Frank Holloway - US grants

Tolerance is a basic pharmacological phenomenon produced when repeated exposure to a given drug dose results in a decreased effect of that dose or an increase in the dose needed to reproduce the initial drug effect. While ethanol tolerance presumably would allow an individual to consume greater quantities of ethanol, its role in the development of problem drinking or alcoholism is still poorly understood. Since tolerance does not readily develop to the "reward" propoerties of ethanol, it may contribute to increased ethanol intake by reducing the "costs" (physiological effects and performance impairment) of drinking, thereby increasing the relative reward value of ethanol. The long-range objective of this proposal is to identify those antecedent and temporal factors or mechanisms which influence the development and maintenance of tolerance to several of ethanol's behavioral effects. While recent research often has examined the relative contributions of behavioral (e.g., learned adjustments from intoxicated practice) vs. physiological changes (e.g., changes in cellular adaptation) factors in tolerance development, the results of such studies can best be regarded as preliminary since only single ethanol test doses are typically employed. The rat operant model to be used in this proposal has proven sensitive to the development of tolerance for ethanol's rate-decreasing and rate-increasing effects. Such changes are reflected by a 1-2-fold shift in the ethanol dose effect curve which persists for up to six months. Such tolerance appears to depend both on intoxicated practice and some threshold exposure to ethanol. Using the latter methodologies, the specific aims of this proposal are to investigate tolerance development to ethanol's effects on operant performance. The specific questions to be addressed are: (1) how the rate, magnitude and persistence of tolerance vary as a function of the number and pattern of and/or ethanol dose prior to intoxicated practice sessions; (2) the relative contribution of intoxicated practice and amount of ethanol exposure per se; (3) the dependence of long-term tolerance on environmental factors; and (4) the dependence of such tolerance on task demand characteristics. The data generated by this research should clarify the role of instrumental or "skill" learning in ethanol tolerance and specificity of such learned adjustments.

caffeine; drug abuse;

We have recently reported that "legal" over-the-counter stimulants, when combined in appropriate dose ratios could engender drug-appropriate responding in amphetamine and cocaine drug discrimination tasks in rats. These results suggest that these legal stimulants may mimic the subjective effects of these psychomotor stimulants. Little is known about the abuse liability profile of these duplicitous drugs. The present proposal would extend the analysis of these legal stimulant combinations (e.g., caffeine (CAF), ephedrine (EPH), and phenylpropanolamine (PPA)). Project I utilizes a 4-hour limited access cocaine self-administration task to assess the "reinforcing" properties of these duplicitous drug combinations using: (1) substitution tests, (2) preloading, and (3) progressive ratio schedules of reinforcement. Food and water will be available 20 h per day under concurrent FR10 schedules of reinforcement. The total amount and pattern of food and water consumption will be used as an index of behavioral toxicity of all drug challenges/conditions. Project II is designed to assess the discriminative stimulus properties of dual and triple combinations of legal stimulants (CAF + EPH, CAF + PPA, and CAF + EPH + PPA) and the cross-generalization profiles with the prototypic psychomotor stimulants cocaine [COC], d-amphetamine, and methamphetamine. The influence of drug and experimental history on the self-administration of cocaine will be assessed in Project II also. Two groups of rats will be utilized to assess the relative contribution of drug discrimination history (COC vs. saline, and the CAF + EPH + PPA combination vs. saline) on subsequent self-administration of COC. Three other groups will be yoked to the subjects in these discrimination tasks to match for drug history. Project III will assess the affective components of the stimulant withdrawal syndrome using two different 3-choice drug discrimination tasks (5 mg/kg chlordiazepoxide vs. saline vs. 15 mg/kg pentylenetetrazol and .03 mg/kg haloperidol vs. saline vs. 10 mg/kg COC). High dose pretreatments and 3-day chronic periods of both COC and the triple stimulant combination will be used to assess the "rebound" phenomena. In sum, the biobehavioral assays in this proposal would provide information concerning the abuse liability profile of these "legal" stimulants relative to that for cocaine. If these duplicitous drug compounds mimic the subjective effects of cocaine but lack cocaine's robust rewarding property and its withdrawal and behaviorally toxic effects, they might eventually provide a potential "methadone-model" of cocaine supplementation therapy.

Acute ethanol withdrawal ("hangover") is a major concern in settings where any compromise to one's sense of well-being or performance could lead to dangerous (e.g., automobile driving) and even disastrous results (e.g., health care or aviation industries). However, its role in alcohol abuse and alcoholism is still poorly understood. Our animal studies show that acute ethanol withdrawal resembles the alcohol abstinence syndrome produced after the cessation of chronic alcohol exposure. This state represents a generally, high-dose, delayed ethanol effect (EDE), defined by a pattern of physiologic, behavioral, and subjective features, maximal 12-30 hours after a single dose. While infrequently studied, the EDE, or "hangover" state, like the chronic withdrawal state, may provide the occasion for performance impairment and increases in ethanol consumption to "self-medicate" the dysphoric symptoms accompanying such withdrawal. The physiological/theoretical basis for both acute and chronic withdrawal effects has been viewed as a biphasic "opponent-process" response, reflecting an adjustment of homeostatic systems governing the particular biobehavioral processes being measured. However, our recent telemetry data of EEG, temperature, and locomotor activity in rats given single ethanol doses suggest an alternative explanation for EDE, i.e., low to moderate doses phase-shift-and high doses disrupt the circadian rhythms which regulate the variation of these variables throughout the day. In other words, at least a component of the EDE closely resembles the circadian phase-shifts and desynchrony effects (PSE) associated with "jet-lag" and shift-work cycles. Our proposed studies are intended to further elucidate the physiological, behavioral, and subjective features of EDE, to explore its possible linkage with other conditions which also produce circadian rhythm disruptions (PSE), and to clarify its role in promoting ethanol consumption. Four projects will use a rat model and research designs and methods common in chronobiological research. Project-A will determine whether ethanol-induced changes in activity and temperature actually resemble or interact with rhythm disturbances produced by phase-shifts of the environment light-dark (LD) cycle (PSE). We now have shown that rats can be trained to make specific responses when the EDE-state is present. EDE-specific responses persist for 18-40 hours after a single high dose of ethanol, but are blocked by acute ethanol. Project-B will use this EDE- discrimination model to determine (a) whether PSE states have interoceptive features which are discriminated as being like the trained EDE-state and (b) the common pharmacological mechanisms mediating both states. Project-C will assess whether EDE and/or PSE states are indeed aversive (tests with state-specific place conditioning). Project-D will examine whether the EDE and/or PSE states enhance oral ethanol intake. The last two studies will provide data on whether "hangover" actually contributes to ethanol intake, perhaps by some "self-medication" of the aversive properties of the EDE state.

Tolerance to ethanol (ETOH) develops when repeated exposure to a given dose results in a decreased effect for that dose and an increase in the dose required to reproduce the initial ETOH dose effect. While ETOH tolerance and dependence may develop independently, a possible relationship may exist between tolerance development and the acquisition of sustained ETOH intake and eventual physical dependence. For example, tolerance development or behavioral adjustments to the disruptive or dysphoric properties of ETOH might set the occasion for increased ETOH intake, by reducing the "costs" of drinking, thereby enhancing its reward effects. Prior studies using a pre/post ETOH administration design with schedule-controlled behaviors have demonstrated 2-3 fold shifts to the right in the dose-effect curves in the pre-session ETOH group, with only minor tolerance development in the post- session groups. However, recently post-session ETOH treatments have resulted in significant shifts in the dose-effect curves without any intoxicated practice sessions. These data suggested an acute ETOH delayed effect developing approximately 22 hours post-administration, produced rate reductions in operant performance. Tolerance to these delayed ETOH rate- reducing effects developed and affected the magnitude of ETOH tolerance to its acute intoxicating effects. Preliminary data from this laboratory, not only supports the hypothesis that development of behavioral tolerance may reverse ETOH's aversive effects and "unmask" its underlying reward/hedonic properties, but also indicates drug/behavior histories involving ETOH oral self-administration (OSA) or ETOH discrimination may do the same. The present proposal represents a systematic examination of the role that development of behavioral tolerance may play in modulating ETOH's motivational effects in a rat model. Project I of the present proposal will examine the development of tolerance to ETOH's immediate and/or delayed effects using an FR-30 schedule of operant performance sensitive primarily to ETOH's suppressant effects on behavior. Several controls will be used, including pre-session saline, post-session ETOH and groups with no ETOH or behavioral histories. We then will examine the contribution of such tolerance to ETOH's subsequent motivational effects as measured by three different behavioral assays: (a) conditioned place preference (or aversion), (b) conditioned taste aversion, and (c) oral ETOH acceptance and preference. Project II, using a pre-/post-chronic ETOH design, will systematically examine the impact that development of behavioral tolerance on several parameters of oral ethanol self-administration established by a "sucrose-fading" procedure, including: (a) shifts in baseline ethanol concentration-consumption curve, (b) dose-effect analysis of ETOH's immediate and delayed modulation of ETOH intake when given as a "bolus" prior to the OSA-session. The data generated by this research should clarify the role of: (1) the relative contribution of ETOH's acute and delayed behavioral effects on tolerance development; (2) the impact of such tolerance development on subsequent assays for ETOH's positive-rewarding and/or negative-aversive properties; and (3) the impact of such tolerance development on ETOH consumption itself and on the manner in which such consumption is modulated by recent ETOH experience.