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.     

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.     

Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice

Rationale: Direct or indirect stimulation of dopamine receptors increases locomotor activity in mice. Determining the role played by D₁ and D₂ dopamine receptors in the mediation of this activity can be difficult due to the wide variety of experimental paradigms used to investigate these phenomena. Objectives: This study set out to compare the role of selective antagonism of dopamine D₁ and D₂ receptors on the hyperactivity induced by a range of stimulants. Methods: Mice were habituated to perspex locomotor activity boxes (30×30× 30 cm) and activity was measured via photobeam interrupts. Results: Haloperidol and clozapine both reduced the hyperactivity induced by MK-801. Haloperidol did so only at a dose that also decreased spontaneous activity (0.1 mg/kg), whereas clozapine reduced MK-801-induced hyperactivity at a dose that had no effect on spontaneous activity (1.25 mg/kg). The D₁ antagonist SCH23390 (0.01 mg/kg) reduced hyperlocomotion induced by amphetamine (2.5 mg/kg), cocaine (10 mg/kg) and C-APB (1.0 mg/kg) at doses that did not consistently alter spontaneous activity, whereas the selective D₂ antagonist raclopride only attenuated the hyperlocomotion induced by amphetamine, cocaine and C-APB at doses in excess of the minimum dose required to attenuate spontaneous locomotor activity significantly. The latency to peak levels of hyperlocomotion induced by MK-801 (0.3 mg/kg) was delayed by SCH23390 (0.1 mg/kg) but peak levels of activity were not reduced. Conclusions: The results of the present study suggest that selective blockade of D₁ receptors suppresses amphetamine and cocaine-induced hyperactivity in mice but not MK-801-induced locomotor activity. Received: 1 January 1998 / Final version: 4 March 1999     

Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement

Several experiments investigated the involvement of D₁ and D₂ dopamine receptors in the ventral striatum in the control over behaviour by a conditioned reinforcer using an acquisition of new response procedure. Intra-accumbens infusion of either the D₁ receptor antagonist, SCH 23390, or the D₂ receptor antagonist, raclopride, completely blocked the potentiative effects of intra-accumbensd-amphetamine on responding with conditioned reinforcement and reduced responding to control levels. SCH 23390 was more potent than raclopride. At higher doses in the absence ofd-amphetamine, both antagonists also blocked the preference for responding on the lever producing the conditioned reinforcer. Intra-accumbens infusions of either the D₁ receptor agonist, SKF 38393, or the D_2/3 receptor agonist, LY 171555 (quinpirole), selectively potentiated responding on the lever producing the conditioned reinforcer. Various combined infusions of the D₁ and D₂ agonists in specific low doses had additive, but not synergistic, effects on responding with conditioned reinforcement. None of the drugs affected the drinking of water in deprived subjects when infused intra-accumbens. These results suggest that both D₁ and D₂ receptors in the nucleus accumbens are involved in mediating the effects of dopamine in potentiating the control over behaviour by conditioned reinforcers.     

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.     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D₁ receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3–300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100–300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D₁ receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D₁ receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D₁ agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D₁ receptor subtype.     

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.     

The NMDA positive modulatord-cycloserine potentiates the neuroleptic activity of D1 and D2 dopamine receptor blockers in the rat

According to the view that N-methyl-d-aspartate (NMDA) agonists could be seen as putative therapeutic agents in schizophrenia, the present study was aimed at investigating whether the NMDA positive modulatord-cycloserine (DCS) could show neuroleptic activity. When given alone, DCS (1.5, 3, 6, 12 mg/kg) failed to affect the stereotyped behavior induced by 0.5 mg/kg SC apomorphine, a test routinely used to detect neuroleptic activity. Nevertheless, the administration of different doses of DCS (1.5, 3, 6 mg/kg) in combination with the D₁ dopamine receptor blocker SCH 23390 or the D₂ antagonist YM 09151-2, both given in doses which by themselves were ineffective in blocking apomorphine elicited behavior, induced a dose- dependent neuroleptic effect. Furthermore, the positive NMDA modulator allowed (–)-sulpiride, which given alone never antagonized the apomorphine-induced stereotypy, to exhibit a full neuroleptic activity. The lower dose of DCS effective in potentiating antipsychotic effect of dopaminergic blockers also counteracted the behavioral response (hypermotility) induced by the NMDA negative modulator MK-801 (0.25 mg/kg), thus indicating the specificity of DCS effect. The results strengthen the view that drugs which increase NMDA receptor function could be a useful supplement in the therapy of psychotic disorders.     

Effect of chronic treatment with dizocilpine (MK-801) on the behavioral response to dopamine receptor agonists in the rat

The D₂ or D₁ dopamine receptor blockers (–)-sulpiride or SCH 23390 antagonized, in a dose dependent manner, the hypermotility induced by the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 (0.25 mg/kg IP). MK-801 induced hyperactivity was not detected when rats were observed on days 7, 14 or 21 of 21 daily injections of MK-801. This lack of hyperactivity was also noted 5 days after the last administration of the repeated treatment with MK-801. The hypermotility induced by the D₂ dopamine receptor agonist LY 171555 (0.3 mg/kg IP) was reduced 5 days following repeated treatment (21 days) with MK-801, while no change in the behavioral responses to the selective D₁ agonist, SKF 38393, or the mixed D₁/D₂ agent apomorphine was detected. The results, although suggesting the involvement of dopaminergic pathways in the behavioral effect of MK-801, are conflicting with regard to the underlying mechanisms and to the adaptive changes of dopaminergic system following repeated NMDA receptor blockade.     

Central sympathomimetic activity of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine (MK-801), a substance with potent anticonvulsant,central sympathomimetic,and apparent anxiolytic properties

MK-801 at doses < 100 μg/kg given orally induced an ipsilaterally directed directed rotational response in rats with a unilateral nigrostriatal lesion produced by 6-hydroxydopamine. (+)-Amphetamine, amfonelic acid, and methylphenidate also evoked ipsilateral turning with their dose-response lines lying considerably to the right of that for MK-801. Rotations caused by a standard test dose of 50 μg/kg of MK-801 were reduced by pretreatment with haloperidol (ED₅₀ = 0.068 mg/kg IP), clozapine (ED₅₀ = 3.35 mg/kg IP), or prazosin (ED₅₀ = 0.15 mg/kg SC). MK-801-induced turning was also inhibited by pretreatment with α-methyl-p-tyrosine (α-MPT) and blocked by reserpine. Locomotor activity in mice was increased by MK-801, amfonelic acid, (+)-amphetamine, and methylphenidate. Following administration p.o., MK-801 was the most potent in this regard and methylphenidate the least. Stimulation of locomotor activity by equivalent doses of the four compounds was differentially affected by pretreatment with α-MPT or reserpine, Reserpinization abolished the increase in activity usually produced by MK-801, amfonelic acid and methylphenidate, whereas (+)-amphetamine was only partially (36%) inhibited. Locomotor stimulation by (+)-amphetamine was, on the other hand, markedly reduced in α-MPT-pretreated mice, while the actions of the other three compounds were not singnificantly altered. The ability of all four compounds to increase motor activity was significantly antagonized by haloperidol, but prazosin at the dose (3 mg/kg SC) examined was an effective antagonist of only MK-801 and (+)-amphetamine. MK-801 has effects in rodents resembling indirect-acting central sympathomimetic substances such as amfonelic acid, (+)-amphetamine, and methylphenidate. The central sympathomimetic actions of MK-801 are mediated via catecholamine-dependent processes. Results from the drug-interaction studies in mice (locomotor activity) indicate that the precise mechanism of action of MK-801 differs from that of the other three compounds.     

Differential attenuation of d-amphetamine-induced disruption of conditional discrimination performance by dopamine and serotonin antagonists

Rationale Recent experimental findings suggest that a core cognitive deficit of schizophrenia is the degraded ability to use task-setting cues to guide goal-directed behaviour, that this deficit is evident in acute as well as chronic schizophrenia, and that such deficits can me modelled in animals using conditional discrimination tasks.Objective To establish the reversal potential of D₁, D₂ and 5-HT receptor antagonists acutely, and D₁ and D₂ receptor antagonists chronically, on d-amphetamine-induced disruption of a conditional discrimination task that depends on the ability to use task-setting cues to direct goal directed performance.Method A conditional discrimination paradigm was employed in which rats learned to respond on an appropriate lever, conditional upon specific auditory stimuli.Results d-Amphetamine (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pre-treatment with the selective D₁ antagonist SCH 23390 and the atypical anti-psychotic clozapine (Cloz). Acute pre-treatment with the selective D₂ antagonist eticlopride (Eti) and the anti-psychotic haloperidol (Hal) failed to reverse d-amphetamine disruption, as did pre-treatment with the selective 5HT_1A antagonist WAY 100635 and the selective 5HT_2A/C antagonist ritanserin. However, Eti and Hal did reverse d-amphetamine-induced task disruption when administered chronically (as did SCH 23390, α-flupenthixol and Cloz).Conclusions These results suggest that D₁ receptors are involved in tasks that require the use of conditional relationships and that D₂ receptor antagonism can come to exert a similar influence after chronic treatment.     

A comparison of the effects of the D1 receptor antagonists SCH 23390 and SCH 39166 on suppression of feeding behavior by the D1 agonist SKF38393

The hypophagic effect of the D₁ receptor agonist SKF 38393 is not dose-dependently antagonized by the D₁ antagonist SCH 23390. Moreover, the receptor specificity of this interaction remains in question, since SCH 23390 has significant activity at both 5-HT₂ and 5-HT_1C receptors, and SKF 38393 also interacts with 5-HT_1C receptors. To determine the relative significance of these actions, a comparison was made between the anorectic effects in rats of SCH 23390 (0.1–1.0 mg/kg) and the benzonaphthazepine SCH 39166 (0.1–3.0 mg/kg), a D₁ antagonist with negligible affinity for 5-HT sites. Both compounds inhibited food-intake dose-dependently, with SCH 23390 being approximately twice as potent as SCH 39166. Behaviorally inactive and active doses of both antagonists were tested in combination with the D₁ agonist SKF 38393 (10–56 mg/kg). Neither antagonist was able to produce more than a marginal attenuation of the agonist-induced hypophagia. This demonstrates that previous failures to reverse the behavioral actions of SKF 38393 by SCH 23390 were not due to specific actions of this particular antagonist. Finally, like SCH 23390, SCH 39166 (0.3 mg/kg) was able to attenuate fully the anorectic effects of the D₁ agonist SKF 82958 (1.0 and 3.0 mg/kg), demonstrating that neither compound is intrinsically unable to block D₁ receptor-mediated hypophagia. The results demonstrate the generality of the D₁ antagonist-mediated effect on feeding and call into question the use of SKF 38393 as a D₁ agonist in studies of feeding, and perhaps in other contexts as well.     

Potentiation of pentazocine conditioned place preference by tripelennamine in rats

The effects of tripelennamine on place preference conditioning in rats with pentazocine were investigated. Pentazocine at a dose of 2 mg/kg (IP) slightly, but not significantly, induced a place preference. Concurrent dosing of pentazocine (2 mg/kg, IP) and tripelennamine (2.5 mg/kg, SC) significantly and prominently produced a place preference, although administration of tripelennamine (2.5 mg/kg, SC) alone did not. Chronic infusion of a dopamine D₁ receptor antagonist, SCH23390 (1.0 mg/kg/day) during conditioning abolished the appetitive effect of pentazocine potentiated by the combination with tripelennamine. In conclusion, it is suggested that the dopaminergic system, especially at the D₁ receptor, plays an important role in the potentiation effect of tripelennamine on the pentazocine-induced place preference.     

Co-treatment with antidepressants and aripiprazole reversed the MK-801-induced some negative symptoms of schizophrenia in rats

BackgroundSchizophrenia is a chronic, most devastating psychiatric illness that impairs mental and social functioning. A few clinical reports have suggested that antidepressant drugs are able to augment the activity of atypical antipsychotic drugs, thus effectively improving treatment of some negative symptoms of schizophrenia.MethodsThe aim of the present study was to investigate the effect of the antidepressant escitalopram or mirtazapine and aripiprazole (an atypical antipsychotic), given separately or jointly, on the deficits induced by MK-801(a noncompetitive N-methyl-d-aspartate receptor antagonist) in the social interaction test in male Sprague-Dawley rats. The social interaction was measured for 10 min, starting 4 h after MK-801 (0.1 mg/kg) administration. Antidepressants and aripiprazole were given 60 and 30 min before the test, respectively. WAY 100635 (a 5-HT_1A antagonist) and SCH 23390 (a dopamine D₁ antagonist) were give 20 min before the tests.ResultsThe present results showed that MK-801 (0.1 mg/kg)-induced deficits in the social interaction test. Aripiprazole (0.1 and 0.3 mg/kg) reversed those effects. Co-treatment with an ineffective dose of aripiprazole (0.03 mg/kg) and escitalopram (5 and 10 mg/kg) or mirtazapine (5 mg/kg) abolished the deficits evoked by MK-801, and those effects were especially blocked by a 5-HT_1A receptor antagonist (WAY 100635) or partly by dopamine D₁ receptor antagonist (SCH 23390).ConclusionsThe obtained results suggest that amelioration of the antipsychotic-like effect of aripiprazole by antidepressants in the MK-801-induced some negative symptoms of schizophrenia in rats may be associated with serotonin 5-HT_1A and to a lesser degree with dopamine D₁ receptors.     

Role of specific dopamine receptor subtypes in amphetamine discrimination

Biochemical, electrophysiological, and behavioral experiments suggest that the dopamine D-1 and D-2 receptor subtypes functionally interact. In rats trained to discriminate 1.0 mg/kg d-amphetamine, substitution with the D-2 agonist quinpirole (0.1–2.0 mg/kg) produces amphetaminelever responding, whereas the D-1 agonist SKF 38393 (0.3–10.0 mg/kg) elicits only saline-appropriate responding. Combining either quinpirole (0.05–0.5 mg/kg) or SKF 38393 (0.5–10.0 mg/kg) with 0.3 mg/kg d-amphetamine results in dose-dependent increases in amphetamine-lever responding. Conversely, the D-1 antagonist SCH 23390 (0.02–0.1 mg/kg) antagonizes the discrimination produced by 0.7 mg/kg d-amphetamine. Additional combination studies examined the effect of DA receptor drugs on discrimination when quinpirole is substituted in d-amphetamine trained rats. SKF 38393 (0.5–7.0 mg/kg) fails to increase the amphetamine-appropriate lever response produced by either 0.05 or 0.2 mg/kg quinpirole. Similarly, SCH 23390 (0.01–0.1 mg/kg) fails to antagonize the amphetamine-lever responding produced by either 0.2 or 0.5 mg/kg quinpirole. Haloperidol (0.02–0.2 mg/kg) does antagonize the amphetamine-appropriate response produced by quinpirole substitution. The d-amphetamine discrimination studies indicate that stimulating D-2 receptors alone or D-1 receptors in the presence of d-amphetamine yields d-amphetamine-lever responding, and suggests that D-1/D-2 receptors can functionally interact to alter discrimination behavior. Quinpirole substitution, on the other hand, shows an insensitivity to D-1 receptor manipulations.     

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.     

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     

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     

Dopaminergic behaviour stereospecifically promoted by the D1 agonist R-SK & F 38393 and selectively blocked by the D1 antagonist SCH 23390

The selective D₁ dopamine receptor agonist R-SK & F 38393 (20 mg/kg), but not its S-antipode, stereospecifically promoted episodes of prominent grooming behaviour. Typical stereotyped behaviour, such at that induced by apomorphine, was not seen. Grooming responses to 20 mg/kg R-SK & F 38393 were blocked by 0.1–0.5 mg/kg of the selective D₁ antagonist SCH 23390 but not by 1.0–5.0 mg/kg of the selective D₂ antagonist metoclopramide, while stereotyped behaviour induced by 0.5 mg/kg apomorphine was blocked by both antagonists. These results are consistent with certain individual dopaminergic behaviours such as grooming being mediated by D₁ receptors. Other dopaminergic syndromes may involve complex functional interactions between D₁ and D₂ receptors.