Because benzodiazepines (BZ) and other anxiolytics are among the mode widely prescribed of all medications, anxiolytic misuse, abuse, and physiological dependence have been of increasing concern. This project will use drug discrimination procedures in laboratory animals to provide data relevant to issues of vulnerability to sedative/anxiolytic drug abuse and to the correspondence between molecular mechanisms of action and stimulus effects of anxiolytics. Drug discrimination procedures are useful because they can provide highly selective behavioral measures of CNS activity which may be analogous to human subjective drug effects. One objective is to explore the possible interrelationships between the discriminative stimulus and reinforcing effects of drugs by investigating (1) the effects of a history or drug self-administration on subsequent drug stimulus generalization, (2) the effects of specific drug discrimination training on subsequent drug self-administration and (3) drug discriminative stimulus effects in the context of ongoing self- administration. A second objective, particularly important because of increasing applications of the drug discrimination procedure in preclinical screening of anxiolytics, is to study the conditions under which the sedative/anxiolytic generalization profile broadens or narrows. One experiment involves appetitive and aversive training conditions, and another involves increasing the specificity of generalization test results by training a discrimination between sedative/anxiolytic drugs that otherwise show overlapping generalization profiles. A third major objective is to investigate the correspondence between molecular mechanisms of action of anxiolytics and their discriminative stimulus effects. One experiment will explore central mediation of the discriminative stimulus effects of BZ-receptor ligands by comparing results of centrally versus systemically administered compounds. Another experiment investigates the degree to which specificity of activity of a drug with respect to neurotransmitter systems implicated in the generation and amelioration of anxiety corresponds with its generalization profile in the drug discrimination paradigm. A fourth objective is to investigate the influence of chronic BZ administration on stimulus properties of BZ receptor ligand. One experiment will use a high-versus low- dose BZ training condition to determine whether BZ tolerance is reflected in lever choice during chronic drug administration. Another experiment will study whether qualitative and/or quantitative changes in discriminative stimulus effects of BZ receptor ligands (agonists, antagonists, and inverse agonists) under lorazepam and Beta-carboline training conditions occur as a function of BZ tolerance and dependence.
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