Chronic

In contrast to acute intoxication, chronic cocaine administration results in neurotransmitter depletion. This is evidenced by a compensatory increase in postsynaptic receptor sensitivity for dopamine and noradrenaline, increased tyrosine hydroxylase activity (a major enzyme in norepinephrine and dopamine synthesis), and hyperprolactinemia. These are expected results for a negative feedback system. Chronic use is also associated with volume losses in the prefrontal cortex and nucleus accumbens. In addition, striatal dopamine response is significantly lower in cocaine abusers during withdrawal than in cocaine nonabusers. Furthermore, lower levels of dopamine receptors in the striatum are associated with lower metabolism in the orbitofrontal cortex and anterior cingulate gyrus in cocaine-addicted subjects (Goldstein & Volkow, 2002).

Clinical features of chronic cocaine use include depression, fatigue, poor concentration, loss of self-esteem, decreased libido, mild parkinsonian features (myoclonus, tremor, bradykinesis), paranoia, and insomnia. Tolerance to the stimulant effects of cocaine, particularly the anorexic effects, develops rapidly. However, repeated phasic use of low-dose cocaine can lead to enhanced sensitivity and potentiation of motor activity, including exaggerated "startle" reactions, dyskinesias, and postural abnormalities. Increased stereotypical behavior and a toxic psychosis can occur after repeated cocaine use. The elimination half-life of cocaine is under 1 hour by the intravenous route, and just over 1 hour by the intranasal route. The physiological and subjective effects due to cocaine correlate well with plasma levels (Javaid, Fischman, Schuster, Dekirmenjian, & Davis, 1978), although, with repeated use, pharmacodynamic tachyphylaxis does occur. Cocaine euphoria is of short duration, with a 10- to 20-second "rush," followed by 15-20 minutes of a lower level of euphoria and the subsequent onset of irritability and craving. Cocaine users who try to maintain the euphoric state readminister the drug frequently, until their supply disappears. Cocaine binges average 12 hours but can last as long as 7 consecutive days.

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