Sedation and sleep induced by high doses of apomorphine after blockade of D-1 receptors by SCH 23390

The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.     

Effect of apomorphine on oxytocin concentrations in different brain areas and plasma of male rats

The effect of the dopamine (DA) agonist, apomorphine, on oxytocin concentrations in the hypothalamus, hippocampus, septum and plasma was studied in male rats. Apomorphine dose dependently increased the concentration of oxytocin in the plasma and hippocampus, the minimal effective dose being 80 micrograms/kg s.c., which induced a 65% increase in plasma and a 45% increase in the hippocampus. The maximal effect (210 and 125% above controls) was induced with 240 micrograms/kg s.c. In contrast, there was a significant decrease (32%) in the oxytocin concentration in the hypothalamus, but only after the highest doses of apomorphine, while no change was found in the septum. The apomorphine effect in the hippocampus and hypothalamus was prevented by the mixed DA D-1/D-2 receptor blocker, haloperidol (0.3 mg/kg i.p.), and by the DA D-2 receptor blocker, (-)-sulpiride (20 mg/kg i.p.), but not by the DA D-1 receptor blocker, SCH 23390 (0.2 mg/kg s.c.). Similar effects were found in plasma, although SCH 23390 inhibited the apomorphine effect by 45%. Our results suggest that apomorphine stimulates oxytocinergic transmission in male rats and provide biochemical support for the hypothesis that a DA-oxytocin link exists in the central nervous system.     

Influences of dopamine receptors on chewing behaviour in rats.

1. Intraperitoneal (i.p.) injection of different doses of pilocarpine induced purposeless chewing in rats. Physostigmine (i.p.), but not neostigmine (i.p.) also induced chewing behaviour. 2. Subcutaneous (s.c.) pretreatment of animals with the D-1 receptor blocker SCH 23390 decreased the number of chews induced by pilocarpine. 3. The D-2 dopamine antagonist sulpiride (i.p.) and anticholinergic atropine (i.p.) pretreatment also decreased the frequency of chews induced by the drug. 4. The response induced by pilocarpine (1 mg/kg i.p.) also was dose-dependently decreased in animals pretreated with apomorphine (0.25-1 mg/kg s.c.). 5. Administration of low doses of apomorphine (s.c.) also induced chewing, which was decreased with increasing the doses of the drug. 6. Chewing-induced by apomorphine was decreased by sulpiride or atropine and increased by SCH 23390 pretreatment. 7. Single administration of D-2 dopamine agonist bromocriptine also showed a slight but significant purposeless chewing, which was decreased by sulpiride pretreatment. 8. Single administration of D-2 agonist quinpirole, D-1 agonist SKF 38393 or D-1 antagonist SCH 23390, but not sulpiride caused a slight chewing. 9. It may be concluded that D-1 or D-2 activation exert opposite influences on chewing behaviour in rats, although to prove this effect more elucidation is needed.     

Effect of the dopamine D-1 antagonist SCH 23390 on rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats

The experiments concerned the effects of the D-1 dopamine antagonist SCH 23390 on the rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats. SCH 23390 dose dependently inhibited the rotational behaviour induced by apomorphine. A significant inhibitory effect was obtained after 0.05 mg/kg s.c. of SCH 23390, which involved a change of the typical two-peak pattern of rotation induced by apomorphine. While the first peak of rotation was not significantly modified, the last peak of rotation induced by apomorphine was inhibited in a dose-dependent manner. No significant inhibition of the total rotation induced by pergolide was observed after SCH 23390 pretreatment. SCH 23390 seemed to enhance the duration of the rotation induced by pergolide, resulting in an increase in the total number of turns. However, the intensity of the maximal peak of rotation induced by pergolide was significantly inhibited after 5.0 mg/kg s.c. of SCH 23390. Comparison of the potency with which SCH 23390 inhibited the apomorphine- and pergolide-induced maximal peaks of rotation reveals that SCH 23390 was approximately 100 times more potent in inhibiting the apomorphine than the pergolide response. The results, compared with those in our previous report, show that the D-2 dopamine antagonist sulpiride was 1000 times more potent in inhibiting the pergolide than the apomorphine rotation. The present results support the hypothesis that apomorphine and pergolide induce rotation in 6-hydroxy-dopamine denervated rats by differential actions on D-1 and D-2 receptor sites.     

Catalepsy induced by SCH 23390 in rats

The ability of SCH 23390 as compared to haloperidol to produce catalepsy in rats was evaluated in three tests for catalepsy. SCH 23390 produced catalepsy in all three tests with ED50 (mg/kg s.c.) of 0.017 on the vertical grid, 0.023 on the horizontal bar and 0.038 on the 'four corks'. Haloperidol produced catalepsy with ED50 (mg/kg s.c.) of 0.048 on the vertical grid, 0.042 on the horizontal bar and 0.065 on the four corks. Catalepsy by SCH 23390 and by haloperidol was prevented by scopolamine and potentiated by alpha-methyl-p-tyrosine pretreatment. Catalepsy induced by SCH 23390 was also prevented by specific D-2 receptor agonists such as pergolide, lisuride and bromocriptine but not by the D-1 receptor agonist SKF 38393. The results demonstrate that SCH 23390 is potently cataleptogenic and that the catalepsy it produces has a pharmacologic profile typical of that produced by potent and specific D-2 antagonists.     

Nicotine-induced grooming: a possible dopaminergic and/or cholinergic mechanism

The ability of nicotine, to induce grooming in rats was studied. Grooming was induced by i.p. injection of different doses (0.0675-0.5 mg/kg) of nicotine to rats. The effect was dose-dependent. However, the response was decreased with increasing doses of the drug from 0.25-0.5 mg/kg. Administration of the dopamine (DA) D1/D2 receptor agonist apomorphine (0.025-5 mg/kg, i.p.) also caused grooming in a dose-dependent manner. High doses of apomorphine (0.1-0.5 mg/kg, i.p.) also induced a lower degree of response. Combination of a low dose of nicotine (0.0675 mg/kg) with different doses of apomorphine did not show any interaction. However, there was an interaction between a high dose of nicotine and apomorphine. Thus, combination of a higher dose of nicotine (0.125 mg/kg) with apomorphine, reduced apomorphine-induced grooming. The muscarinic receptor antagonist atropine (5 and 10 mg/kg), peripheral nicotinic receptor antagonist hexamethonium (5 and 10 mg/kg), central nicotinic receptor antagonist mecamylamine (1 and 3 mg/kg) and D1 DA receptor antagonist SCH23390 (0.05 and 0.1 mg/kg) all decreased the response to nicotine. Atropine, mecamylamine and SCH23390 by themselves reduced spontaneous grooming. It is concluded that nicotine elicits grooming indirectly through a possible D1 dopaminergic mechanism. However, muscarinic and nicotinic cholinergic mechanism(s) may be involved.     

The D-1 antagonist SCH 23390 stimulates while the D-1 agonist SKF 38393 fails to affect dopamine release in the dorsal caudate of freely moving rats

SCH 23390, from doses of 0.012 mg/kg s.c., dose dependently stimulated the release of dopamine (DA) and the output of its metabolites, dihydroxyphenylacetic acid and homovanillic acid, in the dorsal caudate of freely moving rats implanted with transcerebral dialysis fibers. SKF 38393 failed to modify DA release and metabolism at doses of 5, 10 and 25 mg/kg s.c. but at 25 mg/kg s.c. it abolished the effect of 0.025 mg/kg of SCH 23390. Administration of gamma-butyrolactone (700 mg/kg s.c.), which blocks the firing of DA neurons, prevented the effect of 0.050 mg/kg s.c. SCH 23390. The results indicate that D-1 receptors control the release of DA, probably through stimulation of the firing of DA neurons.     

Antagonism of apomorphine-induced yawning by SCH 23390: Evidence against the autoreceptor hypothesis

The ability of apomorphine to induce yawning (YWG) in normal and reserpinized rats and its interaction with SCH 23390, a potent and specific D-1 receptor antagonist, was studied. Apomorphine was more potent in inducing YWG in reserpine-pretreated as compared to control rats. SCH 23390, in low doses (0.05 mg/kg SC), was able to significantly reduce the YWG evoked by apomorphine both in control and in reserpine-pretreated rats. The results indicate that D-1 receptors contribute to YWG elicited by apomorphine and contradict the idea that this effect is mediated by DA autoreceptors.     

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.     

D1 receptor blockade stereospecifically impairs the acquisition of drug-conditioned place preference and place aversion

The motivational effects of dopamine (DA) D1 receptor blockade and its influence on the motivational effects of amphetamine (1.0mg/kg s.c.), morphine (1.0mg/kg s.c.) and lithium (40mg/kg s.c.) were studied in a place-conditioning paradigm. Drugs tested were two potent D1 receptor antagonists, SCH 23390 and SCH 39166, that differ in the poor affinity of the latter for 5-HT(2) receptors, and SCH 23388, the inactive enantiomer of SCH 23390. SCH 23390 and SCH 39166, at low doses (12.5 and 25μg/kg s.c.), paired for 30min with one compartment, elicited place aversion. Higher doses of the D1 antagonists or pairing for 60min with one compartment failed to elicit place aversion. SCH 39166 (50μg/kg s.c.) paired with both compartments completely prevented the place-aversion elicited by SCH 23390 (12.5μg/kg s.c.). SCH 23390 and SCH 39166 at low doses (12.5 and 25μg/kg s.c. respectively), paired with both compartments, abolished amphetamine-induced place preference. The D1 antagonists also impaired the acquisition of morphine-induced place preference and lithium-induced place aversion but only at higher doses (50 and 100μg/kg s.c.). These effects were stereospecific as the inactive enantiomer SCH 23388, up to a dose of 500μg/kg s.c. failed to impair the acquisition of amphetamine and morphine-induced place preference. It is concluded that DA plays a dual role in motivation: one role is that of assigning motivational valence to stimuli in relation to changes in DA transmission; another role of DA relates to the learning process involved in the acquisition of positive as well as negative incentive properties by otherwise neutral stimuli (incentive learning).     

Behavioural stimulation is induced by separate dopamine D-1 and D-2 receptor sites in reserpine-pretreated but not in normal rats

The dopamine (DA) D-1 agonist SK&F 38393 as well as the D-2 agonist pergolide and the mixed D-1/D-2 agonist apomorphine induced strong hypermotility and oral stereotypy in rats pretreated with a daily dose of reserpine for 2 and in particular for 4 days (3 and 5 injections, respectively). SK&F 38393 had no behavioural stimulant effect in saline-pretreated rats, whereas pergolide and apomorphine produced stimulation, although only after higher doses. Agonists at 5-HT and muscarinic receptors and at alpha 1-adrenoceptors were ineffective in reserpine-pretreated rats whereas the alpha 2-adrenoceptor agonist, clonidine, and the muscarinic antagonist, scopolamine, produced weak locomotor stimulation. The hypermotility induced by SK&F 38393 in reserpinized rats was blocked by pretreatment with the DA D-1 antagonists, SCH 23390 and SK&F 83566c, whereas the DA D-2 antagonists, YM 09151-2, clebopride and spiroperidol were weak or ineffective. In contrast pergolide-induced hypermotility was blocked by low doses of the D-2 antagonists but was weakly or not influenced by the D-1 antagonists. Selectivity ratios between drug potencies in the two models ranged from 65 to more than 600. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, blocked the effect of both SK&F 38393 and pergolide. The alpha 1-adrenoceptor antagonist, prazosin, and the 5-HT2 receptor antagonist, ketanserin, did not modify the effect of SK&F 38393 or pergolide. Stereotyped behaviour induced by a high pergolide dose in normal rats was, in contrast to the effect in reserpinized rats, blocked by low doses of either SCH 23390 or spiroperidol. Finally, the hypermotility induced by apomorphine in reserpinized rats was markedly antagonized by both SCH 23390 and spiroperidol. The results suggest a close relation between D-1 and D-2 receptor sites in normal rats. After prolonged reserpine treatment, the D-1 agonist acquires full DA agonist efficacy. Furthermore, behavioural stimulation under these conditions is mediated by two separate D-1 and D-2 receptor sites which can be manipulated independently by antagonists. The mechanism by which this phenomenon occurs is unknown but the adaptational changes show close similarities to those observed after 6-hydroxyDA-induced denervation.     

The rise of body temperature induced by the stimulation of dopamine D1 receptors is increased in acutely reserpinized mice

In naive mice, the selective D1 agonist, SK&F 38393 (7.5-30 mg/kg s.c.), induced a significant rise of body temperature (0.5-1 degree C) which was antagonized by SCH 23390 (100 micrograms/kg s.c.) and by flupenthixol (0.4 mg/kg i.p.). In mice treated with reserpine (5 mg/kg s.c.) 18 h before testing, which on its own caused intense hypothermia (10-12 degrees C), SK&F 38393 (1.87-30 mg/kg s.c.) induced a dose-dependent and more marked rise of body temperature (5-7 degrees C). Similarly, SK&F 38393 (30 mg/kg s.c.) partially prevented reserpine-induced hypothermia. The central origin of the SK&F 38393 effects in reserpine-treated mice is indicated by the rise of body temperature induced by the i.c.v. administration of the drug (12.5-50 micrograms per mice). The SK&F 38393-induced rise of body temperature in acutely reserpinized mice was antagonized by SCH 23390 (50-200 micrograms/kg s.c.), clozapine (1.87-30 mg/kg i.p.) or chlorpromazine (2-32 mg/kg i.p.) but not by metoclopramide (25 or 100 mg/kg i.p.) or amisulpride (12.5 or 50 mg/kg). In naive mice, apomorphine (1 mg/kg s.c.) or LY 171555 (0.4 mg/kg s.c.) induced hypothermia which was antagonized by amisulpride (12.5 mg/kg i.p.); a transiently increased body temperature was even measured 30 min after apomorphine injection in amisulpride-treated mice. Apomorphine (1 mg/kg s.c.) induced a rise of body temperature in acutely reserpinized mice which was significantly reduced by SCH 23390 (50 and 200 micrograms/kg s.c.) and significantly increased by amisulpride (12.5 and 50 mg/kg i.p.). These data suggest that pharmacologically different dopamine receptor subtypes mediate different effects on body temperature in mice: D1 dopamine receptors mediate a rise of body temperature which is increased in hypothermic reserpinized animals and dopamine receptors of the D4 subtype mediate the decrease of body temperature in naive mice.     

Ontogeny of locomotor activity and grooming in the young rat: role of dopamine D1 and D2 receptors

Locomotor activity and grooming were assessed in 11- and 17-day-old rat pups after treatment with selective dopamine (DA) D-1 and D-2 agonists (SKF 38393 and quinpirole, respectively) and antagonists (SCH 23390 and sulpiride, respectively). Quinpirole enhanced the locomotor activity of both the 11- and 17-day-olds, effects antagonized by either SCH 23390 or sulpiride. Drug-induced increases in grooming were apparent only after high doses (30.0 mg/kg i.p.) of SKF 38393 (11- and 17-day-olds) or when SKF 38393 (15.0 mg/kg i.p.) was given in conjunction with sulpiride (11-day-olds). In general, these results suggest that challenge with selective DA agonists and antagonists induces patterns of responding which are similar to those typically observed in adult rats. Moreover, these results indicate that rat pups, like adults, require a functioning DA D-1 receptor system for the expression of DA D-2-mediated activity.     

Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo

Summary The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2).Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg).Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.We conclude from these data that DA release in rat striatum is autoregulated by independent D-1 and D-2 receptor-linked mechanisms. In contrast, the level of DA metabolism is controlled by a D-2 receptor-coupled mechanism which can be influenced by the D-1 receptor. This study provides further evidence that DA release and DA synthesis/metabolism are able to change independent of each other.     

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.     

SCH 23390 and its S-enantiomer stereoselectively prevent EEG and behavioral activation induced by dopamine agonists in the rabbit

The selective D-1 dopamine antagonist SCH 23390 (R-enantiomer) and its unselective S-enantiomer (SCH 23388) were compared for their ability to prevent EEG and behavioral activation induced by the dopamine receptor agonists SKF 38393, apomorphine and LY 171555 in the rabbit. SCH 23390, at very low doses (0.003 mg/kg IV), inhibited EEG responses elicited by SKF 38393 and apomorphine, while the S-enantiomer displayed similar effects at doses at least 300-fold higher (1-3 mg/kg IV). Both isomers were approximately equipotent in preventing behavioral excitation caused by the D-2 agonist LY 171555. The dose of SCH 23390 interacting with LY 171555 was at least 100-fold higher than that effective for D-1 mediated responses. Conversely, the doses of S-enantiomer which prevented the stimulating effects induced by the different dopamine agonists were similar. The data demonstrate the stereoselectivity of the R-isomer SCH 23390 for blockade of D-1 receptors in vivo and provide evidence for the sensitivity of the EEG models in studying D-1 mediated responses.     

Hypothermia in mice: D2 dopamine receptor mediation and absence of spare receptors

The nonselective dopamine (DA) receptor agonists R(-)apomorphine (APO) and R(-)-N-n-propylnorapomorphine (NPA) elicited dose- and time-dependent hypothermia in mice with ED50 values of 300 and 18 micrograms/kg, respectively. The selective D2 agonist quinpirole (LY 171555) also elicited dose-dependent hypothermia, whereas the selective D1 agonist SKF 38393 had no effect. The selective D1 and D2 antagonists SCH 23390 (1 mg/kg) and sulpiride (200 mg/kg), respectively, did not significantly alter body temperature. The hypothermic effect of a maximal dose of NPA (0.2 mg/kg) was not blocked by SCH 23390 (1 mg/kg) but was significantly attenuated (p less than 0.001) by pretreatment with sulpiride (200 mg/kg). Pretreatment with sulpiride (200 mg/kg) produced a parallel, 40-fold shift to the right of the dose-response curve for NPA. Partial, irreversible DA receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (2 mg/kg) reduced the maximal hypothermic effect of NPA (to 49% of control) without altering its ED50. Analysis of the data indicated a linear relationship between DA receptor occupancy and hypothermic response. The results demonstrate that DA agonist-induced hypothermia in mice is mediated by D2 receptors and that there is no receptor reserved for this response.     

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)     

The effect of acute and chronic treatment with SCH 23390 on the spontaneous activity of midbrain dopamine neurons

The effect of acute and chronic administration of SCH 23390 on the spontaneous activity of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) was studied. Two groups of rats were given an acute subcutaneous (s.c.) injection of the specific D-1 DA receptor block SCH 23390 (0.5 or 1.0 mg/kg). In four separate chronic experiments, SCH 23390 was administered repeatedly for 21 days either s.c. (0.5 or 1 mg/kg) or orally (5 or 10 mg/kg). No change in the number of spontaneously active DA neurons was found either after acute or chronic treatment with SCH 23390. On the other hand, chronic (21 days) haloperidol (0.5 mg/kg per os) produced a marked reduction in the number of spontaneously active DA neurons both in the SNc and VTA, a finding previously shown to be due to the development of depolarization block. It is concluded that chronic D-1 DA receptor blockade, may not be involved in the development of depolarization block produced by chronic treatment with antipsychotic drugs.     

Effect of chronic treatment with SCH 23390 and haloperidol on spontaneous activity of dopamine neurones in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in rats

The effect of chronic treatment (21 days s.c.) with SCH 23390 and haloperidol on spontaneously active DA neurones in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) was studied in rats by means of single unit recording techniques. The specific DA D-1 receptor antagonist SCH 23390 was injected twice daily in one of the following doses: 0.06, 0.23, 0.46 or 0.90 mumol/kg. SCH 23390 decreased the number of spontaneously active neurones in SNC and VTA to the same extent. The DA D-2 receptor antagonist haloperidol was injected once daily in one of the following doses: 0.05, 0.21 or 1.7 mumol/kg and induced a decrease in the number of spontaneously active DA neurones in SNC and VTA. These results suggest that SCH 23390 has a profile similar to that of haloperidol and that SCH 23390 has clinical antipsychotic activity but also induces extrapyramidal side-effects.