Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors.

Although dopaminergic transmission has been strongly implicated in alcohol self-administration, the involvement of specific dopamine receptor subtypes has not been well established. We studied the ethanol preference and sensitivity of D2-receptor-deficient mice to directly evaluate whether dopamine D2 receptors contribute to alcohol (ethanol) consumption. We report a marked aversion to ethanol in these mice, relative to the high preference and consumption exhibited by wild-type littermates. Sensitivity to ethanol-induced locomotor impairment was also reduced in these mutant mice, although they showed a normal locomotor depressant response to the dopamine D1 antagonist SCH-23390. These data demonstrate that dopamine signaling via D2 receptors is an essential component of the molecular pathway determining ethanol self-administration and sensitivity.

Naltrexone effects on ethanol drinking acquisition and on established ethanol consumption in C57BL/6J mice.

Naltrexone's success as a treatment agent for alcoholism seems to be due to its ability to reduce craving in abstinent, dependent individuals and to reduce the pleasure associated with subsequent intake. However, more study is needed to establish the optimal amount of time that naltrexone treatment should be continued. Little information seems to have been collected regarding the most effective dosing regimen for reducing alcohol craving and consumption, and the usefulness of opiate antagonists in the prevention of alcohol dependence in nonaddicts, rather than just as a treatment agent in addicted individuals, also deserves further study. The alcohol-preferring C57BL/6J (B6) mice were used to: (1) study naltrexone effects on consumption in established drinkers using an increasing dosing regimen, (2) study naltrexone effects on the acquisition of ethanol drinking, and (3) study the effects of chronic naltrexone from timed-release pellets on drinking in alcohol-naive mice. Naltrexone reduced ethanol preference in established drinkers, but its effects waned at increasing doses. Naltrexone slowed the acquisition of ethanol drinking, but was ineffective when readministered after a phase when ethanol was offered in the absence of naltrexone. Mice with chronic naltrexone pellets consumed greater amounts of ethanol and showed higher ethanol preference than did placebo-pelleted animals. The observed reduced efficacy of naltrexone with increasing dosage and chronic treatment may have been due to naltrexone-induced opiate receptor changes. Such changes are presumably more likely to occur when naltrexone doses remain high or perhaps accumulate. Thus, dose and frequency of administration may be important factors in determining naltrexone's effectiveness in treating alcohol dependence.

Quantitative trait loci affecting methamphetamine responses in BXD recombinant inbred mouse strains.

Individual differences in most behavioral and pharmacological responses to abused drugs are dependent on both genetic and environmental factors. The genetic influences on the complex phenotypes related to drug abuse have been difficult to study using classical genetic analyses. Quantitative trait locus (QTL) mapping is a method that has been used successfully to examine genetic contributions to some of these traits by correlating allelic variation in polymorphic genetic markers of known chromosomal location with variation in drug-response phenotypes. We evaluated several behavioral responses to multiple doses of methamphetamine (METH) in C57BL/6J (B6), DBA/2J (D2), and 25 of their recombinant inbred (BXD RI) strains. Stereotyped chewing, horizontal home cage activity, and changes in body temperature after 0, 4, 8, or 16 mg/kg METH, as well as stereotyped climbing behavior after 16 mg/kg METH, were examined. Associations (p < 0.01) between METH sensitivity and allelic status at multiple microsatellite genetic markers were subsequently determined for each response. QTLs were provisionally identified for each phenotype, some unique to a particular behavior and others that appeared to influence multiple phenotypes. Candidate genes suggested by these analyses included several that mapped near genes relevant for the neurotransmitters acetylcholine and glutamate. The locations of QTLs provisionally identified by this analysis were compared with QTLs hypothesized in other studies to influence methamphetamine- and cocaine-related phenotypes. In several instances, QTLs appeared to overlap, which is consistent with idea that common neural substrates underlie some responses to psychostimulants.

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.

Prophylactic treatment of BALB/c mice with cyclosporine A and its analog B-5-49 enhances resistance to Leishmania major.

The effect of cyclosporine A (Cs A) and its analog B-5-49 on Leishmania major in vitro and in vivo in the highly susceptible BALB/c mouse strain has been investigated. In vitro, both of these drugs showed significant toxicity toward L. major, but only at relatively high levels (greater than 25 micrograms/ml). However, at 5 and 10 micrograms/ml, levels which correspond more closely to physiologically achievable concentrations, no growth-inhibitory effect in vitro was observed. On administration of the drugs to animals with established lesions, no beneficial effect was observed and, in fact, some exacerbation of lesion development and disease progression was noted. Surprisingly, a majority of the mice treated prophylactically with Cs A for a period of 7 consecutive days beginning 1 day before infection with L. major did not develop ulcerated cutaneous lesions, although some footpad swelling was observed 10 days to 2 wk after infection. These resistant animals displayed a sustained DTH after infection, and were resistant to further challenge with virulent L. major. Prophylactic treatment with the B-5-49 analog of Cs A was also effective in enhancing resistance to L. major infection in BALB/c mice, although to a somewhat lesser degree. Because the cyclosporines tested do not appear to be directly toxic nor inhibitory in vivo for established L. major infections, it appears that these drugs may be effective in modulating the induction stage of the immune response toward the parasites in the BALB/c mouse in such a way as to allow a protective immunity to develop.