Biomedical subjects

C L Cunningham

Publications and source records attributed to C L Cunningham.

At least 37 records · Page 2Linked to original sources

PubMed1998

Intravenous self-administration of ethanol in beta-endorphin-deficient mice.

Extensive research on both human alcoholics and in animal models of alcoholism has implicated the release of endogenous opioids in the consumption of ethanol. Various experiments using opioid antagonists have indicated that these drugs cause both humans and animals to decrease their consumption of ethanol. However, it remains unclear exactly which of the endogenous opioids mediates the rewarding effects of ethanol. The present experiment used intravenous self-administration of ethanol to determine whether beta-endorphin (BE)-deficient mice differed from wild-type (WT) mice in ethanol self-administration. The BE-deficient mice completely lack BE, but are otherwise similar to the WT mice. By using intravenous self-administration, we were able to rule out any ability of BE to mediate differences in ethanol consumption via palatability factors alone. Both types of mice were 7 generations backcrossed onto a C57BL/6J inbred strain background. During nine daily, 2-hr free-operant sessions, 14 BE-deficient and 17 WT mice could nosepoke for 75 mg/kg ethanol infusions delivered intravenously on an fixed-ratio 3 schedule with a 2-sec time-out after each reinforcer delivery. Reinforcer delivery occurred following nosepokes in only one of two holes. Contrary to what was expected, BE-deficient mice acquired selective operant responding for ethanol, whereas WT mice did not. Although the two genotypes did not differ in either operant or locomotor behavior during the first session, by the end of the nine sessions, BE deficient mice were reliably nosepoking for ethanol, whereas WT mice were not. These findings may indicate that BE is not essential for the postingestive reinforcing effects of ethanol in these animals.

Alcoholism↗

PubMed1998

Ethanol-induced conditioned taste aversion in BXD recombinant inbred mice.

Genetic differences in sensitivity to ethanol's aversive effects may play an important role in the development of alcohol-seeking behavior and alcoholism. The present study examined the development of ethanol-induced conditioned taste aversion in 20 BXD/Ty recombinant inbred strains of mice and their progenitor inbred strains, C57BL/6J (B6) and DBA/2J (D2). Adult male mice were given 1-hr access to a saccharin-flavored solution every 48 hr for 12 days. After all but the first and last saccharin access periods, they received ethanol injections (0, 2, or 4 g/kg, i.p.). Separate groups of unpaired control mice received 4 g/kg of ethanol 1 hr after water access. Saline control mice were also used for examining preference across a wide range of saccharin concentrations (0.019 to 4.864% w/v). As expected, saccharin consumption during taste conditioning declined over conditioning trials in a dose-dependent manner, indicating development of ethanol-induced conditioned taste aversion. Correlational analyses using strain means from recently published papers indicated no significant genetic correlation between taste conditioning and two phenotypes thought to reflect ethanol reinforcement or reward (ethanol drinking, conditioned place preference). However, there were significant genetic correlations between taste conditioning at the high dose and sensitivity to ethanol-induced hypothermia, rotarod ataxia, and acute withdrawal. Quantitative trait locus (QTL) analyses of strain means indicated that taste aversion was associated (p < 0.01) with genetic markers on nine chromosomes (1, 2, 3, 4, 6, 7, 9, 11, and 17). These QTLs were located near several candidate genes, including genes encoding several different acetylcholine receptor subunits, the delta opioid receptor, and two serotonin receptors (1B and 1D). QTLs for saccharin preference were located on several of the same chromosomes (2, 3, 4, 6, and 11). Two of these saccharin QTLs overlap candidate genes influencing sensitivity to sweet or bitter taste stimuli. In general, these findings support the conclusion that multiple genes influence ethanol-induced conditioned taste aversion. Some of these genes appear to influence taste sensitivity, whereas others appear to mediate sensitivity to aversive pharmacological effects of ethanol.

Alcohol Drinking↗

PubMed1997

Flavor preference conditioning by oral self-administration of ethanol.

Oral self-administration and operant tasks have been used successfully to confirm ethanol's positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS-). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol's efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS- in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol's rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol's nutrient and pharmacological effects both contributed to the development of conditioned flavor preference.

Alcohol Drinking↗

PubMed1997

Rewarding effect of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one in mice.

The GABAA-receptor agonist neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) has anxiolytic and locomotor stimulant effects and shares some subjective properties with benzodiazepines, barbiturates and ethanol, but there have been no studies of its reinforcing or rewarding effects. The present study examined the rewarding properties of 3 alpha,5 alpha-P using the conditioned place preference paradigm. Male DBA/2J mice received four pairings of a distinctive floor stimulus with 3 alpha,5 alpha-P (3.2, 10 or 17 mg/kg, IP) in an unbiased conditioning procedure. On alternate days a different distinctive floor was paired with vehicle. At the lowest dose (3.2 mg/kg), there was no difference between conditioning subgroups in preference for the drug-paired floor type, indicating an absence of place conditioning. However, a dose-dependent conditioned preference was evident at the higher doses as shown by the greater amount of time spent on the floor paired with 3 alpha,5 alpha-P. In addition, 3 alpha,5 alpha-P produced a dose-dependent increase in locomotor activity, which was significant following the 17 mg/kg dose. A control study showed no effect of the beta-cyclodextrin vehicle on place conditioning in the absence of neurosteroid. These results provide the first demonstration that 3 alpha,5 alpha-P, an endogenous modulator of GABAA receptor function, possesses rewarding properties using the conditioned place preference paradigm.

Animals↗

PubMed1997

The effects of naloxone on expression and acquisition of ethanol place conditioning in rats.

Naloxone has been shown to facilitate extinction of ethanol-induced conditioned place preference (CPP) in mice. The present-study extended these findings by examining naloxone's effect on the expression (Experiment 1) and acquisition (Experiment 2) of place conditioning with ethanol in rats. In Experiment 1, after place conditioning with ethanol (1.8 g/kg, I.P.), groups N0, N1.5, and N10 received 0, 1.5, or 10 mg/kg naloxone before testing. As expected, ethanol produced a robust conditioned place aversion (CPA). However, naloxone had no effect on expression of CPA. In contrast to studies with mice, the endogenous opioid system does not appear to be involved in the conditioned motivational effects of ethanol in rats. In Experiment 2, groups SE1 and SE2, NS(1.5), NE(1.5), and NE(10), received ethanol alone (1.2 g/kg), naloxone alone (1.5 mg/kg), naloxone 1.5 mg/kg plus ethanol, and naloxone 10 mg/kg plus ethanol during acquisition, respectively. All naloxone-treated groups exhibited CPA. Moreover, group NE(1.5) showed a stronger CPA than group NS(1.5). The CPA produced by coadministration of naloxone and ethanol was attributed to naloxone's effects on the neural processes underlying ethanol's unconditioned aversive effects, or to other nonspecific effects on ethanol's motivational properties.

Animals↗

PubMed1997

Intravenous ethanol self-administration in C57BL/6J and DBA/2J mice.

Two strains of mice, C57BL/6J (B6) and DBA/2J (D2) were allowed to self-administer intravenous (iv) ethanol. These two strains were selected because they differ greatly in their preference for drinking ethanol solutions: B6 mice are preferrers, whereas D2 mice are avoiders of ethanol. Of interest was whether these strains would also differ in self-administration of iv ethanol when taste factors presumably do not influence consumption. Mice were trained with either 60, 75, or 90 mg/kg per infusion. Mice from both strains acquired nose-poking for all of these doses on an FR-3 schedule of reinforcement during 2-hr daily sessions. Additionally, mice in both strains acquired an equal preference for nosepoking on the side resulting in ethanol infusion, compared with the side that had no scheduled consequence, although B6 mice took somewhat more ethanol early in training than did D2 mice. Mice in both strains achieved equal levels of responding at the conclusion of training, when response rates had stabilized. A subset of animals were then tested at doses of ethanol ranging from 25 to 125 mg/kg per infusion. Although their responding tended to decrease over time regardless of changes in the unit dose of ethanol, these mice showed lower response rates for higher doses of ethanol, and less responding for saline than for ethanol. Together, these findings imply that iv ethanol has reinforcing properties in both these strains, despite the strain difference in preference for oral ethanol. Self-administration of iv ethanol in mice may prove a valuable addition to existing animal models for the study of ethanol reward.

Alcohol Drinking↗

PubMed1996

Genetic differences in naloxone enhancement of ethanol-induced conditioned taste aversion.

The influence of the opioid system on acquisition of an ethanol-induced conditioned taste aversion was examined in alcohol-preferring and avoiding inbred strains of mice (C57BL/6J and DBA/2J). Fluid-deprived mice from each strain received either ethanol alone, naloxone alone, or both ethanol and naloxone immediately after access to a novel tasting fluid. Naloxone alone (1 or 3 mg/kg) did not induce a conditioned taste aversion in either strain of mice. Administration of ethanol (1.5 g/kg) to DBA/2J mice produced a moderate taste aversion that was not affected by co-administration of naloxone. Although ethanol administered alone (3 g/kg) did not cause a taste aversion in C57BL/6J mice, the combination of ethanol and the higher dose of naloxone produced a significant taste aversion that increased across trials. A second experiment addressed the possibility that naloxone failed to enhance the ethanol-induced condition taste aversion in DBA/2J mice due to a "floor" effect on consumption. A lower ethanol dose (1 g/kg) was given alone or in combination with naloxone (1 or 3 mg/kg). Again, ethanol produced a moderate conditioned taste aversion that was not potentiated by naloxone. Subsequent conditioning with a high ethanol dose produced further suppression of intake, confirming that naloxone's failure to enhance aversion on earlier trials was not due to a "floor" effect. These data demonstrate a strain specific interaction between the aversive effect of ethanol and naloxone. More specifically, the results indicate that blockade of opioid receptors enhances the aversive effect of ethanol in C57BL/6J but not DBA/2J mice, suggesting that genetically determined differences in the endogenous opioid system of alcohol-preferring mice may mitigate ethanol's aversive effect.

Animals↗

PubMed1996

Pavlovian conditioning of morphine hyperthermia: assessment of interstimulus interval and CS-US overlap.

The present study examined the effect of interstimulus interval on acquisition of conditioned thermal responses produced by trials in which a light/noise stimulus (CS) was repeatedly paired with infusion of morphine sulphate (US). Rats were implanted with a chronic intravenous catheter for drug delivery and a biotelemetry device for remote monitoring of core body temperature. In experiment 1, different groups received morphine either 0.5 (group P0.5) or 15 min (group P15) after onset of the 15-min CS. A third group was exposed to an identical number of CS and US presentations but in an explicitly unpaired manner (group UP). After repeated exposure to morphine, all groups showed a more rapid rise in body temperature in response to drug infusion. Test presentations of CS alone revealed conditioned hyperthermic responses to CS in groups P0.5 and P15. However, the response of the P15 group was smaller than that of the P0.5 group, suggesting weaker conditioning at the longer interstimulus interval. The contribution of CS-US overlap to the diminished associative strength observed in the P15 group was assessed in experiment 2. Groups P0.5/15 and P0.5/30 received infusions of morphine 0.5 min after onset of a 15- or 30-min CS, respectively. Group P15/30 received morphine 15 min after onset of a 30 min CS, whereas group UP/30 received explicitly unpaired presentations of the US and a 30-min CS. Enhancement of the hyperthermic effect of morphine was observed in all groups after ten conditioning trials. Test presentations of the CS without drug revealed that all paired groups had acquired conditioned hyperthermic responses. These results support the conclusion that drug-induced conditioning can occur at relatively long interstimulus intervals when there is sufficient temporal overlap between the CS and unconditioned response evoked by the drug US.

Acoustic Stimulation↗

PubMed1995

Haloperidol prevents ethanol-stimulated locomotor activity but fails to block sensitization.

The effect of the dopamine receptor antagonist haloperidol on the development of sensitization to ethanol-induced increases in locomotor activity was examined in DBA/2J mice. In Experiment 1, different groups of mice were given saline or ethanol (2 g/kg) immediately before each of four locomotor activity sessions (48-h intervals), and 1 h after pretreatment with saline, 0.10 or 0.15 mg/kg haloperidol. During a subsequent test, mice showed locomotor sensitization despite blockade of ethanol stimulated activity by haloperidol on the first conditioning trial. Moreover, test session activity was reduced in subjects that had previously received haloperidol, even though haloperidol was not present during testing. The second experiment examined the nature of the latter finding by comparing subjects that received equal exposure to haloperidol but differed in the pairing of its administration with the activity chambers. After four conditioning trials, each group was tested in the absence of haloperidol. Mice that had previously received haloperidol paired with the activity chambers were less active than control groups, suggesting development of a conditioned suppression of activity. Overall, these results suggest a dissociation of the neurobiological mechanisms that mediate the acute locomotor stimulant effects of ethanol and those mediating sensitization. Further, these studies illustrate the importance of antagonist-alone control groups that assess the possible influence of associative learning induced by the antagonist itself.

Animals↗

PubMed1995

Localization of genes influencing ethanol-induced conditioned place preference and locomotor activity in BXD recombinant inbred mice.

Genetic differences in ethanol's ability to induce conditioned place preference were studied in 20 BXD Recombinant Inbred (RI) mouse strains and in the C57BL/6J and DBA/2J progenitor strains. Male mice from each strain were exposed to a Pavlovian conditioning procedure in which a distinctive floor stimulus (CS+) was paired four times with ethanol (2 g/kg). A different floor stimulus (CS-) was paired with saline. Control mice were injected only with saline. Floor preference testing without ethanol revealed significant genetic differences in conditioned place preference, with some strains spending nearly 80% time on the ethanol-paired floor while others spent only 50% (i.e., no preference). Control mice showed genetic differences in unconditioned preference for the floor cues, but unconditioned preference was not genetically correlated with conditioned preference. There were also substantial genetic differences in ethanol-stimulated activity, but contrary to psychomotor stimulant theory, ethanol-induced activity on conditioning trials was not positively correlated with strength of conditioned place preference. However, there was a significant negative genetic correlation (r = -0.42) between test session activity and preference. Quantitative trait loci (QTL) analyses showed strong associations (P < 0.01) between conditioned place preference and marker loci on chromosomes 4, 8, 9, 18 and 19. Weaker associations (0.01 < P < 0.05) were identified on several other chromosomes. Analysis also yielded several significant QTL for unconditioned preference, ethanol-stimulated activity, and sensitization. Overall, these data support the conclusion that genotype influences ethanol-induced conditioned place preference, presumably via genetic differences in sensitivity to ethanol's rewarding effects. Moreover, several chromosomal regions containing candidate genes of potential relevance to ethanol-induced conditioned place preference have been identified.

Animals↗

PubMed1995

Genetic differences in intravenous cocaine self-administration between C57BL/6J and DBA/2J mice.

In experiment 1, two different strains of mice [C57BL/6J (B6) and DBA/2J (D2)] were allowed to nosepoke for 5 microliters intravenous (IV) infusions during 2-h daily sessions. Two nosepoke holes were available, only one of which was reinforced on an FR-3 schedule with a 10-s time-out indicated by a light inside the reinforced nosepoke hole. During the first nine sessions, infusions were saline. On subsequent sessions, mice acquired nosepoking for 0.5 mg/kg cocaine. Finally, all mice were extinguished by again receiving only saline infusions. Cocaine acted as a reinforcer in both strains. In experiment 2, different mice from the same two strains were allowed to acquire nosepoking for IV cocaine at one of three unit doses (0.5, 1.0, or 2.0 mg/kg). Although there were no effects of unit dose on rate of acquisition, B6 mice were faster in acquiring self-administration behavior than were D2 mice. Experiment 3 assessed behavior in the same mice, after acquisition had occurred. D2 mice nosepoked at a lower rate at asymptote than did B6 mice, but with a higher preference for the cocaine reinforced hole. Unit doses of cocaine were then manipulated within subjects, from 0.125 to 2.0 mg/kg per infusion. Higher doses yielded lower response rates than lower doses, both between and within subjects. Behavior in D2 mice relative to B6 mice also appeared to be shifted to the left of the dose-response curve measured within-subjects. Together, these findings indicate that although cocaine serves as a reinforcer in both strains, there are genetic differences in the pattern of cocaine self-administration between these two mouse strains.

Animals↗

PubMed1995

Intravenous cocaine self-administration in the C57BL/6J mouse.

Freely behaving C57BL/6J mice with intrajugular catheters were trained to nose-poke for cocaine (0.75 mg/kg per 5-microliters infusion) under a fixed-ratio-10 schedule of reinforcement. Mice were given a choice between two nose-poke holes on opposite sides of the apparatus. Nose-pokes by experimental (O) subjects (operant group) were reinforced on only one side and reinforcer delivery coincided with the onset of a 10-s time-out light stimulus. Drug delivery to control subjects (yoked group) was determined by the behavior of O mice. Nose-poke rate increased in O subjects, whereas yoked subjects did not acquire the nose-poking response. Moreover, nose-poking was selective for the cocaine-paired side in O subjects. When saline infusions were substituted for cocaine (i.e., extinction), nose-poking in O subjects decreased, whereas yoked controls were unaffected. O subjects developed a preference for the drug-associated side of the apparatus during extinction. Overall, these data offer strong evidence of cocaine-directed behavior in the C57BL/6 inbred mouse strain. More generally, these findings support the feasibility of using intravenous self-administration to assess reinforcement in genetically well-defined populations.

Animals↗

PubMed1994

Modulation of ethanol reinforcement by conditioned hyperthermia.

The present study was designed to determine whether a signal for availability of self-administered ethanol would acquire the ability to elicit a conditioned thermal response and to alter ethanol self-administration. Non-deprived male albino rats (n = 8) were exposed to a differential conditioning procedure in which brief (30-min) periods of access to sweetened ethanol on a fixed-ratio operant schedule were either signalled (CS+trials) or unsignalled (Blank+trials). A different stimulus signalled trials on which barpressing was not reinforced (CS-trials). Body temperature was recorded continuously from implanted telemetry devices. As in previous studies involving experimenter-administered ethanol injections, the stimulus paired with self-administered ethanol (CS+) acquired the ability to elicit a conditioned increase in body temperature. Moreover, barpressing for ethanol was greater on signalled trials (CS+) than on unsignalled trials (Blank+), indicating that ethanol's reinforcing efficacy was altered by CS+. Ethanol self-administration was significantly correlated with the anticipatory increase in body temperature on CS+ trials (Pearson r = +0.77). When ethanol was removed, leaving sucrose alone as the reinforcer, the signal's effect on barpressing was eliminated. This finding suggests the signal's effect depended on ethanol's pharmacological properties. In general, these data are consistent with theories that attribute the signal's effect to conditioned changes in motivation to obtain ethanol or to an interaction between the conditioned response and ethanol's unconditioned effects. The specific pattern of results appears to support hypotheses linking ethanol's thermal and motivational effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗

PubMed1994

Motivational properties of ethanol in mice selectively bred for ethanol-induced locomotor differences.

Ethanol-induced locomotor stimulation has been proposed to be positively correlated with the rewarding effects of ethanol (Wise and Bozarth 1987). The present experiments provided a test of this hypothesis using a genetic model. Three behavioral indices of the motivational effects of ethanol (drinking, taste conditioning, place conditioning) were examined in mice from two independent FAST lines, selectively bred for sensitivity to ethanol-induced locomotor stimulation, and mice from two independent SLOW lines, selectively bred for insensitivity to ethanol-induced locomotor stimulation. In a single-bottle procedure, mice were allowed access to drinking tubes containing ethanol in a concentration (1-12% v/v) that increased over 24 consecutive days. FAST mice consumed greater amounts of ethanol solution. In a two-bottle procedure, mice were allowed access to tubes containing water or various concentrations of ethanol (2-8% v/v) over 6 days. FAST mice generally showed greater preference for ethanol solutions than SLOW mice. In a conditioned taste aversion procedure, mice received access to saccharin solution followed by injection of 2.5 g/kg ethanol (IP). SLOW mice developed aversion to the saccharin flavor more readily than FAST mice. In a series of place conditioning experiments, tactile stimuli were paired with various doses of ethanol (0.8-2.0 g/kg). During conditioning, FAST mice showed locomotor stimulation after 1.0, 1.2 and 2.0 g/kg ethanol while SLOW mice did not. During testing, mice conditioned with 1.2 g/kg and 2.0 g/kg ethanol showed conditioned place preference, but there were no line differences in magnitude of preference. These results indicate that genetic selection for sensitivity to ethanol-stimulated activity has resulted in genetic differences in ethanol drinking and ethanol-induced conditioned taste aversion but not ethanol-induced conditioned place preference. Overall, these data provide mixed support for the psychomotor stimulant theory of addiction.

Alcohol Drinking↗

PubMed1993

Drug-induced hypothermia and conditioned place aversion.

This study examined the relationship between ethanol's thermal and motivational effects in a place conditioning task. In three experiments, male albino rats were exposed to a differential conditioning procedure that paired a distinctive tactile stimulus with ethanol (1.2 or 1.8 g/kg) or lithium chloride (3 meq/kg); a different stimulus was paired with saline. Different groups were exposed to ambient temperatures (Ta) of 5 degrees, 21 degrees or 32 degrees C during each 60-min conditioning trial. Both ethanol and lithium chloride produced hypothermia and conditioned place aversion in rats conditioned at normal Ta. Exposure to high Ta reduced drug-induced hypothermia, increased activity, and decreased conditioned place aversion. Exposure to low Ta did not enhance drug-induced hypothermia or change conditioned place aversion. In general, these findings support the suggestion that the hedonic effects of ethanol and lithium chloride interact with their thermal effects.

Animals↗

PubMed1993

Pavlovian conditioning of heart rate and body temperature with morphine: effects of CS duration.

Rats were exposed to a conditioning procedure that varied the duration of overlap between a light-noise conditioned stimulus (CS) and the effects of a morphine (5 mg/kg) unconditioned stimulus (US). Three paired (P) groups differed in CS duration (5, 15, or 60 min) but had the same CS-US interval (30 s). A control group (U) received explicitly unpaired presentations of CS and US. P groups showed CS-specific attenuation of the bradycardic response and enhancement of the hyperthermic response to morphine. During placebo tests, the CS elicited conditioned increases in heart rate and body temperature in Groups P15 and P60. Group P5 showed a conditioned increase in heart rate but not in body temperature. Overall, strength of conditioning was directly related to CS duration. These data indicate that duration of overlap between a CS and drug-induced changes in a target response system is an important determinant of Pavlovian drug conditioning.

Animals↗

PubMed1992

Haloperidol does not alter expression of ethanol-induced conditioned place preference.

A recent experiment (Risinger et al., Psychopharmacology, 107 (1992) 453-456) has shown that haloperidol does not prevent acquisition of ethanol-induced conditioned place preference, suggesting that dopaminergic mechanisms do not mediate the primary rewarding properties of ethanol. The present experiment examined whether haloperidol would prevent the expression of conditioned reward to ethanol-paired stimuli using the place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP). A different stimulus was paired with saline. Before preference testing, different groups received one of three doses of haloperidol (0, 0.05 or 0.1 mg/kg); ethanol was not given. Haloperidol produced a dose-dependent decrease in locomotor activity, but did not affect conditioned place preference. These results suggest that expression of ethanol-induced conditioned place preference is mediated by non-dopaminergic mechanisms.

Animals↗

PubMed1992

Genetic determinants of ethanol reinforcement.

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.

Animals↗