Intravenous self-administration of midazolam in the rat : behavioral and neurochemical characterization

Benzodiazepines are one of the most commonly prescribed classes of psychoactive compounds. Given the widespread use of these drugs in clinical populations, concern has developed over the extent of their abuse potential. Experimental analysis of the abuse potential of benzodiazepines, using animal models of drug self-administration, has produced inconsistent results. The lack of robust evidence for self-administration of benzodiazepines has been interpreted as reflecting a limited reinforcement efficacy of benzodiazepines in the rat. However, the failure to observe reliable self-administration of benzodiazepines in rats may be a function of the experimental protocols that have been employed to date. Previous experiments have generally used long-acting benzodiazepines while concurrently permitting the subjects limited access to the drug. Accordingly, the present experiments assessed the extent to which naive rats would self-administer midazolam, a short-acting benzodiazepine, when given unlimited access to the drug. In addition, a series of experiments were designed to assess the role of specific neural substrates in mediating the reinforcing effects of midazolam. Naive rats given continuous drug access exhibit reliable and stable rates of responding for intravenous infusions of midazolam. Response contingent infusions of midazolam resulted in greater rates of responding than did infusions of saline (Experiment I). Midazolam also supported stable rates of responding in a two lever discriminated responding paradigm. The rats responded at greater rates on the reinforced lever than the nonreinforced lever and were able to track the changing reinforcement contingencies (Experiment II). Midazolam self-administration was characterized by an inverse relationship between dose and rate of responding during the first dose transfer session after which no consistent relationship was observed (Experiment III). Initially, rats exhibited a temporal pattern of responding for midazolam with peak responding occurring during the dark phase of the light:dark cycle (Experiments I, II, and III). However, rats given prolonged access to midazolam exhibited a stable pattern of responding across the light:dark cycle (Experiment II). Administration of Ro 15-1788 elicited an increase in self-administration of midazolam suggesting that blockade of central benzodiazepine receptors attenuates the reinforcing effects of the drug (Experiment IV). Previously, it has been suggested that all drugs of abuse elicit an increase in extracellular DA concentration in the nucleus accumbens and that the drug-induced increase in DA concentrations may mediate the reinforcing effects of these drugs. In view of this evidence, Experiments V and VI assessed the effects of midazolam on extracellular DA concentration in the nucleus accumbens of freely moving rats. Subcutaneous injections of midazolam elicited a decrease in extracellular DA, DOPAC and HVA concentrations (Experiments Va and VI). Repeated intravenous infusions of midazolam, delivered in a manner that mimicked the pattern of drug self-administration exhibited during peak responding for midazolam, also elicited a decrease in extracellular DA concentrations in the nucleus accumbens (Experiment Vb). In conclusion, the present experiments indicate that midazolam is reinforcing in naive rats given unlimited access to the drug and that the reinforcing effects may be mediated by central benzodiazepine receptors. In contrast to other drugs of abuse, the reinforcing effects of midazolam are not mediated by an increase in the activity of mesoaccumbens DA neurons.Medicine, Faculty ofGraduat