Addiction to Cocaine and Amphetamine

but not DA reuptake, produce neither significant reinforcement in animal models nor euphoria in humans. Laboratory of Molecular and Developmental Neuroscience Moreover, antidepressants do not produce dependence in humans even with very long-term use. In addition, Massachusetts General Hospital Harvard Medical School lesioning of DA terminals within the NAc or full pharmacological blockade of DA receptors inhibits cocaine or Boston, Massachusetts 02114 amphetamine self-administration (reviewed by Self and Nestler, 1995). It is also significant that mice lacking the Addiction to the psychostimulant drugs, of which co-DAT are entirely insensitive to the locomotor stimulant caine and the amphetamine derivatives are the most effects of cocaine or amphetamine (Giros et al., 1996). important, is one of the foremost public health problems The precise contributions of different postsynaptic DA in the United States. Cocaine and amphetamine share receptors to reinforcement have yet to be fully estab-two critical properties with other addictive drugs: they lished because of the lack of adequately selective antag-are reinforcing when administered acutely (i.e., drug use onists directed against the five known DA receptors. entails repeated drug use) and produce compulsive use Studies of drug self-administration in mice with disrup-if administered chronically with adequate dose and fre-tions in the genes encoding each of the different DA quency. receptors as well as the DAT may also prove informative; The mesoaccumbens dopamine (DA) pathway, ex-however, the difficulty of establishing drug self-adminis-tending from the ventral tegmental area (VTA) of the tration in the mouse strains currently used for homolo-midbrain to the nucleus accumbens (NAc; the major gous recombination and the problem of developmental component of the ventral striatum), has been identified compensation has slowed this type of analysis. Based as the critical shared substrate of the reinforcing effects on pharmacological data available to date, both D1 fam-of cocaine, amphetamine, and all other addictive drugs ily and D2 family DA receptors contribute to cocaine (Koob, 1996 [this issue of Neuron]). Drugs such as co-and amphetamine reinforcement (reviewed by Self and caine and amphetamine are thought to be addictive Nestler, 1995), although it is the D1 receptor that has because they produce significant molecular adaptations been implicated in cocaine-and amphetamine-induced both within and outside the mesoaccumbens circuitry plasticity to date. that alter the function of neurons that regulate motivated Addiction to Cocaine and Amphetamine behavior and emotion. Progress has been made in iden-The acute reinforcing effects of cocaine and amphet-tifying both the properties of drugs …