els and identifying mechanisms at the systems, cellular, and molecular levels of analysis.

Agonists

An alternative approach to the treatment of drug dependence is the use of pharmacotherapies to alleviate the signs and symptoms of abstinence and, thus, alleviate at least part of the motivational state driving the dependence. One model for this approach that has met with significant clinical success is methadone detoxification and methadone maintenance. Early animal studies identified methadone as an orally active, long-acting opioid agonist that could block and prevent opiate withdrawal (Bigelow and Preston, 1995). An even longer-acting opiate agonist levo-alpha-acetylmethadol (LAAM) has long been under clinical investigation and is now approved by the Food and Drug Administration (FDA) for the treatment of opiate dependence (Bigelow and Preston, 1995). Nonopioid drugs, developed preclinically which also block some of the signs and symptoms of opiate withdrawal, include alpha-2-noradrenergic agonists such as clonidine. Little success has been reported, however, in preclinical attempts to block the withdrawal associated with cocaine in either animals or humans, largely because the withdrawal models have been limited (Markou and Koob, 1991); thus, development of a better model of withdrawal is also critical for progress in this area. There is some evidence that dopamine agonists can attenuate cocaine withdrawal, but the dopamine receptor subtype involved is unknown. Given the limited success of bromocriptine in the clinic, D-1 agonists, partial agonists, or even less selective dopamine agonists should be explored. Recent evidence suggests that D1 agonists are more effective than D-2 agonists in blunting the reinstatement of cocaine self-administration in animals subjected to extinction (Self et al., 1996). Ethanol withdrawal can be effectively blocked by benzodiazepines, and they continue to be the treatment of choice for detoxification (O'Brien et al., 1995). Nicotine withdrawal can be effectively eliminated by chronic, slow-release forms of nicotine delivery, an approach that forms the basis for the nicotine patch, nicotine gum, and nicotine spray in humans (Russell, 1991; Fiore et al., 1992).

Brain Imaging

Until recently, the contribution of regional brain function and neurotransmitter systems to the causes and consequences of drug abuse and other brain diseases could be addressed only indirectly through measurement of blood and cerebrospinal fluid neurotransmitter metabolites, drug challenges, and gross neurophysiological measures such as the electroen-



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