Cocaine dependence dopamine transporter

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

Somoza EC, Winhusen TM, Bridge TP, et al An open-label pilot study of methylpheni-date in the treatment of cocaine-dependent patients with adult attention deficit/ hyperactivity disorder. J Addict Dis 23 77—92, 2004 Sora 1, Wichems C, Takahashi N, et al Cocaine reward models conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95 7699-7704, 1998 Soral, Hall FS, Andrews AM, etal Molecular mechanisms of cocaine reward combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Nad Acad Sci U S A 98 5300-5305, 2001 Spear J, Alderton D Psychosis associated with prescribed dexamphetamine use 0etter). 

DA TRANSPORTER AND COCAINE DEPENDENCE 5.2.1 Regulation of the Dopamine Transporter (DAT) by Cocaine... 

Dopamine is removed from the synapse via two mechanisms. First, COMT degrades intrasynaptic DA. Second, the dopamine transporter (DAT) [see (4) in Fig. 2.9], a Na /CD-dependent neurotransmitter transporter, transports DA in either direction, depending on the concentration gradient. The DAT is blocked selectively by drugs such as cocaine, amphetamine, bupropion, and nomifensine. 

At higher doses, cocaine can produce undesirable effects, including tremor, emotional lability, restlessness, irritability, paranoia, panic, and repetitive stereotyped behavior. At even higher doses, it can induce intense anxiety, paranoia, and hallucinations, along with hypertension, tachycardia, ventricular irritability, hyperthermia, and respiratory depression. In overdose, cocaine can cause acute heart failure, stroke, and seizures. Acute intoxication with cocaine produces these various clinical effects, depending on the dose these effects are mediated by inhibition of the dopamine transporter and in turn by the effects of excessive dopamine activity in dopamine synapses, as well as by norepinephrine and serotonin in their respective synapses. 

Staley JK, Basile M, Wetli CV, Hearn WL, Flynn DD, Ruttenber AJ, Mash DC (1993) Differential regulation of the dopamine transporter in cocaine overdose deaths. In Harris LS (Ed), NIDA Res Monograph Proceedings of the 55 th Annual College on Problems of Drug Dependence Meeting, p. 32, Washington, D.C. 

Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, et al. 2000. Amphetamine-induced loss of human dopamine transporter activity an internalization-dependent and cocaine-sensitive mechanism. Proc. Natl. Acad. Sci. USA 97 6850-55... 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

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