ing effects of heroin and morphine, and the most important brain sites for the acute reinforcing actions of those drugs appear to be in the ventral tegmental area and the nucleus accumbens. Opiates stimulate the release of dopamine in the terminal areas of the mesolimbic dopamine system, and there also appears to be a dopamine-independent action in the region of the nucleus accumbens on neuronal systems that receive a dopaminergic input (Koob, 1992a).

Ethanol and other sedative hypnotics clearly have multiple sites of action for their acute reinforcing effects, which depend on facilitation of GABAergic neurotransmission, stimulation of dopamine release at low doses, activation of endogenous opioid peptide systems, and antagonism of serotonergic and glutamatergic neurotransmission. The exact sites for these actions are under study but appear again to involve the mesolimbic dopamine system and its connections in the basal forebrain, particularly in limbic areas such as the amygdala.

Nicotine is a direct agonist at brain nicotinic acetylcholine receptors, which are widely distributed throughout the brain. Nicotine self-administration is blocked by dopamine antagonists and opioid peptide antagonists, and both a nicotinic acetylcholine antagonist and an opiate antagonist have been shown to precipitate nicotine withdrawal in rodents (Malin et al., 1993, 1994). Nicotine is thus thought to activate both the mesolimbic dopamine system and opioid peptide systems in the same neural circuitry associated with other drugs of abuse (Corrigall et al., 1992).

The neurobiological substrates for the acute reinforcing actions of psychedelic drugs are less well understood. Indeed, rodents and nonhuman primates will not self-administer psychedelic drugs. Lysergic acid diethylamide (LSD) clearly involves a serotonergic action, possibly as a postsynaptic agonist. However, the brain sites and specific subtypes involved are still under study. Little is known about the neurobiology of the acute reinforcing actions of marijuana, but the cloning of the tetrahydrocannabinol (THC) receptor and the discovery of endogenous THC compounds in the brain offer exciting new approaches to this question, discussed below (Matsuda et al., 1990; Devane et al., 1992).

Neural Substrates for Drug Tolerance

The neural substrates for drug tolerance overlap significantly with those associated with dependence because tolerance and dependence may be components of the same neuroadaptive process. Tolerance also involves associative processes (processes of learning where previously neutral stimuli come to acquire significance through pairing with biologically significant events), however, and the role of associative processes has been most explored in the context of opiate drugs and sedative-hypnotics

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