We studied this class of drugs not only because they are among the most widely prescribed drugs for the treatment of anxiety ( Uhlenhuth et al., 1995 Baldessarini, 1996), but also since these drugs can decrease plasma corticosterone ( Keim and Sigg, 1977), cortisol and ACTH ( Meador-Woodruff and Greden, 1988 Torpy et al., 1993) and attenuate cocaine-induced increases in plasma corticosterone ( Yang et al., 1992). In our earliest work in this area, we investigated the effects of benzodiazepine receptor agonists on intravenous cocaine self-administration in rats. In this context, we have investigated the effects of drugs that attenuate HPA axis activity on cocaine self-administration and the drugand cue-induced reinstatement of extinguished cocaine seeking ( Goeders, 2004, 2007).
Over the last several years, our laboratory, as well as a number of others, has explored the complex relationship between stress and the subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis in psychomotor stimulant reinforcement ( Goeders, 2002, 2007 Majewska, 2002 Winhusen and Somoza, 2001 Sarnyai et al, 2001).
Therefore, although these drugs produce their effects through distinct mechanisms, an additive effect on cocaine self-administration is obtained when these drugs are administered together, suggesting that combinations of low doses of metyrapone and oxazepam may be useful in reducing cocaine seeking with a reduced incidence of unwanted side effects and a decreased potential for abuse. Changes in pharmacokinetics or endocrine function do not appear to mediate these effects, suggesting a central mechanism of action. Combinations of metyrapone and oxazepam at doses that produced no observable effects when administered separately significantly reduced cocaine self-administration without affecting food-maintained responding during the same sessions. Behavioral, endocrine and pharmacokinetic measures of the effects of the combination of metyrapone and oxazepam on cocaine reward are presented.
In the experiments described in this manuscript, we tested the effects of various doses of metyrapone and oxazepam against several doses of self-administered cocaine. Two classes of drugs that we have studied include corticosterone synthesis inhibitors (e.g., metyrapone) and benzodiazepine receptor agonists (e.g., oxazepam). For several years, our laboratory has investigated the role for the HPA axis in cocaine reinforcement.
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