factor in motivating individuals to seek out and self-administer opiates and alcohol. The phenomenon of physical dependence, however, does not produce drug-seeking behavior in the majority of individuals made physically dependent in the course of treatment with an opiate for a medical condition. The neural substrates for the physical signs of withdrawal are, in fact, not well understood. There is evidence that the changes in body temperature associated with opiate withdrawal may be due to interactions in the hypothalamus. The neural substrates for many of the other physical signs are distributed widely throughout the brain. Much evidence implicates the nucleus locus coeruleus (a nucleus containing exclusively norepinephrine neurons located in the brain stem region called the pons) in the activational properties and stresslike effects of opiate withdrawal (Aghajanian, 1978; Taylor et al., 1988; Maldonado et al., 1992). Little evidence exists for the neural substrates of ethanol withdrawal, but some neuropharmacological mechanisms have been identified including a decrease in GABAergic function, an increase in glutamatergic function (Grant et al., 1990; Tabakoff and Hoffman, 1992; Koob et al., 1994b), and related changes in calcium channel function (Littleton et al., 1992).

Additional research has begun to focus on the neural substrates and neuropharmacological mechanisms of the negative affective states associated with drug withdrawal—effects that probably produce much of the negative reinforcement associated with drug dependence. The same neural systems implicated in the positive reinforcing effects of drugs of abuse have been shown to be involved in those motivational effects. Evidence suggests that reward thresholds are increased (decrease in reward) following chronic administration of all major drugs of abuse, including opiates, psychostimulants, alcohol, nicotine, and THC. These effects reflect changes in the activity of the same mesolimbic system (midbrain-forebrain system) implicated in the positive reinforcing effects of drugs and can last up to 72 hours (Schaefer and Michael, 1986; Markou and Koob, 1991; Koob et al., 1993, 1994b; Schulteis et al., 1994, 1995).

The neurobiology of the change in reward function associated with drug dependence is a very active area of current research. Decreases in the function of neurochemical systems associated with the same neurotransmitters implicated in the acute reinforcing effects of drugs have been observed during withdrawal following chronic administration of cocaine, opiates, and ethanol. One example is where dopamine function in the nucleus accumbens appears to be decreased during cocaine, opiate, and ethanol withdrawal as measured by in vivo microdialysis (Weiss et al., 1992). Also, there is evidence of decreased opioid peptide receptor function in the nucleus accumbens during opiate withdrawal (Nestler, 1992). Serotonin function also appears to be decreased during acute withdrawal from psychostimulants and ethanol in the nucleus accumbens



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