Repeated co-treatment with imipramine and amantadine induces hippocampal brain-derived neurotrophic factor gene expression in rats.

The problem of drug-resistant depression indicates a strong need for alternative antidepressant therapies. In our earlier papers we described synergistic, antidepressant-like effects of a combination of imipramine (IMI) and amantadine (AMA) in the forced swimming test in rats, an animal model of depression. Moreover, preliminary clinical data showed that the above-mentioned combination had beneficial effects in treatment-resistant patients. In addition, a number of studies predicted a role of the brain-derived neurotrophic factor (BDNF) in the mechanism of action of antidepressant drugs (ADs). Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment with IMI (5 or 10 mg/kg) and AMA (10 mg/kg), given separately or jointly (twice daily for 14 day), on mRNA level (the Northern blot) in the hippocampus and cerebral cortex. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was dissected 24 h after the last dose of IMI and AMA. We also studied the effect of repeated treatment with IMI and AMA on the action of 5-HT(1A)- and 5-HT(2A) receptor agonists (8-OH-DPAT and (+/-)DOI, respectively) in behavioral tests. The obtained results showed that in the hippocampus IMI (10 mg/kg), and in the cerebral cortex IMI (5 and 10 mg/kg) and AMA (10 mg/kg) significantly elevated BDNF mRNA level. Joint administration of IMI (5 or 10 mg/kg) and AMA (10 mg/kg) induced a more potent increase BDNF gene expression in the hippocampus (but not in cerebral cortex) and either inhibited the behavioral syndrome induced by (+/-)DOI or did not change the action of 8-OH-DPAT (compared to treatment with either drug alone). The obtained results suggest that the enhancement of BDNF gene expression may be essential for the therapeutic effect of co-administration of IMI and AMA to drug-resistant depressed patients, and that among other mechanisms, 5-HT(2A) receptors possibly play some role in this effect.

The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats.

Data acquired to date show that some sigma receptor ligands reveal "antidepressant-like" activity in the forced swim test in mice and rats. Moreover, our preliminary results suggested that joint administration of sigma receptor ligands and amantadine (AMA, a glutamatergic/NMDA receptor antagonist) caused a positive interaction in the Porsolt test in rats, as had already been observed in the case of co-treatment with clinically active antidepressants and AMA. The aim of the present study was to examine the effect of combined administration of sigma1 or sigma2 receptor agonists, SA4503 or siramesine, respectively, and AMA or memantine (MEM) (uncompetitive NMDA receptor antagonist). SA4503 or siramesine given jointly with MEM (as well as with AMA) decreased the immobility time in rats. The effect of SA4503 and AMA co-administration was antagonized by progesterone, a sigma1 receptor antagonistic neurosteroid. Combined treatment with siramesine and AMA was modified by neither progesterone nor BD1047 (a novel sigma antagonist with preferential affinity for sigma1 sites); but it was counteracted by sulpiride and prazosin (a dopamine D2- and an alpha1-adrenergic receptor antagonist, respectively). The "antidepressant-like" effect induced by siramesine and MEM was not antagonized by progesterone, but was attenuated by BD1047, sulpiride and prazosin. The obtained results give support to the hypothesis that sigma (particularly sigma1) receptors may be one of the possible mechanisms by which drugs induce antidepressant-like activity in the forced swim test, and that this effect may be enhanced by NMDA receptor antagonists. Combined treatment with sigma ligands and AMA or MEM (applied in the clinic) may be an alternative to the treatment of antidepressant-resistant depressive patients in the future.

Effect of combined treatment with imipramine and metyrapone on the immobility time, the activity of hypothalamo-pituitary-adrenocortical axis and immunological parameters in the forced swimming test in the rat.

Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.

Repeated treatment with mirtazepine induces brain-derived neurotrophic factor gene expression in rats.

Recent studies indicate a role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression, as well as in the mechanism of action of antidepressant drugs (ADs). It has been shown that serum BDNF levels are decreased in depressed patients. Moreover, antidepressant treatment increases serum BDNF levels and it is positively correlated with medication response. In addition, repeated administration of ADs induces an increase in rat hippocampal or cortical BDNF gene expression. Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment (twice daily for 14 days) of the new AD mirtazapine (5 or 10 mg/kg) on BDNF mRNA level (the Northern blot) in rat hippocampus and cerebral cortex. Imipramine was used as a reference compound. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was collected 24 h after the last doses of mirtazapine and imipramine. We also studied the effect of repeated mirtazapine on the action of the 5-HT2A receptor agonist (+/-)DOI in the behavioral test (head twitches induced by (+/-)DOI) in rats. The obtained results showed that, like imipramine (10 mg/kg), mirtazapine (10 mg/kg) increased BDNF gene expression in both the examined brain regions: in the hippocampus by 24.0 and 26.5%, in the cerebral cortex by 29.9 and 41.5%, respectively, compared with the vehicle-treated control. Neither mirtazapine nor imipramine administered repeatedly at a lower dose (5 mg/kg) significantly changed BDNF mRNA levels in the hippocampus and cerebral cortex. Repeated treatment with mirtazapine (10, but not 5 mg/kg) inhibited the behavioral syndrome induced by (+/-)DOI. This study provides first conclusive evidence that repeated mirtazapine administration increases BDNF mRNA levels; moreover, it indicates that the enhancement of BDNF gene expression may be essential for the clinical effect of mirtazapine.

Anxiolytic- and antidepressant-like effects of 7-OH-DPAT, preferential dopamine D3 receptor agonist, in rats.

The aim of the present study was to examine a potential anxiolytic- and antidepressant-like action of (+)-7-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (7-OH-DPAT), a preferential dopamine D(3) receptor agonist, and N-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl}-2-naphthylcarboxamide (BP 897), a partial dopamine D(3) receptor agonist, in male Wistar rats. Diazepam or imipramine were used as reference compounds. The anxiolytic-like effect of those drugs was tested in the elevated plus-maze test. The antidepressant-like effect was estimated using the forced swimming test. The obtained results showed that 7-OH-DPAT at low doses and BP 897 (like diazepam) induced anxiolytic-like effects in the elevated plus-maze test. 7-OH-DPAT, BP 897 and diazepam, tested at the doses effective in the model of anxiolytic-like actions, did not affect motor coordination. Moreover, 7-OH-DPAT at higher doses, like imipramine, showed antidepressant-like effect, significantly reducing immobility time in the forced swimming test. Combined treatment with 7-OH-DPAT and imipramine induced a stronger effect in Porsolt's test than administration of either drug alone, but did not increase the locomotor activity. In contrast, BP 897 was inactive in the forced swimming test when given alone but it potentiated the antidepressant-like effect of imipramine. These data suggest that preferential D(3) receptor agonists may play a role in the therapy of anxiety and/or depression, however, further studies are necessary to elucidate the mechanism of these actions.

Behavioral pharmacology of sigma-ligands.

Sigma (sigma) receptors, first defined as a subclass of opioid receptors, later confounded with the high affinity phencyclidine (PCP) binding sites, now are regarded as unique binding sites, distinct from opiate and PCP receptors, and related to higher brain function. The investigation of functional significance of sigma receptors in the brain has been hampered for many years by relative lack of specific tool drugs and by the unavailability of their coherent classification into postulated agonists and antagonists. However, a potential involvement of sigma receptors in psychotic disorders was first suggested soon after their discovery. The sigma receptors are classified into two subtypes, sigma (1) and sigma (2) receptors, of which the first was recently cloned from rodent and human tissues while the second has not yet been fully characterized. Although the precise mechanism of the functional response of these receptors is still uncertain, it is accepted that sigma receptors can modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic and dopaminergic ones. The sigma receptors have been postulated to be involved in numerous pharmacological and physiological functions, including motor disorders, psychotic disorders, neuroprotective mechanisms. In the last years, a number of compounds with a high affinity and selectivity for sigma binding sites have been discovered and investigated for their therapeutic potential. In this review, we try to summarize the behavioral effects of sigma receptor ligands that have been described, and their activity in animal models related to some brain disorders, especially schizophrenia and affective disorders.

A potential antidepressant activity of SA4503, a selective sigma 1 receptor agonist.

The aim of the present study was to examine SA4503 [1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride], a novel selective receptor agonist, in respect of its potential antidepressant action. To this end we used a forced swimming test in rats to study SA4503 alone, as well as its interaction with imipramine, a classic tricyclic antidepressant. SA4503 decreased the immobility time in the forced swimming test in rats (although only at one of the three doses used); at the same time it did not change the locomotor activity recorded under the same experimental conditions. Moreover, SA4503 showed a synergistic effect with imipramine in the forced swimming test (both those compounds given jointly decreased the immobility time, but were ineffective when administered separately). It had previously been shown that repeated administration of antidepressants with different pharmacological profiles enhanced the action of D-amphetamine, quinpirole and other dopamine stimulants. SA4503 administered repeatedly increased the locomotor hyperactivity induced by D-amphetamine and quinpirole (a dopamine D /D receptor agonist), but not by (+/-)-7-hydroxy-dipropyloamino-tetralin hydrobromide [(+/-)-7-OH-DPAT; a dopamine D receptor agonist]. The results presented in this paper support the suggestion that SA4503 may have potential antidepressive properties.

Effect of repeated treatment with tianeptine and fluoxetine on central dopamine D(2) /D(3) receptors.

Tianeptine (TIA) is an antidepressant drug that has been shown to decrease extracellular serotonin level and reveals no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated TIA treatment induced any adaptive changes in the central dopamine D(2)/D(3) system (behavioural and biochemical) similar to those reported earlier for tricyclic antidepressants. Experiments were carried out on male Wistar rats. TIA was administered at a dose of 5 and 10 mg/kg once or repeatedly (twice daily for 14 days). Fluoxetine (FLU), used as a reference compound, was also administered at a dose of 10 mg/kg. The results obtained showed that TIA or FLU administered repeatedly increased the hyperlocomotion induced by D-amphetamine and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT). Biochemical study revealed a decrease in the [(3)H]7-OH-DPAT binding sites after acute and repeated treatment with TIA or FLU in the islands of Calleja minor, as well as in the shell part of nucleus accumbens septi. On the other hand, both TIA and FLU administered repeatedly increased the binding of [(3)H]quinpirole (a D(2)/D(3) receptor agonist) in the nucleus caudatus as well as in the core part of the nucleus accumbens septi. Similar effects have been observed when dopamine D(2)/D(3) receptors were visualized with the use of [3H]raclopride, a dopamine D(2)/D(3) receptor antagonist. However, TIA and FLU induced a decrease in the level of mRNA encoding for dopamine D(2) receptors, not only after repeated but also after acute treatment. These results indicate that repeated TIA and FLU administration induces adaptive changes in the dopaminergic D(2)/D(3) system and especially enhances the functional responsiveness of dopamine D(2) and D(3) receptors. However, the question of whether this increased responsiveness is important for clinical antidepressant efficacy remains open.

Effect of repeated treatment with tianeptine and fluoxetine on the central alpha(1)-adrenergic system.

Tianeptine (TIA) is an antidepressant drug which enhances the reuptake of serotonin but, in contrast to tricyclics, shows no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated TIA treatment induced adaptive changes in the alpha(1)-adrenergic system, similar to those reported by us earlier for tricyclic antidepressants. The experiments were carried out on male mice and rats. TIA was administered at a dose of 5 or 10mg/kg once or repeatedly (twice daily for 14 days) and fluoxetine (FLU), used as a reference compound, at a dose of 10mg/kg. The obtained results showed that TIA administered repeatedly potentiated the methoxamine- and phenylephrine (PHEN)-induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice, the effects mediated by alpha(1)-adrenoceptors. TIA given repeatedly (but not acutely) increased the binding (B(max)) of alpha(1)-adrenergic receptors in cerebral cortex for [(3)H]prazosin. However, the ability of the alpha(1)-adrenoceptor agonist PHEN to compete for these sites was not significantly changed. The above results indicate that repeated TIA administration increases the responsiveness of the alpha(1)-adrenergic system (behavioural and biochemical changes). On the other hand, FLU did not affect any behavioural and biochemical changes in this system.

Repeated imipramine treatment enhances the 7-OH-DPAT-induced hyperactivity in rats: the role of dopamine D2 and D3 receptors.

Previous studies have shown that antidepressant drugs with different pharmacological profiles, administered repeatedly, increase the locomotor hyperactivity induced by various dopaminomimetics, among others by (+/-)7-hydroxydipropylaminotetralin (7-OH-DPAT). Since, according to a recent study, this drug shows a high affinity for not only dopamine D3 but also dopamine D2 receptors, a question arises whether dopamine D3 receptors are involved in the increase in 7-OH-DPAT-elicited locomotor hyperactivity induced by repeated treatment with antidepressant drugs. The aim of the present study was to investigate the effect of imipramine (IMI), administered repeatedly, on the hyperactivity induced by 7-OH-DPAT, a dopamine D3 receptor-preferring agonist. Male Wistar rats were treated with IMI (10 mg/kg po) either acutely (single dose) or repeatedly (twice daily for 14 days). The locomotor hyperactivity induced by 7-OH-DPAT (3 mg/kg sc) was measured in photoresistor actometers. The influence of nafadotride (0.2 and 0.4 mg/kg ip), a dopamine D3-preferring antagonist or sulpiride (10 and 25 mg/kg ip), a dopamine D2/D3 antagonist, on the 7-OH-DPAT-induced locomotor hyperactivity was studied. Nafadotride (in both doses used) or sulpiride (in the higher dose only) reduced (by about 50%) the hyperactivity induced by 7-OH-DPAT. Combined treatment with nafadotride (0.2 mg/kg) and sulpiride (25 mg/kg) completely abolished the effect of 7-OH-DPAT. IMI administered repeatedly (but not acutely) enhanced the 7-OH-DPAT-induced hyperactivity. Neither nafadotride, 0.2 mg/kg (or sulpiride, 10 mg/kg), given alone nor combined treatment with both these substances changed the hyperactivity induced by repeated treatment with IMI and 7-OH-DPAT (given 2 h after the last dose of IMI). Joint treatment with nafadotride, 0.2 mg/kg, and sulpiride, 25 mg/kg, completely abolished the enhancing effect of repeated treatment with IMI and 7-OH-DPAT. The above results indicate that both types of dopamine receptors, D3 and D2, may play a substantial role in the mechanism of the 7-OH-DPAT-induced hyperactivity, as well as in the increase evoked by repeated treatment with IMI in rats.

Repeated treatment with SA4503, a selective sigma1 receptor agonist, up-regulates alpha-adrenergic system. a behavioral study.

The obtained results indicate that SA4503, a selective sigma1 receptor agonist, given repeatedly (but not acutely) enhanced the effects of phenylephrine, alpha1-adrenoceptor agonist, and clonidine (stimulating the postsynaptic alpha1-adrenoceptors at high dose) in behavioral models (hyperexploratory activity in rats and aggressiveness in mice, respectively).

Combined treatment with NMDA antagonist, CGP 37849, and sigma receptor agonists, SA4503 or DTG, decreases the neuroleptic-induced catalepsy in rats.

The obtained results indicate that joint administration of CGP 37849, a competitive NMDA receptor antagonist, and SA4503, a sigma1 (sigma1) receptor agonist or DTG, sigma 1/2 receptor agonist, evoked anticataleptic effect at doses which were ineffective when each of the compounds was given alone.

Pharmacological profile of milnacipran, a new antidepressant, given acutely.

Pharmacological effects of acute treatment with milnacipran (MIL), a clinically active antidepressant (a noradrenaline [NA] and 5-hydroxytryptamine [5-HT] reuptake inhibitor without any affinity for neurotransmitter receptors) were studied in mice and rats. MIL inhibited the reserpine- or apomorphine-induced hypothermia in mice and enhanced the L-5-hydroxytryptophan-induced head twitches in rats. It reduced the immobility time in Porsolt's test in mice and rats, but either did not change the locomotor activity (mice) or decreased it (rats). MIL changed neither the clonidine-induced aggressiveness in mice nor the behavioral syndrome induced by oxotremorine in rats. The obtained results indicate that MIL, given acutely, shows a pharmacological profile similar to that of tricyclic NA and 5-HT reuptake inhibitors. In contrast to the antidepressants mentioned above, MIL does not exhibit an alpha1-adrenolytic or cholinolytic activity (in vivo tests).

The anticataleptic effect of 7-OH-DPAT: are dopamine D3 receptors involved?

The paper examined the effect of 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin), a dopamine D3 receptors-prefering agonist, on the catalepsy evoked by reserpine, haloperidol and fluphenazine in rats (male Wistar), as well as the influence of nafadotride, a dopamine D3 receptors-prefering antagonist, on that effect. The obtained results show that 7-OH-DPAT, as well as L-DOPA, a drug of choice in the therapy of Parkinson's disease, used for comparison, antagonize the catalepsy induced by reserpine, haloperidol and fluphenazine. Nafadotride, used in a dose (0.2 mg/kg) which inhibits the 7-OH-DPAT-evoked locomotor hyperactivity but does not affect the hypermotility induced by amphetamine and quinpirole, antagonizes the anticataleptic effect of 7-OH-DPAT or L-DOPA. It is therefore assumed that dopamine D3 receptors are involved in the anticataleptic effect of both 7-OH-DPAT and L-DOPA.

Effect of sigma ligands on the cocaine-induced convulsions in mice.

It has been hypothesized that some of negative effects exerted by cocaine are mediated via sigma (sigma) receptors. This report demonstrates the effects of selective sigma ligands, panamesine, DTG, rimcazole and SA 4503, on the cocaine-induced convulsions in mice and locomotor hyperactivity in rats. Only panamesine decreased both these effects of cocaine, whereas DTG and rimcazole increased the total time of cocaine-evoked convulsions and locomotor activity. SA 4503 slightly enhanced and prolonged cocaine-induced convulsions but it was ineffective in locomotor hyperactivity test. Moreover, the increase in cocaine-induced locomotor hyperactivity evoked by DTG was antagonized by panamesine. The obtained results indicate that panamesine, a selective sigma ligand with a preference for sigma1 receptor subtype and potential antagonistic activity, decreased the effects of cocaine. DTG and rimcazole (potential sigma1/sigma2 sites agonists) as well as SA 4503 (potential sigma1 site agonist) showed rather opposite effects. These findings support the idea that sigma2 receptor subtype is involved in psychomotor stimulant effects of cocaine while sigma1 receptor subtype participates in the cocaine-induced convulsions. In addition, sigma receptor antagonists (especially sigma1 ones) are able to antagonize toxic effects of cocaine while sigma agonists facilitate them.

Repeated trimipramine induces dopamine D2/D3 and alpha1-adrenergic up-regulation.

Trimipramine (TRI), which shows a clinical antidepressant activity, is chemically related to imipramine but does not inhibit the reuptake of noradrenaline and 5-hydroxytryptamine, nor does it induce beta-adrenergic down-regulation. The mechanism of its antidepressant activity is still unknown. The aim of the present study was to find out whether TRI given repeatedly was able to induce adaptive changes in the dopaminergic and alpha1-adrenergic systems, demonstrated by us previously for various antidepressants. TRI was given to male Wistar rats and male Albino Swiss mice perorally twice daily for 14 days. In the acute experiment TRI (given i.p.) does not antagonize the reserpine hypothermia in mice and does not potentiate the 5-hydroxytryptophan head twitches in rats. TRI given repeatedly to rats increases the locomotor hyperactivity induced by d-amphetamine, quinpirole and (+)-7-hydroxy-dipropyloaminotetralin (dopamine D2 and D3 effects). The stereotypies induced by d-amphetamine or apomorphine are not potentiated by TRI. It increases the behaviour stimulation evoked by phenylephrine (given intraventricularly) in rats, evaluated in the open field test as well as the aggressiveness evoked by clonidine in mice, both these effects being mediated by an alpha1-adrenergic receptor. It may be concluded that, like other tricyclic antidepressants studied previously, TRI given repeatedly increases the responsiveness of brain dopamine D2 and D3 (locomotor activity but not stereotypy) as well as alpha1-adrenergic receptors to their agonists. A question arises whether the reuptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity.

Effect of EMD 57445, the selective sigma receptor ligand, on the turnover and release of dopamine.

EMD 57445 (1, 3 and 10 mg/kg, po), a selective sigma receptor ligand without an affinity to dopamine receptors, induced potent, dose-dependent increases in the tissue DOPAC and HVA levels in the rat brain cortex, nucleus accumbens and striatum. The extracellular DOPAC and HVA levels after EMD 57445 and (3 and 10 mg/kg, po) administrations, measured by microdialysis in the rat prefrontal cortex, were also increased, without significant effects on the outflow of dopamine.

Effect of local intracerebral administration of EMD 57445, a selective sigma receptor ligand, on the locomotor activity of the rat.

EMD 57445 is a new compound which has been characterized by high affinity for sigma receptor sites. It has not been shown to bind to any other receptors, including dopamine ones. However, hitherto existing data (behavioral as well as biochemical) have suggested that this drug exhibits functional antidopaminergic activity. Therefore, in the present study, the local cerebral administration of EMD 57445 has been used in order to better elucidate the actual site of action of this compound in the central nervous system. EMD 57445 given unilaterally into the nucleus accumbens, striatum and lateral ventricle decreases the locomotor activity of the rats, the effect being the most pronounced in the case of administration into the nucleus accumbens. Moreover, unilateral intraaccumbal injection of EMD 57445 significantly diminishes apomorphine (given peripherally)-induced hyperactivity. Local administration of EMD 57445 into the prefrontal cortex of the rats also attenuated the locomotor activity but the effect was statistically significant only after bilateral administration of the compound. Additionally, the lack of influence of EMD 57445, administered po, on the dopamine D1 and D2 receptor binding in the striatal membranes was observed in these studies. However, in limbic forebrain the density of D2 receptors decreased after the higher dose of EMD 57445. In conclusion, the results obtained in this paper support the hypothesis that EMD 57445 exerts antidopaminergic activity through indirect inhibition of dopamine system.

The behavioural effects of pramipexole, a novel dopamine receptor agonist.

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydroc hlo ride) is a novel dopamine D2 family receptor agonist with a predominant action on D2 autoreceptors and with some D3 vs. D2 receptor preference. The central behavioural effects of pramipexole given subcutaneously to rats (male Wistar) and mice (Albino Swiss) are presented in this paper. Used in low doses (0.001-0.1 mg/kg), pramipexole induced locomotor hypoactivity which was antagonized by a low dose of spiperone; at higher doses (0.3, 1 mg/kg) it evoked hyperactivity which was inhibited by haloperidol, sulpiride and clozapine, but not by SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride). Pramipexole (0.1-1.0 mg/kg) antagonized the akinesia induced by combined pretreatment with reserpine (5 mg/kg) and alpha-methyl-p-tyrosine (250 mg/kg). Pramipexole (0.1-1 mg/kg) potentiated the hyperkinetic effect of L-DOPA (L-3,4-dihydroxyphenylalanine) (50 and 200 mg/kg, together with benserazide, 50 mg/kg) in naive and monoamine-depleted (reserpine + alpha-methyl-p-tyrosine) rats. The higher doses of pramipexole (1 and 3 mg/kg) evoked stereotypy which was antagonized by pretreatment with sulpiride or clozapine. The catalepsy induced by haloperidol, spiperone or fluphenazine was antagonized by pramipexole (1-3 mg/kg). Pramipexole (1 mg/kg) induced hypothermia in mice, which was antagonized by sulpiride. The obtained results indicate that pramipexole: (i) at low doses stimulates the dopamine D2 presynaptic autoreceptors; (ii) at higher doses stimulates dopamine D2 postsynaptic receptors. An effect on the dopamine D3 receptor cannot be excluded. At low doses pramipexole may have antipsychotic activity, and at higher ones antiparkinsonian activity.