Brain opioid mechanisms in amphetamine induced behaviours

Amphetamine abuse and dependence are global health problems, affecting large numbers of individuals. Despite extensive research efforts, there has been no evidence-based pharmacotherapy available for amphetamine dependence. However, recent clinical trials have suggested that the opioid receptor antagonist naltrexone reduces drug consumption and craving in amphetamine dependent patients. To further elucidate the interaction between amphetamine and the endogenous opioid system, the present thesis investigated the effect of naltrexone on amphetamine-induced behaviours in the rat. In addition, the effect of naltrexone on specific amphetamine-induced changes in brain neurochemistry, i.e. dopamine release in the striatum, was investigated using both in vivo microdialysis in animals as well as PET imaging in humans. Firstly, the effect of naltrexone on drug-induced reinstatement was investigated in animals previously self-administering amphetamine. Naltrexone significantly attenuated drug-seeking behaviour induced by a low priming dose of amphetamine. The effect of naltrexone was not due to a general disruption of behaviour since the same doses of naltrexone had no effect on operant responding maintained by food. Next, the effect of naltrexone on different phases of the conditioned place preference paradigm was investigated. Naltrexone had no effect on the acquisition, expression or on the reinstatement of amphetamine-induced place preference. Further, naltrexone by itself did not induce place preference or place aversion. In contrast, naltrexone significantly attenuated the locomotor response to a priming dose of amphetamine on reinstatement, without altering general locomotor behaviour. A behavioural sensitization paradigm was used to further investigate the involvement of the endogenous opioid system in amphetamine cueand drug-induced drug seeking behaviour. A single dose of naltrexone attenuated the amphetamine-induced locomotor activity in response to a drug challenge during the expression of sensitization. In addition, pre-treatment with naltrexone blocked the conditioned locomotor response induced by reexposure to the context previously associated with amphetamine. Finally, possible interactions between amphetamine and naltrexone were investigated using both preclinical and clinical experimental models, i.e. in vivo microdialysis in rats and PET imaging in humans. Amphetamine induced a dose-dependent increase in dopamine release in the rat striatum, and a reduction in [C]raclopride binding in the human that corresponded with a marked increase in self-reported rating of drug effects (high, arousal and liking). An acute dose of naltrexone attenuated the subjective effects of amphetamine, without altering the amphetamine-induced changes in [C]raclopride binding in the ventral striatum. Taken together, the results from the present thesis show an involvement of the endogenous opioid system in some, but not all, amphetamine-induced behaviours. The results strengthen the hypothesis that the endogenous opioid system could be a potential target for the treatment of amphetamine dependence. LIST OF PUBLICATIONS This thesis is based on the following publications, which will be referred to in the text by their Roman numerals: I. J. Haggkvist, S. Lindholm and J. Franck The Opioid Receptor Antagonist Naltrexone Attenuates Reinstatement of Amphetamine Drug-Seeking in the Rat Behavioural Brain Research, 2009, 197(1):219-224 II. J. Haggkvist, S. Lindholm and J. Franck The Effect of Naltrexone on Amphetamine-induced Conditioned Place Preference and Locomotor Behaviour in the Rat Addiction Biology, 2009, 14: 260-269 III. J. Haggkvist, C. Bjorkholm, P. Steensland, S. Lindholm, J. Franck, B. Schilstrom Naltrexone Attenuates Amphetamine-Induced Locomotor Sensitization in the Rat Submitted Manuscript IV. J. Haggkvist *, N. Jayaram-Lindstrom*, T Malmlof, T. Saijo, C. Halldin, S. Lindholm, B. Schilstrom, A-L Nordstrom, J. Franck Effects of Naltrexone on Amphetamine-Induced Changes in the Brain Dopamine System Manuscript * Authors contributed equally