Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues.

This review gives an overview of recent findings and developments in research on brain mechanisms of reward and reinforcement from studies using the place preference conditioning paradigm, with emphasis on those studies that have been published within the last decade. Methodological issues of the paradigm (such as design of the conditioning apparatus, biased vs unbiased conditioning, state dependency effects) are discussed. Results from studies using systemic and local (intracranial) drug administration, natural reinforcers, and non-drug treatments and from studies examining the effects of lesions are presented. Papers reporting on conditioned place aversion (CPA) experiments are also included. A special emphasis is put on the issue of tolerance and sensitization to the rewarding properties of drugs. Transmitter systems that have been investigated with respect to their involvement in brain reward mechanisms include dopamine, opioids, acetylcholine, GABA, serotonin, glutamate, substance P, and cholecystokinin, the motivational significance of which has been examined either directly, by using respective agonist or antagonist drugs, or indirectly, by studying the effects of these drugs on the reward induced by other drugs. For a number of these transmitters, detailed studies have been conducted to delineate the receptor subtype(s) responsible for the mediation of the observed drug effects, particularly in the case of dopamine, the opioids, serotonin and glutamate. Brain sites that have been implicated in the mediation of drug-induced place conditioning include the 'traditional' brain reward sites, ventral tegmental area and nucleus accumbens, but the medial prefrontal cortex, ventral pallidum, amygdala and the pedunculopontine tegmental nucleus have also been shown to play important roles in the mediation of place conditioning induced by drugs or natural reinforcers. Thus, although the paradigm has also been criticized because of some inherent methodological problems, it is clear that during the past decade place preference conditioning has become a valuable and firmly established and very widely used tool in behavioural pharmacology and addiction research.