Differences In Initial Sensitivity Research Articles

High Alcohol-Preferring Mice Show Reaction to Loss of Ethanol Reward Following Repeated Binge Drinking.

Beyond yielding high blood ethanol (EtOH) concentrations (BECs), binge-drinking models allow examination of drinking patterns which may be associated with EtOH's rewarding effects, including front-loading and consummatory successive negative contrast (cSNC), a decrease in intake when only water is available to subjects expecting EtOH. The goals of the current study were to broaden our understanding of these reward-related behaviors during binge EtOH access in high alcohol-preferring (HAP) replicate lines (HAP2 and HAP3) of mice selectively bred to prefer alcohol. We hypothesized that both lines would show evidence of front-loading during binge EtOH access and that we would find a cSNC effect in groups where EtOH was replaced with water, as these results have been shown previously in HAP1 mice. HAP replicate 2 and replicate 3 female and male mice were given 2hours of EtOH or water access in the home cage for 15 consecutive days using "drinking in the dark" (DID) procedures. Mice received the same fluid (either 20% unsweetened EtOH or water) for the first 14days. However, on the 15th day, half of the mice from these 2 groups were provided with the opposite assigned fluid (EtOH groups received water and vice versa). Intake was measured in 1-minute bins using specialized sipper tubes, which allowed within-session analyses of binge-drinking patterns. EtOH front-loading was observed in both replicates. HAP3 mice displayed front-loading on the first day of EtOH access, whereas front-loading developed following alcohol experience in HAP2 mice, which may suggest differences in initial sensitivity to EtOH reward. Consummatory SNC, which manifests as lower water intake in mice expecting EtOH as compared to mice expecting water, was observed in both replicates. These findings increase confidence that defined changes in home cage consummatory behavior are driven by the incentive value of EtOH. The presence of cSNC across HAP replicates indicates that this reaction to loss of reward is genetically mediated, which suggests that there is a biological mechanism that might be targeted.

Genetic Dissection of Acute Ethanol Responsive Gene Networks in Prefrontal Cortex: Functional and Mechanistic Implications

BackgroundIndividual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol.ResultsAcute ethanol altered the expression of ∼2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol's effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity.Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3β, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b, Gria1, Sncb and Nell2.ConclusionsThe ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders.

Variability in initial nicotine sensitivity due to sex, history of other drug use, and parental smoking

Initial sensitivity to nicotine's effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose–response effects of nasal spray nicotine (0, 5, 10μg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.

Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long–Evans rats

Epidemiological evidence suggests that adolescents may exhibit a unique susceptibility to the motivational effects of nicotine compared to adults. In contrast to the hypothesis of an enhanced vulnerability to nicotine during adolescence, we have observed that nicotine is less reinforcing in adolescent compared to adult rats using a progressive ratio reinforcement schedule in an operant self-administration procedure, although prior operant conditioning experience may have masked differences in initial sensitivity to nicotine. This study examined the spontaneous acquisition of nicotine self-administration in adolescent (postnatal day (PD) 31) and adult (PD87) male Wistar and Long-Evans rats. Rats self-administered nicotine (0.015 or 0.03 mg/kg/infusion, i.v.) during 2-h operant conditioning sessions under fixed-ratio-1 (FR1) and FR3 reinforcement schedules for six sessions each. A subset of rats (adolescents: PD42, adults: PD98) underwent extinction of responding and nicotine priming-induced reinstatement (0.15 mg/kg, s.c.). In a separate group of rats, saccharin self-administration (0.1 ml of 0.2% w/v) was tested to determine the specificity of our findings with nicotine. A greater proportion of adult compared to adolescent rats acquired self-administration of 0.015 mg/kg/infusion nicotine, but both age groups readily acquired self-administration of 0.03 mg/kg/infusion nicotine and saccharin. Age differences in extinction of responding for nicotine or saccharin depended upon strain, but priming-induced reinstatement was similar across age and strain. The current findings are consistent with those obtained under a more demanding progressive ratio reinforcement schedule and suggest that adolescents, compared to adults, may not be as sensitive to the reinforcing effects of nicotine.

Assessment of alcohol tolerance in adolescents.

To improve assessment of the DSM-IV alcohol tolerance criterion in adolescents, this study tested the performance of a minimum percentage increase in drinking quantity, and a proxy measure of tolerance (i.e., average heavy-drinking quantity per occasion) in identifying adolescents with alcohol dependence. Two adolescent samples were examined. In one sample (N = 415, 58% male, 79% white, 57% clinical), a modified version of the SCID was used to determine DSM-IV alcohol diagnoses, and lifetime drinking history data were collected by interview. In the second sample (N = 470, 60% male, 76% white, 100% clinical), the Adolescent Diagnostic Interview was used to determine DSM-IV alcohol diagnoses and to collect data on initial- and current-drinking quantities needed to become intoxicated. The performance of a percentage increase and average heavy-drinking quantity in identifying those with dependence was evaluated using receiver operating characteristic analysis. The utility of a percentage increase definition was limited by the high degree of variability in initial-drinking quantities. Percentage increase may underassign the tolerance symptom when initial-drinking quantities are high and overassign the symptom when initial-drinking quantities are low. Average heavy-drinking quantity per occasion, combined with a minimum frequency of drinking, demonstrated better performance than any percentage increase definition. Alternatives to a change-based (e.g., percentage increase) definition of tolerance warrant study due to limits of change-based definitions when initial-drinking quantity shows a high degree of variability. The variability in initial-drinking quantity may reflect individual differences in initial sensitivity that need to be considered in tolerance assessment.

Reliability of individual differences in initial sensitivity and acute tolerance to nitrous oxide hypothermia

On average, the hypothermia exhibited by rats receiving 60% nitrous oxide (N 2O) eventually abates despite the continued inhalation of the drug (i.e., acute tolerance develops). However, large individual differences occur in both the magnitude of hypothermia achieved and the degree of acute tolerance that develops. To determine whether the degree of temperature loss and subsequent recovery during N 2O administration are reliable characteristics of an individual, we measured intraperitoneal temperature via telemetry in 77 Long–Evans rats that each received 60% N 2O for 5 h during two sessions separated by 14 days. Good intersession reliability (Pearson's r) was observed for simple change and adjusted change scores for both initial N 2O temperature sensitivity (.61≤ r≤.62), and acute tolerance development (.46≤ r≤.52). In a separate experiment, three groups of rats were selected based on their individual body temperature patterns during an initial N 2O administration: (1) insensitive to N 2O hypothermia ( n=8); (2) marked hypothermia followed by acute tolerance development ( n=6); and (3) marked hypothermia followed by little acute tolerance development ( n=6). When retested 10 days later, each group exhibited a body temperature profile similar to that observed during the initial N 2O exposure. Thus, the temperature profile observed during a rat's initial exposure to 60% N 2O reflects a reproducible response for that animal.

Genetic differences in tolerance and sensitization to the sedative/hypnotic effects of alcohol

Initial sensitivity to alcohol and the development of alcohol tolerance were examined in rats of the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines. All rats received two alcohol injections (3.0 g/kg b.wt., IP) separated by either 1 or 2 days. P rats were less sensitive to the behaviorally impairing effects of alcohol than were NP rats, as evidenced by a longer latency to lose righting reflex (RR) and a shorter time to recover RR following an initial alcohol injection. When 1 day separated the two alcohol injections, P rats recovered the RR more rapidly following a second injection compared to the first, indicating that the P rats developed tolerance to the sedative/hypnotic effects of alcohol. In contrast, the NP rats recovered the RR more slowly following the second injection compared to the first, indicating that the NP rats developed sensitization to alcohol. Tolerance in the P line and sensitization in the NP line disappeared when 2 days separated the two alcohol injections. Line differences in initial sensitivity and tolerance/sensitization to the behaviorally impairing effects of alcohol may contribute to the differences in alcohol consumption observed in the P and NP lines.

Tolerance to morphine "anorexia" is not contingent on experience with food while in the drugged state.

To determine whether tolerance to morphine-induced anorexia requires access to milk while intoxicated, rats were given chronic injections of morphine (10 or 20 mg/kg) either before (before subgroups) or after (after subgroups) access to milk on alternate days. There were marked individual differences in initial sensitivity to the drug. After chronic treatment, there was little difference in the level of tolerance in subjects given morphine either before or after access to milk. On the intervening nondrug days, rats in the before subgroups consistently drank less milk than the other subgroups. This effect was not the result of withdrawal distress. Substitution of saline for morphine (20 mg/kg) on a scheduled drug day resulted in enhanced milk intakes in both the before and after subgroups. The results suggest that tolerance to morphine anorexia does not involve instrumental learning.

Caffeine and human behavior: arousal, anxiety, and performance effects.

A review of the recent literature shows the role of caffeine in the physiology, mood, and behavior of persons to be a complex one including changes in arousal, anxiety, and performance. Questions are raised as to what degree the physiological effects of caffeine are due to central nervous system stimulation and/or result from the release of catecholamines. Anxiety resulting from both high levels of caffeine (caffeinism) and caffeine withdrawal plus an association between caffeine and depression are discussed. Performance effects are mixed, with both increases and decreases reported. Effects on mental tasks are related to personality variables. The possible role of differences in initial sensitivity, adaptation to caffeine, and/or interactions with nicotine and alcohol is discussed. The present paper reviews these studies, discusses their implications for both clinical and experimental work, summarizes the major unresolved issues, and makes suggestions for new and continuing areas of research.

Effects of initial tolerance on acquired tolerance to alcohol in two selectively bred rat strains

The extent to which initial sensitivity to alcohol influences acquired tolerance was investigated in two selectively bred rat lines. These two lines have been selectively bred for differences in initial sensitivity to alcohol. The most affected (MA) line shows about a 90% reduction in motor activity following a 1.5 g/kg dose of alcohol compared with only a 40% reduction in least affected (LA) animals. In an initial investigation using stabilimeter activity, MA animals demonstrated increased tolerance following regular alcohol exposure, while LA animals showed little change from their initial levels of tolerance. In a second study following a similar intubation procedure, tolerance was assessed by sleeping time. Both MA and LA rats evidenced increased tolerance to alcohol, although MA animals did not approach the levels of tolerance shown by LA animals. In both studies the amount of initial tolerance was correlated with the degree of acquired tolerance. The potential for using these animals in the study of the underlying mechanisms of tolerance is discussed.