Voluntary ethanol drinking in C57BL/6J and DBA/2J mice before and after sensitization to the locomotor stimulant effects of ethanol.

RATIONALE: Drug-induced sensitization has been associated with enhanced drug self-administration and may contribute to drug addiction. OBJECTIVES: We investigated the possible association between sensitization to the locomotor stimulant effects of ethanol (EtOH) and voluntary EtOH consumption. METHODS: Mice of the EtOH-avoiding DBA/2J (D2) and EtOH-preferring C57BL/6J (B6) inbred strains were offered the choice of an EtOH solution versus tap water (EtOH-experienced) or just water (Na), and voluntary consumption was measured. Mice from each condition then received repeated EtOH or saline injections, and locomotor responses were measured. Subsequently, all mice were offered the choice of EtOH versus water, and voluntary consumption was again measured. A subsequent study examined relative susceptibility of D2 and B6 mice to EtOH-induced locomotor sensitization. RESULTS: Voluntary EtOH consumption induced locomotor sensitization to an EtOH challenge in B6 mice. D2 mice consumed little EtOH, but developed sensitization with repeated EtOH treatments as expected. EtOH consumption was not altered in EtOH-sensitized D2 mice. Unexpectedly, B6 mice developed significant sensitization, and following sensitization, the EtOH-experienced EtOH-sensitized group consumed more EtOH than their EtOH-experienced salinetreated (non-sensitized) counterparts. In an independent study, B6 mice required between three and five EtOH injections to express sensitization, whereas for D2 mice, between one and three EtOH exposures were sufficient. CONCLUSIONS: Development of sensitization to the locomotor stimulant effects of EtOH may be associated with increased EtOH consumption in mice with high initial avidity for EtOH. In the same mice, voluntary EtOH consumption can also produce behavioral sensitization to the effects of EtOH.

Attenuation of ethanol-induced conditioned taste aversion in mice sensitized to the locomotor stimulant effects of ethanol.

This study examined the effect of repeated ethanol (EtOH) injections that induced behavioral sensitization on subsequent acquisition of EtOH- and lithium chloride (LiCl)-induced conditioned taste aversion (CTA). CTA acquisition was assessed in independent groups of EtOH-sensitized and nonsensitized genetically heterogeneous female mice after injections of saline; 1, 2, or 4 g/kg EtOH; or 2 or 4 mEq/kg LiCl. Saline and 1 g/kg EtOH did not induce CTA. Four g/kg EtOH and 4 mEq/kg LiCl induced similar levels of CTA in EtOH-sensitized and nonsensitized groups. CTA induced by 2 g/kg EtOH and 2 mEq/kg LiCl was attenuated in EtOH-sensitized mice compared with nonsensitized counterparts. Thus, a sensitizing regimen of EtOH preexposure resulted in both a decrease in EtOH and LiCl aversion and an increase in EtOH locomotor sensitivity; such changes could ultimately contribute to enhanced EtOH intake and potentially to EtOH abuse.

Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations.

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.

Duration of sensitization to the locomotor stimulant effects of ethanol in mice.

Behavioral sensitization to the psychomotor stimulant effects of some drugs can be quite persistent, lasting for weeks to months after cessation of drug exposure. We investigated the duration of sensitization to the locomotor stimulant effects of 2.0 g/kg ethanol (EtOH) and determined whether repeated EtOH administration would lead to alterations in blood EtOH clearance rates. Female mice were injected (IP) daily for up to 10 consecutive days with saline or EtOH. Baseline activity and acute EtOH locomotor responses were evaluated in Omnitech automated activity monitors (10-min test), with horizontal distance traveled as the measure of locomotion. Locomotor activity response to EtOH was reevaluated immediately after the final daily EtOH injection, and at 5-day intervals during which no EtOH was administered. Tail blood samples for determination of blood ethanol concentrations (BECs) were collected from EtOH-treated mice at the end of activity sessions. Sensitization lasted for up to 29 days, and in two of three of the behavioral sensitization studies, repeated EtOH treatment resulted in elevated BECs. There was no significant effect of repeated EtOH exposure on EtOH clearance rate in a study involving no behavioral testing. The demonstration of persistent behavioral sensitization may imply a lasting hypersensitivity of certain neural pathways to EtOH, thus increasing the reinforcing value of EtOH and the probability of relapse to EtOH drinking after abstinence.

Behavioral sensitization to ethanol: genetics and the effects of stress.

Some aspects of drug abuse syndromes may be influenced by sensitization to some drug effects. This enhancement of drug effect has been associated with prior drug exposure and with exposure to stressful stimuli. It has been postulated that sensitization to psychomotor stimulant drug effects influences sensitivity to drug reward. The drugs of abuse best characterized for sensitization phenomena include cocaine, amphetamine, and morphine. In general, ethanol's molecular mechanisms of action have been difficult to define relative to drugs with known receptor or transporter binding sites and, likewise, ethanol sensitization has been less thoroughly examined. Evidence supporting the existence of behavioral sensitization to ethanol, for genetic differences in the occurrence of ethanol sensitization, and for the influence of corticosterone on the development of ethanol sensitization is reviewed herein. There appear to be different genetic determinants of acute drug sensitivity and sensitization. Cross-sensitization between stress and ethanol suggest a potential role for hypothalamic-pituitary-adrenal (HPA) axis associated changes in ethanol sensitization, consistent with mechanisms likely contributing to sensitization to other abused drugs. Furthermore, glucocorticoid receptors appear to mediate both ethanol- and stress-induced sensitization to ethanol. A biological link between drug reward and drug sensitization involving HPA axis hormones may exist and, thus, study of the sensitization process may elucidate mechanisms relevant to drug abuse.

Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors.

Substantial evidence links alcohol drinking and serotonin (5-HT) functioning in animals. Lowered central 5-HT neurotransmission has been found in a subgroup of alcoholics, possibly those with more aggressive, assaultive tendencies. Several rodent studies have also suggested that intact 5-HT systems are important determinants of sensitivity and/or tolerance to ethanol-induced ataxia and hypothermia. Null mutant mice lacking the 5-HT1B receptor gene (5-HT1B-/-) have been developed that display enhanced aggression and altered 5-HT release in slice preparations from some, but not all, brain areas. We characterized these mice for sensitivity to several effects of ethanol. Mutant mice drank twice as much ethanol as wild-type mice, and voluntarily ingested solutions containing up to 20% ethanol in water. Their intake of food and water, and of sucrose, saccharin and quinine solutions, was normal. Mutants were less sensitive than wild-types on a test of ethanol-induced ataxia and, with repeated drug administration, tended to develop tolerance more slowly. In tests of ethanol withdrawal and metabolism, mutants and wild-type mice showed equivalent responses. Our results suggest that the 5-HT1B receptor participates in the regulation of ethanol drinking, and demonstrate that serotonergic manipulations lead to reduced responsiveness to certain ataxic effects of ethanol without affecting dependence.

Evaluation of potential genetic associations between ethanol tolerance and sensitization in BXD/Ty recombinant inbred mice.

Ethanol (EtOH) has both locomotor stimulant and locomotor ataxic effects. Repeated EtOH treatment can result in the development of behavioral sensitization (increased sensitivity) similar to that seen with the classical stimulant drugs amphetamine and cocaine. However, it has been suggested for EtOH that sensitization may be a by-product of the development of tolerance to the sedative/ataxic effects of EtOH. It is also possible that the converse is true: that tolerance develops as the result of sensitization development. We examined this notion by measuring EtOH sensitization and tolerance in the BXD/Ty recombinant inbred strains. Changes in locomotor activation and grid test ataxia were used as the measures of sensitization and tolerance, respectively. If a genetic relationship exists between sensitization and tolerance, then those strains most susceptible to sensitization should also develop the most robust tolerance. Genetic correlations did not support the presence of this relationship. In addition, the use of the BXD/Ty recombinant inbred strains enabled us to perform gene mapping by quantitative trait locus analysis for activity and ataxia measures. We found that 28% to 79% of the genetic variation in the various activity and ataxia responses could be explained by the identified quantitative trait loci associations. However, when associations of gene markers with behavioral phenotypes were compared, we obtained no strong evidence for common genes determining magnitude of sensitization and tolerance. Thus the results of this study do not support the hypothesis that sensitization results from development of tolerance to the sedative/ataxic effects of EtOH or, conversely, that tolerance is a by-product of sensitization.

Critical role for glucocorticoid receptors in stress- and ethanol-induced locomotor sensitization.

Locomotor sensitization, the augmentation of the locomotor-activating effects of stimuli with repeated exposure, is being evaluated as a partial model for several phenomena including drug addiction. Alteration of dopaminergic systems has been found in sensitized animals and dopamine neurotransmission appears to be crucial for the expression of sensitized behaviors. However, stress hormones, which are released after exposure to many of the stimuli that produce sensitization, may also be involved in the development of this phenomenon. Corticosterone appears to be important in the development of amphetamine sensitization and glucocorticoid receptors (GR) have been hypothesized to mediate this effect. The purpose of these experiments was first, to determine whether repeated restraint stress sensitizes DBA/2J mice to the activating effect of ethanol (EtOH), and second, to explore the role of GR in stress- and EtOH-induced sensitization with the GR antagonist, RU 38486. This antagonist was administered before restraint or i.p. EtOH (1.5 g/kg) on each of 10 consecutive days of pretreatment. In addition, plasma corticosterone levels were determined at various points throughout the pretreatment period and on test days. The results demonstrated that 10 consecutive days of 2-hr restraint sensitized mice to EtOH's locomotor-stimulating effect. Both stress- and EtOH-induced sensitization were attenuated by administration of RU 38486 during the pretreatment phase.(ABSTRACT TRUNCATED AT 250 WORDS)