John L. Falk - US grants

In recent research, the production of a short (3 hr), daily ethanol binge in animals by the schedule-induced polydipsia technique resulted in the development of unequivocal physical dependence. This plan proposes to use a sensitive, fine-motor control task to delineate how quickly daily binge episodes produce dependence, and how soon after each daily episode tremulousness begins. Related studies will determine (a) vulnerability to the reacquisition of dependence, (b) the role of blood ethanol peak height, compared to simple maintained elevation, in producing dependence, and (c) the development of motivated behavior, which is specific to attaining ethanol that results from limited, daily binge episodes. This research is relevant to understanding the insidious development of ethanol dependence and its evolution as a reinforcer which may result from daily episodes of before, during, and after-dinner drinking in humans. The second major goal is to introduce behavioral alternatives into the binge-inducing situation which might behaviorally immunize animals against the acquisition of chronic binging. The relative success of these maneuvers, and their resiliancy with respect to relapse in the face of subsequent binging have applications with respect to ethanol overindulgence prevention strategies.

The studies proposed will evaluate the consequences of chronic exposure to benzodiazepines (BZs) on: (a) a fine-motor control task, and (b) the possible development of tolerance to their anxiolytic action. Also, (c) concurrent and historical pharmacological variables affecting the abuse potential of BZs, as assessed by the schedule-induced polydipsia techniques, will be explored. The behavioral and pharmacological properties of the residual "rebound" state which can develop with chronic use of ultra-short-acting BZs will be analyzed with the motor task. Both caffeine and midazolam produce fine-motor task disruption when given alone; their acute and chronic interactive effects will evaluate whether caffeine-taking or its withdrawal ameliorates or exacerbates this disruption. The minimally-effective doses of various anxiolytic agents on a saline-ingestion test have correlated highly with their clinical efficacies. This test, and an extension of it, will be applied to the analysis of new putative anxiolytics, as well as to the problem of possible tolerance development to anxiolytic action. Serum drug levels will be tracked and related to the consequences of chronic drug-taking.

This proposal studies the behavioral pharmacology of oral cocaine self-administration. The optimal conditions for the induction of cocaine overindulgence in rats will be established by varying drug concentration and the food-schedule induction parameters which are known to produce excessive behaviors. The effect commonly- used and abuse licit agents (nicotine and caffeine) might have in increasing schedule-induced cocaine intake will be determined, as well as possible attenuating effects of promising therapeutic (desipramine) and blocking agents (e.g., chlorpromazine and pimozide). A number of commodities and activities will be tested as behavioral alternatives to available cocaine under the excessive-behavior-generating conditions. Extensive exposure to prior experiences with non-drug, highly-preferred substances such as saccharin (which are then made unavailable) under conditions that should induce cocaine abuse may block its development, as may pre-adaptation to the inducing conditions. The possibility that prior overindulgence of nicotine or caffeine may predispose to cocaine abuse development will be explored. The effect of parenteral cocaine injection on a fine motor control task will be determined, as well as the interactive effects of caffeine and of nicotine with chronic cocaine on this kind of performance. Serum cocaine and metabolite levels will be correlated with behavioral effects.

The determinants and consequences of excessive oral drug self-administration by schedule-induced polydipsia will be explored, emphasizing oral cocaine (COC) and benzodiazepine (BZ) abuse variables and fine-motor performance consequences: (A: COC) (1) The amelioration of excessive COC intake by acute and chronic treatment with possible therapeutic agents (e.g., desipramine, mazindol) and by (2) alternatives to COC ingestion (e.g., other solutions, activity wheel). (3) Exacerbation of COC abuse by injections of nicotine (NIC) and caffeine (CAF). (4) The gateways to exacerbated COC abuse by first instituting a history of licit-drug polydipsia (NIC, CAF), and (5) possible behavioral immunization (history of situational alternatives) against COC abuse acquisition. The consequences of acute and chronic injection and withdrawal of COC for discriminative motor performance, as well as COC interactions with NIC and CAF. (B: BZ) (1) The amelioration of excessive BZ intake by blockers (Ro 15-1788, CGS 8216) and (2) its exacerbation by CAF or a history of sedative (ethanol) abuse. (3) Acute and chronic drug anxiolytic action evaluation by a method employing the exaggerated ingestion of NaC1 solutions by such agents. (3) The fine motor control consequences of daily rebound from chronic exposure to midazolam (e.g., as perhaps exaggerated by inverse agonist [FG 7142] probes) and of midazolam-CAF interactions. For both COC and BZs, serum levels of drug and metabolites will be measured, both with respect to chronic amounts abused and the levels associated with motor performance disruption.

(1) The initiation of oral reinforcing efficacy for benzodiazepines (BZs) will be studied in animals at abusive intake levels using a drug preference procedure under schedule-induced polydipsia conditions. A possible decrease in the reinforcing threshold of oral BZs by psychomotor stimulants, particularly caffeine, a threshold shift by the BZ antagonist flumazenil, as well as the serum pharmacokinetics relevant to oral BZ reinforcing function, will be studied. (2) The synergistic action of combined midazolam and caffeine injections in disrupting fine- motor task performance will be analyzed using a variety of spontaneous and programmed motor measures. These studies may implicate caffeine (and other stimulants) in motor problems of the elderly (specifically falling) that involve BZs and are not reducible to BZ sedative action. The behavioral and pharmacologic generality of BZ-xanthine synergism will be characterized. (3) The behavioral implications of the increase in apparent clearance of serum caffeine that results from chronic exposure to midazolam will be explored with the possibility that part of the BZ discontinuance syndrome may be attributable to caffeinism. (4) Clarification of the acute and chronic pharmacokinetics of BZ-stimulant combinations will parallel behavioral studies in the delineation of the mechanism of BZ-xanthine synergism. (5) There will be study of a alprazolam-caffeine interactions for a possible synergistic disruption of fine-motor control, which might be relevant to triggering or worsening panic disorder. Also, the effect of BZs on theophylline's behavioral effects will be noted in relation to tremor produced by therapeutic doses of theophylline, particularly by the oral route.

DESCRIPTION: (Applicant's Abstract) Experiments with rats will determine whether drug doses (cocaine, PCP, caffeine, midazolam, hexobarbital, nicotine) that are delivered by either intragastric or IV cannula contingent upon drinking a specific fluid can institute an oral preference for the solution drunk, whether it is (a) a drug solution or (b) a neutral-flavored solution, in order to ascertain whether oral drug preferences and abuse can be initiated solely by pharmacological events, a relation not yet clearly established. The pharmacological events (e.g., serum drug and metabolite levels) consequent to gastric and IV drug delivery will be delineated, as well as the intragastric and IV drug reinforcement thresholds, to effect the pharmacokinetic-pharmacodynamic modeling of drug reinforcement, which clarification may prove useful in the design of drug agonist therapies. The pharmacological events initiating and sustaining oral drug self-administration will be compared to the environmental events (schedule-induced polydipsia) which also can give rise to chronic oral drug self-administration. The degree to which drug self-administration compromises ensuing timing behavior will measure the behaviorally toxic consequences of acute and chronic drug-taking. Temporal, stimulus control, and pharmacological factors affecting the relapse to oral cocaine solution preference will be evaluated.

(1) The initiation of oral reinforcing efficacy for benzodiazepines (BZs) will be studied in animals at abusive intake levels using a drug preference procedure under schedule-induced polydipsia conditions. A possible decrease in the reinforcing threshold of oral BZs by psychomotor stimulants, particularly caffeine, a threshold shift by the BZ antagonist flumazenil, as well as the serum pharmacokinetics relevant to oral BZ reinforcing function, will be studied. (2) The synergistic action of combined midazolam and caffeine injections in disrupting fine- motor task performance will be analyzed using a variety of spontaneous and programmed motor measures. These studies may implicate caffeine (and other stimulants) in motor problems of the elderly (specifically falling) that involve BZs and are not reducible to BZ sedative action. The behavioral and pharmacologic generality of BZ-xanthine synergism will be characterized. (3) The behavioral implications of the increase in apparent clearance of serum caffeine that results from chronic exposure to midazolam will be explored with the possibility that part of the BZ discontinuance syndrome may be attributable to caffeinism. (4) Clarification of the acute and chronic pharmacokinetics of BZ-stimulant combinations will parallel behavioral studies in the delineation of the mechanism of BZ-xanthine synergism. (5) There will be study of a alprazolam-caffeine interactions for a possible synergistic disruption of fine-motor control, which might be relevant to triggering or worsening panic disorder. Also, the effect of BZs on theophylline's behavioral effects will be noted in relation to tremor produced by therapeutic doses of theophylline, particularly by the oral route.

Request for ADAMHA Research Scientist Award. (1) Oral, schedule-induced (S-I) drug overindulgence, and chronic drug preference compared to vehicle, will be studied, especially as determined by the history of the environmental stimulus control (S/D) of preference, and current pharmacological factors. Drugs considered will be extended from cocaine to caffeine, midazolam and nicotine. Emphasis will be on tracing the situational sources initiating and maintaining drug abuse under conditions wherein pharmacologic impact is minimized, but functionally significant (oral route), while the environmental determination (S-I and S/D control) of the behavior maximized. This endeavors to clarify drug abuse initiation by an analysis of the gateways, both situational and pharmacologic, that make its acquisition probable. (2) Excessive drug intake can compromise ensuing behavioral functions. Both unconditioned behavior (e.g., locomotor activity) and psychomotor performance (e.g., fine-motor control and timing behaviors) will be measured after acute and chronic oral drug self-administration, and the resulting profiles related to a drug's measured serum concentration-time profile. (3) Results from oral self-administration will be compared to those of parenteral drug imposition. The aim is to predict whether serum pharmacokinetic concentration-time profiles of parent compounds and their active metabolites predict the concurrent behavior-time profiles. (4) Studies pay special attention to the behavior and kinetics of drug interactions, as concurrent use and abuse of substances, both licit and illicit, commonly occurs.