Cocaine chronic effects

Recent investigations into intracellular events have begun to define the postsynaptic events through which TCAs appear to exert their effects (Morinobu et ah, 1995). One of the observations made was down-regulation of transcription factors for early gene products such as c-Fos. C-Fos is normally produced in response to periods of stress. In research with rats, TCAs as well as other antidepressants have been shown to decrease the expression of c-Fos in areas of frontal cortex after chronic but not acute treatment. Other psychotropic medications (e.g., cocaine and haloperidol) with similar acute effects on norepinephrine/serotonin neurotransmission have not shown this same chronic effect. It has been speculated that the decreased production of c-Fos is the end product of a cascade of events stimulated by increased norepinephrine levels (Morinobu et ah, 1995). 

The chronic effects show rapid emaciation and severe psychic disturbances, insomnia, hallucinations, apathy, melancholia, and suicidal mania. The pupils are inconstant. Acne is common. It is claimed that considerable tolerance is acquired, so that the daily hypodermic consumption may reach 2.5 g or even 10 g. Morphinists are relatively tolerant to cocaine. Sudden withdrawal leads to abstinence symptoms similar to morphine. With cocaine snuffing, where smaller amounts are used in intermittent debauches, the chronic effects such as the craving and the abstinence symptoms are proportionately less marked. Such patients develop atrophic rhinitis, with characteristic ulceration of the nasal fossae — also present in people who snuff heroin. 

Cardiovascular effects include tachycardia, hypertension, and increased cardiac irritability large intravenous doses can cause cardiac failure. Cardiac dysrhythmias have been ascribed to a direct toxic effect of cocaine and a secondary sensitization of ventricular tissue to catecholamines (17), along with slowed cardiac conduction secondary to local anesthetic effects. Myocardial infarction has increased as a complication of cocaine abuse (7,8). Dilated cardiomyopathies, with subsequent recurrent myocardial infarction, have been associated with long-term use of cocaine, raising the possibility of chronic effects on the heart (18). Many victims have evidence of pre-existing fixed coronary artery disease precipitated by cocaine (SEDA-9, 35) (19-21). However, myocardial infarction has been noted even in young intranasal users with no evidence of coronary disease (22), defined by autopsy or angiography (23,24). If applied to mucous membranes, cocaine causes local vasoconstriction, and, with chronic use, necrosis. 

Arousal and attention have been investigated in 180 healthy nursery infants before hospital discharge and at 1 month of age (281). Cocaine-exposed infants showed a lack of arousal-modulated attention and preferred faster frequencies of stimulation, regardless of arousal condition compared with non-exposed infants. There were similar differences 1 month after birth, showing that these effects persisted beyond the period of presence of cocaine or its metabolites at birth. These effects were independent of absence of prenatal care, alcohol use, minority status, or sex, suggesting a direct and even chronic effect of intrauterine cocaine exposure on arousal-modulated attention and presumably on the developing nervous system of the infants. 

Antipsychotic medications are indicated in the treatment of acute and chronic psychotic disorders. These include schizophrenia, schizoaffective disorder, and manic states occurring as part of a bipolar disorder or schizoaffective disorder. The co-adminstration of antipsychotic medication with antidepressants has also been shown to increase the remission rate of severe depressive episodes that are accompanied by psychotic symptoms. Antipsychotic medications are frequently used in the management of agitation associated with delirium, dementia, and toxic effects of both prescribed medications (e.g. L-dopa used in Parkinson s disease) and illicit dtugs (e.g. cocaine, amphetamines, andPCP). They are also indicated in the management of tics that result from Gilles de la Tourette s syndrome, and widely used to control the motor and behavioural manifestations of Huntington s disease. 

The development of effective pharmacotherapy has lagged behind progress in understanding the reward mechanisms and chronic impairments underlying stimulant abuse. Pharmacological and behavioral treatment approaches that have been used for cocaine abuse have not been as widely tested for the treatment of amphetamine abuse, limiting what can be offered for treatment of this disorder. No treatment agents are approved by the FDA for treatment of cocaine or amphetamine dependence. 

Hitori, A. Suddath, R.L. and Wyatt, R.J. Effect of chronic cocaine withdrawal on dopamine uptake sites in the rat frontal cortex. Biol Psychiatry 25 (Suppl) 48A, 1989. 

Post, R.M. Weiss, S.R.B. Pert, A. and Uhde, T.W. Chronic cocaine administration Sensitization and kindling effects. In Fisher, Raskin, Uhlenhuth, eds. Cocaine Clinical and Behavioral Aspects. Oxford Oxford University Press, 1987. pp. 109-173. 

Nation JR, Liver,ore CL, Burkey RT. 1996. Chronic lead exposure attenuates sensitization to the locomotor-stimulating effects of cocaine. Drug Alcohol Dependence 41 143-149. 

Haile, C.N., GrandPre, T., Kosten, T.A. Chronic unpredictable stress, but not chronic predictable stress, enhances the sensitivity to the behavioral effects of cocaine in rats. Psychopharmacology. 154 213, 2001. 

Hiroi, N., Brown, J.R., Haile, C.N. et al. FosB mutant mice loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine s psychomotor and rewarding effects. Proc. Natl. Acad. Sci. U.S.A. 94 10397, 1997. 

Hitri A., Little K., Ellinwood D. Effect of cocaine on dopamine transporter receptors depends on routes of chronic cocaine administration. Neuropsychopharmacology. 14 205, 1996. 

Telia S. Differential blockade of chronic versus acute effects of intravenous cocaine by dopamine receptor antagonists. Pharmacol. Biochem. Behav. 48 151, 1994. 

Nader M.A., Daunais J.B., Moore T. et al. Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys initial and chronic exposure. Neuropsychopharmacology. 27 35, 2002. 

Volkow N., Fowler J., Wolf A. et al. Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am. J. Psychiatry. 147 719, 1990. 

Collins S.L., Kunko P.M., Ladenheim B., Cadet J.L., Carroll F.I., Izenwasser S. Chronic cocaine increases kappa-opioid receptor density lack of effect by selective dopamine uptake inhibitors. Synapse. 45 153, 2002. 

---