Time-dependent changes in alcohol-seeking behaviour during abstinence.

Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behaviour even after protracted abstinence. The purpose of the present study was to assess time-dependent changes in alcohol-seeking behaviour in rats trained to respond for alcohol. The rats were re-exposed to alcohol-associated stimuli after 1, 28 or 56 days of withdrawal. During the re-exposure session, the rats were first allowed to respond in extinction. Then, reinstatement of alcohol-seeking behaviour was evoked by a complex of discrete alcohol-associated cues (auditory and light cues combined with taste and smell of alcohol). Extinction behaviour depended on abstinence duration with maximal responding after 28-day abstinence. Reinstatement of alcohol-seeking behaviour evoked by the discrete cues was highest after 56-day abstinence. No correlations were found between individual alcohol intakes, extinction behaviour and cue-induced reinstatement. These results suggest that: (i) alcohol-seeking behaviour may become more intense after long-term imposed abstinence; (ii) alcohol self-administration, extinction behaviour, and reinstatement of alcohol-seeking behaviour may be regulated by separate neural mechanisms.     

Exposure to amphetamine in rats during periadolescence establishes behavioural and extrastriatal neural sensitization in adulthood

Drug abuse during adolescence may predispose towards later adult substance abuse and major depressive disorders (Brook et al., 2002). The purpose of the present study was to characterize whether behavioural sensitization to amphetamine occurred in adult rats following adolescent exposure to amphetamine [low (2 mg/kg.d) or high (10 mg/kg.d) i.p. for 10 d] and the pattern of neural activation associated with sensitized behaviour, in male Sprague-Dawley rats. Following initial treatment (post-natal days 33-41) and a subsequent 4-wk period of abstinence, rats initially treated with either amphetamine regime showed a similar sensitized locomotor activity upon re-challenge with amphetamine (1.5 mg/kg i.p.) compared to rats acutely challenged with this dose of amphetamine. Fos-IR expression in the "high" sensitized group was significantly greater than acutely challenged rats in all quadrants of the CPu. Both "low" and "high" sensitized groups demonstrated heightened Fos expression relative to acutely challenged rats in the medial and central amygdala, as well as rostroventrolateral medulla, whereas Fos-IR in the locus coeruleus and substantia nigra pars reticulata was significantly increased only in the "high" sensitized group compared to acute. Double-labelling for tyrosine hydroxylase confirmed an absence of Fos-IR in A9 and A10 regions. The present study has shown a robust and persistent sensitization in adulthood to amphetamine re-challenge following initial adolescent exposure in rats. This manifestation of sensitization apparently results in widespread neural activation in limbic and autonomic structures.     

Di-n-propylacetate-induced abstinence behaviour as a possible correlate of increased GABA-ergic activity in the rat

Administration of di-n-propylacetate (DPA), an inhibitor of SSA-dehydrogenase, produces in naive rats abstinence behaviour which can be blocked by morphine and bicuculline and may be useful as a behavioural correlate of increased GABA-ergic activity. The usefulness of this model has been demonstrated by studying the effec of bicuculline, picrotoxin, strychnine, morphine, aminooxyacetic acid, 3-mercaptopropionate and thiosemicarbazide on DPA-induced abstinence behaviour. Behaviour was suppressed both by bicuculline or picrotoxin, while the selective glycine antagonist strychnine was ineffective. A comparable syndrome could not be evoked by treatment with aminooxyacetic acid, a GABA-transaminase inhibitor, indicating that the effect of DPA was not caused by inhibition of this enzyme. Instead, aminooxyacetic acid suppressed the DPA-induced abstinence behaviour, suggesting that two GABA-ergic systems with opposite effects on behaviour can be distinguished. The syndrome was also suppressed by convulsant doses of 3-mercaptopropionate, while thiosemicarbazide was ineffective. Abstinence behaviour was further suppressed by morphine with an ED₅₀ of 0.5 mg/kg and this action could be clearly separated from its depressant effect on locomotor activity in non-treated animals. These results suggest that morphine receptors may be involved in DPA-induced abstinence behaviour. Based on these experiments a model has been proposed for GABA-ergic terminals being under the inhibitory influence of GABA-ergic autoreceptors. It is proposed that DPA-induced abstinence behaviour may be useful as a model of increased GABA-ergic activity to aid study of the regulation and properties of the GABA-ergic system in vivo.     

Repeated weekly exposure to MDMA, methamphetamine or their combination: long-term behavioural and neurochemical effects in rats

In recent work we have documented lasting adverse neurochemical and behavioural effects in rats given short-term 'binge' dosing with methylenedioxymethamphetamine (MDMA, Ecstasy), methamphetamine (METH) or their combination. Here we investigated whether similar effects persist in rats given 16 weekly injections followed by a 10 week period of abstinence. Female rats received MDMA (8 mg/kg, i.p.), METH (8 mg/kg), or a MDMA/METH combination (4 mg/kg MDMA + 4 mg/kg METH), once a week for 16 weeks, with locomotor activity and body temperature measured on weeks 1, 8 and 16. The MDMA and MDMA/METH groups showed acute drug-induced hyperthermia on week 1 only. MDMA-treated rats demonstrated an acute hyperactivity while METH and MDMA/METH treated rats showed pronounced stereotypy. Seven weeks after drug-treatment concluded, a decrease in social interaction was observed in all chronically drug-treated rats. No group differences were evident on the emergence, object recognition or forced swim tests. Neurochemical analysis revealed modest noradrenaline and serotonin depletion in chronically treated rats that was not evident following a single equivalent administration. These results indicate that although chronic, intermittent exposure to MDMA, METH or their combination, may not lead to significant long-term monoamine depletion, lasting adverse behavioural effects may persist, especially those related to social behaviour.     

Drinking in the year after treatment as a predictor of three-year drinking outcomes

OBJECTIVE: Previous research suggests that abstinence from alcohol during the first year posttreatment for alcohol-use disorders (AUDs) is an important, independent predictor of longer-term alcohol consumption and related functioning. The purpose of this study was to test the hypothesis that abstinence during the first year posttreatment initiation predicts alcohol use at Months 37-39. A second aim of this study was to explore the relationship between "moderate" drinking in the first year and drinking at Months 37-39. METHOD: Secondary data analyses were conducted on the outpatient Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) sample (N = 952 at baseline and 802 at Months 37-39). For these analyses, participants were classified first as abstainers, moderate drinkers, or heavy drinkers based on their alcohol use in the first year posttreatment initiation. RESULTS: Analyses of covariance showed that the first-year drinker classification predicted both percentage of days abstinent and drinks per drinking day at Months 37-39. Subsequent analyses showed that the abstainers functioned significantly better than (1) both of the other drinker groups combined and (2) either of the other two groups, which did not differ from each other on either measure of alcohol use. A third set of exploratory analyses evaluated first-year abstinence and heavy drinking as continuous variables and showed an essentially linear relationship between them and drinking at 3 years. CONCLUSIONS: This study confirmed the strong relationship between first-year abstinence and later drinking but did not show that participants who engaged in moderate drinking during the first year had positive alcohol-use outcomes at 3 years. The clinical implications of the findings, their generalizability to different populations of individuals presenting for specialty alcohol treatment, and future research directions are discussed.     

Lesions of the dorsomedial frontal cortex block sensitization to the positive-reinforcing effects of cocaine

Previous studies have reported that rats exposed to a binge-abstinence history of cocaine self-administration exhibit sensitization to the positive-reinforcing effects of cocaine on a progressive ratio (PR) schedule of reinforcement. The purpose of the present study was to determine whether lesions of the dorsomedial frontal cortex block sensitization to the reinforcing effects of cocaine in rats with a history of binge-abstinence self-administration. Separate groups of male rats received bilateral infusions of either ibotenic acid (lesion) or sterile saline (sham) into the dorsomedial frontal cortex, or were left undisturbed (intact). All rats were then implanted with jugular catheters and trained to self-administer cocaine. Following acquisition, cocaine was made available on a PR schedule of reinforcement and breakpoints were determined in each group. Rats were then exposed to a discrete-trials (DT) procedure in which cocaine was made available during 10-min discrete-trials that occurred every 15 min (i.e., 4 times per hr) during daily, 24-hr sessions. This procedure elicited a "binge" in all groups, during which high rates of responding were maintained over a period of 1-2 days. After 10 days, the DT procedure was terminated, and no cocaine was available for the next 7 days. Following 7 days of forced "abstinence", cocaine-reinforced breakpoints were redetermined on the PR schedule. Prior to the DT procedure, no differences were observed in breakpoints across the three groups. Following the 7-day abstinence period, breakpoints on the PR schedule increased significantly in intact and sham rats, indicating an increase in the reinforcing efficacy of cocaine. In contrast, breakpoints did not increase in lesion rats, and were similar to those obtained prior to the binge-abstinence history. These data suggest that lesions of the dorsomedial frontal cortex block sensitization to the positive-reinforcing effects of cocaine in rats with a history of binge-abstinence self-administration.     

Persistence of conduct disorders and their relation to early initiation of smoking and alcohol drinking in a prospective ELSPAC Study

The important risk factors of early initiation of smoking and alcohol drinking are: prosmoking family and peers, conduct disorders and delinquency, poor academic performance. The data obtained by physicians, teachers and children were collected at the age of 11 years. Children were divided into group A (without symptoms), Group B (with one or more symptoms). For statistic analysis, the programme EPI INFO was used.During the period between 7 and 11 years, new children with problematic behaviour (178=3.9%) were diagnosed in Group A, while substantial decreasing of children previously included in Group B was seen (by 59.1%). Together 7.05% of 11 years old children visited specialists (psychologists) due to their conduct disorders: 6.8% from Group A and 12.3% from Group B. Children more often than their teachers reported the frequent occurrence of conduct disorder. About 20% of children smoked, and more than 40% had tasted alcohol. However, the differences between Groups A and B were not significant. Our prospective study has demonstrated the possibility of misinterpretation of behavioural outputs. Children with previous behavioural problems had not a higher risk for early smoking and alcohol use.     

Evaluation of the acute effects of amitriptyline and fluoxetine on anxiety using grooming analysis algorithm in rats

The tricyclic amitriptyline and the selective serotonin reuptake inhibitor fluoxetine have distinct actions in animal models of anxiety, though both antidepressants are used against anxiety disorders. Grooming behavioural sequencing, rather than its general "activity" measures, has been suggested to measure effectively the pharmacologically induced anxiolytic and anxiogenic-like effects in rats and mice. In the present study, the acute effects of amitriptyline and fluoxetine on anxiety were re-evaluated by using an analysis algorithm in novelty-induced grooming activity in rats. Additionally, the effects on anxiety-like behaviour in the hole board were examined. Amitriptyline (5 and 10 mg/kg) and fluoxetine (5 and 10 mg/kg) not only affected the traditional gross measures, but also produced changes in incorrect transitions and regional distribution of grooming behaviour. High dose of fluoxetine showed an anxiogenic-like profile by reducing head dipping and rearing in the hole board. Depending on the effects on the behavioural microstructure of grooming activity, present findings imply that amitriptyline may possess anxiogenic and fluoxetine may possess anxiolytic activities. However, measures of hole board do not fully support this suggestion.     

Acamprosate: a review of its use in the maintenance of abstinence in patients with alcohol dependence

Acamprosate (Campral delayed-release tablet), a synthetic compound with a similar structure to that of the neurotransmitter GABA and the neuromodulator taurine, facilitates the maintenance of abstinence in detoxified alcohol-dependent patients. Although the precise mechanism(s) of action of the drug remains to be fully elucidated, it appears that it most likely involves beneficial modulation of the glutamatergic neurotransmitter system, including antagonism of the mGLu5 metabotropic glutamate receptor, to counteract the imbalance between the glutamatergic and GABAergic systems associated with chronic alcohol exposure and alcohol withdrawal. In several double-blind, placebo-controlled trials of up to 12 months' duration, acamprosate effectively maintained complete abstinence in detoxified alcohol-dependent patients, irrespective of disease severity or the type of psychosocial support. The drug showed better efficacy than placebo and was very well tolerated. Limited data from a relatively well designed trial indicate that the drug has similar efficacy to that of naltrexone and that combination therapy with these two agents provides better efficacy than acamprosate monotherapy, although multicentre direct head-to-head investigations are required to fully establish the potential of this combination. The drug may be particularly useful in those with hepatic impairment and/or liver disease. Thus, in combination with psychosocial and behavioural management programmes, acamprosate is a promising option for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal.     

Maternal separation increases alcohol-drinking behaviour and reduces endocannabinoid levels in the mouse striatum and prefrontal cortex

Childhood adversity is associated with an increased risk of mood, anxiety and substance use disorders. Maternal separation is a reliable rodent model of early life adversity that leads to depression-like symptoms, which may increase the vulnerability to alcohol consumption during adolescence. However, the specific alterations in the pattern of alcohol consumption induced by maternal separation and the underlying molecular mechanisms are still unclear. The purpose of this study is to evaluate the long-term effects of maternal separation with early weaning (MSEW) on emotional and social behaviour, alcohol rewarding properties, and alcohol consumption, abstinence and relapse in adolescent male C57BL/6 mice. In addition, endocannabinoid and monoamine levels were analysed in discrete brain areas. Results showed that MSEW mice presented emotional alterations related to depressive-like behaviour and modified endocannabinoid levels in the striatum and the prefrontal cortex. MSEW mice also showed impairments in alcohol-induced conditioned place preference and higher alcohol intake in a model of binge drinking. Moreover, MSEW animals displayed a higher propensity to relapse in the two-bottle choice paradigm following a period of alcohol abstinence associated with reduced monoamine levels in the striatum. Such results indicate that exposure to early life stress increased the vulnerability to alcohol binge-drinking during adolescence, which may be partially explained by decreased sensitivity to alcohol rewarding properties and the ability to potentiate alcohol intake following a period of abstinence.     

Time-course of the effects of chronic delta 9-tetrahydrocannabinol on behaviour, body temperature, brain amines and withdrawal-like behaviour in the rat

The effects of clomipramine HCl (15 mg kg-1 i.p.) on behaviour, body temperature and brain amines were investigated in rats that had been chronically treated twice daily with increasing doses of delta 9-tetrahydrocannabinol (delta 9-THC, 2-6 mg kg-1 i.v.). delta 9-THC produced a biphasic change in behaviour, stimulation followed by depression, and a pronounced hypothermia. Tolerance developed rapidly to these effects of delta 9-THC. Chronic treatment with delta 9-THC reduced the levels of homovanillic acid, 5-hydroxytryptamine and noradrenaline. The level of dopamine was not altered with chronic treatment and tolerance appeared to develop to the increased levels of 5-hydroxyindoleacetic acid induced by delta 9-THC. Injection of clomipramine, 12-14 h after 2, 5 or 10 days of delta 9-THC treatment induced characteristic changes in the rats behaviour which consisted of writhes, backward kicking, wet shakes, jumps ataxia and front paw and whole body tremor. The severity of the behavioural changes appeared to be dependent on the period of delta 9-THC administration and they were not accompanied by a change in body temperature or consistent changes in brain amines or metabolites. The results indicate that physical dependence on delta 9-THC may occur since clomipramine is able to precipitate changes in behaviour, indicative on an abstinence syndrome, in rats chronically treated with delta 9-THC. It is suggested that tryptaminergic mechanisms are altered during chronic delta 9-THC treatment and that clomipramine induces the behavioural changes by interacting with an altered tryptaminergic system.     

We are in the dark here: induction of depression- and anxiety-like behaviours in the diurnal fat sand rat, by short daylight or melatonin injections

Circadian rhythms are considered an important factor in the aetiology, expression and treatment of major affective disorders, including seasonal affective disorder (SAD). However, data on the effects of daylight length manipulation or melatonin administration are complex. It has been suggested that since diurnal and nocturnal mammals differ significantly in their physiological and behavioural responses to daylight, diurnal rodents offer a preferable model of disorders related to circadian rhythms in the diurnal human. We previously found that diurnal fat sand rats maintained under short daylight (SD), show depression-like behaviour in the forced swim test (FST). The present study was designed to test additional behaviours related to affective disorders and study the involvement of melatonin in these behaviours. Sand rats were divided into short-daylight (SD, 5 h light:19 h dark) and long-daylight (LD, 12 h light:12 h dark) groups, and received 100 microg melatonin or vehicle administration for 3 wk (5 h and 8.5 h after light onset in the LD room). Animals were then tested for reward-seeking behaviour (saccharin consumption), anxiety (elevated plus-maze), aggression (resident-intruder test), and depression-like behaviour (FST). SD or melatonin administration resulted in a depressed/anxious-like behavioural phenotype including reduced reward seeking, increased anxiety, decreased aggression and decreased activity in the FST, supporting the notion that in a diurnal animal, reduced light results in a variety of behavioural changes that may model depression and anxiety; and that melatonin may be a significant factor in these changes. We suggest that the sand rat may offer an excellent model species to explore the interactions between daylight, affective behaviour and the related underlying mechanisms.     

Correlation of rat cortical Fas-associated death domain (FADD) protein phosphorylation with the severity of spontaneous morphine abstinence syndrome: role of α(2)-adrenoceptors and extracellular signal-regulated kinases

Fas-associated death domain (FADD) phosphorylation was recently implicated in opiate-induced neuroplasticity. To further explore the role of FADD in the mechanisms of morphine-induced physical dependence, the regulation of cortical p-FADD (and their interactions with α(2)-adrenoceptors and other signalling pathways) was assessed during spontaneous opiate withdrawal (SW) in morphine-dependent rats (10-100 mg/kg for 6 days). The main results indicated that oligomeric p-FADD in the cerebral cortex mirrored the time course of morphine SW (12-96 h), which resulted in a striking correlation between p-FADD and the intensity (behavioural scores) of morphine abstinence (Spearman correlation coefficient: 0.59, n = 39, p < 0.0001). The inactivation of brain α(2)-adrenoceptors (EEDQ at SW 12 h) further enhanced morphine abstinence intensity and cortical p-FADD content at SW 24 h. The disruption of ERK1/2 signalling (SL 327 at SW 4 h and SW 8 h) did not alter morphine abstinence at SW 12 h, but it attenuated the behavioural syndrome at SW 24 h. This inhibition of ERK1/2, however, did not prevent the up-regulation of oligomeric p-FADD at SW 12 h and 24 h. These data indicate that cortical oligomeric p-FADD, mainly through an interaction with inhibitory α(2)-adrenoceptors, plays a functional role in the behavioural expression of morphine abstinence in rats.     

Social isolation of rats increases the density of cholecystokinin receptors in the frontal cortex and abolishes the anti-exploratory effect of caerulein

Summary The role of cholecystokinin (CCK) receptors in the development of anxiety caused by social isolation of rats was studied using the elevated plus-maze and receptor binding techniques. The isolation of male Wistar rats significantly reduced their exploratory activity in the elevated plus-maze compared with that of rats kept in groups of four. Caerulein (0.1–5 g/kg s.c.), an agonist at CCK receptors, only at the highest dose (5 g/kg) significantly decreased the exploratory behaviour of rats housed in groups, but not in the isolated rats. By contrast, small doses of caerulein (0.1–0.5 g/kg) even tended to increase the behavioural activity of isolated rats in the plus-maze test.In parallel to the behavioural changes, isolation of the rats increased the number of [³H]pCCK-8 binding sites in the frontal cortex, but not in the other forebrain structures (the mesolimbic area, striatum and hippocampus). Isolation did not affect the density of benzodiazepine receptors in the frontal cortex.In conclusion, the isolation of rats for 7 days produced anxiogenic-like effect on the behaviour of rats and increased the number of CCK receptors in the frontal cortex without affecting benzodiazepine receptors.Correspondence to E. Vasar at the above address     

Different behavioural patterns induced by apomorphine: evidence that the method of administration determines the behavioural response to the drug

The behavioural effects of s.c. injected apomorphine was studied on habituated rats in a test-box designed to measure 8 different components of behaviour. Apomorphine, 1 mg/kg, induced two different behaviours: The "G-type" of behaviour characterized by compulsive gnawing and the "LS-type" of behaviour characterized by increased locomotion, sniffing and repetitive head and limb movements. G-type behaviour was induced when apomorphine, dissolved by heating, was injected s.c. into the flank of the animal. LS-type behaviour was induced both when apomorphine, dissolved by heating, was injected s.c. into the neck and when it was dissolved by heating together with a high concentration of ascorbic acid (1 mg/ml) and injected s.c. into the flank. G-type behaviour could not be elicited by changing the dose which induced LS-type behaviour or vice versa. We therefore conclude that these different behavioural effects of apomorphine were not dose--response effects but were elicited by at least two different synaptic mechanisms in the brain. Experimentally induced changes from one of these apomorphine-induced behaviours to another can therefore not merely be interpreted as a change in the intensity of the behavioural response as is done in e.g. commonly used stereotypy rating scales.     

A systematic review of the effectiveness of the community reinforcement approach in alcohol, cocaine and opioid addiction

The community reinforcement approach (CRA) has been applied in the treatment of disorders resulting from alcohol, cocaine and opioid use. The objectives were to review the effectiveness of (1) CRA compared with usual care, and (2) CRA versus CRA plus contingency management. Studies were selected through a literature search of RCTs focusing on substance abuse. The search yielded 11 studies of mainly high methodological quality. The results of CRA, when compared to usual care: there is strong evidence that CRA is more effective with regard to number of drinking days, and conflicting evidence with regard to continuous abstinence in the alcohol treatment. There is moderate evidence that CRA with disulfiram is more effective in terms of number of drinking days, and limited evidence that there is no difference in effect in terms of continuous abstinence. Furthermore, there is strong evidence that CRA with "incentives" is more effective with regard to cocaine abstinence. There is limited evidence that CRA with "incentives" is more effective in an opioid detoxification program. There is limited evidence that CRA is more effective in a methadone maintenance program. Finally, there is strong evidence that CRA with abstinence-contingent "incentives" is more effective than CRA (non-contingent incentives) treatment aimed at cocaine abstinence.     

Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: An [C]diprenorphine PET study

The importance of the opioid receptor system in substance dependence is increasingly recognised. We used PET with the non-selective tracer [¹¹C]diprenorphine to examine opioid receptor binding in early abstinence from alcohol dependence and the relationship to craving. We recruited 11 alcohol dependent patients and 13 controls. Subjects underwent one [¹¹C]diprenorphine PET scan in early abstinence from dependent alcohol use ( 2 weeks) and 2 months later if continuously abstinent. Global and regional [¹¹C]diprenorphine volumes of distribution (VD) were increased in alcohol dependent patients compared with controls but did not reach significance. We demonstrated a correlation between global and regional [¹¹C]diprenorphine VD and craving in alcohol dependent patients which persisted in the anterior cingulate cortex into extended abstinence. This confirms previous work showing increased opioid receptor availability in early abstinence from substances of abuse and correlation with craving suggesting that the opioid system plays a fundamental role in this phase of addiction.     

Variation in health care provider definitions of moderate consumption of alcohol as related to recommendations regarding alcohol consumption during pregnancy: results from a Canadian survey

Women rely on health care providers for general health care and preconception counseling, including advice on alcohol consumption. Definitions of moderate consumption may differ by individual provider, resulting in inconsistency in advice and lack of clarity for patients both before and during pregnancy. The objective of this study was to determine if health care providers' definition of moderate alcohol consumption was associated with advice to pregnant women regarding alcohol use during pregnancy and to describe health care providers' communication regarding alcohol consumption. Between October 2001 and October 2002, a survey was mailed to a national random sample of 3114 Canadian obstetricians and gynecologists, midwives, and family physicians. The main outcome measure was questionnaire responses regarding knowledge and prevention issues related to alcohol and pregnancy as well as provider characteristics. Response rates ranged from 31.1% among family physicians to 63.5% among midwives. Moderate alcohol consumption among nonpregnant women was defined as 1 to 2 drinks per occasion by about 89% of providers and did not relate to recommendations during pregnancy. Those who recommended abstinence during pregnancy were more likely to define moderation as 4 or more occasions per week as compared with those who did not recommend abstinence (P=0.022). Fewer than 50% of providers frequently defined "moderation" for their patients. More family physicians (90.0%) than obstetricians (83.9%) or midwives (81.1%) recommended alcohol abstinence during pregnancy (overall 87.8%, P=0.005). Thus, there is opportunity for providers to appropriately counsel their patients by advising alcohol abstinence during pregnancy and more frequently defining "moderation" for all clients.     

The effects of sodium valproate on γ-aminobutyrate metabolism and behaviour in naive and ethanolamine-O-sulphate pretreated rats and mice

Sodium valproate was injected acutely (400 mg/kg i.p.) into naive and ethanoloamine-O-sulphate chronically pretreated rats and mice, in an attempt to gain further insight into the effects of this anticonvulsant on GABA metabolism. Sodium valproate significantly enhanced the activity of GAD in the medulla and pons, cerebellum and midhrain regions of rats, and partially relieved the suppression of GAD activity caused by chronic GABA-transaminase inhibition in whole mouse brain. In combination with EOS, sodium valproate caused behavioural excitation in mice which was similar to that sometimes seen with high doses of some GABA-T inhibitors. Pretreatment with EOS potentiated the characteristic abstinence behaviour caused by sodium valproate in rats, though no further significant rise in cerebral GABA levels was observed. In view of the neuronal location of GAD, the elevation of cerebral GABA levels at least in part by potentiation of GAD activity could be involved in the mediation of the anticonvulsant activity of sodium valproate.     

Calcium channel inhibitors suppress the morphine-withdrawal syndrome in rats.

The effects of the Ca2+-channel blockers verapamil and nimodipine, on the behavioural signs of naloxone (1 mg kg-1)-induced abstinence syndrome in morphine-dependent rats, were evaluated. The content of noradrenaline (NA) and of its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured, using high performance liquid chromatography and electrochemical detection or gas chromatography-mass spectrometry, in various brain regions of these animals. Possible interactions of nimodipine and verapamil with opioid receptors were evaluated by examining their ability to displace [3H]-naloxone binding to brain membranes. Verapamil (5, 10 and 50 mg kg-1) and nimodipine (1, 5 and 10 mg kg-1) dose-dependently reduced most of the signs of morphine abstinence. Naloxone-precipitated abstinence decreased the NA content in the cortex, hippocampus, brainstem and cerebellum. In the same brain regions the content of MHPG increased, suggesting an increased release of the amine during morphine abstinence. Nimodipine (10 mg kg-1 i.v.) did not change the content of NA or MHPG in the cortex, hippocampus and brainstem. However, nimodipine pre-treatment markedly reduced the changes in NA and MHPG content induced by the abstinence syndrome. Neither verapamil nor nimodipine displaced [3H]-naloxone from its binding sites. These results suggest that Ca2+-channel blockers suppress the behavioural and neurochemical expressions of morphine abstinence by a mechanism that differs from those of opioids or alpha 2-adrenoceptor agonists.