Barbiturate Withdrawal Research Articles

Mapping a Barbiturate Withdrawal Locus to a 0.44 Mb Interval and Analysis of a Novel Null Mutant Identify a Role forKcnj9(GIRK3) in Withdrawal from Pentobarbital, Zolpidem, and Ethanol

Here, we map a quantitative trait locus (QTL) with a large effect on predisposition to barbiturate (pentobarbital) withdrawal to a 0.44 Mb interval of mouse chromosome 1 syntenic with human 1q23.2. We report a detailed analysis of the genes within this interval and show that it contains 15 known and predicted genes, 12 of which demonstrate validated genotype-dependent transcript expression and/or nonsynonymous coding sequence variation that may underlie the influence of the QTL on withdrawal. These candidates are involved in diverse cellular functions including intracellular trafficking, potassium conductance and spatial buffering, and multimolecular complex dynamics, and indicate both established and novel aspects of neurobiological response to sedative-hypnotics. This work represents a substantial advancement toward identification of the gene(s) that underlie the phenotypic effects of the QTL. We identify Kcnj9 as a particularly promising candidate and report the development of a Kcnj9-null mutant model that exhibits significantly less severe withdrawal from pentobarbital as well as other sedative-hypnotics (zolpidem and ethanol) versus wild-type littermates. Reduced expression of Kcnj9, which encodes GIRK3 (Kir3.3), is associated with less severe sedative-hypnotic withdrawal. A multitude of QTLs for a variety of complex traits, including diverse responses to sedative-hypnotics, have been detected on distal chromosome 1 in mice, and as many as four QTLs on human chromosome 1q have been implicated in human studies of alcohol dependence. Thus, our results will be primary to additional efforts to identify genes involved in a wide variety of behavioral responses to sedative-hypnotics and may directly facilitate progress in human genetics.

5-HT 2C and GABA B receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice

Progress towards elucidating the underlying genetic variation for susceptibility to complex central nervous system (CNS) hyperexcitability states has just begun. Genetic mapping analyses suggest that a gene(s) on mid-chromosome 4 has pleiotropic effects on multiple CNS hyperexcitability states in mice, including alcohol and barbiturate withdrawal and convulsions elicited by chemical and audiogenic stimuli. We recently identified Mpdz within this chromosomal region as a gene that influences alcohol and barbiturate withdrawal convulsions. Mpdz encodes the multi-PDZ domain protein (MPDZ). Currently, there is limited information available about the mechanism by which MPDZ influences drug withdrawal and/or other CNS hyperexcitability states, but may involve its interaction with 5-HT 2C and/or GABA B receptors. One of the most useful tools we have developed thus far is a congenic strain that possesses a segment of chromosome 4 from the C57BL/6J (donor) mouse strain superimposed on a genetic background that is > 99% from the DBA/2J strain. The introduced segment spans the Mpdz gene. Here, we demonstrate that handling-induced convulsions are less severe in congenic vs. background strain mice in response to either a 5-HT 2C receptor antagonist (SB242084) or a GABA B receptor agonist (baclofen), but not a GABA A receptor channel blocker (pentylenetetrazol). These data suggest that allelic variation in Mpdz, or a linked gene, influences SB242084- and baclofen-enhanced convulsions. Our results are consistent with the hypothesis that Mpdz's effects on CNS hyperexcitability, including alcohol and barbiturate withdrawal, involve MPDZ interaction with 5-HT 2C and/or GABA B receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.

Fine mapping of a sedative‐hypnotic drug withdrawal locus on mouse chromosome 11

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABA(A) receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABA(A) receptor gamma2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for alpha1 subunit containing GABA(A) receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABA(A) receptor gamma2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.

Potential pleiotropic effects of Mpdz on vulnerability to seizures.

We previously mapped quantitative trait loci (QTL) responsible for approximately 26% of the genetic variance in acute alcohol and barbiturate (i.e., pentobarbital) withdrawal convulsion liability to a < 1 cM (1.8 Mb) interval of mouse chromosome 4. To date, Mpdz, which encodes the multiple PSD95/DLG/ZO-1 (PDZ) domain protein (MPDZ), is the only gene within the interval shown to have allelic variants that differ in coding sequence and/or expression, making it a strong candidate gene for the QTL. Previous work indicates that Mpdz haplotypes in standard mouse strains encode distinct protein variants (MPDZ1-3), and that MPDZ status is genetically correlated with severity of withdrawal from alcohol and pentobarbital. Here, we report that MPDZ status cosegregates with withdrawal convulsion severity in lines of mice selectively bred for phenotypic differences in severity of acute withdrawal from alcohol [i.e., High Alcohol Withdrawal (HAW) and Low Alcohol Withdrawal (LAW) lines] or pentobarbital [High Pentobarbital Withdrawal (HPW) and Low Pentobarbital Withdrawal (LPW) lines]. These analyses confirm that MPDZ status is associated with severity of alcohol and pentobarbital withdrawal convulsions. Using a panel of standard inbred strains of mice, we assessed the association between MPDZ status with seizures induced by nine chemiconvulsants. Our results show that MPDZ status is genetically correlated with seizure sensitivity to pentylenetetrazol, kainate and other chemiconvulsants. Our results provide evidence that Mpdz may have pleiotropic effects on multiple seizure phenotypes, including seizures associated with withdrawal from two classes of central nervous system (CNS) depressants and sensitivity to specific chemiconvulsants that affect glutaminergic and GABAergic neurotransmission.

Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice.

Quantitative trait locus (QTL) mapping has allowed dramatic progress toward the detection and chromosome mapping of minor and major gene loci involved in murine responses to alcohol and other drugs of abuse. Here we focus on the identification of QTLs for one particular trait relevant to addiction, drug withdrawal following acute or chronic drug administration. To date, five significant QTLs (p < 5 x 10(-5)) and six suggestive QTLs (p < 0.001) have been mapped to specific murine chromosomes for alcohol and pentobarbital withdrawal, indicating the presence of a relevant gene or genes at each location. Overlapping QTLs for alcohol withdrawal and pentobarbital withdrawal are identified on murine chromosomes 1, 4, and 11, and may detect the influence of common genes. For many QTLs, candidate genes with relevant neurobiological function lie within the mapped region. Notably, several QTLs for alcohol and pentobarbital withdrawal are in proximity to genes that directly or indirectly affect GABAA receptor-mediated transmission, which has been implicated in some of the actions of alcohol and other drugs. These include a cluster of GABAA receptor genes and genes encoding the enzymes steroid 5 alpha-reductase-1 (involved in biosynthesis of the neuroactive steroid allopregnanolone) and glutamic acid decarboxylase-1 (involved in GABA biosynthesis). This paper will discuss data that examines the involvement of GABAergic genes in withdrawal and other drug responses, including genetic variation in gene sequence, expression and function.

Changes of [3H]muscimol binding and GABA(A) receptor beta2-subunit mRNA level by tolerance to and withdrawal from pentobarbital in rats.

Effects of continuous pentobarbital administration on binding characteristics of [3H]muscimol were examined by autoradiography, and levels of GABA(A) receptor beta2-subunit mRNA were investigated by in situ hybridization histochemistry in the rat brain. In order to eliminate the induction of hepatic metabolism by systemic administration of pentobarbital, an i.c.v. infusion model of tolerance to and withdrawal from pentobarbital was used. An experimental model of barbiturate tolerance and withdrawal was developed using i.c.v. infusion of pentobarbital (300 microg/10 microl/hr for 7 days) by osmotic minipumps and abrupt withdrawal from pentobarbital. The levels of [3H]muscimol binding were elevated in cingulate of frontal cortex (46%) and granule layer of cerebellum (32%) of rats 24-hr after withdrawal from pentobarbital, while it was only elevated in cingulate (58%) of tolerant rats. The GABA(A) receptor beta2-subunit mRNA was increased in the withdrawal rats only: in the cortex (9-14%), hippocampus (15-21%), inferior colliculus (21%), and granule layer of cerebellum (24%). These results show the involvement of GABA(A) receptor and its beta2-subunit up-regulations in pentobarbital withdrawal rats, and suggest that the levels of [3H]muscimol binding and GABA(A) receptor beta2-subunit mRNA are altered in a region-specific manner during pentobarbital withdrawal.

Barbiturate withdrawal—a nomogram for supplementary dosing after the phenobarbitone loading technique

A case of a woman who presented with a multiple drug overdose and then subsequently had a withdrawal syndrome complicated by seizures and delirium highlights the seriousness of the barbiturate withdrawal syndrome. The patient had a short elimination half-life for phenobarbitone and required supplementary phenobarbitone doses to prevent and treat these complications. We have devised a nomogram which in conjunction with serum levels allows a rapid determination of whether and how much supplementary doses are required during barbiturate withdrawal.

Dihydropyridine-sensitive calcium channels and barbiturate tolerance and withdrawal

We have shown previously that the dihydropyridine calcium channel antagonist nitrendipine, given chronically, prevents the development of ethanol tolerance and physical dependence. The present study examines the effects on barbiturate tolerance and physical dependence. Nitrendipine, given acutely during withdrawal, provided little protection against barbiturate withdrawal, as measured by convulsive behaviour on handling. When nitrendipine was given chronically concurrently with the barbiturate, a prolonged protection against the withdrawal syndrome was seen. Acute nitrendipine significantly increased the latency of seizures in response to the partial benzodiazepine inverse agonist FG7142 during barbiturate withdrawal, but there was no effect on the seizure incidence in response to bicuculline. Chronic treatment with nitrendipine did not alter the development of tolerance to the ataxic or general anaesthetic actions of barbiturates, but evidence was found of a possible interaction between nitrendipine and pentobarbitone, which may have been pharmacokinetic. The results suggest that neuronal calcium channels may be involved to some degree in the development of the changes responsible for barbiturate withdrawal, but to a less extent than found previously for ethanol dependence.

Possible involvement of NMDA receptor‐mediated transmission in barbiturate physical dependence

1. The competitive antagonists at the N-methyl-D-aspartate (NMDA) receptor, CGP39551 and CGP37849, protected against the barbiturate withdrawal syndrome in mice, as measured by ratings of convulsive behaviour on handling. 2. The effective doses of these compounds were lower than those required to prevent seizures due to NMDA in naive animals; these were in turn lower than those needed to prevent the convulsive effects of the alpha-aminobutyric acid (GABA) antagonist, bicuculline. 3. The NMDA-receptor antagonists did not alter the increase in the incidence of convulsions due to the GABAA antagonist, bicuculline, that is seen during barbiturate withdrawal, although the latencies to these convulsions during barbital withdrawal were significantly increased after CGP39551. 4. Barbiturate withdrawal did not affect the convulsive actions of NMDA, whether measured by the incidence of convulsions or by intravenous infusion. 5. The Bmax for [3H]-dizocilpine ([3H]-MK801) binding was significantly increased by chronic barbital treatment in cerebrocortical but not in hippocampal tissues, while the Kd remained unaltered in either case. 6. At 1 h and 24 h after administration of a single dose of barbitone, the Bmax for [3H]-dizocilpine binding was unaltered in cerebrocortical tissue. Acute addition of barbitone in vitro did not alter [3H]-dizocilpine binding or the displacement of binding of thienylcyclohexylpyridine.

Effects of flunarizine and diltiazem on physical dependence on barbital in rats

The effects of flunarizine and diltiazem both on development of physical dependence on barbital and on barbital withdrawal signs in rats were examined using the drug-admixed food (DAF) method. Rars were chronically treated with barbital or barbital in combination with flunarizine (fixed at 1.5 mg/g of food) or diltiazem (fixed at 0.75 mg/g of food)-admixed food on the schedule of gradually increasing doses of barbital. Motor incoordination during the treatment was potentiated by coadministration of flunarizine, but not by coadministration of diltiazem. After the termination of drug treatment, the body weight loss and withdrawal scores were significantly suppressed in the group coadministered flunarizine, but not in that coadministered diltiazem. There were no significant differences in plasma barbital levels after the withdrawal between groups. In the substitution test, flunarizine (20 and 40 mg/kg, IP) significantly suppressed the body weight loss and withdrawal scores after the withdrawal, but diltiazem (20 mg/kg, IP) did not. These results indicated that flunarizine suppressed both the development of physical dependence on barbital and barbital withdrawal signs, mainly according to the suppression of convulsions, but not diltiazem, which is known to poorly penetrate into the brain. Therefore, the present findings suggest that central calcium channels may be involved in both the development of physical dependence on barbital and the appearance of barbital withdrawal signs.

Hypertension and pulmonary oedema associated with ketamine administration in a patient with a history of substance abuse

Cocaine use, frequently associated with other substance abuse, is becoming more common in the pregnant patient. These patients are more likely to experience peripartum complications. A case of hypertension and pulmonary oedema in such a patient, possibly triggered by ketamine, is reported. A tumultuous course in the intensive care unit was resolved when the patient's hypertension and sympathetic reactivity were successfully treated with barbiturates. A number of factors supported a diagnosis of barbiturate withdrawal in this patient, its onset also was related temporally to ketamine administration. Hypertension should be considered a sign of acute barbiturate withdrawal. If a history of cocaine use, particularly crack cocaine, is elicited, one should suspect multiple substance abuse and be especially cautious when administering ketamine.

Pharmacologic considerations in the treatment of substance abuse.

Drug and alcohol abuse continue to be commonly encountered problems in most patient populations. To deal effectively with these problems, the primary care physician must have a thorough knowledge of the pharmacology of commonly abused drugs and the adjunctive agents used in treatment. Management of alcoholism may involve a range of medical interventions, including the treatment of alcohol intoxication, the use of benzodiazepines for alcohol withdrawal, and possibly the short-term administration of disulfiram to maintain sobriety. Successful management of cocaine or amphetamine abuse requires an understanding of the powerful reinforcing properties of these drugs and the unique problems that arise in the recovery period. Barbiturate intoxication and withdrawal are potentially life-threatening events requiring skilled in-patient treatment. Prolonged use of benzodiazepines can lead to drug dependence; successful withdrawal involves gradual dosage reduction. Acute intoxication from marijuana or hallucinogenic drugs may occasionally result in adverse reactions requiring medical intervention, but significant withdrawal reactions are rare. Management of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid antagonists. Promising new pharmacologic approaches are now being successfully applied to the management of opioid dependence. An acceptance of nicotine as the addictive component of tobacco smoke has led to the development of nicotine gum as substitution therapy for cigarette smoking. Successful pharmacologic management of overdose or withdrawal is often the prerequisite for effective long-term treatment and recovery.

Cholinergic mechanisms in physical dependence on barbiturates, ethanol and benzodiazepines.

The aim of this review is to summarize the effects of acute and chronic treatment with barbiturates, ethanol and benzodiazepines on cholinergic mechanisms in the brains of experimental animals. A single dose of each of these substances reduces the turnover of ACh in the brain. Long-term treatment has the opposite effect; complicated interactions including decreased content of ACh are induced. Barbiturates have been shown to bind stereospecifically to muscarinic and nicotinic receptors in the brain, but this has not been observed for ethanol or the benzodiazepines. The effects on the cholinergic system are affected by the length of treatment and choice of treatment regimen. No effect on cholinergic parameters, such as muscarinic receptors, in the brain is observed on withdrawal of ethanol or barbiturate treatment when the animals are still tolerant towards the substances. The increase in the number of muscarinic receptors observed in several brain regions on withdrawal is seen as a sign of cholinergic supersensitivity. The number of receptors returns to normal when abstinence convulsions have occurred. The assumption of a cholinergic influence is supported by the finding that atropine, given as a single dose on the day of withdrawal of barbital, can prevent the muscarinic receptor changes. Furthermore, long-term barbital or ethanol treatment can induce permanent persistent changes in the cholinergic system in the brain. Cognitive defects and a significant permanent reduction in the content of ACh can be measured in rats which have had long-term barbital treatment. Similarly, a reduced number of muscarinic receptors has been measured in different brain regions of chronic alcoholics. Accumulating data support the role of the cholinergic system in expressing symptoms of physical dependence on barbiturates, ethanol and benzodiazepines as well as in the permanent long-term effects observed after end of treatment.

Barbiturate and Narcotic Withdrawal Medical Complications in a 78-Year-Old Female

AbstractA 78-year-old female experienced delirium and myocardial infarction during barbiturate and narcotic withdrawal. Although substance dependence in the geriatric population is rare, this case illustrates the need for clinician awareness of this potential problem when presented with a confused, elderly patient.

Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis

The authors have used intracerebral microdialysis to develop a method for routine monitoring of disturbances in brain energy metabolism in patients in the neurosurgical intensive care unit. Microdialysis was conducted for periods ranging from 2.3 to 8.3 days in four patients (three with severe head injuries and one with severe subarachnoid hemorrhage). Altogether, 4447 chemical analyses from 587 dialysis samples were carried out. Concentrations of the energy-related metabolites lactate, pyruvate, and hypoxanthine were measured, and the lactate:pyruvate ratio was calculated. In addition, the acids glutamate, aspartate, taurine, glutamine, asparagine, and glycine were measured in one patient. The microdialysis data were matched with various clinical events, including intracranial hypertension and therapeutic interventions such as initiation or withdrawal of barbiturates and cerebrospinal fluid drainage. The present study shows that microdialysis can be used for long-term measurement of extracellular fluid (ECF) energy-related metabolites and amino acids in the frontal cortex of neurosurgical patients in a clinical setting. Fluctuations of the measured ECF energy-related substances corresponded to various clinical events presumably involving hypoxia/ischemia. The authors found a 25-fold increase in ECF glutamate, aspartate, and taurine under conditions of energy perturbation, as indicated by high levels of the lactate:pyruvate ratio, lactate, and hypoxanthine. The use of long-term intracerebral microdialysis in patients opens a new field of clinical research, with many possibilities for improving insight into intracranial dynamics in acute cerebral conditions.

抗けいれん剤内服中の母親より出生した多発奇形児（抗けいれん剤胎芽症）の１症例

We experienced a case of supposed anti-convulsant embryopathy, which is a comparatively rare disease. We would like to supply arguments for its diagnosis and also to make examination of the operative time for cleft palate associated with this case.The case is a 7-month-old male infat without siblings, whose parents' blood relative and lineages deny teratogenic diseases, His moher, who was diagnosed as epilepsy at age 9, has so far been taking anticonvulsant drugs (phenobar, sodium valporate, primidon, sultiame) without interruption during the pregnancy. The pregnant course was uneventful except for unique petit mal in gestational months 4 and 5 each but prenatal growth deficiency led to cesarean section at gestational age, 37 weeks and 3 days. The baby weighed 2, 100g (SFD) at birth, and immediately thereafter, barbiturate withdrawal syndrome appeared and multiple anomalies (wide fontanele, low-set ears, hypertelorism, ptosis of eyelids, cleft palate, contracture palmarls, short fingers, clubbed penis, small scrotum, inguinal hernias, undescended testes, etc). were noted. Thereafter, the infant needed longterm internal medical control becaue of postnatal hypognesis and psychomotor retardation. At age 3 (BW, 8, 160g), the infant received palatoplasty, intra-and post-operative courses being uneventful. Now, one year postoperatively, the infant (aged 4 years and weighing 9, 720g) still presents self-dysbasia and allopliasia in thecourse of observation.

Increased response of cerebellar cGMP to kainate but not NMDA or quisqualate following barbital withdrawal from dependent rats

Female Sprague-Dawley rats were maintained on a diet of powdered food containing barbital for 8 weeks before the drug was abruptly withdrawn. Twenty-four hours later both barbital-dependent and control rats were injected intracerebroventricular (i.c.v.) with saline or one of four doses of kainic acid (KA) or in a separate experiment with saline or one of three doses of N-methyl-D-aspartic acid (NMDA) or of quisqualic acid (QA). After 4.5 min, the animals were killed by focused microwave irradiation, and the cerebella were collected. The levels of cyclic guanosine 3′,5′ monophosphate (cGMP) were markedly elevated in the cerebella of barbital-withdrawn rats when compared to controls. When compared to saline treatment, KA, at all dosages, resulted in a significantly greater elevation of cerebellar cGMP in the barbital-withdrawn rats than was induced by drug withdrawal alone. Only the two higher dosages of KA produced a significant elevation of this parameter in the control rats. Unlike KA, neither QA or NMDA produced any greater elevations of cGMP in barbital withdrawn rats than were induced by drug withdrawal alone. These collective results suggest that there is an increase in the response to KA but not QA or NMDA following the withdrawal of barbital from dependent rats.

Managing alcohol, barbiturate and benzodiazepine withdrawal syndromes

Managing alcohol, barbiturate and benzodiazepine withdrawal syndromes

Neuropsychiatric aspects of sedative drug withdrawal

AbstractThe withdrawal syndromes after discontinuance of alcohol, barbiturates, benzodiazepines and other sedative drugs, such as chloral and paraldehyde, are all similar. The severity of a withdrawal reaction is largely determined by the daily dose, the duration of administration and the rate of fall of the drug levels after withdrawal, as well as the propensity of the individual patient. The time course of a withdrawal reaction is determined by the drug's clearance. Alcohol has a half‐life of a few hours; withdrawal symptoms may develop within 6–8 hours of abstinence and convulsions in 12–48 hours. After discontinuance of short‐ or medium‐acting barbiturates (half‐life 8–40 hours) symptoms may develop in 1–3 days, followed by convulsions and delirium after 3–8 days. Symptoms and seizures may develop in the 1–10 days after withdrawal of benezodiazepines.In patients with no prior history of epilepsy the types of seizures most commonly induced by drug withdrawal are generalized convulsions, but partial seizures are not uncommon if there is a focal cerebral lesion, or a previous history of partial seizures. Paroxysmal activity and photosensitivity may occur after barbiturate withdrawal in non‐epileptics, more commonly in severe withdrawal reactions. Similar EEG changes may be seen after alcohol and benzodiazepine withdrawal, but photosensitivity does not appear to have been shown to be a feature of the benzodiazepine withdrawal syndrome.

Anticonvulsive activity of several excitatory amino acid antagonists against barbital withdrawal-induced spontaneous convulsions

Several excitatory amino acid antagonists were tested for an ability to prevent spontaneous convulsions seen during the barbital abstinence syndrome in rats. Barbital-dependent animals were continuously infused intracerebroventricularly (i.c.v.) for the first 48 h following barbital withdrawal with either saline, 2-amino-7-phosphonoheptanoic acid (APH), magnesium sulfate, glutamyldiethyl ester (GDEE) or cis-2,3-piperidine dicarboxylic acid (PDA) using the highest dosages which did not affect normal behavior of the rats. All animals were observed continuously from 12 to 48 h postwithdrawal and the number of spontaneous convulsions observed in each animal was recorded. After this time, animals were killed by focused microwave irradiaton and the cerebellas were collected for determination of cyclic guanosine monophosphate (cGMP) levels. While both APH and MgSO 4 dramatically prevented convulsions, only APH prevented the withdrawal-induced elevation of cerebellar cGMP. PDA and GDEE had no statistically significant effect on either cerebellar cGMP levels or on convulsive activity. Although the effect of GDEE was not statistically significant, the number of convulsions was reduced to 1 3 those seen in control animals. These data implicate N-methyl-d-aspartate (NMDA) receptor-mediated pathways in seizure activity associated with the barbital abstinence syndrome and show that the withdrawal-induced elevation of cerebellar cGMP can occur without the induction of convulsions.