Synergistic blockade of some dopamine-mediated behaviours by (−)-sulpiride and SCH 23390 in the rat

Several studies have indicated that the D2 dopamine receptors mediate the antidopaminergic activity of the neuroleptics; nevertheless, the selective blocker (–)-sulpiride weakly inhibits dopamine-mediated behaviour. The present study investigated whether the concomitant injection of doses of the D1 antagonist SCH 23390, which by themselves are without effect, would enable (–)-sulpiride to express fully neuroleptic activity in the rat. The benzamide YM 09151-2 that strongly inhibits dopamine-mediated behaviour was also studied. Rats receiving different doses of (–)-sulpiride, YM 09151-2 and SCH 23390 given alone or in combination were tested for exploratory activity, apomorphine-induced stereotyped behaviour and hyperactivity elicited by the D2 agonist LY 171555. When given alone, (–)-sulpiride (10, 20 and 40 mg/kg IP) had no effect on exploratory activity and stereotypy. When (–)-sulpiride was administered in combination with an ineffective dose of SCH 23390 (5 g/kg) both responses were significantly inhibited. The combined administration of subthreshold doses of (–)-sulpiride (2.5 mg/kg) and SCH 23390 (2.5 g/kg) significantly inhibited hypermotility induced by LY 171555. Moreover, the combined administration of ineffective doses of YM 09151-2 with subthreshold doses of SCH 23390 strongly inhibited all the behavioural responses. The results indicate that SCH 23390 allowed (–)-sulpiride to exhibit a wider spectrum of neuroleptic activity and potentiated the antidopaminergic activity of YM 09151-2.     

Chronic cocaine enhances defensive behaviour in the laboratory mouse: involvement of D2 dopamine receptors

C57BL/6 male mice injected with a challenge dose (20 mg/kg) of cocaine 72 h after the end of chronic intermittent treatment with the psychostimulant (two daily injections of 20 mg/kg for 10 days) exhibited a clear-cut increase in defensive upright and sideways postures and escape when confronted with a non-drugged conspecific. Treated mice spent 40% of time showing defensive acts over the 5-min testing session. Administration of the selective D2 receptor antagonist (–)-sulpiride (25 mg/kg) before the challenge dose of cocaine completely antagonized the increase in defensive behaviour, while the selective D1 receptor antagonist SCH 23390 (0.25–0.50 mg/kg) did not significantly affect defensive behavioural patterns. These results suggest the involvement of D2 receptors in cocaine-induced hyperdefensiveness. The hypothesis that alteration in D2 receptor functioning produced by chronic cocaine administration may produce hyperdefensiveness possibly due to altered perceptive processes is discussed.     

Behavioral effects of cocaine alone and in combination with selective dopamine antagonists in the squirrel monkey

Effects of cocaine, alone and in combination with the dopaminergic antagonists, SCH 23390 and haloperidol were studied in squirrel monkeys trained to respond under fixed-interval schedules of electric-shock presentation. Cocaine at intermediate doses (0.1 and 0.3 mg/kg) increased rates of responding under the fixed-interval schedule and during 1-min timeout periods that separated each fixed-interval component. Higher doses (1.0–3.0 mg/kg) decreased response rates. Cocaine also dose-dependently altered the temporal pattern of responding characteristic of behavior under fixed-interval schedules. Haloperidol (0.003–0.1 mg/kg) and SCH 23390 (0.001–0.03 mg/kg) dose-dependently decreased rates of responding. A low dose (0.001 mg/kg) of the selective D1 antagonist, SCH 23390, did not appreciably alter the effects of cocaine. Higher doses (0.003–0.01 mg/kg), which when given alone decreased rates of responding, attenuated the increases in response rates produced by cocaine. In addition, the decreases in response rates produced by the higher dose of cocaine were attenuated by 0.01 mg/kg SCH 23390. The alterations in temporal patterning of responding under the fixed-interval schedule were not antagonized by any dose of SCH 23390. Haloperidol (0.003 mg/kg) did not appreciably alter the effects of cocaine; higher doses (0.01–0.03 mg/kg), which when given alone decreased rates of responding, attenuated the increases in response rates produced by 0.1 mg/kg cocaine. The decreases in response rates under the fixed-interval schedule that were produced by higher doses, or the changes in temporal patterning of responding at any dose of cocaine, were not antagonized by any dose of haloperidol that was studied. The present results suggest that the effects of cocaine on schedule-controlled behavior in squirrel monkeys are not the exclusive domain of one dopamine receptor subtype.     

Interaction of haloperidol and SCH 23390 with cocaine and dopamine receptor subtype-selective agonists on schedule-controlled behavior of squirrel monkeys

Involvement of D1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the FI at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased responding. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modification of the temporal distribution of responding. The D2 antagonist haloperidol (0.001–0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quinpirole. In contrast, the D1 antagonist SCH 23390 partially attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not antagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys.     

Stimulation of rat spontaneous locomotion by low doses of haloperidol and (−)-sulpiride: Importance of animal selection and measurement technique

Rats showed differential hyperactivity responses to the dopamine agonist (−)-N-n-propylnorapomorphine ((−)-NPA, 0.0125–0.1 mg/kg s.c.) which allowed their selection as non-responders, low (LA), moderate (MA) or high (HA) activity responders (maximum response to 0.05 mg/kg s.c. (−)-NPA being respectively zero, 10–25, 30–55, 60–85 counts/5 min as measured in photocell cages). This subdivision could be confirmed using treadwheels but not by using Automex activity meters. A second dopamine agonist, (+)-amphetamine, could not differentiate the subgroups as defined by (−)-NPA whether using photocells, treadwheels or Automex activity meters. Non-selected rats and those categorised as non-responders, LA, MA or HA responders to (−)-NPA were subject to low and high doses of the neuroleptic agents (−)-sulpiride and haloperidol. The treadwheels showed non-selected rats to exhibit hyperactivity to low doses of (−)-sulpiride (2.5–10 mg/kg i.p.) and, less markedly, to haloperidol (0.04–0.16 mg/kg i.p). The ability of a low dose of (−)-sulpiride (10 mg/kg i.p.) to stimulate spontaneous locomotion was shown to be highly selective for animals categorised as LA responders to (−)-NPA; low dose haloperidol (0.04 mg/kg i.p.) was less specific, stimulating the locomotion of both LA and MA rats: low dose (−)-sulpiride but not haloperidol depressed the spontaneous locomotion of HA rats. These effects revealed by treadwheel measure were not detected by the use of photocell cages or Automex activity meters. Higher doses of both neuroleptics depressed the locomotor activity of all animals using all measurement techniques. It is concluded that the ability of dopamine antagonists to stimulate or depress the spontaneous locomotor activity of the rat is critically dependent on three factors, dose of drug methodology of locomotor assessment and the basal locomotor responsiveness of the animal to the dopamine agonist (−)-NPA.     

Behavioural interactions involving D1 and D2 dopamine receptors in non-habituated mice

The effects of SKF 38393 (D1-agonist) and SCH 23390 (D1-antagonist) were compared with those of haloperidol (D2 greater than D1-antagonist) and metoclopramide (D2-antagonist) in the absence or presence of apomorphine (D1/D2-agonist) and RU 24213 (D2 agonist) in non-habituated mice. The motor behaviour studied which was typical of the species included sniffing, grooming, rearing and locomotion. Apomorphine and RU 24213 induced frozen inactivity, in small doses and head-down sniffing, coupled with ponderous forward walking, in large doses, consistent with the stimulation of D2 receptors at pre- and postsynaptic sites, respectively. Neither SKF 38393 nor metoclopramide modified rearing or locomotion over a wide range of doses. SKF 38393 promoted sniffing and grooming, while metoclopramide suppressed this behaviour. Apart from increased grooming with SCH 23390 in small doses, both this drug and haloperidol dose-dependently decreased all motor activity. In combination studies, the D2 blockers reversed the effects of stimulation of D2 receptors and released normal behaviour, whereas SCH 23390 converted both the behavioural syndromes mediated by pre- and postsynaptic D2-receptors into severe inactivity (but not catalepsy). The drug SKF 38393 had the opposite effect and promoted motor responding in the presence of D2 stimulation, in doses that were otherwise ineffective by themselves. In this model, SCH 23390 modified behaviour mediated by D2-receptors in a different manner to the D2-receptor antagonists, haloperidol and metoclopramide, suggesting it may interact with a different population of D2-receptors, or with D1-receptors. These and earlier data can be interpreted to mean that both subclasses of the dopamine receptor have distinct and probably interdependent roles in the management of motor behaviour.     

Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations

This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0–250 µg/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.     

The production of asymmetry and circling behaviour following unilateral, intrastriatal administration of neuroleptic agents: a comparison of abilities to antagonise striatal function

The abilities of typical and atypical neuroleptic agents to antagonise at striatal dopamine receptors were determined in the rat. Neuroleptic agents were injected unilaterally into the striatum and asymmetric body posturing/circling behaviour (always ipsilateral to the side of neuroleptic injection) assessed (1) to neuroleptic challenge alone (vehicle injected into the contralateral striatum), (2) as that revealed after neuroleptic challenge by peripherally administered apomorphine or (3) by dopamine injection into the contralateral striatum. Unilateral intrastriatal fluphenazine (1-5 micrograms), cis- and trans-flupenthixol (1-20 micrograms), haloperidol (0.5-5 micrograms), thioridazine (5-10 micrograms), clozapine (1-5 micrograms), tiapride (1-5 micrograms), metoclopramide (1-10 micrograms), (+)-sulpiride (20 micrograms) and piperoxan (10 micrograms) each failed, alone, to cause any postural asymmetry/circling. However, ipsilateral asymmetry was induced by unilateral intrastriatal (-)-sulpiride (1-5 micrograms). In contrast, ipsilateral asymmetry developed when the intrastriatal injection of all neuroleptic agents (excepting (+)-sulpiride and trans-flupenthixol) was followed by peripheral challenge with apomorphine: effective neuroleptic doses were all in the range 0.5-10 micrograms, although (-)-sulpiride was effective at 0.001-0.1 microgram. Active circling was only recorded for (-)-sulpiride and tiapride. The striatal imbalance caused by (-)-sulpiride could be revealed by apomorphine for 24 h, although other intrastriatal neuroleptic responses persisted for 6-8 h. The abilities of all neuroleptic agents to cause striatal imbalance could also be revealed by injecting dopamine into the contralateral striatum (at a dose which alone did not cause any asymmetric motor responding). These intrastriatal injection approaches are forwarded as valuable techniques for determining striatal dopamine antagonist activity in the rodent.     

Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats

This study examined cocaine self-administration after pretreatments with three structurally related compounds that bind selectively to dopamine D3 receptors (D3Rs) relative to the D2 receptor subtype (D2Rs) and exhibit varying intrinsic activities in the forskolin-stimulated adenylyl cyclase assay. The compounds are: a) WC10, a D3R weak partial agonist/antagonist with 42-fold D3R:D2R selectivity, b) WC26, a 51-fold selective D3R partial agonist, c) WC44, a 23-fold selective D3R agonist. Rats were stabilized on a multiple variable-interval 60-s (VI60) schedule with alternating components of sucrose (45 mg pellets) or cocaine reinforcement (0.375 mg/kg, IV) and then tested for effects of the WC compounds (0.0, 1.0, 3.0, 5.6, or 10.0 mg/kg, IP). Another cohort was trained to self-administer cocaine (0.75 mg/kg, IV) on a VI60 schedule then tested with various doses of cocaine available (0.0–1.5 mg/kg, IV) following pretreatment with WC10 (5.6 or 10.0 mg/kg) or WC44 (10.0 mg/kg). WC10 and WC26 decreased both cocaine and sucrose reinforcement rates at the 10.0 mg/kg dose, whereas WC44 decreased only cocaine reinforcement rate at this dose. Furthermore, WC26 and WC44 increased response latency for cocaine but not sucrose. In the cocaine dose–response experiment, WC10 and WC44 flattened the dose-effect function of cocaine reinforcement rate. All compounds decreased spontaneous locomotion. WC10 and WC26 also reduced cocaine-induced locomotion. These results support the targeting of D3Rs for treatments for cocaine dependence. WC26 and WC44, in particular, show promise as they increased the latency to respond for cocaine but not sucrose, suggesting selective reduction of the motivation for cocaine.     

Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists

RATIONALE: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. OBJECTIVES: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. METHODS: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. RESULTS: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function, indicating surmountable antagonism. CONCLUSIONS: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.     

Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat

The effect of the selective D1 antagonist, SCH 23390, and the selective D2 antagonist, spiperone, was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Both SCH 23390 and spiperone pretreatment increased responding up to doses of 10.0 µg/kg, and decreased responding at higher doses. Since rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy, behavior maintained by cocaine was also investigated under a progressive-ratio schedule. The breaking point obtained under this schedule is used as a measure of the efficacy of the reinforcer and this value is not exclusively determined by response rate. With the progressive-ratio schedule, both SCH 23390 and spiperone produced dose-dependent decreases in the highest ratio completed in rats self-administering cocaine. The results obtained using the FR 5 and progressive-ratio schedules suggest that both D1 and D2 receptors are involved in mediating the reinforcing effects of cocaine.     

Nicotine potentiates the behavioral effects of haloperidol.

Nicotine potentiates the catalepsy produced by haloperidol. Furthermore, nicotine as an adjunct to haloperidol produces a remarkable improvement in motor tics in Tourette's syndrome (TS) patients. The present experiments (1) compared the ability of nicotine to potentiate the catalepsy produced by haloperidol or the selective D1 dopamine receptor antagonist SCH 23390 and (2) examined the effects of various doses of nicotine (0.1, 0.2, or 0.3 mg/kg) on haloperidol-induced (0.1, 0.2, or 0.4 mg/kg) catalepsy and locomotor hypoactivity. In the first experiment, nicotine produced a five-fold increase in catalepsy following haloperidol but had no effect on the catalepsy produced by SCH 23390. In the second experiment, nicotine potentiated the cataleptic effects of both the 0.2 and 0.4 but not the 0.1 mg/kg dose of haloperidol. Haloperidol (0.1 and 0.4 mg/kg) also produced a dose-related decrease in locomotion that was significantly potentiated by nicotine (0.1 mg/kg). Nicotine alone did not produce catalepsy or any significant changes in locomotion. These results indicated that nicotine's potentiation of haloperidol-induced catalepsy is likely related to striatal D2 receptor mechanisms. Nicotine potentiated the locomotor effects of doses of haloperidol that were previously found to be subcataleptic, indicating that catalepsy testing may actually underestimate the behavioral interaction between haloperidol and nicotine. Nicotine may prove useful for treating neuroleptic responsive disorders such as TS, schizophrenia, and Huntington's disease.     

The role of D2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice

RATIONALE: Previous studies indicate antagonism of cocaine-stimulated locomotor activity by dopamine D2-like receptor antagonists, but only at doses of the antagonists, that by themselves attenuate locomotor activity, raising questions of the specificity of the interaction and whether it might be due solely to a summation of opposing effects. OBJECTIVES: The interactions of cocaine and several D2-like dopamine antagonists and non-dopamine "physiological antagonists" were compared across a full range of doses in order to fully characterize the interaction and assess the specificity of the effects of dopamine antagonists and cocaine. METHODS: Swiss-Webster mice were treated with either vehicle, a D2-like antagonist (haloperidol, spiperone, raclopride, spiperone, (+) or (-) eticlopride), or a "physiological" antagonist (chlordiazepoxide, clonidine, or R(-) N6-(2-phenylisopropyl)adenosine) and cocaine (5-80 mg/kg) prior to a 30-min locomotor activity test. RESULTS: All test drugs decreased locomotor activity when given alone. All test drugs attenuated cocaine-induced locomotion and decreased peak responding to cocaine. In general, the D2-like antagonists also decreased maximal responding to cocaine and decreased the slope of the ascending limb of the cocaine dose-effect curve, effects not obtained with physiological antagonists. CONCLUSIONS: Blockade of D2-like receptors resulted in an interaction with cocaine that was fundamentally different from that produced through non-dopaminergic mechanisms and appears to be more than a summation of opposing effects. The present data suggest that D2-like receptors are involved in the mechanisms underlying the induction of locomotor activity by cocaine.     

Behavioural profile of partial D2 dopamine receptor agonists

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kgd-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blockedd-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208–911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced byd-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208–911. The profiles of SDZ 208–912 and terguride were intermediary to those of SDZ 208–911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kgd-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dosed-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208–911, preclamol and terguride was accompanied only by the low dosed-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208–912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased byd-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced byd-amphetamine.     

Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice

The group II metabotropic glutamate receptor (mGluR) antagonists LY341495 and LY366457 were profiled for their effects on locomotor activity in mice. Both compounds significantly increased locomotor activity. Observational studies showed that rearing was also selectively increased. LY366457-induced hyperactivity was significantly attenuated by the selective D1 dopamine receptor antagonist SCH23390 and also by the D2 dopamine receptor antagonist haloperidol but only at doses that significantly suppressed spontaneous locomotion. The selective 5-HT(2A) antagonist MDL100907 had no effect on LY366457-induced hyperactivity, while the less selective 5-HT(2A-C) antagonist ritanserin had only a modest effect. In all cases, the doses of antagonists that reduced the locomotor response to LY366457 were greater than those previously shown to reduce the locomotor response to the psychostimulants amphetamine and cocaine and MK-801. Pretreatment with reserpine also significantly attenuated the response to LY366457, possibly implicating a monoaminergic substrate in the mediation of this effect. The phenomenonology and pharmacology of the locomotor activation induced by the mGluR antagonists differs markedly from that induced by locomotor stimulants such as amphetamine, cocaine or MK-801. These results suggest that group II mGluRs may be involved in the tonic suppression of locomotor and exploratory activity, and this suppression can be disinhibited in the presence of a group II mGluR antagonist.     

Strain-dependent effects of post-training cocaine or nomifensine on memory storage involve both D1 and D2 dopamine receptors

Post-training administration of cocaine (1–10 mg/kg) or nomifensine (1–10 mg/kg) dose-dependently improves retention of an inhibitory avoidance response in C57BL16 mice, while impairing it in the DBA/2 strain. The effects on retention performance induced by the psychostimulant and the dopamine (DA) reuptake blocker in C57BL/6 and DBA/2 mice appear to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace is susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not affected by the post-training drug administration. The strain-dependent effects of an intermediate dose (5 mg/kg) of both cocaine and nomifensine were reversed by pretreatment with either selective D₁ or D₂ DA receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D₁ and D₂ receptor types are similarly involved in modulating memory processes. These results show that the effects of cocaine on memory consolidation are related to its dopaminergic action, since they are similar to those produced by nomifensine and, what is more important, are antagonized by pretreatment with DA receptor antagonists. Moreover, they point to possible genotype-dependent factors in DA mediated effects of cocaine on memory consolidation, indicating inbred mice as an experimental tool to investigate neural mechanisms underlying interindividual susceptibility to drug addiction.     

Dopamine D1 (SCH 23390) and D2 (haloperidol) antagonists in drug-naive monkeys

The ability of dopamine D₁ antagonists to produce acute extrapyramidal syndromes (EPS) in nonhuman primates is unclear. Some studies in monkeys show that D₁ antagonists produce acute dystonia, whereas other studies do not report these effects. The central issues that have yielded conflicting results revolve around prior treatment status (neuroleptic-naive versus neuroleptic sensitized) and route of administration (oral versus parenteral). In this study, separate groups of neuroleptic drug-naive cebus monkeys were tested once weekly with intramuscularly administered SCH 23390, a D₁ antagonist, or haloperidol, a D₂ antagonist, across a dose range of 0.01–0.25 mg/kg, and a saline control. Both active drugs, but not saline, produced clinically identical syndromes of acute dystonia and bradykinesia, though haloperidol induced higher symptom scores over a longer duration. Sedation and locomotor activity were unchanged by SCH 23390, but decreased with haloperidol. Factors regarding acute EPS liability in nonhuman primate models and clinical implications in man are discussed.     

Subcortical dopamine and serotonin turnover during acute and subchronic administration of typical and atypical neuroleptics

The effects of acute (1 day) and subchronic (28 days) treatment with three atypical antipsychotic drugs [clozapine, (±)-sulpiride and (–)-3-PPP] on dopamine and serotonin turnover in both the nucleus accumbens (NA) and corpus striatum (CS) of rodents was compared to haloperidol and saline treatment. The equivalent doses of all drugs were determined based upon their ability to compete in vivo for³H-spiperone binding in the NA and CS. All three atypical drugs, compared to haloperidol, produced preferential elevations of dopamine turnover in the NA. Further, the development of tolerance to this effect was more apparent for the three atypical drugs than for haloperidol. Surprisingly, all three atypical drugs, but not haloperidol, produced changes in serotonin turnover, despite the fact that (±)-sulpiride and (–)-3-PPP have no known direct effects on brain serotonin systems. All three atypical drugs produced acute increases in serotonin turnover in both the NA and CS, followed by later decreases.     

Blockade of acquisition of one-way conditioned avoidance responding by haloperidol and metoclopramide but not by thioridazine or clozapine: implications for screening new antipsychotic drugs

The classical neuroleptic drugs haloperidol and pimozide have a strong disruptive effect on the acquisition of conditioned avoidance responding (CAR), yet have relatively little impact on the performance of previously acquired responses. Separate experiments compared the effects of haloperidol, two atypical neuroleptics, thioridazine and clozapine, and a substituted benzamide, metoclopramide, on one-way avoidance by rats. Thioridazine (10–50 mg/kg) and clozapine (1.25–10.0 mg/kg) disrupted both acquisition and performance of CAR. In contrast, haloperidol (0.075–0.150 mg/kg) and metoclopramide (5.0–7.5 mg/kg) completely blocked the acquisition of CAR, yet initially produced only a slight disruption in the performance of a previously acquired response. The ineffectiveness of the atypical neuroleptics in producing a complete disruption of acquisition of CAR may be due to the anticholinergic properties of these drugs. Alternatively, the differences between metoclopramide and the atypical neuroleptics may be due to a preferential effect of metoclopramide on striatal or amygdaloid dopamine neurotransmission. These results suggest that caution should be exercised in using CAR as an animal model for assessing the antipsychotic potential of new pharmacological agents.A preliminary report of these findings was presented at the June 1987 meeting of the Canadian Psychological Association in Vancouver, B.C. (Blackburn et al. 1987)     

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.