Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.8 (FAST)
 758 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper, we present examples of some of the several behaviors which have been taken to indicate the reinforcing efficacy of drugs, including ethanol. Efforts to identify the genetic determinants of these behaviors have employed diverse pharmacogenetic methods. For example, we have used selective breeding to develop mice selected for severe or attenuated ethanol withdrawal and have found that Withdrawal Seizure Prone mice show a greater conditioned preference for ethanol-associated locations than the selected Withdrawal Seizure Resistant line. Similarly, HOT mice, selected for insensitivity to ethanol-induced hypothermia, had greater conditioned place preference after ethanol training than COLD mice, selected for ethanol hypothermic sensitivity. We have also developed selected mouse lines responsive or unresponsive to ethanol-stimulated locomotor activity. These FAST and SLOW lines develop sensitization rather than tolerance to ethanol-induced activity. Using inbred strains of mice, others had shown that strains differed in preference for drinking ethanol solutions. We found that these strains also differed in acceptance of ethanol. Single-gene techniques have been used to show that preference drinking is significantly altered in mutant rodent strains lacking hypothalamic vasopressin, or with nephrogenic diabetes insipidus. In a specific panel of Recombinant Inbred mouse strains, we found that a single gene appeared to control a significant portion of the variance in preference drinking. These examples show that traits putatively related to drug reinforcement show substantial genetic control. Specifically, single-gene methods show promise of identification and mapping of genes related to drug reinforcement.
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PMID:Genetic determinants of ethanol reinforcement. 163 89

The AT (alcohol-tolerant) and ANT (alcohol-nontolerant) rat lines, selected for differential sensitivity to the acute motor-impairing effects of ethanol, have been shown to differ in the ligand binding characteristics of their cerebellar GABAA receptors. In the present study, we characterized these binding differences further and determined whether similar differences are present in other rodent line pairs produced by selective breeding for differences in ethanol sensitivity. The alcohol-insensitive AT rats had more high-affinity [3H]muscimol binding sites in the cerebellum than the alcohol-sensitive ANT rats. The cerebellar "diazepam-insensitive" [3H]Ro 15-4513 binding sites were displaced by several benzodiazepine agonists (diazepam, lorazepam, clonazepam, and midazolam) at micromolar concentrations with greater efficacy in the ANT than the AT rats. Analyses of the displacement curves indicated that the "diazepam-insensitive" [3H]Ro 15-4513 binding sites have 30 to 300 times higher affinity to benzodiazepine agonists in the ANT than AT rats. There was no difference between the rat lines in the displacing potency of Ro 15-1788, a weak partial agonist; Ro 15-4513, a partial inverse agonist; or Ro 5-4864, a peripheral-type benzodiazepine receptor ligand. Thus, the affinity difference seen in the cerebellar [3H]Ro 15-4513 binding sites seems to be specific for benzodiazepine agonists. This difference in affinity may explain the behavioral difference in sensitivity to lorazepam between the rat lines. No differences in [3H]muscimol binding or in the sensitivity of [3H]Ro 15-4513 binding to micromolar diazepam concentrations were found between other rodent line pairs tested (LS/SS, HAS/LAS, HOT/COLD, FAST/SLOW, AA/ANA).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific alterations in the cerebellar GABA(A) receptors of an alcohol-sensitive ANT rat line. 164 6