Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking

Relapse is a major characteristic of drug addiction, and remains the primar y problem in treating drug abuse. Without an understanding of the factors t hat determine renewed drug-seeking, the urge to use drugs, and the persiste nt craving for them, it is unlikely that health care professionals can prov ide effective treatment, Using an animal model of relapse, the author and h er team are studying factors that induce reinstatement of drug-taking behav iour after short and long periods of abstinence, and they are exploring the neurobiological basis of these effects. In their experiments, rats are tra ined to self-administer drugs intravenously by pressing 1 of 2 levers. Duri ng a subsequent period, the drug is no longer available, but the rats are f ree to try to obtain the drug (a period of "extinction training"). After ex tinction of responding, the investigators test for the ability of various e vents to reinitiate drug-seeking. On this background of renewed drug-seekin g or relapse, the investigators search for pharmacological and neurochemica l manipulations that might block or attenuate such behaviour. They have fou nd that the 2 most effective events for reinstating responding after both s hort and long drug-free periods are re-exposure to the drug itself and expo sure to a brief period of stress. The critical neurochemical pathways media ting drug-induced relapse are not identical to those mediating stress-induc ed relapse. Relapse induced by "priming" injections of heroin or cocaine in volves activation of the mesolimbic dopaminergic pathways, whereas relapse induced by stress involves actions of corticotropin-releasing factor (CRF) in the brain, and of brain noradrenergic (NE) systems. In addition, evidenc e shows that CRF and NE may interact at the level of the bed nucleus of the stria terminalis in stress-induced relapse. By contrast, relapse induced b y "priming" injections of drugs is relatively unaffected by manipulation of CRF and NE systems of the brain.