- Email: [email protected]
Gamma-hydroxybutyric acid: A “methadone” for alcoholism?
S-75 Neurosurgery for Mental Disorders in the Decade of the Brain: Current Ethical, Clinical and Scientific Issues but not naive controls, respond to cocaine-related stimuli with self-reports of cocaine craving and activation of cortical areas thought to participate in episodic memory. Thus, metabolic mapping studies in human volunteers have provided information on the acute effects of drugs of abuse and on persistent abnormalities in brain metabolism in drug abusers. The studies provide insight that is needed in order to rationally design medication targeted at specific behavioral features of addictive disorders.
18-74-31 Quantitating Benzodiazepine and Opiate Receptor Sensitivity in Addicts J. Potokar, N. Coupland, S. Wilson, J. Bailey, F. Law, DJ. Nutt. Psychopharmacology Unit, University of Bristol, UK A major difficulty in quantitating benzodiazepine and opiate receptor sensitivity has been the lack of reliability of measures used, such as symptom reports and psychometric tests, both of which may be influenced by motivational factors. We have been using the technique of saccadic eye movement (SEM) analysis to measure the central effects of different drugs. SEMs are involuntary rapid conjugate gaze changes, enabling the eye to centre a target of interest onto the fovea. An infusion of the short TI/2 benzodiazepine, midazolam in volunteers, causes eye movement slowing that is highly correlated with midazolam dose and plasma concentration [I]. We have been extending this paradigm to patients on chronic benzodiazepine therapy; preliminary results show attenuation of SEM velocity which may be a hard measure of the tolerance that occurs with chronic benzodiazepine use. Since opiates also influence SEMs (the superior colliculus, a major relay station for SEMs, contains opiate receptors), we have been measuring them in studies of methadonelbuprenorphine transfer in addicts and find an increase in velocity to parallel self ratings of withdrawal. Traditional measures of opiate function include pupilometry, CRT and CFF. SEMs have several advantages. They are not significantly effected by emotional state, cognitions and accommodation. They have high test/retest reliability are sensitive and therefore a useful tool for probing central opiate function. [II Ball et al (1991) Psychopharmacology 105: 361-367
18-74-5 1 Gamma-Hydroxybutyric Acid: A "Methadone" for Alcoholism? G. Colombo, G.L. Gessa. Departmentof Neuroscience, University of
Cagliari, Italy Gamma-hydroxybutyric acid (GHB) is a normal constituent of the mammalian brain. The existence in brain of specific receptor sites, uptake system, synthesis, metabolizing enzymes and release mechanisms supports the idea that GHB might function as a neurotransmitter in the CNS. Experimental and clinical evidence, summarized here, indicates that GHB is not only an efficacious drug for alcoholism, but may represent an important tool to unravel the elusive mechanism of action of ethanol in brain. The administration of GHB inhibits voluntary alcohol intake in genetically selected alcohol-preferring sP [I] and P [2] rats. Similarly, in alcoholic patients, GHB has been shown to readily suppress alcohol withdrawal symptomatology and to reduce craving for alcohol, alcohol consumption and relapse [3-6]. Experimental evidence indicates that GHB mimics alcohol in different central actions [7]. More recently, drug discrimination studies have shown a symmetrical generalization between alcohol and GHB, in that GHB substitutes for alcohol in its discriminative stimulus effects and vice versa [8]. Moreover, the selective GHE receptor antagonist, NCS-382, has been shown to block not only, as expected, the discriminative stimulus effects of GHB [9], but also those of alcohol (Colombo et al, in preparation). These results suggest that GHB and alcohol elicit the same internal cues by an action on GHB receptors. The latter might represent a target for a novel approach to alcoholism. [I] Fadda F et al, Psychopharmacology 96(Suppl) (1998) 107. [2] June HLet aI, Alcohol. Clin. Exp. Res. 19(5uppl) (1995) 14A. [3] Gallimberti Let al, The Lancet ii (1989) 787-789. [4] Gallimberti Let aI, Alcohol. Clin. Exp. Res. 16(1992) 673-676. [5] Nimmerrichter AAet ai, Alcohol. Clin. Exp. Res. 19(5uppl) (1995) 18A. [6] Di BelloMGet al, Alcologia 7 (1995) 9-16. [7] DianaM et al Brain Res. 566 (1991) 208-211. [8] Colombo G et al, PhysioI. Behav. 57 (1995) 105-111. [9J Colombo G et al, Physio!. Behav. 58 (1995) 587-590.
15-751 Neurosurgery for Mental Disorders in the Decade of the Brain: Current Ethical, Clinical and Scientific Issues
18-74-41 Stimulant-Opiate Interactions in Humans M.W. Fischman, R.W. Foltin. Department of Psychiatry, Columbia
University, New York, NY, USA Cocaine-heroin combinations Cspeedball') are popular with drug abusers. Laboratory data collected with humans suggest that combinations of single doses of intravenous cocaine with an opiate (morphine or buprenorphine, a partial opiate agonist) result in a profile of effects representative of both of them, suggesting that stimulant-opiate combinations can have high abuse liability. Interestingly, research with non-humans showed that cocaine self-administration is attenuated under buprenorphine maintenance, and laboratory data collected with human non-opiate dependent cocaine users indicate that buprenorphine treatment is associated with a decrease in self-administration of 16 and 32 mg/70 kg doses of cocaine, although not with decreases in cocaine "craving" scores. Since those data suggested that buprenorphine might be efficacious in the treatment of opiate dependent cocaine abusers, the effects of buprenorphine maintenance (8 mg sublingual plus oral placebo) and methadone maintenance (60 mg oral plus sublingual placebo) on cocaine self-administration were compared. All subjects were tested under both maintenance conditions. The transition from methadone to buprenorphine engendered moderate withdrawal symptoms which were not controlled by c1onidine, but responded well to several days of oxazepam and chloral hydrate. In general , the subjective and physiological effects of cocaine were similar regardless of the maintenance medication. Choice to self-administer cocaine was differentially affected by the two medications, with fewer 16 and 32 mg170 kg doses self-administered under buprenorphine maintenance. In addition, methadone and buprenorphine maintenance appeared to differentially affect drug craving scores, although the effect was not consistent. Thus, under some conditions, buprenorphine may be more useful than methadone for treating opiate/cocaine abusers. Support: DA-03818 and DA-06234 (NIDA) and MOI-RR-00645 (NIH)
229
I8-75-1 I Neurosurgery for Mental Disorders in the Decade of the Brain. Purpose andIntroduction
P. Mindus (Chair), P. Sachdev (Co-chair).
Purpose: To offer an update on psychiatry's most strikingly braincentered and controversial treatment modality; Neurosurgery for Mental Disorders (NMD). Introduction: Although both unfounded and well-founded criticism has been able to knock it down, "psychosurgery" has not been knocked out. With the recognition that some cases with affective, obsessional, or anxiety disorders prove refractory even to extensive and intensive treatment efforts and remain extremely disabled, interest in NMD has reawakened, and a limited number of operations are carried out today. However, a recent survey among specialists clearly demonstrated a need for an update on NMD. Program: Panelists will discuss aspects of decision making, neuroanatomy, brain imaging, current techniques, contemporary indications and contraindications, expected clinical outcome in different patient populations, and risk-benefit and ethical issues.
I
8-75-2 1 Contemplating Neurosurgery for Refractory OCD. ThePerspective of the Referring Psychiatrist
J. Zohar, Y. Sasson, 1. Hendler, M. Lustig. Division of Psychiatry; Chaim Sheba Medical Center, Tel-Hashomer, Israel Obsessive compulsive disorder (OCD) is the second most prevalent psy-
18-74-31 Quantitating Benzodiazepine and Opiate Receptor Sensitivity in Addicts J. Potokar, N. Coupland, S. Wilson, J. Bailey, F. Law, DJ. Nutt. Psychopharmacology Unit, University of Bristol, UK A major difficulty in quantitating benzodiazepine and opiate receptor sensitivity has been the lack of reliability of measures used, such as symptom reports and psychometric tests, both of which may be influenced by motivational factors. We have been using the technique of saccadic eye movement (SEM) analysis to measure the central effects of different drugs. SEMs are involuntary rapid conjugate gaze changes, enabling the eye to centre a target of interest onto the fovea. An infusion of the short TI/2 benzodiazepine, midazolam in volunteers, causes eye movement slowing that is highly correlated with midazolam dose and plasma concentration [I]. We have been extending this paradigm to patients on chronic benzodiazepine therapy; preliminary results show attenuation of SEM velocity which may be a hard measure of the tolerance that occurs with chronic benzodiazepine use. Since opiates also influence SEMs (the superior colliculus, a major relay station for SEMs, contains opiate receptors), we have been measuring them in studies of methadonelbuprenorphine transfer in addicts and find an increase in velocity to parallel self ratings of withdrawal. Traditional measures of opiate function include pupilometry, CRT and CFF. SEMs have several advantages. They are not significantly effected by emotional state, cognitions and accommodation. They have high test/retest reliability are sensitive and therefore a useful tool for probing central opiate function. [II Ball et al (1991) Psychopharmacology 105: 361-367
18-74-5 1 Gamma-Hydroxybutyric Acid: A "Methadone" for Alcoholism? G. Colombo, G.L. Gessa. Departmentof Neuroscience, University of
Cagliari, Italy Gamma-hydroxybutyric acid (GHB) is a normal constituent of the mammalian brain. The existence in brain of specific receptor sites, uptake system, synthesis, metabolizing enzymes and release mechanisms supports the idea that GHB might function as a neurotransmitter in the CNS. Experimental and clinical evidence, summarized here, indicates that GHB is not only an efficacious drug for alcoholism, but may represent an important tool to unravel the elusive mechanism of action of ethanol in brain. The administration of GHB inhibits voluntary alcohol intake in genetically selected alcohol-preferring sP [I] and P [2] rats. Similarly, in alcoholic patients, GHB has been shown to readily suppress alcohol withdrawal symptomatology and to reduce craving for alcohol, alcohol consumption and relapse [3-6]. Experimental evidence indicates that GHB mimics alcohol in different central actions [7]. More recently, drug discrimination studies have shown a symmetrical generalization between alcohol and GHB, in that GHB substitutes for alcohol in its discriminative stimulus effects and vice versa [8]. Moreover, the selective GHE receptor antagonist, NCS-382, has been shown to block not only, as expected, the discriminative stimulus effects of GHB [9], but also those of alcohol (Colombo et al, in preparation). These results suggest that GHB and alcohol elicit the same internal cues by an action on GHB receptors. The latter might represent a target for a novel approach to alcoholism. [I] Fadda F et al, Psychopharmacology 96(Suppl) (1998) 107. [2] June HLet aI, Alcohol. Clin. Exp. Res. 19(5uppl) (1995) 14A. [3] Gallimberti Let al, The Lancet ii (1989) 787-789. [4] Gallimberti Let aI, Alcohol. Clin. Exp. Res. 16(1992) 673-676. [5] Nimmerrichter AAet ai, Alcohol. Clin. Exp. Res. 19(5uppl) (1995) 18A. [6] Di BelloMGet al, Alcologia 7 (1995) 9-16. [7] DianaM et al Brain Res. 566 (1991) 208-211. [8] Colombo G et al, PhysioI. Behav. 57 (1995) 105-111. [9J Colombo G et al, Physio!. Behav. 58 (1995) 587-590.
15-751 Neurosurgery for Mental Disorders in the Decade of the Brain: Current Ethical, Clinical and Scientific Issues
18-74-41 Stimulant-Opiate Interactions in Humans M.W. Fischman, R.W. Foltin. Department of Psychiatry, Columbia
University, New York, NY, USA Cocaine-heroin combinations Cspeedball') are popular with drug abusers. Laboratory data collected with humans suggest that combinations of single doses of intravenous cocaine with an opiate (morphine or buprenorphine, a partial opiate agonist) result in a profile of effects representative of both of them, suggesting that stimulant-opiate combinations can have high abuse liability. Interestingly, research with non-humans showed that cocaine self-administration is attenuated under buprenorphine maintenance, and laboratory data collected with human non-opiate dependent cocaine users indicate that buprenorphine treatment is associated with a decrease in self-administration of 16 and 32 mg/70 kg doses of cocaine, although not with decreases in cocaine "craving" scores. Since those data suggested that buprenorphine might be efficacious in the treatment of opiate dependent cocaine abusers, the effects of buprenorphine maintenance (8 mg sublingual plus oral placebo) and methadone maintenance (60 mg oral plus sublingual placebo) on cocaine self-administration were compared. All subjects were tested under both maintenance conditions. The transition from methadone to buprenorphine engendered moderate withdrawal symptoms which were not controlled by c1onidine, but responded well to several days of oxazepam and chloral hydrate. In general , the subjective and physiological effects of cocaine were similar regardless of the maintenance medication. Choice to self-administer cocaine was differentially affected by the two medications, with fewer 16 and 32 mg170 kg doses self-administered under buprenorphine maintenance. In addition, methadone and buprenorphine maintenance appeared to differentially affect drug craving scores, although the effect was not consistent. Thus, under some conditions, buprenorphine may be more useful than methadone for treating opiate/cocaine abusers. Support: DA-03818 and DA-06234 (NIDA) and MOI-RR-00645 (NIH)
229
I8-75-1 I Neurosurgery for Mental Disorders in the Decade of the Brain. Purpose andIntroduction
P. Mindus (Chair), P. Sachdev (Co-chair).
Purpose: To offer an update on psychiatry's most strikingly braincentered and controversial treatment modality; Neurosurgery for Mental Disorders (NMD). Introduction: Although both unfounded and well-founded criticism has been able to knock it down, "psychosurgery" has not been knocked out. With the recognition that some cases with affective, obsessional, or anxiety disorders prove refractory even to extensive and intensive treatment efforts and remain extremely disabled, interest in NMD has reawakened, and a limited number of operations are carried out today. However, a recent survey among specialists clearly demonstrated a need for an update on NMD. Program: Panelists will discuss aspects of decision making, neuroanatomy, brain imaging, current techniques, contemporary indications and contraindications, expected clinical outcome in different patient populations, and risk-benefit and ethical issues.
I
8-75-2 1 Contemplating Neurosurgery for Refractory OCD. ThePerspective of the Referring Psychiatrist
J. Zohar, Y. Sasson, 1. Hendler, M. Lustig. Division of Psychiatry; Chaim Sheba Medical Center, Tel-Hashomer, Israel Obsessive compulsive disorder (OCD) is the second most prevalent psy-