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PubMed1984

Inhibition of dihydropteridine reductase from human liver and rat striatal synaptosomes by apomorphine and its analogs.

Dihydropteridine reductase from human liver and rat striatal synaptosomes is noncompetitively inhibited by apomorphine and its analogs. The Ki or I50 values are in the range of 0.6 to 2.9 microM for R-(-)-apomorphine, R-(-)-and S-(+)-2, 10, 11-trihydroxyaporphine, R-(-)-norapomorphine, R-(-)-N-hydroxyethylnorapomorphine, R-(-)-2,10,11-trihydroxy-N-n-propylnoraporphine, R-(-)- and S-(+)-N-n-propylnorapomorphine, and R-(-)-N-chloroethylnorapomorphine; and 13 to 151 microM for R-(-)-2,11-dihydroxy- 10-methoxyaporphine, R-(-)-apocodeine, and S-(+)-bulbocapnine. Structure-activity studies reveal that 10,11-dihydroxy substitution of the D ring of apomorphine is required for the inhibitory effectiveness of these aporphines. Methylation of the 10-hydroxy group reduces, whereas the 2-hydroxyl substitution of the A ring enhances, their inhibitory potency. N-Alkylation variably affects the inhibitory potency of aporphines. In addition, S-(+)-enantiomers of aporphines and dopaminergic antagonists are equally potent as inhibitors of this enzyme, as compared to the corresponding R-(-)-enantiomers and other aporphine agonists. Haloperidol (0.1 to 10 microM) failed to reverse the enzyme inhibitory effectiveness of apomorphine when it was incubated with intact rat striatal synaptosomes prior to or after the addition of apomorphine (0.5 to 1 microM). These results suggest that the inhibitory effects of apomorphine and its analogs against this enzyme are not mediated by their stimulation of dopamine autoreceptors. Since dihydropteridine reductase is required in vivo for the hydroxylation of tyrosine, the inhibition of this enzyme by apomorphine may represent one of several mechanisms by which apomorphine inhibits catecholamine synthesis.

Animals↗
PubMed1981

Avoidance learning and mechanism of the protective effect of apomorphine against hypoxia.

We have analyzed a conditioned avoidance response (CAR) in rats, under both normoxia and hypobaric hypoxia (300 torr), to try to elucidate the mechanism of apomorphine's protective effect against hypoxia. The resistance to hypoxia is markedly increased by apomorphine (1 mg/kg i.p.) and, to a lesser degree, by an alpha-adrenergic pre-synaptic (yohimbine 1 mg/kg i.p.) or post-synaptic (phenoxybenzamine 1 mg/kg i.p.) blocker. The anti-hypoxic property of apomorphine is not altered when associated with domperidone (0.5 mg/kg i.p.), a peripheral blocker of the dopaminergic receptors. Resistance to hypoxia is decreased by propranolol (1 mg/kg i.p.) and pimozide (1 mg/kg i.p.). It is not modified by tylciprine (2 mg/kg i.p.) or by metergoline (2.5 mg/kg i.p.), a blocker of the 5-hydroxytryptamine (5 H T) receptors. However, the association of any of the above pharmacological agents with apomorphine destroys apomorphine's anti-hypoxic effect. There has even been shown a positive potentialisation ( i.e. an increase of the inhibitory effect) between apomorphine, hypoxia, and the added drug. This potentialisation is already noticeable under normoxia for the association of each of the drugs with apomorphine. Free alpha, beta adrenergic, cerebral dopaminergic, and serotoninergic receptors and an intact amine metabolic pathway therefore seem required for apomorphine to develop its anti-hypoxic activity.

Animals↗
PubMed1994

Pharmacokinetics of apomorphine in Parkinson's disease: plasma and cerebrospinal fluid levels in relation to motor responses.

In this study, we measured the relationship between plasma and cerebrospinal fluid (CSF) apomorphine levels and their clinical effects in two patients with Parkinson's disease (PD). After subcutaneous injection of apomorphine, serial samples of plasma and lumbal CSF were taken and serial scoring of motor responses was done using the Webster Rating Scale. The ratio of the highest level of apomorphine in CSF and plasma was 0.036 for patient A and 0.025 for patient B. The time lag between the highest level of apomorphine in plasma and CSF was 20 min for patient A and 10 min for patient B. Plasma levels of apomorphine correlated weakly with clinical motor responses. However, we could establish a highly strong correlation between apomorphine CSF levels and clinical motor responses: 0.93 and 0.89 for patients A and B, respectively. We conclude that a two-compartment pharmacokinetic model explains the clinical effects of apomorphine better than does a one-compartment model. In a two-compartment model, clinical effect can clearly be correlated to apomorphine levels in the central compartment.

Apomorphine↗
PubMed1977

Vasodilatation produced by apomorphine in the hindleg of the dog.

Apomorphine, injected into the dog femoral artery in doses of 0.6 microng or higher, produced a marked increase in femoral blood flow, without a change in blood pressure. No increase in flow was produced by comparable doses of dopamine or morphine. After sympathetic denervation or administration of phenoxybenzamine, the apomorphine vasodilatation was either abolished or greatly reduced. When the vascular tone in the denervated hindleg was restored by sympathetic nerve stimulation, the vasodilatory effect of apomorphine often re-established itself; this was not the cases when the vascular tone was restored by an infusion of noradrenaline. The apomorphine vasodilatation was not antagonized by propranolol or atropine. Mepyramine, in doses that antagonize histamine, often inhibited the apomorphine vasodilatation. Haloperidol, injected i.a., antagonized the apomorphine effect without changing the responses to isopropylnoradrenaline, acetylcholine, histamine and and nitroglycerin. Haloperidol blockade was overcome by increasing the dose of apomorphine. These results suggest that apomorphine dilates the femoral vasculature by an action on a "dopamine receptor." The possibility that the receptor is located on sympathetic nerve endings is discussed.

Animals↗
PubMed2001

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events.

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.

Aged↗
PubMed1997

Substantia nigra pars reticulata single unit activity in normal and 60HDA-lesioned rats: effects of intrastriatal apomorphine and subthalamic lesions.

The spontaneous activity and the response to intrastriatal application of apomorphine of substantia nigra pars reticulata (SNpr) single units was studied in four experimental groups of rats: (1) normal rats; (2) subthalamic nucleus (STN) lesioned rats; (3) rats bearing a 6-hydroxydopamine (60HDA) lesion; and (4) 60HDA-lesioned animals with an additional STN lesion. Thirty-eight percent of units from 60HDA-lesioned rats showed a bursting pattern of spontaneous activity, which was never found in normal rats. STN lesions had no effect on the spontaneous activity of SNpr units from normal rats, but reduced the percentage of burst units in 60HDA-lesioned animals. Intrastriatal apomorphine produced responses in 62% of SNpr units from normal rats and 85% of units from 60HDA-lesioned animals (P < 0.05). In addition, the modifications in the firing rate and in the coefficient of variation of the interspike intervals induced by intrastriatal apomorphine were significantly greater for the units isolated from 60HDA-lesioned rats. In particular, it was noted that all the burst units responded to apomorphine, showing the highest changes in firing rate and coefficient of variation. However, intrastriatal apomorphine did not always turn the activity of burst units into a more physiological pattern. STN lesions reduced the percentage of units responding to intrastriatal apomorphine in normal rats. In 60HDA-lesioned rats, STN lesions reduced the number of responsive units, and their change in mean firing rate and coefficient of variation. Our results show that the STN participates in the genesis of the bursting pattern of activity of SNpr units in 60HDA-lesioned rats, and that STN lesions can partially revert the abnormal spontaneous and apomorphine-induced responses of SNpr units in these animals.

Animals↗
PubMed1992

Impaired activation of the supplementary motor area in Parkinson's disease is reversed when akinesia is treated with apomorphine.

Using positron emission tomography (PET) we previously showed that activation of the putamen, supplementary motor area, and cingulate cortex is impaired in patients with Parkinson's disease (PD) when they are off treatment and perform volitional motor tasks. Evidence suggests that these areas are involved in the generation of internally cued movements in normal subjects. We have now studied the effect of the dopamine agonist apomorphine on cerebral activation when used to treat the akinesia of PD. Regional cerebral blood flow was measured using C15O2 PET in PD patients at rest and when performing paced joystick movements with the right hand in one of four freely chosen directions. All patients used apomorphine regularly, and were studied before treatment, while still "off" but receiving a subcutaneous apomorphine infusion, and when switched "on" with apomorphine. Significant increases in regional cerebral blood flow were determined using statistical parametric mapping. Under resting conditions apomorphine had no effect on focal or global cerebral blood flow. Seven patients with PD performed the motor task adequately in the "off" and "on" states. This group of subjects demonstrated impaired activation of the supplementary motor area and contralateral putamen in the "off" state. Activation of the supplementary motor area significantly improved when the akinesia was reversed with apomorphine. We conclude that the concomitant improvement of supplementary motor area activation and motor function in apomorphine-treated patients with PD provides further evidence for the role of this structure in generating motor programs.

Adult↗
PubMed1992

Ontogeny of apomorphine-induced stereotypy and its D1 and D2 receptor mediation in rats depleted of dopamine as neonates.

The ontogeny of apomorphine-induced stereotypy in rats treated with 6-OHDA (100 micrograms) or its vehicle on postnatal Day 3 was determined on Days 6, 21, or 60-90. Stereotypic sniffing and mouthing behavior were produced by apomorphine in control and DA-depleted animals as early as Day 6. Animals depleted of DA as neonates exhibited supersensitivity to these behavioral effects from Day 6 into adulthood. The relative contributions of D1 and D2 receptor activation to apomorphine-induced behaviors were determined by measuring the ability of specific D1 or D2 antagonists to block these effects in adults. Blockade of D1 receptors with SCH 23390 or D2 receptors with clebopride suppressed apomorphine-induced stereotypy in both vehicle- and 6-OHDA-treated rats. However, adults depleted of DA as neonates were less sensitive to the DA antagonists than were control rats. These results demonstrate that apomorphine-induced stereotypy is present as early as postnatal Day 6. Rats depleted of DA as neonates continue to exhibit these behaviors, even at lower doses of apomorphine than were necessary in control animals. Finally, coactivation of D1 and D2 receptors appears necessary for apomorphine-induced stereotypy in both groups of rats.

Aging↗
PubMed1981

Apomorphine: bioavailability and effect on stereotyped cage climbing in mice.

Plasma levels fo apomorphine and its conjugates were studied following intravenous, intraperitoneal, and oral administrations to mice. Following hydrolysis, apomorphine and its conjugates were assayed by high-performance liquid chromatography. The absolute bioavailability of apomorphine was 4%. A significant first-pass effect due to extensive conjugation in the liver was postulated based on calculated bioavailabilities and comparison of plasma levels of apomorphine and its conjugates following oral, intraperitoneal, and intravenous administrations. Apomorphine-induced stereotypical cage climbing in mice was investigated following administration of apomorphine by the three routes. Analysis of time-course data obtained from the cage-climbing experiments indicated an absolute bioavailability of 16% for apomorphine.

Administration, Oral↗
PubMed2004

Safety of entacapone and apomorphine coadministration in levodopa-treated Parkinson's disease patients: pharmacokinetic and pharmacodynamic results of a multicenter, double-blind, placebo-controlled, cross-over study.

We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three-sequence, three-period, crossover design. Patients were randomly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at baseline and study end. Pharmacokinetic parameters for apomorphine (C(max), AUC, t(max), t(1/2)) were unchanged by the administration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkinson's disease.

Antiparkinson Agents↗
PubMed1993

Apomorphine test for dopaminergic responsiveness: a dose assessment study.

The clinical diagnosis of idiopathic Parkinson's disease (IPD) remains difficult and is supported by a favorable response to levodopa, while failure to respond represents an exclusion criterion. Recently, the response to subcutaneous apomorphine has been suggested as a tool in predicting levodopa responsiveness in parkinsonian syndromes. We administered apomorphine at doses of 10, 50, and 100 micrograms/kg subcutaneously against placebo over two consecutive days in 37 patients with parkinsonism and evaluated the motor response for 90 min after each dose. Subsequently, we compared the motor response with the follow-up response to levodopa therapy and to a final diagnosis. Twenty-seven patients of 37 showed a positive response to apomorphine, and 10 had a negative response. All positive responses to the apomorphine test were obtained with 50 or 100 micrograms/kg doses. Because of the high frequency of side effects with the dose of 100 micrograms/kg, 50 micrograms/kg seems more useful. After an adequate period of levodopa/carbidopa therapy (12-month follow-up), 29 patients improved; 25 of these had demonstrated a positive response to the apomorphine test. The final diagnosis of IPD, made on the basis of an exhaustive clinical and neuroradiological evaluation and on the response to chronic levodopa therapy, was in good agreement with the response to the apomorphine test (predictivity of diagnosis, 86.4%). Our data indicate that subcutaneous apomorphine at the dose of 50 micrograms/kg is a useful tool in the differential diagnosis of parkinsonian syndromes.

Aged↗
PubMed1988

Conditioned behavioural responses to apomorphine: extinction and haloperidol-induced inhibition.

In previous studies it was established that stereotypies (sniffing, licking, gnawing) produced by apomorphine can be conditioned and after repeated pairings with defined conditioned stimuli (auditory, tactile + olfactory) these stereotypies can be observed in the presence of the conditioned stimuli alone. In the present experiments, the extinction of these conditioned stereotypies was studied in one series; in another series, the possible inhibition of conditioned stereotypies by the blocker of dopamine receptors, haloperidol, was measured. The rats were conditioned (or the controls pseudoconditioned, respectively) for either 3 or 10 days with 2.0 mg/kg s.c. apomorphine or 6 days with 0.5 mg/kg s.c. of the drug and by placing them into particular cages in the presence of an auditory and an olfactory stimulus. Under all these conditions, episodes of conditioned stereotypies were observed, when solvent + conditioned stimuli instead of apomorphine was applied 1 day after the last conditioning session (first session of extinction). The conditioned responses seemed to be on the highest level after conditioning with 2.0 mg/kg apomorphine 3 days, lower after conditioning with the same dose on 10 days, and even lower after conditioning for 6 days with 0.5 mg/kg. Under all these conditions, the stereotypies summed up and averaged for the total observation period of 60 min rapidly decreased during the extinction period, so that on day 4 of the extinction period, no further significant differences between conditioned and pseudoconditioned animals were observed, although a short initial period was still observed on the fourth day. On day 3 of extinction, not only an early, but also a late episode of conditioned stereotypies was manifest, interrupted by an almost silent period. The acute (unconditioned) stereotypies produced by 0.5 mg/kg s.c. apomorphine were almost completely suppressed by pretreatment with 0.1 mg/kg i.p. haloperidol. In contrast, the same dose of haloperidol produced a much less pronounced inhibition of conditioned stereotypies after conditioning with the same dose of apomorphine for 6 times. These results, together with previous findings, suggest that the conditioned behavioural effects are not due to an activation of dopaminergic mechanisms during conditioning with apomorphine.

Animals↗
PubMed1988

Haloperidol- and apomorphine-induced changes in pup searching behaviour of house mice.

Maternal pup searching behaviour of lactating house mice treated with apomorphine, haloperidol or saline was examined on a running board with a central depression as a nest. Pup searching was elicited by artificial ultrasonic stimuli: a female moved out from the nest either towards a 50 kHz tone (key stimulus) which is adequate to activate species specific pup searching behaviour or towards a 20 kHz tone (neutral stimulus), thus showing her preference for one of these stimuli. Under apomorphine (0.00625; 0.0125; 0.025 mg/kg) the females preferred the key stimulus. Nevertheless apomorphine (0.00625-0.025 mg/kg) prolonged response latencies and shortened the duration of pup searching. At the highest dose (0.05 mg/kg), apomorphine induced stereotyped sniffing. Haloperidol (0.025; 0.05; 0.1 mg/kg) had opposite effects to apomorphine: it lowered the threshold for elicitation, shortened response latencies and prolonged the duration of pup searching. Females treated with haloperidol (0.025-0.1 mg/kg) did not prefer the key stimulus. Changes in response elicitation and in the performance of pup searching induced by apomorphine and haloperidol, respectively, were assumed to be due to i) a reduced and an increased responsiveness to external stimuli respectively, ii) an enhanced and a reduced tendency for response switching respectively, and iii) a preference for spontaneous behaviour in apomorphine-treated females, with an increased dependence on exteroceptive stimuli following haloperidol.

Acoustic Stimulation↗
PubMed1982

Apomorphine contracts and relaxes circular smooth muscle of guinea-pig stomach via action on adrenoceptor mechanisms.

Nanomolar concentrations of apomorphine caused contractions of the circular smooth muscle from the body region of the guinea-pig stomach, the response showing rapid tachyphylaxis. These contractions were antagonised by yohimbine but not by prazosin, haloperidol, propranolol or methysergide. Higher concentrations of apomorphine caused concentration-related relaxations of the stomach body which were not subject to tachyphylaxis. These were antagonised by propranolol but not by prazosin, yohimbine or haloperidol. Dopamine-induced contractions of the circular smooth muscle from the stomach body were antagonised by apomorphine in nanomolar concentrations; acetylcholine-induced contractions and isoprenaline-, dopamine- and phenylephrine-induced relaxations were unaffected by apomorphine. Thus, it is concluded that the contraction of circular smooth muscle from the stomach body to apomorphine is mediated via an adrenoceptor with characteristics of the alpha2-type, and that a partial agonist-antagonist action prevents subsequent contractile responses to apomorphine and dopamine. Relaxation caused only at higher concentrations of apomorphine is mediated via an adrenoceptor with characteristics of the beta-type.

Acetylcholine↗
PubMed1986

Inhibition of noradrenergic neurotransmission by apomorphine and pergolide in the in situ autoperfused rat renal and superior mesenteric vascular beds.

In vitro studies have provided evidence that presynaptic dopamine receptors are present in the rat renal and superior mesenteric vascular beds. To confirm this in vivo, the effects of locally administered apomorphine and pergolide were studied in the in situ autoperfused renal and superior mesenteric vascular beds. Local infusion of apomorphine (1 microgram X kg-1 X min-1 for 5 min) or pergolide (1 microgram X kg-1 X min-1 for 5 min) into either the renal or the superior mesenteric artery had no effect on perfusion pressure per se. In the renal vascular bed, the pressure response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) was reduced to 49.8 +/- 4.8% by apomorphine and to 54.8 +/- 2.7% by pergolide; in the mesenteric vascular bed, apomorphine reduced the pressure response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) to 53.8 +/- 2.9, pergolide to 52.0 +/- 1.8%. Increases of perfusion pressure in the renal and in the mesenteric vascular bed induced by locally administered noradrenaline were not modified by apomorphine or pergolide. In both vascular beds, the inhibition of the stimulation-evoked pressure responses by apomorphine or pergolide was completely antagonized by local administration of the dopamine receptor antagonist haloperidol in a dose (1 microgram X kg-1) which did not influence the inhibitory effect of the alpha 2-adrenoceptor agonist UK-14,304; the alpha 2-adrenoceptor antagonist rauwolscine, in a dose (100 micrograms X kg-1) which completely antagonized the inhibitory effect of UK-14,304, did not antagonize the inhibitory effects of apomorphine and pergolide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Discriminative stimulus effects of a low dose of apomorphine in the rat.

The discriminative stimulus (DS) effect of apomorphine was investigated in rats trained in a two-lever, food-reinforcement procedure. Rats were given subcutaneous injections of saline or 0.1 mg/kg apomorphine HCl, 15 min before training sessions. The training dose of apomorphine was chosen to activate dopamine autoreceptors selectively. Stimulus generalization studies demonstrated that the DS effects generalized completely to other direct-acting dopaminergic agonists such as N-n-propylnorapomorphine (NPNA), pergolide, lergotrile, and bromocriptine. The indirect-acting dopamine agonists, (+)amphetamine, cocaine, and methylphenidate produced predominantly saline-appropriate lever responses. The DS effect of apomorphine at the training dose was incompletely antagonized by haloperidol or metoclopramide. The dopaminergic antagonists tested, however, also partially generalized to apomorphine. Both enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) produced apomorphine-appropriate lever choice with the (-) enantiomer being slightly more potent. The discriminative property of this (0.1 mg/kg) dose of apomorphine has characteristics consistent with selective dopamine autoreceptor activation.

Animals↗
PubMed1989

Dopamine D-2 antagonists reverse apomorphine-induced decreased water intake in the rat: prediction of antipsychotic drugs with few extrapyramidal side-effects?

Water intake in water deprived rats was decreased by administration of a low dose of apomorphine (0.1 mg/kg s.c.). This dose is too low to induce hyperactivity and stereotypies. Four different dopamine (DA) D-2 antagonists were used to counteract this effect of apomorphine; haloperidol [an antipsychotic inducing extrapyramidal side-effects (EPS)], sulpiride (an antipsychotic inducing less EPS than haloperidol), metoclopramide (not used as an antipsychotic but inducing EPS) and domperidone (not passing through the blood brain barrier). Domperidone did not counteract the apomorphine effect, indicating a central mechanism of action for apomorphine. Metoclopramide did not counteract the apomorphine effect and, in higher doses, water intake was even further reduced. Sulpiride completely counteracted the apomorphine effect but, in higher doses, did not by itself reduce water intake. Haloperidol counteracted the apomorphine effect in a small dose-range and caused a further reduction in the water intake when given in high doses. The results can be explained by the existence of two subpopulations of D-2 receptors related to different functions. The model described may be used in screening experiments aimed at finding new antipsychotic drugs with a low incidence of EPS.

Animals↗
PubMed1990

On the possible involvement of glutamate receptors in conditioning of behavioural effects of apomorphine.

It was shown previously that behavioural effects of apomorphine (locomotor activation and stereotyped behaviour) can be conditioned when they are associated with well-defined environmental stimuli. In the present study, the hypothesis was tested that glutamatergic mechanisms play an important role either in formation of conditioned responses to apomorphine or in the expression of previously established conditioned responses. For this purpose, two blockers of glutamate receptors were applied, either MK-801 (dizocilpine), a non-competitive, but selective blocker of NMDA-type receptors or MLV-6976, a non-selective blocker of glutamate receptors. MK-801 produced some locomotor activation by itself in a dose-dependent way (0.125-0.50 mg/kg ip). The locomotor activation produced by 0.25 mg/kg could not be conditioned. When rats were conditioned 9 times with 2 mg/kg apomorphine after pretreatment with 0.25 mg/kg of MK-801, this pretreatment did not prevent the development of apomorphine-conditioned locomotor activity or stereotypies which appeared when the rats were treated with saline in presence of the conditioned stimuli. Similar results were obtained when rats were conditioned 7 times with the same dose of apomorphine after pretreatment with 20 mg/kg ip MLV-6976, which drug did not induce any visible alterations in motility by itself. When rats were conditioned 7 times with 2 mg/kg apomorphine alone and tested with MK-801 (0.25 mg/kg) in the presence of the conditioned stimuli, neither locomotor activity nor stereotypies appeared as conditioned responses. When rats were conditioned with the same dose of apomorphine alone and tested with MLV-6976 (20 mg/kg ip), stereotypies did not appear as conditioned responses, but some locomotor activity occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗