Biomedical subjects

N J Grahame

Publications and source records attributed to N J Grahame.

At least 19 recordsLinked to original sources

PubMed2001

Alcohol place preference conditioning in high- and low-alcohol preferring selected lines of mice.

High- and low-alcohol preferring (HAP and LAP) selected lines of mice diverge greatly in free-choice alcohol consumption. This study investigated whether the lines differ in a measure of alcohol reward not dependent on drinking, specifically place conditioning. Mice were subjected to a differential conditioning procedure in which four alcohol-paired CS+ trials on one floor cue (0, 1.5, 3, or 4 g/kg; ns=20-24) alternated with four saline-paired CS- trials on a different floor cue. Testing was on a split floor, half CS+ and half CS-. HAP and LAP mice showed no preference at 0 g/kg, and equivalent, moderate preference at 1.5 and 3 g/kg alcohol. At 4 g/kg, LAP, but not HAP mice showed an increase in preference. The present findings imply greater efficacy of alcohol preference conditioning in LAP mice, but do not speak for line differences in sensitivity. Results do not support the hypothesis that selection for high drinking yields greater efficacy of alcohol as a reinforcer when reward is measured using a technique that does not rely on drinking. Low drinking in LAP mice may emerge from innate taste avoidance of alcohol as a result of selective breeding for low preference, which prevents them from encountering alcohol's rewarding, pharmacological effects.

Alcohol Drinking↗

PubMed2001

Effects of acamprosate on sensitization to the locomotor-stimulant effects of alcohol in mice selectively bred for high and low alcohol preference.

Sensitization to the locomotor-stimulant effects of drugs is thought to play an important role in the development of drug-seeking behaviour. We hypothesized that the ability of acamprosate to reduce alcohol relapse rates in recovering alcoholics, and alcohol consumption in rodents, may be related to its ability to reduce sensitization to the locomotor-stimulant effects of alcohol. The purpose of the present study was to determine whether acamprosate reduces the expression of sensitization to the locomotor-stimulant effects of alcohol in lines of mice selectively bred for high (HAP) and low (LAP) alcohol preference. Mice were given six intraperitoneal (i.p.) injections of alcohol (3 g/kg) or saline at 48 h intervals. The test for sensitization to the locomotor-stimulant effects of alcohol consisted of a challenge dose of 2 g/kg i.p. alcohol followed immediately by assessment of locomotor activity for 20 min. Mice were pretreated with either saline or acamprosate (400 mg/kg) at 14 h and again at 2 h before the alcohol challenge. Both HAP and LAP mice showed sensitization to the locomotor-stimulant effects of alcohol. Acamprosate reduced the expression of sensitization to the locomotor-stimulant effects of alcohol in HAP but not LAP mice. These data suggest complex effects of acamprosate on alcohol-stimulated locomotor activity that depend on genotype.

Acamprosate↗

PubMed2001

Approaches to understanding the neurobiological regulation of ethanol self-administration: a young investigators forum.

The article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The co-chairs were Cristine L. Czachowski and Craig J. Slawecki. The presentations were (1) Behavioral assessment of ethanol seeking and self-administration, by Cristine L. Czachowski; (2) Electrophysiological measures of ethanol preference and reinforcing efficacy, by Craig J. Slawecki; (3) Genetic differences in locomotor sensitization and reward phenotypes associated with bidirectional selection for alcohol preference in mice, by Nicholas J. Grahame; (4) Transgenic and knockout mouse models: Powerful tools for investigating the neurobiology of alcoholism, by Todd E. Thiele; and (5) Neurochemical characteristics that may predict ethanol preference in selected P and NP rats: A quantitative microdialysis study, by Simon N. Katner.

Animals↗

PubMed2000

Ethanol locomotor sensitization, but not tolerance correlates with selection for alcohol preference in high- and low-alcohol preferring mice.

RATIONALE: Some theories have advanced a role for both locomotor sensitization and tolerance in the reinforcing properties of drugs. The present studies used selected lines of mice to assess genetic correlations among ethanol drinking, ethanol locomotor sensitization, and tolerance to the depressant effects of ethanol. OBJECTIVES: Ethanol-naive high- and low-alcohol preferring (HAP and LAP) selected lines of mice were tested for locomotor sensitization to ethanol and acquisition of acute functional tolerance to ethanol using the static dowel test. METHODS: For the locomotor sensitization study, mice received four i.p. injections of one of five doses of ethanol (0-3.5 g/kg) at 48-h intervals. On the sensitization test day, 48 h after the last drug administration day, all mice received a 2.0-g/kg ethanol injection. Other mice from the same lines were subjected to a two-injection (3.75 g/kg total), acute functional tolerance procedure assessing disruption of balance on a static dowel. RESULTS: Lines differed neither in the acute locomotor activating nor depressant effects of ethanol. Additionally, neither line's response to the depressant effect of 3.5 g/kg ethanol changed with repeated injection. However, locomotor sensitization was seen in HAP but not LAP mice that had received 2.75 g/kg or 3.5 g/kg ethanol during repeated administration. Both HAP and LAP mice acquired equivalent acute functional tolerance, as measured by an increase in blood ethanol concentration between the first and second recovery measures. CONCLUSIONS: Overall, these findings imply that high ethanol consumption in mice appears to be genetically related to ethanol locomotor sensitization. Additionally, ethanol locomotor sensitization does not appear to be related to tolerance to the depressant effects of ethanol. These findings support a role for sensitization in high alcohol-seeking behavior in mice.

Alcohol Drinking↗

PubMed2000

Naltrexone and alcohol drinking in mice lacking beta-endorphin by site-directed mutagenesis.

Alcohol-induced activation of the opioid system may contribute to the reinforcing properties of alcohol. This study investigated whether elimination of beta-endorphin (BE) synthesis via site-directed mutagenesis in embryonic stem cells would alter alcohol intake in mice. Both BE-deficient and wildtype (WT) mice generated from the targeted stem cells were backcrossed for nine generations onto a C57BL/6 background, and were maintained with ad libitum food and water. Mice had access to alcohol (10% v/v) under the following conditions: 24 h, scheduled access for 2 h/day, following acute (1 or 2 days) or chronic (5 weeks) alcohol deprivation, and scheduled access following six doses of naltrexone (0.125-16.0 mg/kg BW, ip) or saline treatment. Alcohol intake was similar in BE-deficient and WT mice given chronic access to alcohol, but greater in BE-deficient compared with WT mice during the first 10 days of scheduled access to alcohol, but not after more extensive experience with scheduled access. BE-deficient, but not WT mice, increased alcohol intake following 2 days, but not 1 day or 5 weeks, of deprivation. Naltrexone reduced alcohol drinking both in BE-deficient and WT mice, suggesting that drinking is mediated, in part, by activation of opioid receptors in both genotypes.

Alcohol Drinking↗

PubMed2000

Selected lines and inbred strains. Tools in the hunt for the genes involved in alcoholism.

In their quest to elucidate the genetic influences contributing to alcoholism, researchers have long used selected lines and inbred strains of rodents. Selected lines are obtained by repeatedly mating those animals within a population that show extremely high or low values of the desired trait. Inbred strains are generated by mating male and female siblings, irrespective of any particular trait, over several generations. Both of these approaches have provided researchers with extensive knowledge about the genetic and neurobiological mechanisms contributing to alcohol-related traits. However, the use of these models is associated with some limitations, mostly resulting from the inbreeding involved in generating such lines and strains. Nevertheless, these models can offer some advantages over other genetic approaches, such as the analysis of quantitative trait loci or the generation of transgenic and knockout mice.

Alcoholism↗

PubMed1999

Genetic differences in cocaine-induced conditioned place preference in mice depend on conditioning trial duration.

RATIONALE: In previous comparisons with C57BL/6J mice, DBA/2J mice have been characterized as "hyporesponsive" to cocaine's rewarding effect in the conditioned place-preference paradigm. This finding contrasts with other studies showing greater sensitivity of DBA/2J mice to the rewarding effects of ethanol and morphine in the place conditioning task. OBJECTIVES: The purpose of the present study was to examine cocaine- induced place conditioning in both strains using apparatus and procedures similar to those used previously to assess ethanol and morphine preference conditioning. METHODS: Mice from both strains were exposed to an unbiased place-conditioning procedure using 1, 10, or 30 mg/kg cocaine. Conditioning trial duration was 15, 30, or 60 min. RESULTS: In general, C57BL/6J mice displayed a significant conditioned place preference that was relatively unaffected by cocaine dose or trial duration. In contrast, DBA/2J mice showed no place conditioning at the shortest trial duration, but an increasing level of preference as trial duration increased. At the longest trial duration, both strains showed similar levels of place preference. CONCLUSIONS: Genetic differences in sensitivity to cocaine's rewarding effect depend critically on temporal parameters of the place-conditioning procedure. One possible interpretation of these findings is that short trial durations produce conditioned activity responses that interfere more with expression of conditioned place preference in DBA/2J mice than in C57BL/6J mice. More generally, these findings underscore the need for caution when drawing conclusions about genetic differences in place conditioning, especially when using this paradigm to evaluate the effects of gene knockouts or insertions on drug reward.

Analysis of Variance↗

PubMed1999

Ethanol oral self-administration is increased in mutant mice with decreased beta-endorphin expression.

The relationship between ethanol (EtOH) administration and the endogenous opioid system has been studied for many years and a considerable body of evidence supports the contention that EtOH modulates the production and/or release of endogenous opioid peptides. However, substantially less is known about the converse influence: the effect that opioids have on EtOH sensitivity. In this study, we used the beta-endorphin deficient mutant mouse line C57BL/6-Pomc1(tm1Low) to investigate the possible role of a specific opioid peptide on EtOH consumption. Homozygous knockout mice (entirely lacking beta-endorphin), heterozygous mice (50% beta-endorphin expression) and sibling wildtype mice from the same strain were evaluated in a two-bottle free choice paradigm for oral self-administration of EtOH. Across varying EtOH concentrations only the heterozygous mice were found to consistently drink more than wildtype mice. These data support the hypothesis that beta-endorphin modulates the response to EtOH.

Alcohol Drinking↗

PubMed1999

Selective breeding for high and low alcohol preference in mice.

High and low alcohol preference (HAP and LAP, respectively) mice were created by 10 generations of bidirectional selection for differences in two-bottle choice alcohol consumption. The progenitors used for selection were HS/lbg mice, which are a genetically defined, outbred stock. During selection, mice had 24-h, daily access to 10% alcohol (v/v) and water ad libitum for 30 days and were selected based on the alcohol (g/kg) consumed per day over the entire period. Food was available ad libitum. At S10, line means for alcohol consumption differed greatly, with consumption of over 12 g/kg per day in the HAP mice and less than 2 g/kg per day in the LAP mice. Realized heritability for bidirectional selection was approximately 0.2. Female mice consumed more alcohol than male mice. There were no differences between lines in alcohol elimination rate, nor were there line differences in intake of salt or quinine solutions. However, consumption of saccharin solutions was greater in HAP mice than LAP mice, consistent with previous findings of a genetic correlation between sweet preference and alcohol drinking. Because the mouse genome is relatively well characterized, these selected lines should prove a useful tool for assessment of the genetic basis of, and phenotypes that correlate with, alcohol drinking.

Alcohol Drinking↗

PubMed1999

Limited access alcohol drinking in high- and low-alcohol preferring selected lines of mice.

BACKGROUND: Selection studies and genetic analyses of drinking behavior in rodents often involved unlimited access to alcohol over a period of weeks, with water and food freely available. Most studies investigating the pharmacology of alcohol drinking, on the other hand, use procedures in which access to alcohol is limited to a particular time each day. Reconciliation of findings between these two conditions likely depends on their sharing common genetic mechanisms as indicated, for example, by covariation in response to selection. To this end, high- and low-alcohol preferring (HAP and LAP, respectively) mice, selected for differences in 24-hr access alcohol drinking over a 4-week period, were subjected to a limited access alcohol drinking protocol. METHODS: During 2-hr sessions, mice had access to various concentrations of alcohol (7-15%, v/v) in the home cage for 2 hr a day, with ad libitum access to food and water. Additional sessions were conducted with no food present. RESULTS: Although both strains consumed alcohol and water during these sessions, HAP mice drank far more alcohol than did LAP mice. HAP but not LAP mice drank alcohol at a high rate early in the session compared with later in the session. Additionally, HAP mice responded to changes in alcohol concentration, whereas LAP mice did not. Removal of food did not influence alcohol drinking, although water drinking decreased following food removal. HAP mice reached appreciable blood alcohol concentrations after limited access. CONCLUSIONS: These findings indicate that in these selectively bred mice, alcohol drinking during limited and unlimited access may be genetically related, and that drinking during limited access sessions in HAP mice is likely for the pharmacological properties of alcohol.

Alcohol Drinking↗

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↗

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↗

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

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↗

PubMed1995

Assessment of the Rescorla-Wagner model.

The Rescorla-Wagner model has been the most influential theory of associative learning to emerge from the study of animal behavior over the last 25 years. Recently, equivalence to this model has become a benchmark in assessing connectionist models, with such equivalence often achieved by incorporating the Widrow-Hoff delta rule. This article presents the Rescorla-Wagner model's basic assumptions, reviews some of the model's predictive successes and failures, relates the failures to the model's assumptions, and discusses the model's heuristic value. It is concluded that the model has had a positive influence on the study of simple associative learning by stimulating research and contributing to new model development. However, this benefit should neither lead to the model being regarded as inherently "correct" nor imply that its predictions can be profitably used to assess other models.

Association Learning↗

PubMed1993

Temporal encoding as a determinant of blocking.

A blocking paradigm with rats was used to evaluate whether different temporal information is encoded in simultaneous rather than forward associations. During Phase 1, the blocking conditioned stimulus (CS) was simultaneously or forward paired with an unconditioned stimulus (US). During Phase 2, the pretrained CS occurred in compound with a novel target CS that was paired in a simultaneous or forward manner with the US. Forward pretraining resulted in more blocking of a forward than a simultaneously trained target CS, and simultaneous pretraining resulted in more blocking of a simultaneously than a forward trained target CS. Thus, greater blocking occurred when the blocking and blocked CSs had the same temporal relation to the US. The results support the temporal coding hypothesis and question the necessity of predictive information in blocking.

Animals↗

PubMed1993

Local time horizons in Pavlovian learning.

Responding to a conditioned stimulus (CS) is impaired if the CS is trained in the presence of excitatory local context cues. Four lick suppression experiments with rats explored whether this local context effect arises from the influence of excitatory cues that precede or that follow a reinforced target CS. Pretrained nontarget stimuli served as local context cues that occurred (a) immediately before and after the target CS trial, (b) immediately before or after the target CS trial, or (c) only before or after the target CS trial with varying intervals between the nontarget stimulus and target CS. Results indicated similar control over responding to the target CS by the preceding and following nontarget cues. This outcome implies a symmetrical window of memory integration (local time horizon) for a Pavlovian CS. Possible mechanisms underlying the detrimental effect of embedding a CS in an excitatory local context are discussed.

Animals↗