Self-selection Of Alcohol Research Articles

Morphine enhances selection of both sucrose and ethanol in a two-bottle test

The influence of a low dose of morphine on the self-selection of alcohol and sucrose solutions is investigated. When given a choice between sucrose sweetened ethanol and plain water, rats show a significant preference for the sweetened ethanol. However, when given a choice between sweetened ethanol and sweetened water, rats increase consumption of sweetened water. These results suggest that the low-dose morphine enhancement of sweetened alcohol solutions is mediated by the reinforcing properties of sucrose not ethanol. However, when rats received small doses of morphine and a choice between unsweetened ethanol and water, the rats increase consumption of ethanol. Therefore, a low dose of morphine enhances the self-selection of both sucrose and ethanol solutions. This provides additional confirmation that opioids may enhance the rewarding properties of a variety of appetite reinforcers.

Increased alcohol intake in low alcohol drinking rats after chronic infusion of the β-carboline harman into the hippocampus

Harman (1-methyl-β-carboline) has been shown to induce volitional drinking of ethyl alcohol in the rat. The purpose of this study was to examine the long-term effect of sustained delivery of harman into the dorsal hippocampus on the subsequent preference for alcohol in the genetically bred low alcohol drinking (LAD) rat. The individual pattern of preference for alcohol was first determined following a standard 3–30% alcohol self-selection test for 10 days. Thereafter, a cerebral cannula for constant infusion was implanted stereotaxically into the dorsal hippocampus. The cannula was attached to an osmotic minipump implanted subcutaneously, which was filled with either an artificial cerebrospinal fluid (CSF) vehicle or harman. Harman was delivered at a rate of 1.0 or 3.0 μg/h (i.e., 5.5 or 16.5 nmol/h, respectively) for a period of 14 days. Four days after surgery, the rats underwent a second 3–30% alcohol preference test for 10 days. Both doses of arman induced a threefold increase in the voluntary consumption of alcohol, expressed as g/kg per day. This effect of the β-carboline seems to be specific for ethanol because its intake by the LAD rats was increased significantly only when concentrations from 11% to 30% were presented. Harman also enhanced the daily intake of food in a dose-dependent manner, but did not affect body weights or the volumes of water and total fluid consumed. These results, thus, demonstrate that the long-term exposure of hippocampal neurons to harman induces a preference for high concentrations of alcohol even in a line of rats lacking such a genetic predisposition.

A neuroanatomical substrate for alcohol drinking: Identification of tetrahydropapaveroline (THP)-reactive sites in the rat brain

Certain endogenously synthesized adducts, derived from a condensation reaction of a catechol- or indole-amine with a biogenic aldehyde, act in the brain to augment or suppress the drinking of ethyl alcohol. When infused directly into the cerebral ventricles, a tetrahydro-isoquinoline such as tetrahydropapaveroline (THP) can enhance markedly the consumption of alcohol even in noxious concentrations. The present study was undertaken to isolate and identify specific anatomical structures in the limbic-midbrain, limbic-forebrain which mediate the changes in the ingestion of alcohol induced by THP. In adult male Sprague-Dawley rats, a 23 ga guide tube was implanted stereotaxically either unilaterally or bilaterally in cerebral regions extending from coronal planes AP 1.0–10.0. Following recovery, each animal was tested by a standard screen for its self-selection of water versus an alcohol solution offered in 10 concentrations increased on each of 10 days from 3 to 30%. THP was dissolved in an artificial CSF vehicle containing Na 2S 2O 5 or ascorbate and then microinjected in a volume of 1.5–2.0 μl at a depth 1.0–1.5 mm beneath the tip of the guide. After a set of 5 microinjections of THP in a dose of 25, 50 or 250 ng was given over 3 days, the same 10-day alcohol preference sequence was repeated. In nearly all rats, the microinjection series was repeated at either one or two depths 1.0–1.5 mm ventral to the first, after which the same alcohol test was repeated. The results showed that THP induces or sustains significant increases in alcohol intake when the adduct was injected at 16 sites within caudal AP planes 1.0–5.0. Structures sensitive to THP included the substantia nigra, reticular formation, medial lemniscus, zona incerta and medial forebrain bundle. When injected at 21 sites located more rostrally within AP planes 6.5–10.0, THP also evoked significant increments in alcohol intake of a similar magnitude. The reactive loci included the N. accumbens, olfactory tubercle, lateral septum, preoptic area, stria terminalis, medial forebrain bundle and rostral hippocampus. In terms of the efficacy of the dose of THP microinjected, 25, 50 and 250 ng induced alcohol self-selection in 81%, 5% and 14% of the sites, respectively. Repeated microinjections following identical procedures of two control solutions at 46 homologous sites within corresponding coronal planes from AP 1.5–10.0 produced no significant alterations in g/kg or proportional intakes of alcohol. Composite anatomical maps of the THP-reactive sites revealed their integral overlap with dopaminergic pathways which originate in the ventral tegmentum and substantia nigra and project rostrally to structures within the limbic-forebrain. Since the loci also encompass regions containing enkephalin receptors, it is envisaged that a dopamine-enkephalinergic link underlies the mechanism responsible for the initial onset of the aberrant intake of alcohol induced by the aldehyde adduct. Further, we hypothesize that the transient presence of endogenous THP within the diffuse anatomical pathways of the amine-opioid systems likewise modifies permanently their respective receptor populations. This would explain why the reinforcing property and subsequent addictive liability of alcohol are irreversibly maintained.

Buspirone alters alcohol drinking induced in rats by tetrahydropapaveroline injected into brain monoaminergic pathways

The effect of the novel anxiolytic, buspirone, administered systemically was determined in Sprague-Dawley rats induced to drink ethyl alcohol chronically by repeated microinjections of 25 ng/μl tetrahydropapaveroline HBr (THP) into brain-stem monoaminergic pathways. Self-selection of alcohol in concentrations from 3% to 30% was determined for each rat in a free-choice drinking situation with water available as the alternative fluid. After stereotaxic implantation of guide tubes, THP was microinjected repeatedly into striatal lemniscal and preoptic sites which were found to mediate significant increases in alcohol preference. After the baseline level of intake of a single, maximally preferred alcohol concentration was established, each rat was treated with either saline vehicle or buspirone given intramuscularly b.i.d. in doses of 5.0 mg/kg or 20 mg/kg. Overall, the repeated administration of either dose of buspirone produced a significant decrease in the voluntary alcohol intake of the rats as measured by the proportion measure and absolute g of alcohol ingested. However, the alteration in drinking varied from animal to animal with respect to both magnitude and duration of the anxiolytic's effect. The response to busprione seemed to be dependent in part on the individual site in each animal at which THP had been infused to evoke alcohol intake. Post-mortem histological analysis revealed that buspirone-treated rats reduced alcohol consumption by 83% if THP had been microinjected into substantia nigra; by 60% if given in the nucleus accumbens-preoptic area; and by 34% when injected into the medial lemniscus-zona incerta. These results suggest, therefore, that buspirone can exert a specific effect in attenuating the consumption of alcohol of the rat in a free-choice situation. In relation to the differential actions of the anxiolytic, it is envisaged that on an anatomical basis the antagonism of alcohol drinking may be mediated by a pharmacological alteration of circumscribed pathways associated with dopaminergic or serotonergic neurons.

Cyanamide given ICV or systemically to the rat alters subsequent alcohol drinking

Cyanamide or disulfiram serves to suppress volitional intake of alcohol presumably because of the toxic build-up of acetaldehyde dehydrogenase (AIDH). However, the presence of acetaldehyde systemically favors the in vivo synthesis of addictive-like metabolites in the brain which in turn enhance alcohol drinking. The purpose of this investigation, therefore, was to determine whether cyanamide administered to the rat, which did not have access to alcohol during treatment, would nevertheless affect the subsequent preference for alcohol. In the first experiment, cannulae were implanted bilaterally above the cerebral ventricle of 33 adult male Sprague-Dawley rats so that an artificial CSF or a solution of cyanamide could be infused intracerebroventricularly (ICV). Following post-operative recovery, each rat was tested for its alcohol preference by offering it water and a solution of ethyl alcohol which was increased over 8 days from 3–20%. After a single test concentration of alcohol (range of 5–9%) was selected for each individual animal presented with water over a 5-day interval, cyanamide was infused in a volume of 2.5 μl per side three times daily for 4 days in one of the following total doses: 0.03, 0.1, 0.3, 0.5 or 1.0 mg. A second five-day preference test was run, and 6 weeks following cyanamide infusions a final 3–20% alcohol preference screen was run over 8 days. The results showed that a long-term, dose-dependent increase or decrease in alcohol intake occurred in those rats reactive to the drug. Given ICV, the 0.3 mg dose of cyanamide was the most efficacious in significantly augmenting alcohol consumption, whereas the two lower doses also enhanced alcohol intake but in fewer animals. Although the highest ICV dose of 1.0 mg cyanamide consistently suppressed alcohol intake, a dose of 0.5 mg produced mixed effects on the self-selection of alcohol. In the second experiment, either a saline control or cyanamide solution was injected subcutaneously in a dose of 10.0 and 15.0 mg/kg in a group of 11 rats twice a day for three days following an 8-day, 3–30% alcohol preference screen. To test the time course of action of cyanamide on alcohol drinking, a second alcohol preference test was conducted after the injection sequence which was then followed by a third test 6 weeks after the treatment. Cyanamide in both doses augmented alcohol intake which, when tested 6 weeks after cyanamide treatment, persisted in a manner similar to that observed in rats given the drug by the ICV route. Taken together, these findings suggest that an increase in the level of one or more biogenic aldehydes produced endogenously by repeated injections of cyanamide, both in brain and in the periphery, can induce a prolonged enhancement of alcohol drinking

Pre-pregnancy alcohol experience attenuates typical decrease in gestational alcohol consumption in mice

The influence of pre-pregnancy alcohol consumption on alcohol self-selection during pregnancy and lactation was examined in C57BL mice. One group of animals was given a two-bottle choice between water and a 10% w/v ethanol solution for three weeks prior to breeding, throughout pregnancy, and during lactation, while a second group was given the alcohol-water choice beginning on the first day of pregnancy. Relative alcohol intake (g ethanol/kg body weight) as well as alcohol “preference” decreased below pre-pregnancy levels during both pregnancy and lactation. That is, voluntary alcohol consumption was attenuated in pregnant and lactating mice, regardless of strain-typical pre-pregnancy high consumption. However, mice given a choice between alcohol and water prior to pregnancy did not decrease their alcohol consumption during pregnancy as much as mice not given the pre-pregnancy alcohol choice. There was no correlation between pre-pregnancy alcohol consumption and subsequent intake. The mechanism underlying decreased voluntary alcohol consumption during pregnancy remains to be elucidated, but it is clear that prior experience with alcohol influences the phenomenon.

Effect of hippocampal lesions produced by intracerebroventricular kainic acid on alcohol drinking in the rat

An alcohol self-selection test was first given to adult male rats of either the Sprague-Dawley or Long-Evans strain in which the concentrations available with water were increased from 3% to 30% over an eight-day period. Subsequently, the animals were anesthetized and, using stereotaxic procedures, a 1.2 or 2.4 nmole dose of kainic acid was infused bilaterally into the cerebral ventricle (ICV) over a 30-sec interval and in a total volume of 10 μl. When the same alcohol self-selection test was repeated two weeks post-operatively, alcohol intake was significantly suppressed in terms of both g/kg intake per day as well as proportion of alcohol to water selected. Alcohol intake of the control rats infused with the CSF carrier vehicle was unchanged. When a much longer interval of 7–10 min was used to infuse the 2.4 nmole dose of kainic acid ICV, the intake of alcohol of this group also was not significantly changed. Post-mortem histological analysis of forebrain tissue of the kainic acid infused rats confirmed cytological damage to the hippocampus, particularly in cell fields CA3 and CA4, which has been reported previously. Since the hippocampus has been implicated recently in the mechanisms underlying alcohol drinking, our results suggest that a pathological lesion of this limbic-forebrain structure could influence the degree to which alcohol is self-administered in a free-choice situation.

Alcohol drinking induced in the monkey by Tetrahydropapaveroline (THP) infused into the cerebral ventricle

In the female macaque monkey acclimated to a primate cchair, Collision cannulae were stereotaxically implanted bilaterally in the lateral cerebral ventricle. The voluntary self-selection of ethyl alcohol versus water was determined repeatedly during a series of 12-day test sequences in which the concentration of the alcohol solution offered to the primate was increased systematically over 12 successive days from 3% to 30%. Following control preference sequences, the dopamine-dopaldehyde condensation product, tetrahydropapaveroline (THP), was infused daily in each monkey's cerebral ventricle (ICV) in a volume of 200–400 μl. THP was dissolved in an artificial CSF, with pH adjusted to3.8 with 0.1 mg/ml ascorbate, and infused in one of ten doses varying from 0.125–400 μg. Each monkey was administered one low and one high dose of the condensation productt throughout each of two successive alcohol preference tests. When THP was infused in doses of less than 2.0 μg, the monkeys' alcohol preference failed to change. However, a marked increase in alcohol intake, in terms of both g/kg/day as well as the proportion of alcohol to water selected, was produced by THP infused ICV in doses of 5.0 to 20.0 μg. Although average intakes in the latter animals were between 4.0 and 5.0 g/kg/day, the monkeys selected certain concentrations of alcohol in amounts of up to 7.0 g/kg/day. The two highest doses of THP, 40.0 and 400.0 μg, inhibited the self-selection of alcohol even when presented in low, non-aversive concentrations in the 3% to 6% range. Overall, these results with the primate corroborate earlier findings in the rat of abnnormal alcohol intake produced by centrally infused THP. They further support the theory that amine-aldehyde metabolites, if present in certain concentrations in the brain, may constitute a causal neurochemical factor in the addictive or otherwise immoderate drinking of alcohol.

Acute treatment with trimethyltin alters alcohol self-selection.

Male rats of the Long-Evans strain were divided into two equal groups of nine each and given either 7.0 mg/kg trimethyltin (TMT) or 0.9% saline by intragastric gavage. The pattern of self-selection of alcohol in concentrations of 3%--30% was examined in both groups at 21 and 150 days following the gavage. The TMT-treated rat consistently drank less alcohol than did the controls at every concentration of alcohol. This difference in alcohol intake was equally significant when the rats were tested in a food-contingent, schedule-induced polydipsia situation. Further, although the TMT-lesioned animal consumed fewer calories per day in the form of alcohol, their overall daily caloric intakes were slightly higher than those of the controls. These results are interpreted as a consequence of damage to structures of the forebrain and as part of a syndrome of behavioral and neurological pathology.

Aversive factors in alcohol drinking in humans and animals

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 are animal investigations that manipulate the levels of chemical substances in the brain and demonstrate effects of this upon alcohol self-selection. When certain tetrahydroisoquinolines or β -carboline substances are infused into the brain of the rat or monkey, the aversive nature of orally ingested alcohol, particularly in very high concentrations, is overcome. In contrast, however, when a high dose of a tetrahydropapaveroline is infused, the animal's volitional intake of alcohol is inhibited and even weak concentrations of alcohol are rejected. The possible mechanisms for this phenomenon and the recent investigations of agents acting on CNS opiate receptors in reinstating alcohol aversion are considered.

Aversive factors in alcohol drinking in humans and animals

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 are animal investigations that manipulate the levels of chemical substances in the brain and demonstrate effects of this upon alcohol self-selection. When certain tetrahydroisoquinolines or beta-carboline substances are infused into the brain of the rat or monkey, the aversive nature of orally ingested alcohol, particularly in very high concentrations, is overcome. In contrast, however, when a high dose of a tetrahydropapaveroline is infused, the animal's volitional intake of alcohol is inhibited and even weak concentrations of alcohol are rejected. The possible mechanisms for this phenomenon and the recent investigations of agents acting on CNS opiate receptors in reinstating alcohol aversion are considered.

Differential actions on voluntary alcohol intake of tetrahydroisoquinolines or a β-carboline infused chronically in the ventricle of the rat

The alcohol drinking pattern of rats of the Sprague-Dawley strain was determined initially in a free-choice situation where water was offered simultaneously with a solution of alcohol, which was increased in concentration from 3 to 30% over a 12-day interval. A special cannula for the chronic infusion of drugs was implanted subsequently in the lateral cerebral ventricle of each animal. Then, one of four tetrahydroisoquinolines (TIQ) or a β-carboline (tryptoline) was infused directly into the ventricle in a dose ranging from 0.0004–4.0 μg per 4.0 μl. Each amine-aldehyde metabolite, dissolved in a CSF vehicle, was delivered over a 58 sec interval avery 30 min around the clock throughout a second 12-day alcohol preference test. Control infusions of CSF failed to alter the typical aversion to alcohol exhibited by this strain. TIQ itself, infused similarly into the brain, was also without effect. The chronic intraventricular infusion of 1-methyl-3-carboxy-6,7-dihydroxy-TIQ (1M-3C-6,7DHTIQ) or 4,6,7-trihydroxy-TIQ (4,6,7 THTIQ) produced only a moderate increase in voluntary alcohol intake in terms of both the proportion measure and absolute grams of alcohol ingested. However, salsolinol, 6-methoxy-4,7-dihydroxy-TIQ (6M-4,7 DHTIQ) and tryptoline all evoked a significant enhancement in the rats' alcohol preference within 2 to 6 days of the start of the infusions. When a solution of alcohol was offered to the rats in the upper range of concentrations, (i.e., 11 to 30%) the amount of alcohol consumed often reached 10 g per kg per day and in some animals exceeded 15 g per kg per day. Symptoms of intoxication and withdrawal were noted in many of the animals during the course of the infusion of a TIQ or β-carboline. Upon retest for alcohol preference 30 days later, the rats' exagerated self-selection of alcohol persisted even though the chronic infusions of the amine metabolite had ceased. These findings provide further support for the theory that a family of specific alkaloid conjugates acting within the brain are involved in the etiology of the abnormal drinking of alcohol.

Social modification of alcohol consumption in inbred mice.

The strain-specific "preference" for, or "aversion" to, an alcohol solution in a choice situation on the part of C57BL and DBA mice is believed to be under genetic control. But social rearing conditions are now shown to alter the voluntary consumption of alcohol, so that DBA weanling mice housed for 7 weeks with adult C57BL mice increase--and C57BL weanling mice housed with DBA adults decrease--their alcohol intake. Although substantial and highly significant changes in alcohol self-selection occur, strain-specific phenotypes are not reversed.

Dissociation between physical dependence and volitional ethanol consumption: Role of multiple withdrawal episodes

The experiment examined the effects of single and multiple episodes of forced administration of a liquid diet containing ethanol on subsequent volitional ethanol consumption. Rats were subjected to a series of 3 sequences of forced liquid diet consumption lasting 20, 50 and 50 days. One group (AD) received a liquid diet with 35–42% of the calories in the form of ethanol. Another group (SD) received identical diets except sucrose was isocalorically substituted for ethanol. Following each sequence a free-choice test was given in which the rats were allowed to choose between an alcohol diet, a sucrose diet and water. After 20 days of alcohol consumption, rats in the AD group rejected the alcohol diet, despite the occurrence of severe withdrawal symptoms including tail-stiffening, ataxia, tremors and hyperreactivity. During subsequent preference tests, a substantial, but transient, increase in alcohol self-selection was observed. It was concluded that rats may learn the association between alcohol and relief of withdrawal symptoms, but a number of withdrawal episodes are required.

Effects of inescapable shock and shock-produced conflict on self selection of alcohol in rats

In five experiments it was found that stress of inescapable unavoidable shock produced increased self selection of alcohol. These effects were maintained only so long as the shock schedule was continued. Factors such as predictability of shock, shock schedule and nutritional deficiency were found not to alter alcohol consumption substanially. In contrast to the effects of inescapble unavoidable stress, shock-produced conflict did not lead tio the self selection of alcohol. Results were interpreted in terms of a Tension Reduction Hyothesis and the role of control over aversive stimulation.

The effects of orbital and dorsolateral frontal cortical ablations on ethanol self-selection and emotional behaviors in monkeys ( Macaca Nemestrina)

Emotionality and alcohol selection were examined in female pigtail monkeys with dorsolateral or orbitofrontal ablations. Dorsolateral ablations produced a higher selection of the alcohol solution, while orbitofrontal lesions decreased self-selection of alcohol. Changes in emotionality were measured by recording aggresive or aversive behaviors during alcohol loading or placebo loading. Dorsolateral ablations increased the incidence of aggressive behaviors, while orbitofrontal ablations decresed the incidence of aggression. Alcohol “loading” increased aggression in all groups. Orbitofrontal ablations decreased the emission of aversive behaviors although under the alcohol loading condition the number of aversive behaviors exceeded that of both dorsolateral or intact subjects.

Behavior-genetic-dependent self-selection of alcohol in rats.

Behavior-genetic-dependent self-selection of alcohol in rats.

Alcohol aversion in the rat: behavioral assessment of noxious drug effects.

Injections of p-chlorophenylalanine or n-butyraldoxime given after rats were first given a 10-minute drinking test with saccharin or ethanol solutions produced a learned aversion to these solutions. These findings suggest that the reduced self-selection of alcohol (preference) resulting from the administration of these drugs, reported by others, is not specifically alcohol-related. The technique described offers a sensitive procedure for the assessment of unpleasant effects of drugs.

Self-Selection of Alcohol by Animals, Human Variation, and the Etiology of Alcoholism; A Critical Review

The experimental results (to mid-1965) in animals and man bearing upon the factors which may be related to the development of addiction and the etiology of alcoholism have been reviewed. A critical...