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 758 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The universal nature of the stimulant or euphoric effect of addictive drugs suggests that it may be an important predictor of a drug's addiction potential. Furthermore, assessment of stimulant sensitivity could be useful for predicting the liability of individuals to drug abuse. The stimulant actions of abused drugs from different pharmacological classes may share a common biological mechanism. We investigated this notion by assessing the drug responses relative to base-line locomotor activity of mice selectively bred for increased (FAST) and reduced (SLOW) sensitivity to ethanol-induced stimulation. FAST mice were more sensitive than SLOW mice to the stimulant effects of methanol (1.5-3.0 g/kg), t-butanol (0.2-0.6 g/kg), n-propanol (0.15-1.2 g/kg), pentobarbital (10-40 mg/kg) and phenobarbital (15-120 mg/kg). FAST and SLOW mice were similarly stimulated by d-amphetamine (1.25-10 mg/kg) and caffeine (2.5-20 mg/kg). The activity of FAST and SLOW mice was equally depressed by nicotine (0.5-2.0 mg/kg) and morphine (4-75 mg/kg). Finally, FAST mice were unaffected, whereas SLOW mice were depressed by diazepam (1-8 mg/kg). Selection for relative sensitivity to stimulation by ethanol has generalized to other alcohols and to barbiturates, but not to several other abused drugs, including amphetamine. The data presented here support a hypothesized common mechanism of stimulant action for alcohols and barbiturates, and suggest that differences in sensitivity to drug stimulant effects can be seen in the absence of dopamine system differences.
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PMID:Acute sensitivity of FAST and SLOW mice to the effects of abused drugs on locomotor activity. 157 69

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)
Alcohol Clin Exp Res 1991 Mar
PMID:Specific alterations in the cerebellar GABA(A) receptors of an alcohol-sensitive ANT rat line. 164 6

FAST and SLOW mice were selectively bred for differential sensitivity to the acute locomotor stimulant effects of alcohol. On average, FAST mice are stimulated by low alcohol doses, while SLOW mice are depressed or unaffected. We report here that, with chronic treatment, SLOW mice develop tolerance to an acute depressant effect, and subsequently exhibit a stimulant response. No evidence was obtained for tolerance to alcohol's stimulant effects during chronic exposure of FAST mice. However, evidence for the development of a sensitized response was found. If locomotor stimulation reflects reinforcement, and models the alcohol-induced euphoria reported by man, perhaps the absence of tolerance development to reinforcing effects provide a strong impetus for the development of alcoholism.
Alcohol Alcohol Suppl 1991
PMID:Locomotor activity response to chronic ethanol treatment in selectively bred FAST and SLOW mice. 184 25

Selectively bred FAST mice are highly susceptible, while SLOW mice are less susceptible, to the locomotor stimulant effects of ethanol. Heritability estimates indicate that approximately 15% of the variance in the FAST lines is of additive genetic origin, while low susceptibility is ostensibly nonheritable. Inbreeding has increased at the rate of 2% per generation, but fertility has been unaffected. Measurement reliability for sensitivity to this ethanol effect was high when measured in both circular (r = 0.6) and square (r = 0.7) open-fields. In addition, our results indicate that we have selected for differences in sensitivity to ethanol rather than for differences in habituation to the test environment. The difference in response to ethanol between FAST and SLOW mice extended to tests varying in duration, and to a range of ethanol doses. We conclude that the divergence between FAST and SLOW mice generalizes to related test parameters, and speculate that the genetic architecture underlying the locomotor stimulant response may be simpler than previously proposed.
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PMID:Response to selection for ethanol-induced locomotor activation: genetic analyses and selection response characterization. 206 90

Low doses of ethanol (EtOH) stimulate activity in an open field in many strains of laboratory mice. We are selectively breeding two lines of mice to exhibit a large (FAST) response on this test, and two other lines to exhibit a small (SLOW) response (Crabbe et al. 1987). The lines initially diverged in response to EtOH, but despite continued selection pressure, the difference between each pair of FAST and SLOW lines has not increased over generations as much as expected. Our practice has been to test animals on the 1st day after saline injection, and repeat the test after EtOH injection 24 h later. Lister (1987) recently demonstrated that the order in which an animal was exposed to EtOH and saline influenced the magnitude of the response to EtOH, with animals tested initially after EtOH having greater stimulation. Middaugh et al. (1987) recently demonstrated that the magnitude of EtOH stimulation was greater under conditions of relatively bright light than under dim light. Using non-selected Swiss mice, the current experiments essentially confirmed Lister's findings. Using FAST and SLOW mice, the predictions of both groups were tested. Both hypotheses were confirmed. Additionally, these experiments demonstrated that the magnitude of the difference between FAST and SLOW mice was greater under bright light than under dim light. The line difference was also greater when tested in the EtOH-Saline order. In experiments with Swiss mice, the possible role of peritoneal irritation in the EtOH effect was eliminated, and the optimal dose and time for demonstrating the effect was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Environmental variables differentially affect ethanol-stimulated activity in selectively bred mouse lines. 313 87

Starting from a population of genetically heterogeneous mice, selective breeding is being used to develop lines differing in sensitivity to ethanol-induced open-field activity. Mice are tested twice for 4 min in an open field. The first test is between min 2-6 after injection of saline. Twenty-four hr later, a similar test is performed after injection of ethanol (1.5 g/kg). Two independent FAST lines are being selected for ethanol-induced increases in activity, and two independent SLOW lines are being selected for ethanol-induced decreases. After four generations of selection, the lines have diverged significantly. These lines should be useful for exploring the neuropharmacological basis for the activating and rewarding properties of ethanol.
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PMID:Mice genetically selected for differences in open-field activity after ethanol. 365 83

The FAST and SLOW lines of mice are being selectively bred in replicate for differential sensitivities to the locomotor activating effects of ethanol. Whereas FAST-1 and FAST-2 mice are stimulated by 2.0 g/kg ethanol, SLOW-1 and SLOW-2 mice are not stimulated, and are often depressed, by this dose. The dopamine antagonists, SCH-23390 (D1) and raclopride (D2), produced dose-dependent decreases in the locomotor activity of EtOH-naive mice of both lines and replicates; however, FAST and SLOW mice were not differentially sensitive to these effects. The absence of a line difference in activity response to the dopamine antagonists suggests that dopamine receptor function has not been altered by selective breeding for differences in sensitivity to the stimulant effects of ethanol. The ethanol-stimulated activity of FAST-1 and FAST-2 mice was decreased by administration of the dopamine antagonists, haloperidol and raclopride, at doses that had no effect on basal locomotor activity. SCH-23390 decreased ethanol-stimulated activity of FAST-1, but not FAST-2 mice. The ethanol-induced activity changes of SLOW mice were generally unaffected by antagonist administration. These results suggest a role for dopaminergic systems in mediating ethanol-stimulated activity in selectively bred FAST mice. Coadministration of SCH-23390 and raclopride decreased ethanol-induced activation to a greater degree than either drug alone, further suggesting that both D1 and D2 receptor systems contribute to the full expression of the ethanol stimulant response.
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PMID:Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice. 759 19

Brain NMDA receptor responses and their sensitivity to ethanol in vitro were determined in replicate lines of FAST and SLOW mice, selectively bred for differences in sensitivity to the locomotor stimulant effects of a low dose of ethanol. L-Glutamate-stimulated increases in the intracellular free calcium concentration (Cai) were determined in microsacs, a cell-free brain membrane preparation, isolated from hippocampus or cerebral cortex. Previous work showed that L-glutamate-stimulated increases in Cai in microsacs are mediated by activation of NMDA receptors. The concentration response for L-glutamate-stimulated increases in Cai did not differ between the lines in either hippocampal or cerebrocortical microsacs. Ethanol produced a concentration-dependent decrease in L-glutamate-stimulated increases in Cai in hippocampal and cerebrocortical microsacs from SLOW mice, but this effect of ethanol was reduced or absent in microsacs isolated from FAST mice. Resting Cai and the ability of a high ethanol concentration to increase resting Cai did not differ between the lines. These results suggest that differences in the sensitivity of brain NMDA receptors to the effects of ethanol determine, at least in part, differences in the locomotor stimulant effects of low doses of ethanol in FAST and SLOW mice. These differences are not due to ethanol effects on resting Cai.
Alcohol Clin Exp Res 1994 Dec
PMID:Ethanol sensitivity of brain NMDA receptors in mice selectively bred for differences in response to the low-dose locomotor stimulant effects of ethanol. 769 47

Alcohol-induced locomotor stimulation in mice may provide an animal model of human euphoric responses to moderate alcohol (ethanol) doses. If a common mechanism mediates sensitivity to both drug reward (reinforcement) and drug stimulation, rodent models of drug stimulation would provide powerful tools for investigating drug reinforcement. In addition, stimulant sensitivity might provide a simple marker for susceptibility to ethanol reward, and perhaps addiction (e.g., Newlin and Thomson, 1991). This short report describes the use of three genetic mouse models, (1) FAST and SLOW selectively bred lines, (2) BXD Recombinant Inbred Strains, and (3) a panel of inbred strains of diverse genetic origin, to explore mechanisms mediating ethanol stimulation and reinforcement.
Alcohol Alcohol Suppl 1993
PMID:Use of genetically distinct mouse populations to explore ethanol reinforcement. 774 38


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