Role of central histaminergic system in lorazepam withdrawal syndrome in rats.

Effects of histaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with the food in the following dose schedule (in mg/kg given daily x days): 10 x 4, 20 x 4, 40 x 4, 80 x 4, and 120 x 7. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA), and audiogenic seizures. During the withdrawal period, the rats were divided into groups of 10 each. Control-withdrawal group did not receive any drug. The drugs (in mg/kg administered intramuscularly)--L-histidine (50), histamine-N-methyl (2), promethazine (10), pheniramine (10), astemizole (10), and thioperamide (1)--were given separately in other groups daily during the withdrawal period. The withdrawal signs in control group were hyperkinesia, hyperaggression, and audiogenic seizures. L-Histidine, precursor of histamine, and thioperamide, antagonist of H3 receptor, potentiated hyperkinesia, hyperaggression, and audiogenic seizures. Histamine-N-methyl, agonist of H3 receptor, and H1 receptor antagonists, promethazine and pheniramine, blocked all the withdrawal signs. Astemizole, a peripheral antagonist of H1 receptor, could not affect any withdrawal sign. It may be concluded that histamine H1 receptors are facilitatory and H3 receptors are inhibitory for benzodiazepine (BZD) withdrawal syndrome.     

Evaluation of inhibitory effect of diphenhydramine on benzodiazepine dependence in rats

Effect of diphenhydramine was investigated on withdrawal signs in lorazepam dependent rats. Physical dependence was produced by giving lorazepam admixed with the food in the following dose schedule: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 (mg/kg, daily x days). The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), body temperature, reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. Diphenhydramine was administered orally in the dose schedules of once daily (10, 20 and 40 mg/kg) and twice daily (5, 10 and 20 mg/kg) in separate groups during the withdrawal period. The withdrawal signs observed in control group (without diphenhydramine) were hyperkinesia, hyperthermia, hyperaggression and audiogenic seizures. Hyperkinesia and hyperthermia were blocked in all the groups of diphenhydramine-treated rats. FSA was inhibited only by diphenhydramine (10 and 20 mg/kg) given twice daily. Audiogenic seizures were completely blocked by once daily (20 and 40 mg/kg) as well as twice daily (20 mg/kg) doses of diphenhydramine. It may be concluded that diphenhydramine exerts a protective effects on benzodiazepine withdrawal syndrome.     

Morphine withdrawal syndrome: involvement of the dopaminergic system in prepubertal male and female mice

Morphine (MOR) withdrawal signs are more marked in males than in females. Considering that the influence of the dopaminergic system on these differences is unclear, we analyzed dopamine (DA) and dihydroxyphenylacetic-acid (DOPAC) brain levels during naloxone (NAL)-precipitated withdrawal as well as the involvement of D(1) and D(2) receptors in the expression of MOR withdrawal in either sex. Prepubertal Swiss-Webster mice received MOR (2 mg/kg, i.p.) twice daily for 9 days. On the tenth day, dependent animals received NAL (6 mg/kg, i.p.) after MOR and were sacrificed 30 min later. DA and DOPAC concentrations were determined in different brain areas using HPLC with electrochemical detection. Other pool of mice received either a D(1) (SCH 23390; 0.2 mg/kg, i.p.) or D(2) (raclopride; 0.3 mg/kg, i.p.) receptor antagonist before NAL and withdrawal signs were evaluated. DA and DOPAC levels only decreased in striatum and cortex of withdrawn males. Conversely, both DA receptor antagonists decreased the expression of MOR withdrawal signs in either sex. The neurochemical sex differences described here could partially explain the behavioral sex differences observed during MOR withdrawal. Additionally, SCH-23390 and raclopride effects suggest an important role of both DA receptors in the expression of MOR withdrawal in males and females.     

Locomotor stimulation by l-Dopa: Relative importance of noradrenaline receptor activation

The importance of brain noradrenaline synthesis and receptor activation for the hyperkinesia induced by carbidopa plus l-Dopa in reserpine-treated or normal mice was analyzed in four different models. After pretratment with reserpine and the monoamine oxidase inhibitor nialamide, the hyperkinesia induced by l-Dopa (25 mg/kg i.p.) was partly mediated via stimulation of noradrenaline receptors since it was significantly antagonized by the noradrenaline receptor-blocking agent phenoxybenzamine. Treatment with reserpine plus l-Dopa (125 mg/kg i.p.) produced an increase in motor activity probably due to stimulation of dopamine receptors since it was not accompanied by an accumulation of noradrenaline and it was not inhibited by phenoxybenzamine. The hyperkinesia following treatment with reserpine and a higher dose of l-Dopa (250 mg/kg i.p.) was probably due to stimulation of both dopamine and noradrenaline receptors since the dopamine--hydroxylase inhibitor FLA-63 partly reduced the effect of l-Dopa. Phenoxybenzamine potentiated the motor stimulation by l-Dopa (125 mg/kg i.p.) in mice not pretreated with reserpine, perhaps depending on a slight enhancement of the net accumulation of brain dopamine. Thus, noradrenaline receptor activation is of importance for the l-Dopa-induced hyperkinesia, at least after high doses or after monoamine oxidase inhibition.     

Clozapine decreases neuropeptide Y-like immunoreactivity and neuropeptide Y mRNA levels in rat nucleus accumbens.

The aim of this study was to evaluate the effect of acute, subchronic (14 days) and chronic (28 days) intraperitoneal (i.p.) administration of clozapine (10 or 25 mg/kg) on neuropeptide Y (NPY) system activity in the nucleus accumbens of the rat. NPY-like immunoreactivity (NPY-LI) decreased 24 h after subchronic clozapine while NPY mRNA after both acute and subchronic clozapine treatment. NPY-LI levels were also reduced 8 days after cessation of chronic lower-dose treatment. Subchronic (14 days) administration of the 5-HT2A antagonist ketanserin (1 mg/kg i.p.) or the dopamine D2/D3 antagonist (+/-) sulpiride (100 mg/kg i.p.) reduced NPY-LI levels, whereas the dopamine D1-like antagonist SCH 23390 (0.5 mg/kg i.p.), dopamine D4 antagonist L-745,870 (1 mg/kg per os), and alpha1-adrenergic antagonist prazosin (0.2 mg/kg i.p.) had no effect. There were no significant differences between the ketanserin-induced decrease in NPY-LI levels and the effects of the following two-drug combinations: ketanserin and SCH 23390, ketanserin and L-745,870, and ketanserin and prazosin. The study has shown that clozapine reduces NPY system activity in the rat nucleus accumbens. It seems that the action of clozapine is partly mediated by blockade of 5-HT2A and D2/D3 dopaminergic receptors.     

Precipitated and spontaneous withdrawal in baboons after chronic dosing with lorazepam and CGS 9896

In order to assess the ability of lorazepam (20 mg/kg/day) and CGS 9896 (100 mg/kg/day) to produce physical-dependence in baboons, the occurrence of Ro 15-1788 precipitated withdrawal signs and spontaneous withdrawal signs were determined. Lorazepam-treated baboons displayed precipitated withdrawal signs following the administration of Ro 15-1788 (5 mg/kg), and displayed mild to moderate spontaneous withdrawal signs following termination of drug treatment. CGS 9896-treated baboons did not display Ro 15-1788 precipitated withdrawal signs and displayed either no or only mild spontaneous withdrawal signs.     

Precipitated diazepam withdrawal in baboons: effects of dose and duration of diazepam exposure

Baboons were exposed to diazepam via continuous injection at doses of 0.125-20.0 mg/kg per day intragastrically (i.g.) for 7 days or to 20 mg/kg per day, i.g. for 1 h or 1 to 35 days. After diazepam administration, Ro 15-1788, a benzodiazepine antagonist was given (5.0 mg/kg i.m.) and precipitated benzodiazepine withdrawal was evaluated by scoring individual signs. The severity of the withdrawal, as indicated by the number of the different signs as well as by frequency of individual signs, increased as the dose and duration of diazepam exposure were increased. Consistent elevations in diazepam withdrawal signs were evident after a dose as low as 0.25 mg/kg per day for 7 days and after administration of 20 mg/kg per day for as short as 3-7 days. Data also suggested that history of previous benzodiazepine exposure sensitized animals to subsequent development of physical dependence. Overall, this study suggests that benzodiazepines produce meaningful functional changes in the central nervous system after exposure to relatively low doses and after relatively short durations of exposure.     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.     

Clozapine as a drug of dependence

Rationale: In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment. Objective: The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures. Methods: Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study. Results: Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal. Conclusions: Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs. Received: 14 May 1998/Final version: 14 September 1998     

Clozapine reversal of the deficits in coordinated movement induced by D2 receptor blockade does not depend upon antagonism of α2 adrenoceptors

Alpha2 adrenoceptor antagonists have been shown to reverse D2-antagonist-induced catalepsy leading to the hypothesis that the alpha2 antagonistic properties of clozapine underlie the compound's lack of extrapyramidal symptoms in the clinic. The potential for alpha2 antagonists to reverse the motor deficits produced by D2 antagonists (loxapine and haloperidol) was further investigated using a rotating rod (3.5 rpm) test in male Sprague-Dawley rats that requires coordinated movement to perform the task. The effects of loxapine (0.3 mg/kg, s.c.) were dose-dependently and statistically significantly reversed by the administration of clozapine (1,3, 10 mg/kg, i.p., n=10). Isoloxapine (1 mg/kg, i.p.), RX 821002 (2-methoxy-idazoxan; 5.6 mg/kg, i.p.) and yohimbine (5.6 mg/kg, i.p.) did not reverse the effects of loxapine. Furthermore, the motor deficits produced by haloperidol could not be reversed by RX 821002 (5.6 mg/kg, i.p.) or yohimbine (5.6 mg/kg, i.p.). On the other hand, scopolamine (0.03-0.3 mg/kg, i.p.) dose-dependently and statistically significantly antagonised the effects of both loxapine and haloperidol. These results indicate that the anticholinergic rather than the alpha2 antagonistic properties of clozapine may mediate the reversal of the motor deficit induced by D2 antagonism in a rotating rod test.     

Potentiation of ethanol-induced loss of the righting reflex by ascorbic acid in mice: interaction with dopamine antagonists

The present investigation was carried out to determine the effect of ascorbic acid on ethanol-induced loss of the righting reflex (LORR) and the interactions between ascorbic acid and dopamine receptor antagonists in affecting this action of ethanol in mice. To test the effect of each drug on ethanol-induced LORR, ascorbic acid (31.25, 62.5, 125, 250, 500, 1000 mg/kg intraperitoneally [IP]) and dopamine receptor antagonists (haloperidol 0.5, 1.0 mg/kg; L-sulpiride 20, 40, 80 mg/kg; clozapine 0.625, 1.25, 2.5 mg/kg; SCH 23390 0.5, 1.0, 2.0 mg/kg subcutaneously [SC]) were administered, respectively, 30 min before ethanol (4.0 g/kg IP) administration. Ascorbic acid, at the dose of 1000 mg/kg, significantly potentiated ethanol-induced LORR in mice. Dopamine D(2) antagonists haloperidol (0.5, 1.0 mg/kg SC), and L-sulpiride (80 mg/kg SC) also significantly prolonged the duration of LORR induced by ethanol. Clozapine and SCH 23390, at the doses used, did not affect ethanol-induced LORR. In the interaction study, the synergistic effect of ascorbic acid (1000 mg/kg IP) on ethanol-induced LORR was significantly enhanced by dopamine D(2) antagonists haloperidol, L-sulpiride, and clozapine, and the highest dose of dopamine D(1) antagonist SCH 23390. These results suggest that ascorbic acid may potentiate ethanol-induced LORR partially via a mechanism mainly linked to blockade of dopamine D(2) receptors.     

Tardive dyskinesia during and following treatment with haloperidol,haloperidol + biperiden,thioridazine, and clozapine

In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.It is concluded that (1) haloperidol (a strong antidopaminergic neuroleptic) has a more pronounced antihyperkinetic effect than thioridazine and clozapine (weaker antidopaminergic neuroleptics); (2) haloperidol might have a greater tendency to induce tardive dyskinesia than thioridazine; (3) administration of anticholinergics concomitant with neuroleptic drugs antagonizes the antihyperkinetic effect of haloperidol, but may not influence the intensity of tardive dyskinesia after withdrawal of the treatment.     

Increase of dialysate dopamine in the bed nucleus of stria terminalis by clozapine and related neuroleptics.

Neuroleptics are known to stimulate dopamine release in neostriatal terminal areas. In the present study, we have investigated by brain microdialysis in freely moving rats the effect of typical and atypical neuroleptics on dopamine transmission in the bed nucleus of stria terminalis, a dopamine terminal area belonging to the limbic system and recently assigned the so-called extended amygdala. Mean basal dialysate dopamine values were 14.3 f moles/20 microliters sample. Dopamine output in dialysates was increased dose-dependently by clozapine (max + 158%, 298%, and 461% of basal at 5, 10, and 20 mg/kg i.p., respectively), risperidone (max + 115% and 221% of basal at 1 and 3 mg/kg i.p., respectively), olanzapine (max + 138% and 235% of basal at 3 and 6 mg/kg i.p., respectively), BIMG 80 (max + 64% and 164% of basal at 3 and 5 mg/kg i.p., respectively), amperozide (max + 110% and 194% of basal at 3 and 6 mg/kg i.p., respectively). The selective dopamine D4 antagonist L-745,870 increased dialysate dopamine but at rather high doses and not as effectively as clozapine (max + 32%, 89%, and 130% of basal at 2.7, 5.4, and 10.8 mg/kg i.p., respectively). The typical neuroleptic haloperidol (0.1 and 0.5 mg/kg s.c.) and the selective D2 antagonist raclopride (0.14, 0.56, and 2.1 mg/kg s.c.), the serotonergic 5-HT2 antagonist ritanserin (0.5 and 1.5 mg/kg i.p.), and the adrenergic alpha 1 antagonist prazosin (0.91 and 2.73 mg/kg i.p.) did not affect dialysate dopamine in the bed nucleus of stria terminalis. Saline (1 ml/kg s.c. or 3 ml/kg i.p.) did not modify dialysate dopamine. Therefore, atypical neuroleptics share the ability of stimulating dopamine transmission in the bed nucleus of stria terminalis, but this property is not mimicked by any of the drug tested that selectively act on individual receptors among those that are affected by atypical neuroleptics. These observations raise the possibility that the property of increasing dopamine transmission in the bed nucleus of stria terminalis is the result of combined blockade of dopamine, serotonin, and noradrenaline receptors and that might be predictive of an atypical neuroleptic profile.     

Phencyclidine supersensitivity in rats with neonatal dopamine loss

RATIONALE: Disruption in brain dopamine function early in life can lead to enhanced susceptibility to the effects of NMDA receptor antagonists in adulthood, suggesting that animals given neonatal 6-OHDA treatment might provide a model for the altered NMDA receptor function associated with human disease. OBJECTIVE: The present study investigated whether neonatal dopamine lesions lead to supersensitivity to the stimulant effects of two NMDA antagonists, phencyclidine (PCP) and ketamine. METHODS: Sprague-Dawley rats, given dopamine or sham lesions on day 3 of life, were tested as adults for locomotor changes following treatment with NMDA antagonists. RESULTS: Lesioned rats were more sensitive to the stimulant effects of PCP and ketamine than controls. Enhanced sensitivity to PCP emerged in the male lesioned animals following a brief priming regimen with a D(1)-dopamine receptor agonist. Sensitization was also induced by repeated treatments with PCP (5 mg/kg), given at weekly intervals across 4 weeks, with progressive increases in activity significantly enhanced in the lesioned animals. Sensitization to PCP was still evident 3 weeks following chronic PCP treatment. The high rates of PCP-induced locomotion in the lesioned animals were not attenuated by pretreatment with a dopamine antagonist selective for the D(1)-dopamine receptor site (SCH-23390, 0.3 mg/kg) or with haloperidol (0.5 mg/kg), in comparison to controls. Olanzapine (5 mg/kg), an atypical antipsychotic, significantly reduced the response to PCP (5 mg/kg) in lesioned and control animals. CONCLUSIONS: This work confirms that rats with neonatal dopamine loss show enhanced sensitivity to NMDA antagonists, and may provide an animal model for the altered NMDA receptor function observed in human clinical syndromes.     

Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D(1) dopamine antagonists SCH-39166 and A-66359

Rhesus monkeys were trained in a 2-lever, food-reinforced drug discrimination paradigm to discriminate cocaine (0.2 or 0.4mg/kg, i.m., 10min pre-session) from saline. Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with various doses of cocaine alone or in combination with the D(1) dopamine antagonists SCH-39166 or A-66359. Administration of cocaine alone (0.025-0.4mg/kg, i.m.) resulted in a dose-related increase in the percent of responses that occurred on the drug-appropriate lever. Both SCH-39166 (0.05-0.1mg/kg, i.m., 60min pre-session) and A-66359 (0.2-0.4mg/kg, i.m., 30min pre-session) reduced cocaine-appropriate responding from more than 80% to less than 20% at least at one dose combination in all monkeys. Also for both drugs and in all monkeys, the blockade was overcome by increasing the dose of cocaine. SCH-39166 was more potent and longer acting than A-66359. The results provide further evidence that D(1) dopamine receptors are involved in the discriminative stimulus effects of cocaine and that D(1) antagonists may block the subjective effects of cocaine.     

Behavioral pharmacology of abecarnil in baboons: self-injection, drug discrimination and physical dependence

The behavioral effects of abecarnil, a beta-carboline which has been suggested to function as a partial and/or selective agonist at the benzodiazepine receptor, were assessed in baboons. In a chronic administration study, 100mg/kg/day abecarnil for 6-8 weeks produced few signs of sedation: lip droop and intention tremor were observed in two of the four baboons. Flumazenil administration (5mg/kg, i.m.) on day 8 of chronic abecarnil produced only a mild precipitated benzodiazepine withdrawal syndrome. Vehicle substitution after 6-8 weeks of chronic abecarnil produced transient signs of a mild withdrawal syndrome, including decreased food intake, but did not produce vomiting, twitches/jerks or seizures. In a self-injection study, abecarnil (0.032-1.0mg/kg/injection) did not maintain rates of self-injection above vehicle control levels; higher rates of self-injection were maintained in the same animals by cocaine (0.32mg/kg/injection) and triazolam (0.01mg/kg/injection). The highest i.v. abecarnil dose (1.0mg/kg/injection) produced sedation and ataxia in two of the three baboons. In a drug discrimination study, generalization from lorazepam training conditions (1.8mg/kg, p.o.) to abecarnil was an increasing function of dose, and maximal drug lever responding occurred reliably in all baboons 5h after 10-32mg/kg, p.o. abecarnil administration. Flumazenil (0.32mg/kg, i.m.), given 4h after abecarnil, completely antagonized the abecarnil stimulus in test sessions 1h later. The present experiments show that the behavioral profile of abecarnil is clearly distinguisable from that of benzodiazepines.     

Raclopride lessens the ability of clozapine to suppress alcohol drinking in Syrian golden hamsters

Emerging evidence suggests that the atypical antipsychotic clozapine decreases alcohol consumption in patients with schizophrenia, while typical antipsychotics, all of which are potent dopamine (DA) D2 receptor antagonists, do not. We have proposed that clozapine, through its weak DA D2 receptor blocking action, coupled with its ability to potentiate noradrenergic and serotonergic activity, may ameliorate a dysfunction in the mesocorticolimbic DA reward circuitry that underlies alcohol use disorder in patients with schizophrenia. In prior studies, we have demonstrated that clozapine also decreases alcohol drinking in the Syrian golden hamster, but haloperidol does not. The purposes of the current study were: (1) to further assess the effect of clozapine (2 or 4 mg/kg/day, s.c.) on alcohol consumption in hamsters, using a continuous access, 2-bottle choice paradigm; and (2) to examine whether clozapine’s effect on alcohol drinking is affected by increasing its DA D2 blockade through adjunctive use of the potent DA D2 receptor antagonist raclopride (2, 4, or 6 mg/kg/day, s.c.). The major findings were: (1) clozapine suppressed both initiation and maintenance of alcohol drinking in hamsters; and (2) these effects of clozapine were lessened when raclopride was given adjunctively with clozapine. These data suggest that clozapine may limit alcohol drinking in the golden hamster (and possibly in patients with schizophrenia) in part because of its weak blockade of the DA D2 receptor.     

Differential effects of acute administration of haloperidol and clozapine on ethanol-induced ascorbic acid release in rat striatum

Antipsychotic drugs were initially considered to act predominantly through their antagonism at dopamine D(2)-like receptors. However, reports have demonstrated that the typical neuroleptic drug haloperidol and the atypical neuroleptic drug clozapine showed differential actions in clinical, behavioral and biochemical studies. Since ascorbic acid has a potential usefulness in psychological therapeutics, the present study investigates the actions of these two drugs on ethanol-induced ascorbic acid release in the striatum in order to help explain the different mechanisms of these drugs. The results showed that clozapine, at the doses of 15 and 30 mg/kg, i.p., had no effect on basal ascorbic acid release. However, a synergistic tendency at a dose of 15 mg/kg and a significant synergism at a dose of 30 mg/kg were observed on ascorbic acid release when clozapine was used with ethanol. In contrast, haloperidol, at the doses of 0.5, 1.0 and 2.0 mg/kg, i.p., administered alone did not affect the basal release of striatal ascorbic acid, and when used together with ethanol had neither a potentiating nor an antagonizing effect on ethanol-induced ascorbic acid release. Chlorpromazine, a nonselective dopamine receptor antagonist, at the dose of 5 mg/kg, i.p., affected neither the basal nor the ethanol-induced ascorbic acid release. Ritanserin, a 5-HT(2) receptor antagonist, at the dose of 1 mg/kg, s.c., significantly antagonized ethanol-induced ascorbic acid release. These results demonstrate that clozapine dose-dependently potentiates the stimulatory effect of ethanol on striatal ascorbic acid release and this effect of clozapine may not be related to its dopamine D(2) receptor antagonism.     

Is antagonism of alpha3beta4 nicotinic receptors a strategy to reduce morphine dependence?

18-Methoxycoronaridine, a synthetic iboga alkaloid congener, has been previously shown to attenuate several signs of morphine withdrawal in rats. The recently discovered action of 18-methoxycoronaridine to block alpha3beta4 nicotinic receptors may be responsible for this effect. To test this hypothesis the effects of non-selective alpha3beta4 receptor antagonists, dextromethorphan, mecamylamine, bupropion, and their combinations, were assessed on of acute naltrexone-precipitated (1 mg/kg i.p.) morphine withdrawal in rats. Dextromethorphan (5-40 mg/kg, s.c.), mecamylamine (0.25-4 mg/kg, i.p.) and bupropion (10-30 mg/kg, i.p.) alone produced variable effects on signs of withdrawal. However, two low-dose combinations, i.e., dextromethorphan (5 mg/kg, s.c.) and mecamylamine (0.25 mg/kg, i.p.), mecamylamine (0.25 mg/kg, i.p.) and bupropion (10 mg/kg, i.p.) as well as the three-drug combination significantly attenuated diarrhea and weight loss; none of the agents administered alone had these effects. The results of the present study provide evidence that alpha3beta4 nicotinic receptors are involved in the expression of at least two signs of opioid withdrawal.     

The role of group I mGlu receptors in the expression of ethanol-induced conditioned place preference and ethanol withdrawal seizures in rats

In animal models, N-methyl-d-aspartate (NMDA) receptors antagonists inhibit physical dependence and the reinforcing effects of ethanol. The group I metabotropic glutamate (mGlu) receptors antagonists (mGlu1 and mGlu5) attenuate excitatory effect of glutamate by functional modulation of the glutamate/NMDA receptors. The objective of the present study was to evaluate the effects of a selective mGlu5 receptors antagonist—MTEP, and mGlu1 receptors antagonist—EMQMCM, on two processes relevant to alcohol addiction: the expression of ethanol-induced conditioned place preference (CPP) paradigm, and ethanol withdrawal audiogenic seizures in rats. Our experiments indicated that EMQMCM at the doses of 5 and 10 mg/kg, and MTEP at the doses of 2.5 and 5 mg/kg, significantly attenuated the expression of ethanol CPP. Furthermore, both group I mGlu receptor antagonists, i.e. EMQMCM at the dose of 10 mg/kg and MTEP at the dose of 5 mg/kg, attenuated audiogenic seizures induced by the sound stimulus 12 h after withdrawal of ethanol in dependent rats. Our study shows the importance of mGlu5 and mGlu1 receptors for the expression of ethanol-induced CPP and withdrawal seizures, although mGlu5 receptors antagonist (MTEP) was more potent than the antagonist of mGlu1 receptors (EMQMCM).