Indirect sympathomimetics, such as cocaine and amphetamines, have a long history of being used in tonics and other preparations to allay fatigue and sustain performance. These drugs have an equally long history of abuse and dependence, with episodic, collective social amnesia about the behavioral toxicity associated with excessive use. Cocaine and amphetamines have a characteristic abuse cycle that consists of binge administration and withdrawal dysphoria, paranoia, and psychosis-like symptoms as the cycle continues and intensifies. The abuse potential varies with the availability of the drug, both environmentally and physiologically. Intravenous and smoked forms of both cocaine and amphetamines produce much more severe addiction than other routes of administration. Cocaine and amphetamines produce euphoria, increase activity, facilitate performance (particularly in situations of fatigue), and decrease appetite. Amphetamines have medical uses as adjuncts for short-term weight control, in the treatment of attention-deficit/hyperactivity disorder, and in the treatment of narcolepsy. Cocaine has been used as a local anesthetic for mucous membrane anesthesia and vasoconstriction. An inverted U-shaped dose-response function relates the performance-enhancing effects of psychostimulants to dose. The behavioral mechanism of action reflects a behavioral principle in which increases in response rates occur for a given behavior, with a concomitant decrease in the number of response categories. This principle has significant explanatory power not only for the acute stimulant effects of the drugs but also for their pathophysiology.

Significant advances have been made in our understanding of the mechanism of action of psychomotor stimulant drugs at the behavioral, neuropharmacological, and molecular levels that have important implications for understanding the neurobiology of addiction. In the binge/intoxication stage of the addiction cycle, the mesocorticolimbic dopamine system is critically important for the acute reinforcing effects of cocaine and D-amphetamine. Dopamine release in the nucleus accumbens is necessary for intravenous cocaine self-administration. Neural elements in the nucleus accumbens at the cellular level respond to both the self-administration of the drug and the anticipation of drug self-administration. Molecular neuropharmacological studies have revealed important roles for dopamine D1, D2, and D3 receptors. In the withdrawal/negative affect stage, acute psychostimulant withdrawal produces major elevations in brain reward thresholds that may play a critical role in driving the escalation to dependence. At the neurochemical level, decreases in mesocorticolimbic dopamine and serotonin function and increases in the brain stress neurotransmitters CRF and dynorphin appear to be involved in this acute motivational withdrawal syndrome. Stimulation of cAMP-dependent protein kinase and activation of CREB with concomitant expression of dynorphin in the nucleus accumbens may provide one mechanism for motivational tolerance and dependence; the activation of brain stress systems in the amygdala may provide another mechanism. In the preoccupation/anticipation stage of the addiction cycle, animal models of relapse have revealed important roles for the basolateral amygdala and medial prefrontal cortex connections to the nucleus accumbens and extended amygdala, with the neurotransmitters dopamine, glutamate, and CRF all playing important roles. How these circuits are altered by molecular and cellular events following the chronic administration of cocaine and amphetamines to produce the neuroadaptive changes associated with addiction is the subject of intense investigations. Several molecular sites in the medial prefrontal cortex/nucleus accumbens glutamate projection have been proposed to mediate the enhanced glutamatergic signal involved in cocaine-induced reinstatement. Another long-term molecular change that may lead to increased sensitivity to cocaine long after abstinence is increased expression of ΔFosB. Such studies provide key insights into our understanding of the vulnerability to psychostimulant addiction and vulnerability to relapse.

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