The role of reward pathways in the development of drug dependence.

In commenting on the discovery of "opiate" receptors, Goldstein (1976) said: "It seemed unlikely, a priori, that such highly stereospecific receptors should have been developed by nature to interact with alkaloids from the opium poppy" (p. 1081). Endogenous opioid peptides and opioid receptor systems have now been identified in invertebrates that are unlikely to have had ancestors exposed to opium poppies (Kavaliers et al., 1983; Kream et al., 1980; Leung and Stefano, 1984; Stefano et al., 1980). Moreover, endogenous opioids play a role in stress-induced feeding in the slug (Kavaliers and Hirst, 1986) just as they play a role in stress-induced feeding in rodents (Lowy et al., 1980; Morley and Levine, 1980). If we are to understand the actions of opiates and other drugs of abuse we must understand them in terms of their abilities to interact with neural systems that evolved in the service of primitive biological functions, long before any serious incidence of addiction itself. The most primitive axes of the biological substrates of behavior are the axes of approach and withdrawal. Addictive drugs appear to be able to activate the mechanisms of approach, which is termed "positive reinforcement" and to inhibit the mechanisms of withdrawal, which is termed "negative reinforcement." Anatomically distinct sets of pathways have evolved to serve these two forms of reward. Activation of the medial forebrain bundle and associated structures serves positive reinforcement and induces forward locomotion. Approach and forward locomotion are the unconditioned responses to positive reinforcing stimuli such as food and sex partners, and approach to environmental objects and positive reinforcement is induced by electrical stimulation of this structure. The locomotor stimulating effects and the positive reinforcing effects of opiates and psychomotor stimulants result from their activation of this mechanism; stimulants activate the mechanism at the level of dopaminergic synapses of the nucleus accumbens, frontal cortex, and perhaps other forebrain structures, while opiates activate the system at two points: at the level of the dopaminergic synapse and at the level of the afferents to the dopaminergic cell bodies. Ethanol, nicotine, caffeine and phencyclidine stimulate both locomotor activity and dopamine turnover, but their sites of interaction with reward pathways have not yet been identified. Benzodiazepines and barbiturates stimulate locomotor activity without stimulating dopamine turnover; they may interact with reward pathways at a synapse efferent to the dopaminergic link in the pathways.(ABSTRACT TRUNCATED AT 400 WORDS)