PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT(1A) agonist actions. II. Preclinical behavioral effects

PD 158771 has been described in receptor binding and biochemical tests as a partial agonist at dopamine (DA) D2 and D3 receptors as well as an agonist at serotonin (5-HT)(1A) receptors. The present studies describe the profile of PD 158771 in rodent and primate behavioral tests. PD 158771 reduced spontaneous locomotor activity in mice (ED(50)=0.38 mg/kg, i.p.) and rats (ED(50) = 1.2 mg/kg, i.p. and 0.16 mg/kg, s.c.), and reduced amphetamine-stimulated locomotion in mice (ED(50) = 0.13 mg/kg, i.p.). At relatively higher doses up to 3 mg/kg, s.c. in rats, PD 158771 did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. PD 158771 reduced apomorphine stimulated locomotion in rats at a dose 4.6-fold greater than those that reduced spontaneous locomotor activity, indicating weak postsynaptic DA antagonist actions; results consistent with a partial agonist profile. PD 158771 produced anxiolytic-like effects in the water-lick (Vogel) conflict test, effects possibly due to the 5-HT(1A) activity. However, PD 158771 was inactive in the water wheel behavioral despair model in rats, indicating lack of antidepressant properties. Similar to known antipsychotics, PD 158771 produced a potent and long-lasting inhibition of conditioned avoidance responding in squirrel monkeys. In contrast to standard antipsychotics, and similar to clozapine, PD 158771 did not cause catalepsy in rats at a dose 20-fold higher than the ED(50) dose for locomotor inhibition. PD 158771 also had a somewhat lower liability than haloperidol to produce extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. The data indicate that PD 158771 is a DA partial agonist with weak intrinsic activity that selectively activates brain DA autoreceptors. PD 158771 produced behavioral effects consistent with potential antipsychotic and anxiolytic efficacy, and has an improved profile in the extrapyramidal side effect model when compared to certain currently available antipsychotic agents.     

Unusual interactions between the neuroleptic haloperidol, and the dopamine D2 partial agonist, terguride

Terguride is an ergoline derivative which has been reported to act as a partial agonist at central dopamine D2 receptors. Depending on the state of the receptor, terguride may resemble an agonist or an antagonist in its pharmacological effects. The present study investigated interactions of terguride with the dopamine D2 antagonist haloperidol in the rat. Terguride (0.025 mg/kg, i.p.) lowered, whereas haloperidol (0.025 mg/kg, s.c.) increased serum prolactin levels. When given together there was a tendency for prolactin to be lowered, i.e. terguride fully antagonized the action of haloperidol. Both terguride and haloperidol dose-dependently reduced locomotor activity, with terguride being at least 50 times more potent. However, in the presence of a subthreshold dose of haloperidol (0.1 mg/kg), terguride was effective in reducing locomotor activity. Terguride and haloperidol were equally potent in disrupting performance of lever pressing for food on a VI 120 sec schedule (ED(50) values 0.22 and 0.28 mg/kg, respectively). When given together, there was a statistically significant interaction; a terguride dose of 0.2 mg/kg lowered rates of lever pressing when given with vehicle or a low (0.03 mg/kg) haloperidol dose, but antagonized the effect of 0.3 mg/kg haloperidol. Terguride dose-dependently disrupted lever pressing for intracranial stimulation reward (ED(50) value approx. 0.3 mg/kg). Haloperidol (0.26 mg/kg) also disrupted lever pressing but the two drugs together showed no greater effect than haloperidol alone. These observations are discussed in the context of terguride's suggested partial agonistic properties.     

Biochemical and functional studies on EMD 49,980: a potent, selectively presynaptic D-2 dopamine agonist with actions on serotonin systems

EMD 49,980 proved to be a potent and selectively presynaptic D-2 dopamine receptor agonist in biochemical studies with rats. Thus, the gamma-butyrolactone-induced accumulation of dihydroxyphenylalanine, used as a presynaptic model, was antagonized with ED50 values of 0.29 and 0.09 mumol/kg in striatum and t. olfactorium, respectively, with high maximal effects. In contrast, striatal acetylcholine concentrations, reflecting actions at normosensitive postsynaptic D-2 receptors, were only moderately increased by about 30% over a dose range of 2.3-68 mumol/kg. In rats with unilateral nigrostriatal lesions, EMD 49,980 induced long-lasting contralateral turning, indicative of agonistic actions at denervated postsynaptic D-2 receptors. In addition, EMD 49,980 potently inhibited serotonin (5-HT) uptake in vitro and in vivo. Binding studies confirmed D-2 activity in the nM range but, similarly potent effects were observed at 5-HT1A binding sites. Measurement of 5-hydroxytryptophan (5-HTP) accumulation in the n. raphe revealed that, in vivo, the net effect of EMD 49,980 on 5-HT systems is an agonistic one. Control experiments indicate that inhibition of 5-HTP accumulation by EMD 49,980 is induced mainly via direct activation of 5-HT1A receptors, although some contribution due to 5-HT uptake inhibition is likely. Furthermore, results with various reference compounds make it unlikely that there are indirect effects, also via alpha 2-receptors in the models used and support the view that D-2 agonistic, 5-HT uptake inhibiting and 5-HT1A agonistic actions are independent properties of EMD 49,980.     

The pharmacology of pramipexole in the spontaneously hypertensive rat.

Pramipexole (SND-919) administration to spontaneously hypertensive rats resulted in a biphasic response with lower doses (1-30 micrograms/kg) causing a hypotensive response and higher doses (100-1000 micrograms/kg) increasing blood pressure. S-Sulpiride (1 mg/kg i.v.) and domperidone (100 micrograms/kg i.v.) but not SCH 23390(1 microgram/kg per min i.a.), prazosin (0.1 mg/kg i.v.) or rauwolscine (1 mg/kg i.v.) blocked the depressor effect, whereas rauwolscine but not S-sulpiride, SCH 23390 or prazosin blocked the pressor effects. The data indicate that pramipexole stimulates presynaptic DA2 receptors at low doses and postsynaptic alpha 2-receptors at high doses.     

Generalization of serotonin (5-HT)1A agonists and the antipsychotics, clozapine, ziprasidone and S16924, but not haloperidol, to the discriminative stimuli elicited by PD128,907 and 7-OH-DPAT

Rats were trained to recognize a discriminative stimulus (DS) elicited by the dopamine D(2)/D(3) receptor agonist, PD128,907 (0.16 mg/kg, i.p.), which suppressed frontocortical release of dopamine (DA) but not 5-HT. The selective 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, dose-dependently generalized to PD128,907 with effective dose(50)s (ED50s) of 0.08 and 1.5mg/kg, s.c., respectively, and inhibited the release and synthesis of 5-HT but not of DA. The 'atypical' antipsychotic, clozapine, which displays weak partial agonist properties at 5-HT1A receptors, dose-dependently, though partially, generalized to PD128,907 (50%, 2.5mg/kg, s.c.). Further, S16924 and ziprasidone, which in a like manner, display partial agonist activity at 5-HT1A receptors, generalized with ED50s of 0.6 and 2.3mg/kg, s.c., respectively. In contrast, haloperidol, which is devoid of affinity at 5-HT1A sites, was inactive. At doses equivalent to those generalizing to PD128,907, clozapine, S16924 and ziprasidone reduced serotonergic (but not dopaminergic) transmission, whereas haloperidol was inactive. In rats trained to recognize a further D2/D3 agonist, 7-OH-DPAT (0.16 mg/kg, i.p.), generalization was obtained similarly with 8-OH-DPAT (ED50 = 0.07 mg/kg, s.c.), flesinoxan (3.4) and clozapine (0.6), but not with haloperidol. In conclusion, although PD128,907 and 7-OH-DPAT do not directly interact with 5-HT1A receptors or influence serotonergic transmission, their DS properties are mimicked by 5-HT1A receptor agonists at doses activating 5-HT1A but not D2/D3 (auto)receptors. These observations likely account for generalization of clozapine, S16924 and ziprasidone to PD128,907 and 7-OH-DPAT inasmuch as they behave as antagonists at D2/D3 receptors, yet agonists at 5-HT1A (auto)receptors.     

Effects of repeated tiapride administration on anterior pituitary dopamine receptors and prolactin release in the rat

The substituted benzamides tiapride and sulpiride, and the classic neuroleptic haloperidol, were studied in the rat to assess their interaction with the anterior pituitary (AP) dopamine (DA) receptors both in vitro ([3H]spiperone binding) and in vivo prolactin-PRL-release). Tiapride weakly inhibited [3H]spiperone binding in both pituitary and striatal membranes with affinity 5-7 times lower than sulpiride and 400-300 times lower than haloperidol. All three drugs were more potent in displacing [3H]spiperone from striatum than from AP. In vivo, tiapride produced weak and transient stimulation of PRL release reaching a full effect at 2 mg/kg i.p. Similar doses of sulpiride produced longer-lasting effects. Haloperidol was more potent than both benzamides. In prolonged treatments (15 or 60 days), tiapride, given twice daily at 0.5 mg/kg i.p., did not modify [3H]spiperone binding in either AP or striatum, nor did it induce significant changes of basal PRL levels. The challenge with a low threshold dose of TIA (0.2 mg/kg ip) produced similar increases of PRL release in the group either treated with TIA or saline. The data indicate that the benzamides examined have low potency for interaction with DA receptors in pituitary and striatum. In particular, tiapride displayed weaker affinity for AP-DA receptors than the other drugs and induced only slight stimulation of PRL levels. Results from repeated tiapride administration indicate that the drug, at a clinically relevant dose, is unable to modify either kinetic characteristics of DA receptors in the pituitary or plasma PRL levels.     

Does combined treatment with novel antidepressants and a dopamine D3 receptor agonist reproduce cocaine discrimination in rats?

It is established that dopamine (DA) neurotransmission plays a critical role in the behavioral (e.g. discriminative stimulus) effects of cocaine in rodents. Nonetheless, research has also demonstrated that reciprocal signaling between DA and monoamine neurotransmitters, i.e. serotonin (5-HT) and norepinephrine (NE) has important implication for understanding the actions of cocaine. The present study was focussed on the ability of novel antidepressant drugs (milnacipram, reboxetine and venlafaxine), which affect either NE or both 5-HT and NE reuptake mechanism, to alter (enhance or antagonize) the discriminative stimulus effects of cocaine. Moreover, we investigated if the combined treatment with those drugs and a DA D3 receptor agonist (pramipexole) could reproduce cocaine discrimination. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, ip) from saline (ip) in a two-choice, water-reinforced fixed-ratio 20 drug discrimination paradigm. Given alone, none of antidepressant drugs induced substitution for the cocaine-lever responses. Pramipexole (0.25 mg/kg) produced a partial substitution for cocaine (i.e. 43-52% cocaine-lever responding). In combination experiments, milnacipram (10 mg/kg) or reboxetine (10 mg/kg) given with submaximal doses of cocaine (1.25-5 mg/kg) did not affect the cocaine dose-response curve or its ED50 values. Venlafaxine (10 mg/kg) given in combination with submaximal doses of cocaine (0.6-5 mg/kg) produced significant enhancement of cocaine discrimination with a leftward shift in the cocaine dose-response curve and a decrease in its ED50 value. Pretreatment with either milnacipram (10 mg/kg) or reboxetine (10 mg/kg) failed to modulate the partial substitution evoked by pramipexole (0.25 mg/kg). On the other hand, venlafaxine (10 mg/kg) given in combination with a submaximal dose of pramipexole (0.25 mg/kg), which separately elicited 16 and 42% the cocaine-lever responses, produced significant enhancement of cocaine discrimination (up to 99% of the drug-lever responding). These results indicate that the discriminative stimulus effects of cocaine in rats can be enhanced by venlafaxine or mimicked by the combination with this antidepressant drug and the DA D3 receptor agonist. This finding, together with the recent data reporting the lack of rewarding properties of venlafaxine and the attenuation of morphine dependence and withdrwal signs in rats by the drug, may indicate a possible therapeutic use of this antidepressant in cocaine abuse.     

R(-) and S(+) stereoisomers of 11-hydroxy- and 11-methoxy-N-n-propylnoraporphine: central dopaminergic behavioral activity in the rat

R(-)11-Hydroxy-N-n-propylnoraporphine (11-OH-NPa) induced stereotyped behavior in the rat as potently (ED50 = 0.80 mg/kg, i.p.) as R(-)apomorphine (APO) and this effect was blocked by haloperidol; the 11-methoxy congener, R(-)11-MeO-NPa, had a weak effect (ED50 greater than 10 mg/kg) and the S(+) isomers had none. The isomer R(-)11-OH-NPa potentiated locomotion stimulated by apomorphine; S(+)11-OH-NPa inhibited it and the isomers of 11-MeO-NPa were inactive. Catecholaporphines usually are inactive orally, but both R(-) and S(+)11-OH-NPa were similarly potent after oral or parenteral administration. The isomer S(+)11-OH-NPa inhibited spontaneous and apomorphine-induced locomotion (ID50 = 1.8-2.7 mg/kg, p.o. and i.p.) and stereotyped behavior (ID50 = 3 mg/kg, p.o. or i.p.), all without inducing catalepsy. While apomorphine was short-acting (1-2 hr), the effects of R(-)11-OH-NPa persisted up to 6-7 hr and those of the S(+) isomer for at least 2.5 hr; moreover, the efficacy of R(-)11-OH-NPa increased markedly up to 3-4 hr, although its ED50 was independent of time (ED50 = 1.7-1.9 mg/kg, i.p. from 1-3 hr). The total effect of R(-)11-OH-NPa (p.o. or i.p.) over time was more than 10-times greater than that of injected apomorphine. These observations accord with the reported high (nM) affinity of 11-OH-NPa at cerebral DA receptor sites (D2 greater than D1) and weak interactions of the 11-methoxy congener. They support the conclusion that the R(-) and S(+) stereoisomers are neuropharmacologically active, respectively, as DA agonist and apparent antagonist, as was found with the enantiomers of N-n-propylnorapomorphine, perhaps due to the low intrinsic postsynaptic agonist activity of the S(+) isomers. Moreover, 11-OH-NPa was highly bioavailable orally and unusually long-acting; it may be absorbed slowly or have active metabolites. Hydroxy-substitution of aporphines at the 11-position, homologous to the 3-OH of DA, evidently is critical for affinity and activity at the DA receptor. These or other monohydroxyaporphines may represent leads to potentially useful DA agonist or antagonist drugs.     

Differential effects of dopamine D-1 and D-2 receptor agonists on EEG activity and behaviour in the rabbit

SKF 38393, a selective agonist for dopamine D-1 receptors, LY 171555, a selective agonist for D-2 receptors and apomorphine, an agonist for both receptor sites, all induced activation of the electrical activity of the brain (EEG) in the rabbit. While SKF 38393 induced EEG changes without concomitant signs of stereotyped behaviour, the injection of both LY 171555 and apomorphine also elicited marked behavioural effects, mostly stereotyped mouth and head movements. The EEG effects of SKF 38393 were prevented by SCH 23390 (0.003 mg/kg i.v.), but not by (-)-sulpiride (6.2-25 mg/kg i.v.). Haloperidol attenuated the effects induced by SKF 38393 only at a dose (1 mg/kg) that induced EEG changes of its own. Similarly, effects of apomorphine on both EEG and behaviour were prevented by SCH 23390 and to a lesser extent by haloperidol, but not influenced by (-)-sulpiride. Different patterns of interactions were observed when D-2 receptors were selectively stimulated by LY 171555. Behavioural effects induced by LY 171555 were fully inhibited by both (-)-sulpiride (6.2-12.5 mg/kg i.v.) and haloperidol (0.1-0.3 mg/kg i.v.). The drug SCH 23390 attenuated some behavioural components at 0.3 mg/kg (i.v.), a dose at least 100-fold that effective on the EEG effects induced by SKF 38393. However, all these antagonists exerted weak or no effects on EEG activation induced by LY 171555 and did not restore the control patterns at any doses examined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of buspirone on dopamine dependent behaviours in rats

Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.     

The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia

Tardive dyskinesia (TD), a serious complication of antipsychotic dopamine (DA) antagonist treatment, has been hypothesised to develop due to a dominant DA D1 relative to DA D2 receptor function. Recent genetic and pharmacological studies implicate the DA D3 receptor in TD. The present study examined the role of the DA D3 receptor in relation to the DA D1/D2 imbalance hypothesis of TD in nonhuman primates. Eight Cebus monkeys displaying mild to severe TD due to previous chronic exposure to DA D2 antagonists were acutely injected with SKF 81297 (DA D1 agonist) 0.3 and 0.6 mg/kg, pramipexole (DA D3>D2 agonist) 0.025-0.1 mg/kg, CIS-8-OH-PBZI (DA D3 agonist) 5-10 mg/kg and SB-27701-A (DA D3 antagonist) 1-5 mg/kg and rated for oral dyskinesia. SKF 81297, 0.3 and 0.6 mg/kg, exacerbated TD. Pramipexole and CIS-8-OH-PBZI reduced SKF 81297-induced TD, while SB-27701-A had no effect. When administered alone, SB-27701-A increased TD relative to placebo, while pramipexole and CIS-8-OH-PBZI had no significant effect. Pramipexole did, however, ameliorate TD in those monkeys with severe TD. These results point towards a role of the DA D3 receptor in TD, but indicate that the DA D2 receptor may also play an essential role.     

Effects of raclopride on exploratory locomotor activity, treadmill locomotion, conditioned avoidance behaviour and catalepsy in rats: behavioural profile comparisons between raclopride, haloperidol and preclamol

Raclopride, a new potential antipsychotic agent blocking central dopamine (D2) receptors, was found to suppress exploratory locomotor activity, treadmill locomotion and conditioned avoidance response in rats. The threshold dose for effects in these test situations was about 0.5 mg/kg intraperitoneally. A considerably higher dose, 16 mg/kg intraperitoneally, was needed to produce maximal catalepsy. Maximal effects were obtained within 1-2 hrs and the duration of the effect was 2-8 hrs, depending on the test situation. The behavioural profile of raclopride is different from the classic antipsychotic haloperidol, blocking central dopamine (DA) receptors, as well as from the partial DA agonist preclamol, which inhibits central DA neurotransmission by activating DA autoreceptors. Thus, although similar to haloperidol in other respects, comparatively high doses of raclopride are needed to produce catalepsy, indicating less propensity to produce severe extrapyramidal side effects. Raclopride and preclamol are about equipotent in suppressing exploratory locomotor activity. However, raclopride is more potent than preclamol in suppressing treadmill locomotion, conditioned avoidance behaviour and catalepsy.     

The effects of the enantiomers of the dopamine agonist N-0437 on food consumption and yawning behaviour in rats

The enantiomers of the potent and selective dopamine (DA) D-2 receptor agonist 2-(N-propyl-N-thienylethyl-amino)-5-hydroxytetralin, N-0437, were tested for their effects on palatable food consumption and yawning behaviour in rats. (-)-N-0437 (1.0 and 5.0 mumols/kg). This confirms the agonistic action of (-)-N-0437 on postsynaptic receptors as food consumption is considered to be related to stimulation of postsynaptic DA receptors. Yawning behaviour was stimulated by (-)-N-0437 (0.5 mumol/kg) and could be antagonized by the autoreceptor-selective antagonist (+)-UH 232 (25 mumols/kg), which suggests an agonistic action on DA autorecptors. (+)-N-0437 (5.0 and 10.0 mumols/kg) also reduced food consumption and the effect could be antagonized by YM 09151-2 (0.03 mumol/kg). The weaker effect of (+)-N-0437 on food intake in comparison to that induced by (-)-N-0437 can be explained if it assumed that (+)-N-0437 is a partial agonist. (+)-N-0437 did not induce yawning behaviour in rats, suggesting that autoreceptors mediating the release of DA may be involved in stimulating yawning by DA agonists.     

Reversal of stress-induced anhedonia by the dopamine receptor agonist,pramipexole

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D₂ agonist, were studied during 7–9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppression of sucrose intake in stressed animals, increasing sucrose intakes above the levels seen in untreated nonstressed controls. Pramipexole also increased sucrose intake in nonstressed animals; these effects were accompanied by increases in water intake and tended to correlate with weight loss. Drug-treated stressed animals also lost weight, but in this case water intake was unaffected. A second group of animals received a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipexole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two further groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice-weekly) drug treatment. Intermittent pramipexole treatments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6–8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals. Untreated stressed animals showed no evidence of place conditioning. Normal conditioning was seen in both groups of stressed animals treated daily with pramipexole (at 1.0 and 0.1 mg/kg) and in the group treated twice weekly at the higher dose (1.0 mg/kg); intermittent treatment at the lower dose (0.1 mg/kg) was ineffective. The results indicate that pramipexole exerts rapid anti-anhedonic effects in the chronic mild stress model. This conclusion is complicated, but not undermined, by drug-induced weight loss and by the presence of significant drug effects in nonstressed control animals.     

A comparison between some biochemical and behavioural effects produced by neuroleptics

Acute administration of five neuroleptics to rats produced a dose-dependent increase in brain homovanillic acid (HVA) which was of greater magnitude and of longer duration in the corpus striatum than in the tuberculum olfactorium. 4-p-Fluorophenyl-5-N(N'-o-methoxy-phenyl) piperazinoethyl-4-oxazolin-2-one (LR 511) appeared to be 5--10 times more potent than fluanisone and clozapine, as active as chlorpromazine (CPZ) but at least twentyfold less active than haloperidol. Time-course studies on dopamine turnover have indicated that LR 511 at a moderate pharmacological dose has some similarities with clozapine, e.g., a lower difference between striatal and limbic tissues. All the neuroleptics caused inhibition of the conditioned avoidance response and at their ED50S on this parameter (with the exception of clozapine) caused also an equal increment of the cerebral HVA level. At their ED50S on catalepsy, the neuroleptics evoked HVA changes which varied according to the drug tested. Thus, potent cataleptogenic agents caused either strong stimulation of the DA turnover in both brain structures (haloperidol and CPZ) or weak stimulation only in corpus striatum (fluanisone). On the other hand a poor cataleptogenic agent, such as LR 511, was accompanied by the highest HVA levels and also the non-cataleptogenic clozapine at the dose of 40 mg/kg increased the cerebral HVA levels. It is suggested that the acceleration of DA turnover in animals is not an essential prerequisite for predicting the antipsychotic activity in man and that the preferential reactivity of dopaminergic limbic receptors is not necessarily linked to a better ratio of antipsychotic versus extrapyramidal effects in man.     

Involvement of extrapyramidal motor mechanisms in the suppression of locomotor activity by antipsychotic drugs: a comparison between the effects produced by pre- and post-synaptic inhibition of dopaminergic neurotransmission

The effects of two proposed dopaminergic autoreceptor agonists, (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and the azepine derivative B-HT 920, on spontaneous locomotor activity, treadmill locomotion, and catalepsy in the rat have been compared with the effects produced by the postsynaptic dopamine (DA) receptor blocking agent haloperidol. It was found that the threshold dose for suppression of exploratory locomotor activity was 0.5, 0.005 and 0.2 mg/kg for (-)3-PPP, B-HT 920 and haloperidol, respectively. The corresponding doses for suppression of treadmill locomotion were 8.0, 5.12 and 0.2 mg/kg, respectively. Furthermore, (-)3-PPP and B-HT 920, in contrast to haloperidol, did not produce any catalepsy. Thus, using exploratory locomotor activity as an index of limbic forebrain DA functions and treadmill locomotion and catalepsy as indices of extrapyramidal DA functions, the DA autoreceptor agonists, in contrast to the postsynaptic antagonist, show a difference in the doses required to produce these effects. The designation of the behavioral functions as "limbic" or extrapyramidal is supported by the finding that scopolamine, 0.8 mg/kg, antagonized the haloperidol-induced suppression (0.2 mg/kg) of treadmill locomotion, but not the suppression of exploratory locomotor activity.     

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Opposite effects induced by low and high doses of apomorphine on single-trial passive avoidance learning in mice

The effects of apomorphine (0.0125-1 mg/kg, SC), a dopamine (DA) agonist, on passive avoidance learning were assessed in mice which received brief and long foot-shocks in a training test. At low doses, apomorphine stimulates DA autoreceptors. With a shock of brief duration, apomorphine at a low dose (0.05 mg/kg), enhanced the avoidance learning when it was administered 20 min before the training test or the retention test. At high doses, apomorphine stimulates postsynaptic DA receptors. With a shock of long duration, apomorphine at a high dose (1 mg/kg), impaired the avoidance learning when it was administered 20 min before the training test or the retention test. However, apomorphine (0.05 and 1 mg/kg) given immediately after the training test did not have any effect on the avoidance behavior with shocks of either brief or long durations. Apomorphine-induced enhancement of passive avoidance learning was antagonized by sulpiride, but not by haloperidol. These results show that apomorphine induced the opposite effects on the passive avoidance learning depending on the dose or on the reinforcement intensity and suggest that the central DA system may play an important role in modulating memory processes.     

Influence of SCH 23390, a DA1-receptor antagonist, on the behavioural responsiveness to small and large doses of apomorphine in rats

SCH 23390 (SCH), a DA1-receptor antagonist, did not influence the decrease in locomotor activity elicited by a dose of apomorphine (20 micrograms/kg) believed to stimulate DA autoreceptors in rats. Conversely, SCH antagonized the effects on locomotion and the stereotyped behaviour elicited by a dose of apomorphine (1 mg/kg) which stimulates postsynaptic DA receptors. These results showing that the behavioural effects produced by small and large doses of apomorphine are differently affected by SCH, further confirm that DA autoreceptors can be pharmacologically distinguished from postsynaptic DA receptors.     

Differential effects of dopamine D1 and D2 agonists and antagonists on velocity of movement, rearing and grooming in the mouse. Implications for the roles of D1 and D2 receptors

A system combining visual recording of rearing and grooming, with automatic measurement of slow and fast components of locomotion, was examined for its suitability as a means of studying the effects on behaviour of conventional and novel dopaminergic drugs in the mouse. Amphetamine (0.1-10 mg/kg) selectively stimulated fast movements and affected rearing bimodally. Apomorphine (0.01-5 mg/kg) influenced locomotion polyphasically, depressing fast movements and enhancing slow ones, and producing parallel changes in rearing. Both drugs reduced grooming monotonically. A dose of apomorphine (25 micrograms/kg) which is considered to act presynaptically produced haloperidol-resistant sedation, while a larger dose (0.5 mg/kg; with postsynaptic actions) evoked head-down sniffing and ponderous walking that were partially prevented by pretreatment with 0.05 mg/kg haloperidol (D2 blocker), but not 0.01 mg/kg SCH 23390 (D1 blocker). The behavioural effects of haloperidol (0.2-0.4 mg/kg) and SCH 23390 (0.05 mg/kg) were indistinguishable; both drugs caused sedation and inhibited all forms of motor activity. Small doses of SCH 23390 (2-10 micrograms/kg) and large doses of the D1 agonist SKF 38393 (3-10 mg/kg) evoked excessive grooming. The drug SKF 38393 (1-30 mg/kg) had no other effects on motor behaviour, whereas the whole spectrum of pre- and postsynaptic motor responses produced by apomorphine could be duplicated with the D2 agonist RU 24213 (0.05-15 mg/kg). The differential sensitivity of fast and slow components of locomotion to treatment with drug suggests these are qualitatively distinct responses. The results implicate D2 receptors in the mechanisms of locomotion and rearing, and D1 receptors in the expression of grooming.