposure to drugs of abuse, has been used as an animal model for drug craving in humans. The mesoaccumbens dopaminergic system has been proposed to be critically involved in this phenomenon; however, few studies have been designed to systematically investigate the effects of dopaminergic antagonists on development and expression of behavioral sensitization to ethanol in Swiss mice. We first tested the effects of D₁ antagonist SCH-23390 (0-0.03 mg/kg) or D₂ antagonist Sulpiride (0-30 mg/kg) on the locomotor responses to an acute injection of ethanol (2.0 g/kg). Results showed that all tested doses of the antagonists were effective in blocking ethanol's stimulant effects. In another set of experiments, mice were pretreated intraperitoneally with SCH-23390 (0.01 mg/kg) or Sulpiride (10 mg/kg) 30 min before saline or ethanol injection, for 21 days. Locomotor activity was measured weekly for 20 min. Four days following this pretreatment, all mice were challenged with ethanol. Both antagonists attenuated the development of ethanol sensitization, but only SCH-23390 blocked the expression of ethanol sensitization according to this protocol. When we tested a single dose (30 min before tests) of either antagonist in mice treated chronically with ethanol, both antagonists attenuated ethanol-induced effects. The present findings demonstrate that the concomitant administration of ethanol with D₁ but not D₂ antagonist prevented the expression of ethanol sensitization, suggesting that the neuroadaptations underlying ethanol behavioral sensitization depend preferentially on D₁ receptor actions.     

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA(B) receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA(B) receptor agonist baclofen in FAST mice. We hypothesized that GABA(B) receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA(B) receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA(B) receptor activation may instead enhance some of the behavioral effects of morphine.     

Motivational properties of ethanol in mice selectively bred for ethanol-induced locomotor differences

Ethanol-induced locomotor stimulation has been proposed to be positively correlated with the rewarding effects of ethanol (Wise and Bozarth 1987). The present experiments provided a test of this hypothesis using a genetic model. Three behavioral indices of the motivational effects of ethanol (drinking, taste conditioning, place conditioning) were examined in mice from two independent FAST lines, selectively bred for sensitivity to ethanol-induced locomotor stimulation, and mice from two independent SLOW lines, selectively bred for insensitivity to ethanol-induced locomotor stimulation. In a single-bottle procedure, mice were allowed access to drinking tubes containing ethanol in a concentration (1–12% v/v) that increased over 24 consecutive days. FAST mice consumed greater amounts of ethanol solution. In a two-bottle procedure, mice were allowed access to tubes containing water or various concentrations of ethanol (2–8% v/v) over 6 days. FAST mice generally showed greater preference for ethanol solutions than SLOW mice. In a conditioned taste aversion procedure, mice received access to saccharin solution followed by injection of 2.5 g/kg ethanol (IP). SLOW mice developed aversion to the saccharin flavor more readily than FAST mice. In a series of place conditioning experiments, tactile stimuli were paired with various doses of ethanol (0.8–2.0 g/kg). During conditioning, FAST mice showed locomotor stimulation after 1.0, 1.2 and 2.0 g/kg ethanol while SLOW mice did not. During testing, mice conditioned with 1.2 g/kg and 2.0 g/kg ethanol showed conditioned place preference, but there were no line differences in magnitude of preference. These results indicate that genetic selection for sensitivity to ethanol-stimulated activity has resulted in genetic differences in ethanol drinking and ethanol-induced conditioned taste aversion but not ethanol-induced conditioned place preference. Overall, these data provide mixed support for the psychomotor stimulant theory of addiction.     

Naloxone does not attenuate the locomotor effects of ethanol in FAST,SLOW, or two heterogeneous stocks of mice

Rationale Previous studies suggest that some behavioral effects of ethanol and morphine are genetically correlated. For example, mice bred for sensitivity (FAST) or insensitivity (SLOW) to the locomotor stimulant effects of ethanol differ in their locomotor response to morphine. Objective To evaluate a possible common mechanism for these traits, we examined the effect of naloxone, an opioid receptor antagonist, on ethanol- and morphine-induced locomotion in FAST and SLOW mice, as well as on ethanol-induced locomotion in two heterogeneous stocks of mice. Method In experiments 1 and 2, naloxone was given to FAST and SLOW mice 30 min prior to 2 g/kg ethanol or 32 mg/kg morphine, and locomotor activity was measured for 15 min (ethanol) or 30 min (morphine). In experiments 3 and 4, naloxone was administered 30 min prior to 1.25 g/kg ethanol, and locomotor activity was assessed in FAST mice and in a heterogeneous line of mice [Withdrawal Seizure Control (WSC)]. Experiment 5 assessed the effect of naloxone on ethanol-induced stimulation in outbred National Institutes of Health (NIH) Swiss mice. Results There was no effect of naloxone on the locomotor response to ethanol in FAST, SLOW, WSC, or NIH Swiss mice. However, naloxone did significantly attenuate the locomotor effects of morphine in FAST and SLOW mice. Conclusions These results suggest that a common opioidergic mechanism is not responsible for the correlated locomotor responses to ethanol and morphine in FAST and SLOW mice, and that activation of the endogenous opioid system is not critical for the induction of ethanol-induced alterations in activity.     

The anti-influenza drug oseltamivir evokes hypothermia in mice through dopamine D2 receptor activation via central actions

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D₂-selective antagonist L-741,626, but not by D₁/D₅-selective and D₃-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D₂ receptors.     

Lack of effect of dopamine receptor blockade on expression of ethanol-induced conditioned place preference in mice

Abstract Rationale. Self-administration studies have suggested that dopamine (DA) is important for the reinforcing effects of ethanol. However, ethanol place conditioning studies have less consistently demonstrated a role for DA in conditioned place preference. Objectives. The purpose of the present study was to determine whether blockade of D₁, D₂ or D₃ DA receptors would impact the expression of the conditioned place preference induced by ethanol in DBA/2J mice. Methods. Mice underwent an unbiased place conditioning procedure with 2 g/kg ethanol. Prior to the preference test, mice were injected i.p. with SCH23390 (0, 0.015 or 0.03 mg/kg), raclopride (0, 0.3 or 0.6 mg/kg) or U99194A (0, 10 or 20 mg/kg). Results. Ethanol produced a significant conditioned place preference that was not affected by any of the dopamine antagonists tested. Each of the antagonists decreased locomotor activity, though U99194A was minimally effective. Conclusions. These findings suggest that the conditioned reinforcing effects of ethanol in DBA/2J mice as assessed by place conditioning are mediated by non-dopaminergic mechanisms. Electronic Publication     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.     

Stimulation of forward locomotion by SCH-23390 and raclopride in d-amphetamine-treated rats

In d-amphetamine-treated (4.0 mg kg^–1 s.c.) rats the selective dopamine D₁ and D_2/3 receptor antagonists SCH-23390 (2.5–20.0 μg kg^–1 s.c.) and raclopride (12.5–100.0 μg kg^–1 s.c.), respectively, produced a biphasic pattern of effects on forward locomotion, as observed in an open-field arena (≈0.5 m²). Thus, at the low doses of SCH-23390 (2.5–10.0 μg kg^–1) or raclopride (12.5–50.0 μg kg^–1), there was a statistically significant increase in forward locomotion, followed by suppression of the behavior at the higher doses. The SCH-23390-induced (5.0 μg kg^–1) stimulation of forward locomotion was partially antagonized by concomitant raclopride treatment (12.5–25.0 μg kg^–1) and the corresponding raclopride-induced (12.5 μg kg^–1) stimulation was fully antagonized by treatment with SCH-23390 (2.5–5.0 μg kg^–1). Furthermore, the SCH-23390- or raclopride-induced stimulation of forward locomotion was also antagonized by treatment with the α₁-adrenoceptor antagonist prazosin (1.0 mg kg^–1 s.c.). These observations suggest that under conditions of an increased general tone at brain dopamine receptors, there is a mutual inhibitory synergy between dopamine D₁ and D_2/3 receptors. Received: 21 July 1997 / Accepted: 6 March 1998     

Differential effects of catecholamine antagonists on ethanol-induced excitation in mice

Catecholamine antagonists were assessed for their effects on ethanol-induced motor excitation. Motor excitation was measured in male Swiss-Webster mice using an open-field apparatus. Mice were treated with several doses of ethanol and at each dose, mice were pretreated with pimozide, a dopamine D2 antagonist, Schering 23390, a dopamine D1 antagonist, phenoxybenzamine, a noradrenergic alpha-1 antagonist, or yohimbine, a noradrenergic alpha-2 antagonist. Each mouse was subjected to only one dose regimen, and all injections were given IP. Ethanol produced an increase in locomotor activity. The degree to which pimozide attenuated ethanol excitation decreased with increasing ethanol dosage. At the highest dose of ethanol, pimozide increased ethanol excitation. Schering 23390 attenuated ethanol-induced excitation only at doses which affected motor activity per se. Phenoxybenzamine produced a dose-dependent reduction in ethanol excitation. Yohimbine had its greatest effects at the medium dose (4.0 mg/kg). These observations seem to indicate a role for both the dopamine D2 receptor and the noradrenergic alpha-1 receptor in ethanol-induced motor excitation.     

Microcatalepsy and disruption of forelimb usage during operant behavior: differences between dopamine D1 (SCH-23390) and D2 (raclopride) antagonists

In an experiment designed to distinguish between the behavioral consequences of treatment with SCH-23390, a D₁ dopamine receptor blocker, and raclopride, a D₂ antagonist, rats were trained to perform a water-reinforced forelimb operant response. Response rate and the duration of each forelimb contact with the operandum were recorded. In addition, the durations of the rat's visits to the reward well were detected by a photobeam which was blocked by the rat's muzzle as it remained at the reward well. In a between-groups dosing design, separate groups of rats (11–13 rats/group) received SCH-23390 (0, 0.01, 0.02, 0.04, 0.08, 0.12 mg/kg, IP, 30 min) or raclopride (0. 0.05, 0.1, 0.2, 0.4, 0.8 mg/kg, IP, 30 min) for 21 consecutive days. Quantitative analyses indicated that for comparable amounts of operant rate reduction, raclopride had a significantly greater tendency than SCH-23390 to increase the duration of operant responses and to increase the maximum muzzle entry duration (i.e., to induce microcatalepsy). The results support the idea that at relatively low doses D₂ antagonism is more likely than D₁ antagonism to produce effects identified preclinically with extrapyramidal side effects.     

Accentuating effects of nicotine on ethanol response in mice with high genetic predisposition to ethanol-induced locomotor stimulation

BackgroundCo-morbid use of nicotine-containing tobacco products and alcohol is prevalent in alcohol dependent individuals. Common genetic factors could influence initial sensitivity to the independent or interactive effects of these drugs and play a role in their co-abuse.MethodsLocomotor sensitivity to nicotine and ethanol, alone and in combination, was assessed in mice bred for high (FAST) and low (SLOW) sensitivity to the locomotor stimulant effects of ethanol and in an inbred strain of mouse (DBA/2J) that has been shown to have extreme sensitivity to ethanol-induced stimulation in comparison to other strains.ResultsThe effects of nicotine and ethanol, alone and in combination, were dependent on genotype. In FAST and DBA/2J mice that show high sensitivity to ethanol-induced stimulation, nicotine accentuated the locomotor stimulant response to ethanol. This effect was not found in SLOW mice that are not stimulated by ethanol alone.ConclusionsThese data indicate that genes underlying differential sensitivity to the stimulant effects of ethanol alone also influence sensitivity to nicotine in combination with ethanol. Sensitivity to the stimulant effects of nicotine alone does not appear to predict the response to the drug combination, as FAST mice are sensitive to nicotine-induced stimulation, whereas SLOW and DBA/2J mice are not. The combination of nicotine and ethanol may have genotype-dependent effects that could impact co-abuse liability.     

Is the dopaminergic system involved in the central effects of nicotine in mice?

Pretreatment with ineffective doses of the D₁ antagonist SCH23390 but not the D₂ antagonist sulpiride reduced hyperactivity induced by nicotine in mice habituated to the test cage. On the other hand, the D₁ and D₂ antagonists were ineffective in blocking nicotine-induced hypoactivity in naive mice. Finally, SCH23390 and sulpiride did not block the antinociception induced by nicotine. Our data indicate that the dopamine receptors D₁ and D₂ are not involved in all the central effects of nicotine in mice, but seems to be a substrate for locomotor activation induced by nicotine under specific experimental conditions.     

Chronic treatment with the D1 receptor antagonist,SCH 23390, and the D2 receptor antagonist,raclopride, in cebus monkeys withdrawn from previous haloperidol treatment

The effects of chronic treatment with dopamine (DA) D₁ and D₂ receptor antagonists were evaluated in eightcebus apella monkeys with mild oral dyskinesia after previous haloperidol treatment. SCH 23390 (D₁ antagonist) was given daily to investigate the direct behavioural effect during long-term treatment and the subsequent supersensitivity to DA agonists. Raclopride (D₂ antagonist) was investigated for comparison. All drugs were given subcutaneously. SCH 23390 and raclopride induced dystonic syndromes, catalepsy, sedation and reduced locomotor activity. The monkeys developed marked tolerance to the dystonic effect of SCH 23390, while they showed increased sensibility to the dystonic effect of raclopride. Baseline oral dyskinesia (24 h after injection) remained unchanged during D₁ antagonist treatment, while it increased during D₂ antagonist treatment. SCH 23390 induced supersensitivity to the oral dyskinesia- and grooming-inducing effects of SKF 81297 (D₁ agonist) after 9 weeks, while the subsequent treatment with raclopride induced supersensitivity to the reactivity- and stereotypy-inducing effects of quinpirole (D₂ receptor agonist) after 3 weeks. Because of the possibility of a carry-over effect (SKF 81297-induced oral hyperkinesia and grooming), other changes in raclopride-induced behaviours cannot be ruled out. The development of tolerance to the dystonic effect of SCH 23390 and the unchanged baseline oral dyskinesia during SCH 23390 treatment indicate an advantageous profile of side effects of DA D₁ receptor blockade.     

Blockade of adenosine and dopamine receptors inhibits the development of rapid tolerance to ethanol in mice

Rationale Several reports have suggested the involvement of brain adenosine and dopamine receptors in different actions produced by ethanol such as motor incoordination or anxiolytic, hypnotic and reinforcing effects. The co-localization and interaction between adenosine and dopamine receptors in different brain regions has also been well documented. However, few studies have demonstrated the involvement of these mechanisms in the tolerance induced by ethanol. Objectives The aim of the present study was to evaluate the role of adenosine and dopamine receptors in the development of rapid tolerance to ethanol-induced motor incoordination in mice. Methods In connection with the rota-rod apparatus, the effects of acute administration of the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A₁ receptor antagonist) and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A_2A receptor antagonist), together with R(+)-7-cloro-8-hidroxi-3-metil-1-fenil-2,3,4,5-tetrahidro-1H-3-benzazepine (SCH23390, dopamine D₁ receptor antagonist) and sulpiride (dopamine D₂ receptor antagonist), alone or in combination with ethanol (2.25 g/kg, i.p.), were studied. Twenty-four hours after, all animals were re-tested on the rota-rod after receiving the same dose of ethanol. Results The repeated administration of ethanol promoted a significant reduction of motor impairment on day 2 (i.e. rapid tolerance). This effect was blocked by caffeine (3.0–30.0 mg/kg, i.p.), DPCPX (3.0–6.0 mg/kg, i.p.) or SCH23390 (0.01–0.03 mg/kg, s.c.), but not with ZM241385 (0.5–1.0 mg/kg, i.p.) or sulpiride (1.0–3.0 mg/kg, i.p.). Conclusions Our results suggest that the rapid tolerance to ethanol-induced motor impairment in mice may be modulated by adenosine A₁ receptors and dopamine D₁ receptors.     

The dopamine agonism on ADP-stimulated platelets is mediated through D2-like but not D1-like dopamine receptors

Monoamines such as serotonin and epinephrine are known to be involved in platelet activation and aggregation. Dopamine is another monoamine identified in platelets, but published data about its effect on platelets and the receptors involved are controversial. In the present study, we investigated the dopamine agonism in platelets and the receptors involved in these pathways. Platelet-rich plasma (PRP) of healthy individuals was treated with agonists (ADP, epinephrine, dopamine) and various dopamine receptor and transporter antagonists such as SCH-23390, raclopride, clozapine, methylphenidate, and cocaine. Platelet activation was investigated by flow cytometry (CD62P and CD63 surface expression), optical aggregometry, and microaggregate adhesion to collagen IV in a flow chamber system. In our study, dopamine on its own had no effect on platelet activation in the different assays. However, when used in combination with ADP (10 μM), dopamine in a range of 1 to 100 μM significantly potentiated platelet microaggregate formation and adhesion to collagen under low shear flow conditions. Specific antagonists for D2-like receptors (L-741,626, raclopride, and clozapine) completely diminished the dopamine effect at selective concentrations, but not the effect of epinephrine. Neither the D1-like receptor antagonist SCH-23390 nor dopamine transporter antagonists (methylphenidate, cocaine) showed inhibitory effects on the dopamine agonism. Thus, dopamine is an ADP-dependent platelet agonist which acts via D2-like but not D1-like receptors or adrenergic receptors. Because many psychopharmacological drugs are directed to D2-like receptors, platelet dysfunction in patients being treated with such drugs may be linked to these mechanisms.     

Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of parkinson's disease — the differential effects of D1 dopamine antagonists in the primate

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D₁ DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine) and A66359 (1-[2-bromo-4, 5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4 tetrahydroisoquinoline), but not the D₂ DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D₁ DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3-CH₃ analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D₁ DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D₁ DA agonists. These findings demonstrate that the behavioural effects of benzazepine D₁ DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D₁ DA receptor sites, although in the primate, stimulation of D₂ DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D₁ DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D₁ DA antagonists may indicate the involvement of multiple D₁ DA receptor subtypes in mediating benzazepine D₁ DA agonist induced behaviours in the MPTP-treated marmoset.     

Effects of selective dopamine D1- and D2-type receptor antagonists on the development of behavioral sensitization to 7-OH-DPAT

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D₃ receptor agonist 7-OH-DPAT could be prevented by either selective D₁-type or D₂-type dopamine receptor antagonists. In three experiments, male Wistar rats (250–350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D₂-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D₁-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D₂-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms. Received: 28 May 1997/Final version: 2 April 1998