- Email: [email protected]
The effect of some calcium antagonists on phenobarbital withdrawal syndrome in rats
I?5 Addiction
significance. The mammalian receptor is ubiquitously distributed with high concentrations in the outer mitochondrial membrane of several central and peripheral tissues. It is now well established that it plays a critical role in the production of neurosteroids, which are able to alter the electrical properties of neuronal membranes and thus the firing patterns of neurons Animal experiments demonstrated that chronic ethanol exposure increased central omega-3-receptors and stimulates receptor-related mRNA expression of diazepam binding inhibitor (DBI), which is proposed to be an endogenous ligand at the omega-3-receptor. Moreover, alterations in omega-3-receptor density have been found following a variety of pharmacological manipulations, e.g., chronic administration of ethanol, benzodiazepines and certain antiepileptics. Therefore, it has been hypothesized that these receptors might be involved in the development of adaptive biochemical changes, resulting in tolerance and withdrawalsyndromes, such as epileptic seizures. Previous studies found a decreased density of omega-3-receptors on platelets of currently drinking social alcoholics. In contrast, we examined detoxified heavy drinkers, fulfilling at least 5 diagnostic ICD-10 criteria of alcohol dependence. At the time of investigation, the patients had completed a 6 week in-patient abstention program. We evaluated the characteristic binding parameters (Bmax, Kd) of the granulocytic omega-3-receptors by means of a filter binding assay, using the selective isoquinoline carboxamide 3H-PK 11.195. Preliminary results of this ongoing study suggest an increased binding capacity (Bmax) especially in alcoholics with comorbid tobacco dependence (Tab.). (supported by BMBF grant OlEB9410)
arithmeticmean It
Kd [nM]
SD
lp.5.026]
(N = 19) (N = 14)
1.71 * 0.91 1.41 & 0.96 I .62 + 1.09
antagonist. PTZ at a dose of 70 mgAcg S.C.provoked seizures with mild intensity. The cessation for 48 h of the prolong phenobarbital treatment led to appearance of withdrawal syndrome which was character&d by an increase of seizure intensity and of the percentage of rats with tonic seizures. The prolong (14 days) oral treatment with the four calcium antagonists tested in combination with phenobarbital alleviates the signs of phenobarbital withdrawal. The seizure intensity and the percentage of rats with tonic seizures in the group treated with both phenobarbital and flunarizine; phenobarbital and verapamil; phenobarbital and nitrendipine and phenobarbital and nifedipine were significantly lower as compared to the group of rats treated with phenobarbital only. Calcium antagonists realised their effects via: (i) inhibition of Ca*+ entry; (ii) interactions with different neurotransmitters; (iii) action on cerebral circulation, (iv) metabolism; (v) neuronal hyperexcitability. The present data suggest the ability of the four studied calcium antagonists to attenuate the manifestations of anticonvulsant withdrawal as well as the possibility of using calcium antagonists as adjutants in the prolong anticonvulsive therapy. References [1] Little, H.J., Dolin, S.J., Wittington, M.A. (1993) Calcium channel antagonists prevent adaptive reponses to ethanol. Alcohol-alcohol-suppl. 2. 263-267. [2] Wurpel, J.N.D., Iyer, S.N. (1994) Calcium channel blockers verapamil and nimodipine inhibit kindling in adult and immature rats. Epilepsia 35.443449.
(p.5.027(
Toxicological and psychological profile of MDMA (ecstasy) abusers and non-abusers in military conscripts
Bmax [tM/l x lo6 G%UlUlOCyt~S]
Alkoholabhilngige (N = 23) Gesunde Vergleichsprobanden Alkohol- und Tabakabhtigige
S289
239.1 f 278.4 117.1 f 80.9 306.7 f 367.8
The effect of some calcium antagonists on phenobarbital withdrawal syndrome in rats
M. Lazarova, B. Petkova, Y. Delchev’, S. Zlatanova, D. StanevaStoycheva. Institute of Physiology, Bulgarian Academy of Sciences, Sofa, Bulgaria The seizures are the most characteristic symptoms of epilepsy but they appear or accompany other neurological illnesses such as brain ischemia, trauma, intoxications, insults, etc. Having in mind that epilepsy is a wide spread desease with dramatic consequences for the patients and for the society and that anticonvulsive therapy is long-lasting, the investigation of the effect of calcium antagonists on anticonvulsants withdrawal syndrome is of interest both for theory and medical practice. It is known that calcium antagonists posses anticonvulsive activity (Wurpel and Iyer, 1994). There are experimental and clinical data about the protective effect of calcium antagonists on opiate, benzodiazepine or ethanol withdrawal syndrome (Little et al., 1993). However, the influence of calcium antagonists on withdrawal syndrome appearing after the stopping of the prolong treatment with anticonvulsant has not yet been studied. The experiments were aimed at investigating the influence of some calcium antagonists on anticonvulsants withdrawal syndrome. The effects of prolong (14 days) oral treatment with the calcium antagonists flunarizine (10 m&g), verapamil (20 mgkg), nitrendipine (40 mg/kg) and nifedipiine (40 mgAcg)on the withdrawal syndrome after stopping of prolong (14 days) treatment with phenobarbital (5 m&g orally every day) were examined. The pentilenetetrazol (PTZ)-seizure model in male Wistar rats was used. The experiments were carried out at the 48” h after withdrawal of the anticonvulsant drug or the calcium
PA. Sbiz, M.P. Gonzalez, M. Bousotio, J. Bobes. Department ofPsychiatv, Faculty of Medicine, University of Ouiedo. Spain Objectives: To describe the prevalence of MDMA consumption and the toxicological and psychological profile of a sample of young male conscripts from Asturias (Spain). Subjects and Method: The WHO questionnaire for drug consumption, the Eysenck Personality Questionnaire-Adult form (EPQ-A), the Zuckerman Sensation Seeking Scale and the Dupuy Psychological General Well-Being Index (PGWB Index) were administered to 2,859 male conscripts [mean age = 20.300 (2.524)] who entered military service during 1995-97. Results: The total sample was divided into three groups according to the level of drug consumption in the previous year- group 1 (n = 1,950): only legal drugs (tobacco and alcohol), group 2 (n = 673): illegal drugs without ecstasy, group 3 (n = 236): illegal drugs plus ecstasy. Total sample consumption of MDMA- sometimes: 320 (11.2%); in preonth: 134 (4.7%); “pure” consumers of MDMA in previous year: 13 (0.45%); age of commencement: 16.864 (2.993). Consumption of illegal drugs- Compared with group 2, group 3 showed significantly higher levels of consumption of all drugs, except cannabis. Mean rate of drugs consumed- group 2: 1.743 (1.374) group 3: 4.097 (2.579), (p = .OOO). Drug consumption and psychological evaluation. Results are given in the Table. Conclusions: MDMA consumers are polyconsumers of other legal and illegal substances. Those who consume MDMA have a different profile characterized by high sensation seeking, emotional inestability, high levels of psychoticism and impulsivity and believe that they have a poorer general well-being. References [l] Beck J, Rosenbamn M (1994). The pursuit of ecstasy: The MDMA experience. New York: State University of New York Press. 121 Bobes J, Lorenzo P, SBiz PA (1998). Extasis (MDMA): Un abordaje comprehensivo. Barcelona: Masson. (31 O’Connor LE, Berry JW, Morrison A, Brown S (1995). The drug-of-choice phenomenon: Psychological differences among drug users who preferred different drugs. Int. J. Addictions. 30 (5): 541-555
significance. The mammalian receptor is ubiquitously distributed with high concentrations in the outer mitochondrial membrane of several central and peripheral tissues. It is now well established that it plays a critical role in the production of neurosteroids, which are able to alter the electrical properties of neuronal membranes and thus the firing patterns of neurons Animal experiments demonstrated that chronic ethanol exposure increased central omega-3-receptors and stimulates receptor-related mRNA expression of diazepam binding inhibitor (DBI), which is proposed to be an endogenous ligand at the omega-3-receptor. Moreover, alterations in omega-3-receptor density have been found following a variety of pharmacological manipulations, e.g., chronic administration of ethanol, benzodiazepines and certain antiepileptics. Therefore, it has been hypothesized that these receptors might be involved in the development of adaptive biochemical changes, resulting in tolerance and withdrawalsyndromes, such as epileptic seizures. Previous studies found a decreased density of omega-3-receptors on platelets of currently drinking social alcoholics. In contrast, we examined detoxified heavy drinkers, fulfilling at least 5 diagnostic ICD-10 criteria of alcohol dependence. At the time of investigation, the patients had completed a 6 week in-patient abstention program. We evaluated the characteristic binding parameters (Bmax, Kd) of the granulocytic omega-3-receptors by means of a filter binding assay, using the selective isoquinoline carboxamide 3H-PK 11.195. Preliminary results of this ongoing study suggest an increased binding capacity (Bmax) especially in alcoholics with comorbid tobacco dependence (Tab.). (supported by BMBF grant OlEB9410)
arithmeticmean It
Kd [nM]
SD
lp.5.026]
(N = 19) (N = 14)
1.71 * 0.91 1.41 & 0.96 I .62 + 1.09
antagonist. PTZ at a dose of 70 mgAcg S.C.provoked seizures with mild intensity. The cessation for 48 h of the prolong phenobarbital treatment led to appearance of withdrawal syndrome which was character&d by an increase of seizure intensity and of the percentage of rats with tonic seizures. The prolong (14 days) oral treatment with the four calcium antagonists tested in combination with phenobarbital alleviates the signs of phenobarbital withdrawal. The seizure intensity and the percentage of rats with tonic seizures in the group treated with both phenobarbital and flunarizine; phenobarbital and verapamil; phenobarbital and nitrendipine and phenobarbital and nifedipine were significantly lower as compared to the group of rats treated with phenobarbital only. Calcium antagonists realised their effects via: (i) inhibition of Ca*+ entry; (ii) interactions with different neurotransmitters; (iii) action on cerebral circulation, (iv) metabolism; (v) neuronal hyperexcitability. The present data suggest the ability of the four studied calcium antagonists to attenuate the manifestations of anticonvulsant withdrawal as well as the possibility of using calcium antagonists as adjutants in the prolong anticonvulsive therapy. References [1] Little, H.J., Dolin, S.J., Wittington, M.A. (1993) Calcium channel antagonists prevent adaptive reponses to ethanol. Alcohol-alcohol-suppl. 2. 263-267. [2] Wurpel, J.N.D., Iyer, S.N. (1994) Calcium channel blockers verapamil and nimodipine inhibit kindling in adult and immature rats. Epilepsia 35.443449.
(p.5.027(
Toxicological and psychological profile of MDMA (ecstasy) abusers and non-abusers in military conscripts
Bmax [tM/l x lo6 G%UlUlOCyt~S]
Alkoholabhilngige (N = 23) Gesunde Vergleichsprobanden Alkohol- und Tabakabhtigige
S289
239.1 f 278.4 117.1 f 80.9 306.7 f 367.8
The effect of some calcium antagonists on phenobarbital withdrawal syndrome in rats
M. Lazarova, B. Petkova, Y. Delchev’, S. Zlatanova, D. StanevaStoycheva. Institute of Physiology, Bulgarian Academy of Sciences, Sofa, Bulgaria The seizures are the most characteristic symptoms of epilepsy but they appear or accompany other neurological illnesses such as brain ischemia, trauma, intoxications, insults, etc. Having in mind that epilepsy is a wide spread desease with dramatic consequences for the patients and for the society and that anticonvulsive therapy is long-lasting, the investigation of the effect of calcium antagonists on anticonvulsants withdrawal syndrome is of interest both for theory and medical practice. It is known that calcium antagonists posses anticonvulsive activity (Wurpel and Iyer, 1994). There are experimental and clinical data about the protective effect of calcium antagonists on opiate, benzodiazepine or ethanol withdrawal syndrome (Little et al., 1993). However, the influence of calcium antagonists on withdrawal syndrome appearing after the stopping of the prolong treatment with anticonvulsant has not yet been studied. The experiments were aimed at investigating the influence of some calcium antagonists on anticonvulsants withdrawal syndrome. The effects of prolong (14 days) oral treatment with the calcium antagonists flunarizine (10 m&g), verapamil (20 mgkg), nitrendipine (40 mg/kg) and nifedipiine (40 mgAcg)on the withdrawal syndrome after stopping of prolong (14 days) treatment with phenobarbital (5 m&g orally every day) were examined. The pentilenetetrazol (PTZ)-seizure model in male Wistar rats was used. The experiments were carried out at the 48” h after withdrawal of the anticonvulsant drug or the calcium
PA. Sbiz, M.P. Gonzalez, M. Bousotio, J. Bobes. Department ofPsychiatv, Faculty of Medicine, University of Ouiedo. Spain Objectives: To describe the prevalence of MDMA consumption and the toxicological and psychological profile of a sample of young male conscripts from Asturias (Spain). Subjects and Method: The WHO questionnaire for drug consumption, the Eysenck Personality Questionnaire-Adult form (EPQ-A), the Zuckerman Sensation Seeking Scale and the Dupuy Psychological General Well-Being Index (PGWB Index) were administered to 2,859 male conscripts [mean age = 20.300 (2.524)] who entered military service during 1995-97. Results: The total sample was divided into three groups according to the level of drug consumption in the previous year- group 1 (n = 1,950): only legal drugs (tobacco and alcohol), group 2 (n = 673): illegal drugs without ecstasy, group 3 (n = 236): illegal drugs plus ecstasy. Total sample consumption of MDMA- sometimes: 320 (11.2%); in preonth: 134 (4.7%); “pure” consumers of MDMA in previous year: 13 (0.45%); age of commencement: 16.864 (2.993). Consumption of illegal drugs- Compared with group 2, group 3 showed significantly higher levels of consumption of all drugs, except cannabis. Mean rate of drugs consumed- group 2: 1.743 (1.374) group 3: 4.097 (2.579), (p = .OOO). Drug consumption and psychological evaluation. Results are given in the Table. Conclusions: MDMA consumers are polyconsumers of other legal and illegal substances. Those who consume MDMA have a different profile characterized by high sensation seeking, emotional inestability, high levels of psychoticism and impulsivity and believe that they have a poorer general well-being. References [l] Beck J, Rosenbamn M (1994). The pursuit of ecstasy: The MDMA experience. New York: State University of New York Press. 121 Bobes J, Lorenzo P, SBiz PA (1998). Extasis (MDMA): Un abordaje comprehensivo. Barcelona: Masson. (31 O’Connor LE, Berry JW, Morrison A, Brown S (1995). The drug-of-choice phenomenon: Psychological differences among drug users who preferred different drugs. Int. J. Addictions. 30 (5): 541-555