Haloperidol, raclopride, and eticlopride induce microcatalepsy during operant performance in rats, but clozapine and SCH 23390 do not

 The purpose of this work was (1) to assess the ability of selected antipsychotic and comparison drugs to induce arrest of movement phenomena during operant responding and (2) to evaluate the capacity of muscarinic anitcholinergics to block such effects. The effects of haloperidol (0.02–0.12 mg/kg, IP, 45 min), raclopride (0.05–0.80 mg/kg, IP, 30 min) eticlopride (0.02–0.16 mg/kg, IP, 45 min), clozapine (1.0–8.0 mg/kg, IP, 60 min) and SCH 23390 (0.01–0.16 mg/kg, IP, 30 min) were administered to rats for 4 weeks in a between-groups dosing design. Operant responses in 15 min and the maximum duration of the rat’s muzzle entry into the reinforcement dipper well (the measure of arrest of movement that reflected microcatalepsy) were the quantitative measures of behavior. The D₂ antagonists dose-relatedly decreased operant responding and increased maximum muzzle duration, effects that were significantly reversed by the anticholinergic scopolamine (0.1 mg/kg) or atropine (6.0 mg/kg). Although the atypical antipsychotic drug clozapine and the selective D₁ antagonist SCH 23390 both significantly reduced operant responding, these drugs did not produce microcatalepsy. The results suggested that microcatalepsy expressed in the context of ongoing operant behavior may model low-dose extrapyramidal side effects. Received: 12 January 1998 / Final version: 27 March 1998     

Dopamine D1 and D2 antagonists attenuate amphetamine-produced enhancement of responding for conditioned reward in rats

It has been suggested that the dopamine D₁ receptor may play an important role in reward. The present study was undertaken to investigate the roles of dopamine D₁ and D₂ receptor subtypes in responding for conditioned reward. This was done by examining the effects of the D₁ antagonist SCH 23390 and the D₂ antagonists pimozide and metoclopramide on amphetamine-produced enhancement of responding for conditioned reward. The procedure consisted of three distinct phases. During the pre-exposure phase the rats were exposed to an operant chamber containing two levers. One lever produced a lights-off stimulus (3 s) and the other a tone stimulus (3 s). This was followed by four conditioning sessions during which the levers were removed and the rats were exposed to pairings of the lights-off stimulus with food. This phase was followed by two test sessions during which the levers were present and the number of responses made on each was calculated as a ratio of the number of responses made during the pre-exposure phase. A group receiving the vehicle during the test sessions showed a greater ratio of responding for the light-off stimulus than the tone stimulus, indicating that the lights-off stimulus had become a conditioned reward. Amphetamine (0.1, 1.0, 2.0 and 5.0 mg/kg, IP, 5 min prior to test) specifically enhanced responding on the lever producing conditioned reward. SCH 23390 (5.0 and 10.0 µg/kg, SC, 2 h before test) and pimozide (0.1 and 0.2 mg/kg, IP, 4 h before test) dose-dependently shifted the peak in the amphetamine dose-response function to the right, indicating an attenuation of conditioned reward. Metoclopramide (1.0, 5.0 and 7.5 mg/kg, IP, 1 h before test) reduced the amphetamine-produced enhancement of responding for conditioned reward but failed to shift the amphetamine dose-response function. These results provide evidence that both D₁ and D₂ receptor subtypes are essential in responding for conditioned reward.     

Self-administration of the D1 agonist SKF 82958 is mediated by D1, not D2, receptors

We have previously reported that two D₁ dopamine agonists, SKF 82958 and SKF 77434, are readily self-administered by rats. However, due to the limited selectivities of these agents, it was not possible to attribute their reinforcing effects exclusively to their D₁ actions. To assess the relative involvement of D₁ and D₂ receptors in SKF 82958 reinforcement, rats were pretreated 30 min before self-administration sessions with either the D₁-selective antagonist (+)SCH 23390 or the D₂-selective antagonist raclopride. The D₁ antagonist (+)SCH 23390 (5–20 µg/kg, SC) produced significant, dose-related (compensatory) increases in SKF 82958; in contrast, the D₂ antagonist raclopride (25–400 µg/kg, SC) did not significantly increase SKF 82958 self-administration, although raclopride did increase cocaine self-administration. Compensatory increases in self-administration rates are thought to reflect antagonist-induced reductions in drug reinforcement. Hence, we conclude that SKF 82958 self-administration depends on activation of a D₁-regulated reinforcement substrate.This work was supported by U.S.P.H.S. grants DA-05107, DA-05379, and DA-07747. All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH pub. no. 86-23, revised 1985).     

Bromocriptine enhancement of responding for conditioned reward depends on intact D1 receptor function

It has been suggested that reward-related learning may require intact functioning at the dopamine D₁ receptor. The present experiment tested this hypothesis by challenging the reward-enhancing effects of the D₂ agonist, bromocriptine, with a D₁ antagonist, SCH 23390. For comparison, the effects of the D₂ antagonist, pimozide, were also evaluated. Male rats (n=240) were pre-exposed to a chamber with two levers, one producing a 3-s lights-off stimulus and the other a 3-s tone stimulus. Four conditioning sessions followed, during which levers were absent and presentations of the lights-off stimulus were paired with food. Testing consisted of comparing presses on each lever after conditioning to before conditioning for each rat. Control groups showed a significantly greater increase in responding for lights-off than tone, indicating that the lights-off stimulus had become a conditioned reward. Results showed that bromocriptine (0.25–10.0 mg/kg, IP, 60 min before test session) enhanced responding at doses of 2.5 and 5.0 mg/kg significantly more on the conditioned reward lever than on the other lever. The lowest dose of SCH 23390 (1.0 µg/kg, SC, 2 h before testing) eliminated the bromocriptine-produced enhancement at 2.5 mg/kg and a significant enhancement was seen at 10.0 mg/kg. The higher doses of SCH 23390 (5.0 and 10.0 µg/kg) eliminated the bromocriptine effect and the conditioned reward effect itself, respectively. The low dose of pimozide (0.1 mg/kg, IP, 4 h before test session) eliminated the bromocriptine-produced enhancement at 2.5 and 5.0 mg/kg and a significant enhancement was now seen at 10.0 mg/kg; the higher dose (0.2 mg/kg) appeared to block the conditioned reward effect itself. These results suggest that both SCH 23390 and pimozide interfered with the reward-enhancing effects of bromocriptine. Thus, the present results suggest that reward-related learning can be enhanced through D₂ receptor stimulation with bromocriptine and that this effect appears to depend on intact D₁ receptor function.     

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     

Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D₁ or D₂ selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D₁ dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D₂ dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D₁ or D₂ dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.Portions of this paper were presented at the 1992 Society for Neuroscience meetings, Anaheim, Cal., USA     

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.     

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.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

Differential contributions of dopaminergic D1- and D2-like receptors to cognitive function in rhesus monkeys

Rationale Dopaminergic neurotransmission is critically involved in many aspects of complex behavior and cognition beyond reward/reinforcement and motor function. Mental and behavioral disorders associated with major disruptions of dopamine neurotransmission, including schizophrenia, attention deficit/hyperactivity disorder, Parkinson’s disease, Huntington’s disease, and substance abuse produce constellations of neuropsychological deficits in learning, memory, and attention in addition to other defining symptoms.Objective To delineate the role dopaminergic D₁- and D₂-like receptor subtypes play in complex brain functions.Materials and methods Monkeys (N=6) were trained on cognitive tests adapted from a human neuropsychological assessment battery (CAmbridge Neuropsychological Test Automated Battery). The battery included tests of spatial working memory (self-ordered spatial search task), visuo-spatial associative memory and learning (visuo-spatial paired associates learning task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function (bimanual motor skill task, BMS; rotating turntable task, RTT) were also included. The effects of the dopamine D₂-like antagonist raclopride (10–56 μg/kg, i.m.) and the D₁-like antagonist SCH23390 (SCH, 3.2–56 μg/kg, i.m.) on cognitive performance were then determined.Results Deficits on PR, RTT, and BMS performance were observed after both raclopride and SCH23390. Spatial working memory accuracy was reduced to a greater extent by raclopride than by SCH, which was unexpected, given prior reports on the involvement of D₁ signaling for spatial working memory in monkeys. Deficits were observed on vsPAL performance after raclopride, but not after SCH23390.Conclusions The intriguing results suggest a greater contribution of D₂- over D₁-like receptors to both spatial working memory and object–location associative memory.     

Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats

The effects of blockade of opioid and dopamine receptors on relapse to heroin-seeking induced by footshock stress and re-exposure to heroin were examined in a reinstatement procedure. Male rats were trained to self-administer heroin (100 µg/kg per infusion, IV; four 3-h sessions/day for 8–11 consecutive days). Extinction sessions were given for 5–7 days during which saline was substituted for heroin. In nine groups, the effects on relapse induced by footshock (10 min, 0.5 mA, 0.5 s on with a mean off period of 40 s), heroin priming (0.25 mg/kg), and saline priming were studied after pretreatment with either naltrexone (1 or 10 mg/kg, SC), the D₁-like receptor antagonist SCH 23390 (0.05 or 0.1 mg/kg, IP), the D₂-like receptor antagonist raclopride (0.25 or 0.5 mg/kg, IP), the mixed dopamine antagonist flupenthixol decanoate (3 or 6 mg/kg, IM), or IP injection of saline (control condition). Naltrexone, flupenthixol, raclopride, and the highest dose of SCH 23390 attenuated heroin-induced relapse: only the mixed DA receptor antagonist, flupenthixol, attenuated footshock-induced relapse. These results, and those from microdialysis showing that heroin elicits greater locomotor activity and DA release in the nucleus accumbens than footshock, suggest that the neurochemical events underlying stress- and heroin-induced relapse are not identical.     

Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

  Rationale: Previous work has demonstrated that cholinomimetic-induced tremulous jaw movements in rats have temporal and pharmacological characteristics similar to parkinsonian tremor. Objective: This rodent model was used to characterize the putative antiparkinsonian effects of the full D₁ dopamine receptor agonist, SKF 82958. Methods: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experiments studied the pharmacological characteristics of the reversal of pilocarpine-induced jaw movements by SKF 82958. Results: SKF 82958 (0.5–2.0 mg/kg IP) reduced the tremulous jaw movements induced by pilocarpine. The suppressive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D₁ dopamine receptor antagonist SCH 23390 (0.025–0.2 mg/kg IP); SCH 23390 was about 16 times more potent than the D₂ antagonist raclopride at reversing the effects of SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependently reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the substantia nigra pars reticulata also dose-dependently reversed the reduction by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 23390 (2.0 μg/side) into control sites dorsal to the striatum or substantia nigra had no effects on the action of SKF 82958. Intranigral (SNr) injections of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. Conclusions: These data suggest that the antiparkinsonian actions of SKF 82958 may be due to stimulation of D₁ receptors in the ventrolateral striatum and substantia nigra pars reticulata. In addition, these results indicate that GABA mechanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D₁ agonists. Received: 9 June 1998 / Final version: 10 October 1998     

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958

  Rationale: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D₁ and D₂ receptors. Objectives: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D₁ receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D₁ and D₂ receptor using a varied range of startle-eliciting intensities. Methods: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D₁ receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D₁ or D₂ receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). Results: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. Conclusions: These data suggest that dopamine D₁ receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D₁/D₂ receptor interaction whereby D₂ receptor activation is necessary for the full expression of the D₁ receptor-mediated enhancement of startle. Received: 10 October 1998 / Final version: 11 January 1999     

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D₁ or D₂ selective dopamine antagonists. In three experiments, male rats received 10–21 daily injections of a selective D₁ (SCH 23390; 0 or 0.5 mg/kg IP) or D₂ (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D₁ receptors.Portions of this paper were presented at the 1990 Society for Neuroscience meetings, St. Louis, MO, USA     

Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice

The FAST and SLOW lines of mice are being selectively bred in replicate for differential sensitivities to the locomotor activating effects of ethanol. Whereas FAST-1 and FAST-2 mice are stimulated by 2.0 g/kg ethanol, SLOW-1 and SLOW-2 mice are not stimulated, and are often depressed, by this dose. The dopamine antagonists, SCH-23390 (D₁) and raclopride (D₂), produced dose-dependent decreases in the locomotor activity of EtOH-naive mice of both lines and replicates; however, FAST and SLOW mice were not differentially sensitive to these effects. The absence of a line difference in activity response to the dopamine antagonists suggests that dopamine receptor function has not been altered by selective breeding for differences in sensitivity to the stimulant effects of ethanol. The ethanol-stimulated activity of FAST-1 and FAST-2 mice was decreased by administration of the dopamine antagonists, haloperidol and raclopride, at doses that had no effect on basal locomotor activity. SCH-23390 decreased ethanol-stimulated activity of FAST-1, but not FAST-2 mice. The ethanol-induced activity changes of SLOW mice were generally unaffected by antagonist administration. These results suggest a role for dopaminergic systems in mediating ethanol-stimulated activity in selectively bred FAST mice. Coadministration of SCH-23390 and raclopride decreased ethanol-induced activation to a greater degree than either drug alone, further suggesting that both D₁ and D₂ receptor systems contribute to the full expression of the ethanol stimulant response.This work was supported by the Department of Veterans Affairs, by NIAAA grants AA06498 and AA08621 (J.C.C. and T.J.P.), and by an N. L. Tartar Research Fellowship from the Medical Research Foundation of Oregon (E.H.S.). A portion of this work was completed in partial fulfillment of the requirements for Master of Science degree, Department of Medical Psychology, Oregon Health Sciences University (E.H.S.).     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Effects of D2 dopamine receptor blockade with raclopride on intracranial self-stimulation and food-reinforced operant behaviour

To examine the involvement of D2 dopamine receptors in the neural mechanism of reinforcement, raclopride tartrate, a D2 specific dopamine antagonist with a relatively fast central action, was injected into 32 rats. The D2 antagonist reduced bar-pressing responses reinforced with electrical stimulation of the ventral tegmental area (ED₅₀=0.079 mol/kg) and those reinforced with food (ED₅₀=0.58 mol/kg) in 18–30 min after IP injection. The reduction in response rates could not be attributed to an interference with motor functions. An increase in the frequency of brain-stimulation pulses and a change in the schedule of food reinforcement, which respectively increased the baseline rate of responding, did not alter the effectiveness of raclopride. SCH 23390, a D1-specific dopamine antagonist, was sensitive to similar manipulation of reinforcement. These results seem to suggest that D1 and D2 antagonists may be acting at different locations in the neural mechanism underlying the reinforcement of operant behaviour.     

Effect of clozapine upon schedule-induced polydipsia (SIP) resembles neither the actions of dopamine D1 nor D2 blockade

The effects of clozapine (CLOZ) upon acquired schedule-induced polydipsia in rats were compared to the effects of the dopamine (DA) D₁ antagonist SCH 23390 (SCH) and the DA D₂ antagonist raclopride (RAC). All three compounds suppressed water consumption, but only SCH and RAC decreased drinking efficiency. SCH was the only compound with an effect on panel pressing (PP), causing suppression even at a dose without effect upon water intake. SCH also affected the temporal pattern of licking (TPL) at all doses, while clozapine, 10 mg/kg, only affected the pattern acutely, and raclopride was without effect. In conclusion, PP and the TPL are more sensitive to D₁ than D₂ blockade. While PP and the TPL are more sensitive than water intake to D₁ blockade, the opposite is true for D₂ blockade. It is possible to differentiate between DA D₁/D₂ antagonists and CLOZ in this model, focusing upon reduction in water consumption, with and without reduction in drinking efficiency. Furthermore, it is possible to differentiate between D₁ and D₂ blockade by analyzing water consumption, PP and the TPL.     

Studies on electroencephalogram (EEG) in rats suggest that moderate doses of cocaine ord-amphetamine activate D1 rather than D2 receptors

The effects of cocaine andd-amphetamine, two psychomotor stimulant drugs with pronounced addictive properties, on the electroencephalogram (EEG) of rats were studied by telemetric recordings from the skull in non-anesthetized, freely moving rats. The electrocorticogram (ECoG) was recorded. Both cocaine (10 mg/kg IP) andd-amphetamine (0.4 mg/kg IP) produced a desynchronization, characterized by a general lowering in power in all of the frequency bands. These effects of both drugs were mimicked by the selective agonist at D₁ receptors SK&F 38393 (3 mg/kg SC) and were reversed by the antagonist at D₁ receptors SCH 23390 (0.2 mg/kg IP) but not influenced by haloperidol (0.1 mg/kg IP) in a dose which is likely to block D₂ rather than D₁ receptors. These doses of cocaine ord-amphetamine did not produce stereotyped behaviour and slight, if any, increases in locomotor activity only. Large doses of cocaine (30 mg/kg IP) ord-amphetamine (4 mg/kg IP) produced stereotyped behaviour and alterations in EEG which are, based on previous own studies, characteristic for additional stimulation of D₂ receptors. This was manifest in a selective increase in power of the alpha-1 band. A similar effect was also produced by the agonist both at D₁ and D₂ receptors, apomorphine (0.5 mg/kg SC). These results suggest that moderate, but probably rewarding doses of cocaine ord-amphetamine mainly activate D₁ dopamine receptors. This activation might be relevant for the rewarding properties of these drugs.     

D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D₁-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P < 0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D₁-like receptor antagonist (P < 0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P < 0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P < 0.05). These results suggest a role for D₁-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.