such as alcohol (Young and Goudie, 1995). Both operant (behavioral tolerance) and classical (context-dependent tolerance) conditioning have been shown to play a role in drug tolerance, and mechanisms for these associative processes may involve several neurotransmitters independent of their role in dependence. Norepinephrine and serotonin have long been known to be involved in the development of tolerance to ethanol and barbiturates (Tabakoff and Hoffman, 1992). More recently, administration of glutamate antagonists has been shown to block the development of tolerance, again consistent with an associative component of tolerance (Trujillo and Akil, 1991).

Mechanisms of tolerance at the molecular level often overlap with those of dependence (Nestler et al., 1993).3 For example, up-regulation of the cAMP pathway could be a mechanism of tolerance; the changes would be expected to oppose the acute actions of opiates of inhibiting adenylyl cyclase. In addition, tolerance seems to involve the functional uncoupling of opioid receptors from their G proteins. The mechanisms underlying this uncoupling remain unknown but could involve drug-induced changes in the phosphorylation state of the receptors or G proteins that reduce their affinity for each other. Another possible mechanism of tolerance involves drug-induced changes in the ion channels that mediate the acute effects of drugs. For example, alterations in the phosphorylation state, amount, or even type of channel conceivably could contribute to drug tolerance (Nestler, 1992).

Neural Substrates of Withdrawal

Withdrawal from chronic use of drugs of abuse is characterized by a dependence syndrome that is made up of two elements. The objectively observable physical signs of alcohol withdrawal are tremor and autonomic hyperactivity; abdominal discomfort and pain are associated with opiate withdrawal. The self-reported "psychological" signs of drug withdrawal, which may be considered more motivational, are usually different components of a negative emotional state including dysphoria, depression, anxiety, and malaise (Koob et al., 1993) and are difficult to measure directly in animals. Behavioral history is a primary determinant of whether withdrawal and the negative affective state associated with it produce drug-seeking behavior. For individuals with a history of selfmedication of opiates and alcohol, physical dependence is an important


Tolerance and dependence can be separated operationally at the molecular level in vitro, but at the systems level they are usually related when the same dependent variable is measured for both constructs.

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