The epidemiology of motor neuron diseases: a review of recent studies.

As the incidence and mortality rates of motor neuron diseases (MNDs) have been reported to increase steadily over the 1950s-1980s decades, we compared the results of the most recent studies (1990s decade) with the ones reported for those earlier periods. The relevant literature was retrieved on a keyword basis from online medical and official death statistics databases. Fifteen European and North American studies were analyzed, for comparison with the results reported in review papers. The 1990s incidence and mortality rates of MND average at 1.89 per 100,000/year and 1.91 per 100,000/year, respectively, thus yielding increases of 46% and 57% over the 1960s-1970s decades, respectively. This increase appears mainly due to Southern Europe countries, to female gender and to patients aged 75 years and over.Thus, the results of this analysis (i) confirm that the incidence of, and mortality from, MNDs continued to increase during the 1990s and, (ii) suggest that this increase could be partly due to increased life expectancy. Other factors might also contribute, such as better diagnosis since El Escorial criteria, and better accuracy of death certificate collection.However, a real increase in the incidence of MNDs, possibly related to environmental factors, cannot be excluded.

Social olfactory recognition in rodents: deterioration with age, cerebral ischaemia and septal lesion.

Social olfactory recognition in rodents has been shown to assess short-term memory and to be sensitive to cholinergic drugs. It is based on the investigation of a juvenile by an adult rat and is measured by a reduction in duration of exploration during the second of two successive exposures lasting 5min. The present experiments further characterize rodent social recognition in pathophysiological models known to impair memory. Social recognition was distrupted by ageing in both rats and mice, by vincristine-induced septal lesion and by damaging the CA1 hippocampal layer after cerebral ischaemia in rats. These memory deficits could be compensated by reducing the time interval between the two presentations of the juvenile and/or by prolonging the juvenile encounter. Similarly, muscarinic agonists (arecoline, SR 46559A) counterbalanced the memory impairment in the three models. The present results indicate that the hippocampus plays a key role in social recognition. They suggest that in the three pathophysiological models, memory ability is still present although it is of very short duration; however, it can still be improved by pharmacological treatments.

Pharmacological activity of cholecystokinin analogues modified in the Met28-Gly29 region.

Analogues of the C-terminal octapeptide of cholecystokinin (CCK) modified in the Met28-Gly29 region, were tested for their ability to interact with peripheral cholecystokinin receptors on rat pancreatic acini and to stimulate amylase secretion. These analogues were further evaluated for their ability to recognize central CCK receptors on guinea pig brain membranes. The behavioral effect of these analogues was also tested after intrastriatal injection into mice. It appeared that these analogues were full CCK agonists in the peripheral system. Although some induced dopaminomimetic effects after intrastriatal injection into mice, being as potent as the C-terminal octapeptide of cholecystokinin (CCK-8), others did not have any effect and were able to antagonize CCK-8 actions in the striatum. The results of this study confirm that one can obtain very potent CCK analogues by modifying the peptide bond between Met28 and Gly29, and that this modification can produce either CCK agonists or antagonists of CCK-induced dopamine transmission in the striatum.

Effects of repeated administration of tetrahydroaminoacridine (THA) on muscarinic receptor subtypes in the rat brain.

The effects of a chronic treatment (21 days) with the acetylcholinesterase (AChE) inhibitor tetrahydroaminoacridine (THA) on muscarinic receptors subtypes were investigated at various times after the last administration of the drug, in various brain areas including cortex, striatum, hippocampus and cerebellum. Forty eight hours after the end of chronic THA treatment, the number of muscarinic receptors, labelled with [(3)H]NMS, was significantly lowered in the cortex and the striatum but not in the hippocampus or cerebellum. High affinity pirenzepine binding sites (M(1) receptors), directly assayed using [(3)H]pirenzepine saturation assays or estimated by pirenzepine [(3)H]NMS competition, were lowered only in the cortex and in the striatum of THA-treated rats. In contrast, the number of low affinity pirenzepine sites (M(2) receptors), was not significantly modified. At shorter wash-out period (18 h), the density of M(1) receptors decreased by 26, 46 and 52% in the hippocampus, cerebral cortex and striatum, respectively. In all cases, K(d) values remained unchanged suggesting that the loss of M(1) sites was not due to a modification of radioligand affinity for the receptors. Although THA displayed a micromolar affinity for M(1) and M(2) receptors in vitro, this AChE inhibitor did not interfere with the receptor assays since no trace of residual free THA was detected in rat brain at 48 h post-treatment. These results suggest that chronic treatment with THA produced a selective down-regulation of M(1) receptors; they also indicate that these receptors may be regulated differently in cortical, striatal, hippocampal or cerebellar regions.

Cholinomimetic activities of minaprine.

The cholinomimetic activities of the antidepressant drug minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morpholinoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses. Minaprine and SR 95070B antagonized rotations induced by an intrastriatal injection of pirenzepine in mice, after intraperitoneal and/or oral administration. Minaprine also antagonized atropine-induced mydriasis in mice. Both minaprine and SR 95070B potentiated the tremorigenic effect of oxotremorine without inducing tremor when injected alone. Finally, minaprine and SR 95070B, after parenteral and/or oral injection, antagonized the scopolamine-induced deficit in passive avoidance learning, and enhanced short-term retention in the social memory test, in rats. The muscarinic agonists arecoline, oxotremorine and RS 86 [2-ethyl-8-methyl-2,8 diazaspiro-4,5 decan-1,3 dion hydrobromide], as well as the acetylcholine esterase inhibitors physostigmine and tacrine were active in most of these models. These results indicate that minaprine, and its metabolite SR 95070B, have cholinomimetic activities which could be, at least in part, mediated by their selective affinity for M1 muscarinic receptors. Thus minaprine could represent a potential useful drug for the treatment of senile dementias and cognitive impairments occurring in elderly people.

Cerebral-activating (EEG) properties of two inverse agonists and of an antagonist at the benzodiazepine receptor in the rat.

In order to assess the effects of inverse benzodiazepine agonists and antagonists on brain function, computerized EEG (CEEG) analysis was performed in rats following the i.p. administration of SR 95195 (7-phenyl-3-methyl-1,2,4 triazolo-[4,3-b]pyridazine) and CGS 8216 (2-phenylpyrazolo-[4,3c]-quinoline-3-[5H]-one) two benzodiazepine receptor inverse agonists (BRIAGs) and of flumazepil (Ro 15-1788), a benzodiazepine receptor antagonist (BRANT). The EEG effects of SR 95195 (3, 10, 30 and 60 mg/kg), CGS 8216 (10 and 30 mg/kg) and flumazepil (3, 10, 30 and 60 mg/kg) were compared to those of the psychostimulant drugs DL-amphetamine (0.1, 0.3 and 1 mg/kg), and caffeine (10 and 30 mg/kg) and those of aniracetam (100 and 300 mg/kg), a nootropic pyrrolidone derivative. The CEEG profiles of SR 95195, CGS 8216 and flumazepil were mainly characterized by a power increase in the 20-32 Hz frequency range and by a power reduction in the 8-16 Hz range. These effects were quite similar to those of the psychostimulants DL-amphetamine and caffeine as well as to those of the nootropic aniracetam. Other psychotropic drugs with CNS-depressant properties, namely diazepam (10 mg/kg p.o.), pentobarbital (30 mg/kg p.o.), chlorpromazine (10 mg/kg i.p.) and imipramine (10 mg/kg i.p.) induced quite different EEG power modifications. These results show that BRIAGs and BRANTs possess a marked intrinsic activity at the central level and suggest that this activity is CNS-activating in nature.

Pharmacological characterization of the aminopyridazine SR 95639A, a selective M1 muscarinic agonist.

In order to design a selective M1 muscarinic agonist, we synthesized SR 95639A (morpholinoethylamino-3-benzocyclohepta-(5,6-c)-pyridazine, dihydrochloride), a semi-rigid analogue of the aminopyridazine antidepressant drug minaprine. SR 95639A displaced [3H]pirenzepine from its binding sites in rat hippocampal membranes with an IC50 value of 0.27 microM. It only weakly displaced [3H]N-methylscopolamine from cerebellar, cardiac and ileal membranes (10-48 microM), and, up to 100 microM, did not interact with the main other receptors of the rat brain. In rat isolated sympathetic ganglia, SR 95639A induced dose-dependent depolarizations which were antagonized by pirenzepine, and dose dependently suppressed the M current. These latter effects were also pirenzepine-sensitive. After i.p. or oral treatment in mice, SR 95639A never induced the classical cholinergic syndrome, up to lethal doses. Finally, SR 95639A (i.p. and p.o.) antagonized contralateral rotations induced by intrastriatal injection of pirenzepine, in mice. These results suggest that SR 95639A is a selective agonist at central muscarinic M1 receptors and may represent a useful tool for further characterization of the nature and function of muscarinic receptor subtypes.

3-aminopyridazine derivatives with atypical antidepressant, serotonergic, and dopaminergic activities.

Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring.

Systemic injection of pirenzepine induces a deficit in passive avoidance learning in rats.

When injected IP, the M1 muscarinic receptor antagonist pirenzepine dose-dependently induced a deficit in passive avoidance learning in rats. This activity was optimal at 75 mg/kg injected 1 h before the acquisition session. The deficit induced by pirenzepine was antagonized by oxotremorine (0.03-0.3 mg/kg SC) and physostigmine (0.1 mg/kg SC), but not neostigmine. By comparison, under the same experimental conditions, physostigmine and oxotremorine also antagonized the deficit induced by an equipotent dose of scopolamine (0.5 mg/kg IP), although the activity of physostigmine appeared stronger against scopolamine than against pirenzepine. These results suggest that pirenzepine could produce a centrally-mediated behavioural disruption when injected systemically.

Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists, but not by psychostimulants.

The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. In this study the effect of various psychotropic drugs on this investigatory behaviour was examined. The procedure was as follows: an unfamiliar juvenile rat was placed in the home cage of an adult rat for 5 min. The time spent by the adult rat in investigating the juvenile was recorded. The adult rat was then immediately treated with vehicle or test compounds, and was again exposed for 5 min to the same juvenile 2 h later. At this time point vehicle-treated rats no longer recognized the juvenile rat, i.e. the time of investigation was similar to that observed during the first presentation. Arecoline (1 and 3 mg/kg IP), physostigmine (0.05 and 0.1 mg/kg SC), RS86 (0.5 mg/IP) and nicotine (0.125 and 0.5 mg/kg IP) reduced in a dose-dependent fashion the time spent in investigating the juvenile during the second exposure. This result cannot be attributed to nonspecific effects, since it was not observed when a different juvenile was used for the second exposure. The effect of arecoline was reversed by scopolamine, but not by methylscopolamine. Aniracetam reduced investigatory behaviour at the dose of 50 mg/kg IP. FG 7142 (5 mg/kg IP) and beta-CCM (0.4 mg/kg IP) were also active and their effect was reversed by Ro 15-1788. DL-Amphetamine (0.5 and 1 mg/kg IP), nomifensine (1.25-10 mg/kg IP) and strychnine (0.25 and 0.5 mg/kg IP) were ineffective or reduced this behaviour unspecifically.(ABSTRACT TRUNCATED AT 250 WORDS)

A pseudopeptide that is a potent cholecystokinin agonist in the peripheral system is able to inhibit the dopamine-like effects of cholecystokinin in the striatum.

There are no known specific effective cholecystokinin (CCK) receptor antagonists of both peripheral and central nervous systems. Here, we describe experiments which demonstrate that a synthetic pseudopeptide analogue of CCK-7 is a potent agonist in the peripheral system and behaves as a selective and highly potent inhibitor of the dopamine-like effects of CCK in the striatum. This compound, t-butyloxycarbonyl-Tyr (SO3H)-Nle psi (COCH2)Gly-Trp-Nle-Asp-Phe-NH2, is able to stimulate enzyme secretion from rat pancreatic acini, with high efficacy and potency. It is also very potent in inhibiting the binding of labeled CCK-8 to rat pancreatic acini (IC50 = 5 nM) and to guinea pig and mouse brain membranes (IC50 = 0.7 nM). However, this compound is able to antagonize the effects of intrastriatally injected t-butyloxycarbonyl-[Nle28,31] CCK-8 in mice, with high potency.

Monoamine oxidase-inhibiting properties of SR 95191, a new pyridazine derivative, in the rat: evidence for selective and reversible inhibition of monoamine oxidase type A in vivo but not in vitro.

In rodents, SR 95191 [3-(2-morpholinoethylamino)-4-cyano-6-phenylpyridazine] has been shown to be active in animal models of depression. The profile of activity of SR 95191 suggests that the compound is a selective and short-acting type A monoamine oxidase (MAO) inhibitor (MAOI) in vivo. In the present study, the interaction of SR 95191 with MAO-A and MAO-B activity was further examined in vivo and in vitro. In brain, liver, and duodenum of pretreated rats, SR 95191 selectively inhibited MAO-A (ED50 = 3-5 mg/kg, p.o.), whereas MAO-B was only weakly inhibited for doses as high as 300 mg/kg, p.o. In vivo, SR 95191 (1-100 mg/kg, p.o.) antagonized, in a dose-dependent fashion, the irreversible inhibition of brain and liver MAO-A induced by phenelzine. Finally, dopamine and 5-hydroxytryptamine depleted from their striatal stores by tetrabenazine were able to displace SR 95191 from the active site of MAO-A. However, ex vivo, kinetic studies showed that the inhibitory effect of SR 95191 (1-10 mg/kg) towards MAO-A was noncompetitive and was unchanged after dilution or dialysis. In vitro, the inhibition of brain MAO-A, but not MAO-B, by SR 95191 was time dependent, with a 19-fold decrease in the IC50 values being observed over a 30-min incubation period (140 to 7.5 microM). At this time, the SR 95191-induced inhibition of MAO-A was not removed by repeated washings. When the reaction was started by adding the homogenate without prior preincubation with SR 95191, the inhibition of brain MAO-A was fully competitive (Ki = 68 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characterization of the physostigmine stimulus in rats.

Rats were trained to discriminate 0.10 mg/kg SC physostigmine from saline in a two-lever food-reinforced task. There was generalization to the acetylcholine esterase inhibitor THA as well as to the muscarinic receptor agonists arecoline, oxotremorine and RS 86, but not to neostigmine or nicotine. The physostigmine cue was blocked by SC scopolamine hydrobromide and by ICV pirenzepine, but not by scopolamine methylbromide or by mecamylamine. These antagonism studies suggest that the discriminative cue elicited by physostigmine might be mainly mediated by central M1 receptors.

Characterization of the scopolamine stimulus in rats.

The discriminative stimulus properties of scopolamine, a potent antagonist at muscarinic receptors, were used for testing the discriminative effects of drugs known to act on cholinergic transmission. Rats were trained in a standard two-bar operant conditioning procedure with food as the reinforcer, according to a FR10 schedule. The training dose of scopolamine was progressively reduced from 0.25 mg/kg SC to the low dose of 0.062 mg/kg SC. Scopolamine yielded an accurate discrimination in all the six rats tested. The generalization gradient resulted in an ED50 of 0.027 mg/kg. The scopolamine cue lasted for 1 h and was of central origin, since it was not mimicked by scopolamine methylbromide. The scopolamine stimulus generalized to atropine and trihexyphenidyl (respective ED50 values 2.20 and 0.21 mg/kg SC). Atropine depressed rate of responding, while trihexyphenidyl did not. Antagonism experiments with both direct agonists at the muscarinic receptor (arecoline and oxotremorine) and indirect agonists, i.e., inhibitors of the acetylcholine esterase [physostigmine and tetrahydroaminoacridine (THA)], led to inconsistent results. Increasing the doses of the agonists in order to block the scopolamine cue may be limited by their rate suppressant effect on responding. Based upon previously published results, it is suggested that the muscarinic agonist cue is more useful than the antagonist cue for investigating muscarinic transmission.

Effects of intracerebroventricular pirenzepine on muscarinic discriminations in rats.

In rats, mixed M1/M2 muscarinic ligands induce a discrimination which is of central origin and selectively mediated by either one or both muscarinic receptor subtypes. In the present study we examined the effects of intracerebroventricular (i.c.v.) pirenzepine, a relatively selective M1 receptor antagonist which does not cross the blood-brain barrier, on muscarinic discriminations. Groups of six rats were trained to discriminate, in a two-lever operant task, either 0.062 mg/kg subcutaneous (s.c.) scopolamine or 0.075 mg/kg s.c. oxotremorine. When the rats had been well trained in the procedure, the discriminative effects of various i.c.v. muscarinic ligands were examined. Scopolamine (1.5-12 micrograms i.c.v.), but not pirenzepine (20-40 micrograms i.c.v.), generalized to s.c. scopolamine. Oxotremorine (0.75-6 micrograms i.c.v.) generalized to s.c. oxotremorine. Scopolamine (12 micrograms i.c.v.), but not pirenzepine (20-40 micrograms i.c.v.), antagonized the oxotremorine cue. These results suggest that activation of the M1 receptor is not the prominent component of muscarinic stimulus control.

Behavioural evidence for a selective GABA-A antagonistic activity of SR 95103 and SR 42641 after intrastriatal injection in mice.

Two pyridazinyl GABA derivatives, SR 95103 and SR 42641 have recently been described as selective GABAA receptor antagonists. We have now investigated the behavioural effects of SR 95103 and SR 42641 after intrastriatal injection in mice. When injected into the right striatum, SR 95103 (0.01-0.5 microgram), SR 42641 (0.0001-0.01 microgram) and bicuculline methiodide (0.005-0.05 microgram) induced contralateral rotations which were antagonized by intraperitoneal injection of muscimol. In contrast, the intrastriatal injection of the GABAA receptor agonist muscimol induced ipsilateral rotations. Muscimol-induced turning was antagonized by SR 95103 (10-30 mg/kg), SR 42641 (1-10 mg/kg) and (+)-bicuculline (0.125-0.5 mg/kg) injected intraperitoneally, but not by strychnine. Intrastriatal glycine also induced ipsilateral rotations which were antagonized by strychnine (0.01-0.3 mg/kg i.p.) but not by (+)-bicuculline, SR 95103 or SR 42641. These results suggest that SR 95103 and SR 42641 induce turning through a selective blockade of GABAA receptors within the striatum.

Antagonism by cholinomimetic drugs of the turning induced by intrastriatal pirenzepine in mice.

In order to investigate the behavioural effect of selective blockade of M1 muscarinic receptors in the forebrain, and to characterize a new model for the evaluation of muscarinic agonistic activity, the effect of intrastriatally injected pirenzepine was studied in mice. The direct injection of pirenzepine (0.01-1 microgram/mouse) into the right striatum of conscious mice resulted in contralateral turning behaviour. When injected intraperitoneally (IP) 15 min before pirenzepine (1 microgram), the muscarinic receptor agonists arecoline and pilocarpine (0.3-3 mg/kg), oxotremorine (0.003-0.03 mg/kg) and RS 86 (0.03-1 mg/kg) antagonized pirenzepine-induced turning, as did the choline-esterase inhibitor physostigmine (0.01-0.1 mg/kg) and the nootropic drug aniracetam (10-30 mg/kg). Haloperidol (0.03-0.3 mg/kg IP) weakly, but significantly, decreased the effect of pirenzepine, whereas (+/-) sulpiride (3-100 mg/kg) failed to affect it. Finally, (+/-)-amphetamine (0.1-3 mg/kg IP), citalopram (1-30 mg/kg IP) and muscimol (0.03-0.3 mg/kg IP) failed to modify pirenzepine-induced turning when administered prior to intrastriatal pirenzepine. These results suggest an involvement of M1 muscarinic receptors in rotational behaviour, and indicate that pirenzepine-induced turning may represent a new model for studying the central activity of cholinomimetic drugs.

SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. I. Psychopharmacological profile in rodents.

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenyl-pyridazine], a novel compound, has been shown in preliminary experiments to inhibit type A monoamine oxidase (MAO). This report describes the activities of SR 95191 in behavioral experiments in mice and rats and shows that SR 95191 has the profile of a selective type A MAO inhibitor (MAOI). Moreover, SR 95191 also possesses dopamine (DA) stimulant properties. The activities of SR 95191 were compared to those of the MAOIs moclobemide, clorgyline, pargyline and l-deprenyl, as well as to those of the antidepressant drugs imipramine, nomifensine and indalpine and to those of the DAergic drugs (+)-amphetamine and apomorphine. SR 95191 p.o. antagonized the effects of reserpine in mice and rats, decreased immobility in the mouse despair test, antagonized haloperidol-induced catalepsy in rats and potentiated 5-hydroxytryptophan in mice and rats with an overall potency which was half that of imipramine. SR 95191, like moclobemide, did not potentiate yohimbine-induced lethality and did not antagonize oxotremorine-induced tremor. Like selective type A MAOIs, SR 95191 potentiated 5-hydroxytryptophan-induced tremor without affecting beta-phenethylamine-induced stereotypies in mice. SR 95191 did not antagonize 3-hydroxy-4-methyl-alpha-phenylethylamine-induced hyperthermia. Like all DA stimulant drugs, SR 95191 induced stereotypies in rats, which were blocked by haloperidol and alpha-methylparatyrosine, and induced contralateral turning in mice with a unilateral striatal 6-hydroxydopamine lesion. Based on these results, it is postulated that SR 95191 has a unique profile of activity combining the properties of a selective type A MAO inhibitor and those of an atypical DAergic drug.

SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. II. Biochemical characterization of monoamine oxidase inhibition.

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenylpyridazine] is a novel psychotropic drug which possesses the pharmacological properties of a selective, reversible type A monoamine oxidase inhibitor (MAOI). The MAOI activity of SR 95191 was examined in the rat brain, liver and duodenum and compared to that of clorgyline, harmaline, l-deprenyl, moclobemide and cimoxatone. In vitro, SR 95191 selectively inhibited MAO-A and was less potent than cimoxatone, clorgyline and harmaline, but was more potent than moclobemide. Ex vivo, SR 95191 also preferentially inhibited MAO-A in the brain and was 6 and 13 times less potent than cimoxatone and moclobemide, respectively. Like all MAO-A inhibitors, SR 95191 in vivo caused a dose-dependent increase in striatal 3-methoxytyramine, dopamine, serotonin and in hypothalamic norepinephrine contents. A concomitant decrease in deaminated metabolites was observed. SR 95191 inhibited peripheral MAO activity in liver and duodenum. In brain, liver and duodenum, MAO inhibition induced by SR 95191 was short-lasting. Repeated dosing for 14 days did not enhance MAO-A inhibition. Like all reversible MAOIs, SR 95191 antagonized the long-lasting MAO-A inhibition induced by clorgyline. Finally, SR 95191 did not affect monoamine uptake either in vitro or in vivo and did not interact in vitro with a variety of neurotransmitter or drug receptor sites. Based on these results it is postulated that SR 95191 is a selective and reversible type A MAOI of medium potency, which may be of therapeutic benefit in depressed patients.

Induction of turning by direct intrastriatal injection of dopaminomimetic drugs in mice: pharmacological analysis of a simple screening model.

A new simple model designed for the screening of dopaminomimetic drugs in mice is presented. When injected directly into the right striatum of conscious mice, the dopamine (DA) receptor agonists apomorphine, SKF 38393 and bromocryptine, the indirect DAmimetic drugs (+)-amphetamine and nomifensine, the atypical DAergic antidepressant drug minaprine, induced contralateral rotations. Rotations induced by DA mimetics were antagonized by i.p. injected haloperidol. A pretreatment with the D1 antagonist SCH 23390 (s.c.) antagonized the turning induced by apomorphine or by the D1 agonist SKF 38393, and, to a lesser extent, that induced by the D2 agonist bromocryptine. In contrast, the D2 antagonist (-)-sulpiride (i.p.) blocked the effects of the 3 agonists to the same extent. A pretreatment with alpha-methylparatyrosine (i.p.) antagonized rotations induced by bromocryptine, (+)-amphetamine and minaprine, but not those induced by nomifensine or apomorphine. The results suggest that this model could represent a useful screening tool for the search of new DAmimetic drugs, and for the assessment of DA receptor blockade.