Although the sympathomimetic actions and cardiovascular complications of cocaine are ascribed to inhibition of norepinephrine (NE) reuptake, this hypothesis has not been tested in humans. We asked (a) whether cocaine can inhibit NE reuptake in the human peripheral circulation and (b) whether the NE-mediated peripheral vasoconstriction is the main mechanism mediating blood pressure-raising effect of cocaine.
In 15 healthy cocaine-naive subjects, we measured blood pressure, forearm blood flow, and forearm venous NE concentration during administration of (a) intrabrachial cocaine (0.15 and 15 mg), which produced no systemic neurohormonal effects, and (b) intranasal cocaine (2 mg/kg). Intrabrachial cocaine (0.15 mg) increased venous forearm NE concentration by 82% and vascular resistance by 71% (P<0.01). Increasing the intrabrachial cocaine dose by 100-fold to match the venous cocaine level of massive cocaine overdose caused a small additional increase in venous forearm NE concentration without causing significant additional vasoconstriction. Although intranasal cocaine (2 mg/kg) matched the venous cocaine concentrations caused by 0.15 mg of intrabrachial cocaine, venous NE concentration was unchanged as sympathetic nerve activity (SNA) decreased reflexively as the result of an increase in blood pressure. When SNA was restored to baseline by blunting the cocaine-induced rise in blood pressure (baroreflex activation) with nitroprusside, venous NE concentration increased to the same level caused by intrabrachial cocaine.
In healthy cocaine-naive individuals, cocaine can inhibit NE reuptake in the human peripheral circulation. However, this mechanism does not contribute importantly to the blood pressure-raising effect of cocaine because activation of baroreceptor reflexes decreases SNA, the neural stimulus for NE release.
"An additional finding was an increase in systolic blood pressure that correlated with change in precuneus activity as elicited by MPH. This results is consistent with a role for the central nervous system (CNS) in mediating the cardiovascular effects of stimulants (Vongpatanasin et al., 1999; Tuncel et al., 2002) as well as neuroimaging findings of a correlation between the CNS (e.g., stimulant-induced dopamine release as measured by positron emission tomography) and cardiovascular measures (e.g., stimulant-induced increases in systolic blood pressure) as a result of stimulant administration (Volkow et al., 1993). This finding is of potential interest as it suggests changes in the systolic blood pressure as a biomarker for MPH response, as described earlier (Li et al., 2010b). "
[Show abstract][Hide abstract] ABSTRACT: Many previous studies suggest the potential of psychostimulants in improving cognitive functioning. Our earlier pharmacological brain imaging study showed that intravenous methylphenidate (MPH) improves inhibitory control by altering cortico-striato-thalamic activations in cocaine-dependent (CD) individuals. Here we provide additional evidence for the effects of MPH in restoring cerebral activations during cognitive performance. Ten CD individuals performed a stop signal task (SST) during functional magnetic resonance imaging (fMRI) in two sessions, in which either MPH (0.5mg/kg body weight) or saline was administered intravenously. In the SST, a frequent go signal instructs participants to make a speeded response and a less frequent stop signal instructs them to withhold the response. Our previous work described increased activation of the precuneus/posterior cingulate cortex and ventromedial prefrontal cortex-regions of the default mode network (DMN)-before participants committed a stop error in healthy control but not CD individuals (Bednarski et al., 2011). The current results showed that, compared to saline, MPH restored error-preceding activations of DMN regions in CD individuals. The extent of the changes in precuneus activity was correlated with MPH-elicited increase in systolic blood pressure. These findings suggest that the influence of MPH on cerebral activations may extend beyond cognitive control and provide additional evidence warranting future studies to investigate the neural mechanisms and physiological markers of the efficacy of agonist therapy in cocaine dependence.
"Injection of any drug is associated with endocarditis (Guerot et al., 2002). Cocaine-induced tachycardia and hypertension play a role in many of these sequelae (Tuncel et al., 2002), accounted for in part by direct reduction in vagal tone (Newlin et al., 2000). Injected cocaine causes a dose-dependent prolongation of the QT segment of the cardiac cycle, raising the risk of potentially fatal arrhythmias (Haigney et al., 2006), particularly among those with genetic predispositions for QT prolongation (Karch, 2005). "
[Show abstract][Hide abstract] ABSTRACT: A procedure is outlined for comparing dependence potential and acute toxicity across a broad range of abused psychoactive substances. Tentative results, based on an extensive literature review of 20 substances, suggested that the margin of safety ("therapeutic index") varied dramatically between substances. Intravenous heroin appeared to have the greatest risk of dependence and acute lethality; oral psilocybin appeared to have the least. Hazards due to behavioral deficits, perceptual distortion, or chronic illness were not factored into the assessments.
The American Journal of Drug and Alcohol Abuse 02/1993; 19(3):263-81. DOI:10.3109/00952999309001618 · 1.78 Impact Factor
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