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Aversive factors in alcohol drinking in humans and animals
102
In vitro studies on rat striatal slices showed that GABA inhibited, in a specific fashion, the potassium-induced release of met-enkephalin, whilst a series of further putative neurotransmitters and morphine were ineffective in modulating this release. Similar experiments on isolated pituitaries revealed distinct release characteristics for /3-endorphin operating in the anterior lobe as compared to the intermediate lobe and differential effects of drugs in manipulating release from these. The hypothalamic corticotropin releasing factor and [ Lys] vasopressin induce release from the anterior lobe only, whereas release from the intermediate lobe was found to be under a dopaminergic inhibitory control. In uivo studies in rats showed that the levels of opioid peptides remain rather stable under acute drug treatment. (However, one has to bear in mind that measurement of levels provides only a limited degree of information concerning the functional state of a system; the possibilities of measuring turnover rates of peptides being, presently, limited.) Significant decrease in the content of opioid peptides in rat striatum was found after acute benzodiazepine treatment, a change apparently mediated via a GABAergic mechanism. The opposite effect (an increase) was observed after chronic diazepam treatment. Characteristic changes in opioid peptide content have been found after chronic treatment with various drugs: a decrease in some brain areas and in the intermediate lobe after prolonged morphine treatment, an effect also produced by chronic alcohol treatment, but not by some other opiates. An opposite effect was observed after chronic neuroleptic treatment. Incorporation studies with labelled amino acid in isolated cells of the intermediate lobe revealed that these changes take place largely at the level of precursor (proopiocortin) formation whilst the enzymatic processing of this precursor is not greatly affected. The implications of these findings in terms of an endorphin-deficit theory of addiction are discussed.
R AVERSIVE ANIMALS ROBERT
FACTORS
D. MYERS
IN ALCOHOL
DRINKING
IN HUMANS
AND
and JOHN A. EWING
Center for Alcohol Studies, Hill, NC 27514 (U.S.A.)
School
of Medicine,
University
of North
Carolina,
Chapel
In human subjects there is a wide range of response to the taste of alcohol in varying concentrations. What some people find totally aversive may be accepted with relish by others. Both individual and racial responses to ingested or injected alcohol can be aversive, since markedly dysphoric experiences can occur. Human studies also suggest that the euphorigenic properties of alcohol are very variable between subjects and that this correlates with characteristics of biogenic amines present in the body.
Except for relatively low concentrations the laboratory rat, used commonly in alcohol drinking experiments, avoids the selection of alcohol. Paralleling human studies there are animal investigations that manipulate the levels of chemical substances in the brain and demonstrate effects of this upon alcohol selection. For example, differential lesioning by neurotoxins of catechol and indoleamine pathways in the brain of the rat can markedly affect the voluntary selection of alcohol solutions in a wide range of concentrations. When certain tetrahydroisoquinolines or p-carboline substances are infused into the brain of the rat, the aversive nature of orally ingested alcohol, particularly in very high concentrations, is overcome. The possible mechanisms for this phenomenon and the recent investigations of agents acting on CNS opiate receptors in reinstating alcohol aversion will be discussed. Supported by grants from Center for Alcohol Studies, North Carolina Alcoholism Research Authority, National Institute on Alcohol Abuse and Alcoholism. 110 NEUROHYPOPHYSEAL PEPTIDE INFLUENCES ON ETHANOL TOLERANCE AND ACUTE EFFECTS OF ETHANOL RONALD
F. RITZMANN,
Department of Physiology West Side Medical Center,
PAULA
L. HOFFMAN*
and Biophysics, University Chicago, IL 60612 (U.S.A.)
and BORIS TABAKOFF of Illinois Medical
Center,
und VA
Administration of the neurohypophyseal hormone [ Arg’] vasopressin (AVP) was previously shown to prolong ethanol tolerance in mice, once this tolerance had been established. Drug tolerance and certain memory-related processes, such as consolidation have been proposed to share underlying mechanisms, in that both are examples of CNS adaptive processes. We therefore wished to investigate the effects on ethanol tolerance of some other neurohypophyseal peptides which have been found to attenuate amnesia and/or inhibit extinction of avoidance responses. Male C57Bl mice were fed a liquid diet containing 7% ethanol or an equicaloric amount of sucrose for seven days. On the eighth day all mice received the sucrose-containing diet (withdrawal). One day after withdrawal mice were divided into subgroups which received daily subcutaneous injections of saline or peptide. Animals were tested for tolerance to the hypothermic and sedative effects of ethanol at one day and eight days after withdrawal. Both AVP (40 nmole/kg) as shown previously, and des-glycinamideg-[ Lys] vasopressin (DGLVP), an analog devoid of endocrinological activity, maintained ethanol tolerance in the ethanol-treated animals up to eight days after withdrawal, a time when animals not receiving peptides were no longer tolerant. On the other hand, control and ethanol-exposed animals which were treated daily with 40 nmole/kg cyclo(Leu-Gly), the cyclic derivative of the C-terminal dipeptide of
In vitro studies on rat striatal slices showed that GABA inhibited, in a specific fashion, the potassium-induced release of met-enkephalin, whilst a series of further putative neurotransmitters and morphine were ineffective in modulating this release. Similar experiments on isolated pituitaries revealed distinct release characteristics for /3-endorphin operating in the anterior lobe as compared to the intermediate lobe and differential effects of drugs in manipulating release from these. The hypothalamic corticotropin releasing factor and [ Lys] vasopressin induce release from the anterior lobe only, whereas release from the intermediate lobe was found to be under a dopaminergic inhibitory control. In uivo studies in rats showed that the levels of opioid peptides remain rather stable under acute drug treatment. (However, one has to bear in mind that measurement of levels provides only a limited degree of information concerning the functional state of a system; the possibilities of measuring turnover rates of peptides being, presently, limited.) Significant decrease in the content of opioid peptides in rat striatum was found after acute benzodiazepine treatment, a change apparently mediated via a GABAergic mechanism. The opposite effect (an increase) was observed after chronic diazepam treatment. Characteristic changes in opioid peptide content have been found after chronic treatment with various drugs: a decrease in some brain areas and in the intermediate lobe after prolonged morphine treatment, an effect also produced by chronic alcohol treatment, but not by some other opiates. An opposite effect was observed after chronic neuroleptic treatment. Incorporation studies with labelled amino acid in isolated cells of the intermediate lobe revealed that these changes take place largely at the level of precursor (proopiocortin) formation whilst the enzymatic processing of this precursor is not greatly affected. The implications of these findings in terms of an endorphin-deficit theory of addiction are discussed.
R AVERSIVE ANIMALS ROBERT
FACTORS
D. MYERS
IN ALCOHOL
DRINKING
IN HUMANS
AND
and JOHN A. EWING
Center for Alcohol Studies, Hill, NC 27514 (U.S.A.)
School
of Medicine,
University
of North
Carolina,
Chapel
In human subjects there is a wide range of response to the taste of alcohol in varying concentrations. What some people find totally aversive may be accepted with relish by others. Both individual and racial responses to ingested or injected alcohol can be aversive, since markedly dysphoric experiences can occur. Human studies also suggest that the euphorigenic properties of alcohol are very variable between subjects and that this correlates with characteristics of biogenic amines present in the body.
Except for relatively low concentrations the laboratory rat, used commonly in alcohol drinking experiments, avoids the selection of alcohol. Paralleling human studies there are animal investigations that manipulate the levels of chemical substances in the brain and demonstrate effects of this upon alcohol selection. For example, differential lesioning by neurotoxins of catechol and indoleamine pathways in the brain of the rat can markedly affect the voluntary selection of alcohol solutions in a wide range of concentrations. When certain tetrahydroisoquinolines or p-carboline substances are infused into the brain of the rat, the aversive nature of orally ingested alcohol, particularly in very high concentrations, is overcome. The possible mechanisms for this phenomenon and the recent investigations of agents acting on CNS opiate receptors in reinstating alcohol aversion will be discussed. Supported by grants from Center for Alcohol Studies, North Carolina Alcoholism Research Authority, National Institute on Alcohol Abuse and Alcoholism. 110 NEUROHYPOPHYSEAL PEPTIDE INFLUENCES ON ETHANOL TOLERANCE AND ACUTE EFFECTS OF ETHANOL RONALD
F. RITZMANN,
Department of Physiology West Side Medical Center,
PAULA
L. HOFFMAN*
and Biophysics, University Chicago, IL 60612 (U.S.A.)
and BORIS TABAKOFF of Illinois Medical
Center,
und VA
Administration of the neurohypophyseal hormone [ Arg’] vasopressin (AVP) was previously shown to prolong ethanol tolerance in mice, once this tolerance had been established. Drug tolerance and certain memory-related processes, such as consolidation have been proposed to share underlying mechanisms, in that both are examples of CNS adaptive processes. We therefore wished to investigate the effects on ethanol tolerance of some other neurohypophyseal peptides which have been found to attenuate amnesia and/or inhibit extinction of avoidance responses. Male C57Bl mice were fed a liquid diet containing 7% ethanol or an equicaloric amount of sucrose for seven days. On the eighth day all mice received the sucrose-containing diet (withdrawal). One day after withdrawal mice were divided into subgroups which received daily subcutaneous injections of saline or peptide. Animals were tested for tolerance to the hypothermic and sedative effects of ethanol at one day and eight days after withdrawal. Both AVP (40 nmole/kg) as shown previously, and des-glycinamideg-[ Lys] vasopressin (DGLVP), an analog devoid of endocrinological activity, maintained ethanol tolerance in the ethanol-treated animals up to eight days after withdrawal, a time when animals not receiving peptides were no longer tolerant. On the other hand, control and ethanol-exposed animals which were treated daily with 40 nmole/kg cyclo(Leu-Gly), the cyclic derivative of the C-terminal dipeptide of