Effects of Opioid Antagonists on the Abuse-Related Effects of Psychomotor Stimulants and Nicotine

Abstract

Psychomotor stimulant abuse continues to be a major health problem. Despite intensive study, pharmacological therapies for the treatment of stimulant addiction and the prevention of relapse are lacking. Furthermore, although certain individuals may be at greater risk for the development of compulsive drug-seeking behavior, the neural substrates mediating individual differences in sensitivity to the behavioral effects of stimulants are unknown. Opioid receptors and their endogenous ligands are present in high concentrations in brain circuits upon which psychostimulants act to exert control over behavior. Studies in humans and experimental animals have shown that the activity of endogenous opioid systems is altered in response to psychostimulants. It is also apparent that the administration of nonselective opioid receptor antagonists can profoundly affect the responsiveness of an individual to these agents. In the past decade, antagonists selective for the various opioid receptor types have become available. These agents have been used to probe the function of endogenous opioid systems and have provided important insights as to the role of μ-, μ-, and K-opioid receptor systems in mediating the actions of psychostimulants. This chapter will review preclinical data examining the influence of opioid receptor antagonists on the behavioral and neurochemical effects of psychostimulants. We will provide evidence that opioid receptor antagonists can attenuate or exacerbate several effects of psychostimulants that are linked to their abuse liability. Furthermore, we will show that the effects of opioid receptor antagonists is dependent on the receptor type targeted as well as on the psychostimulant tested, the prior drug history of an individual, and the animal model employed.