Cardiovascular Changes Induced By Drugs of Abuse

National Institute On Drug Abuse

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Abstract

Research over the past year has focused on the cardiovascular effects of adenosine receptor subtype agonists and antagonists in rats and of kappa receptor agonists in squirrel monkeys. Adenosine plays a role in the behavioral effects of caffeine, one of the most widely used drugs in the world. Rats are implanted with telemetry devices for recording blood pressure and heart rate. Various adenosine agonists and antagonists were then administered and blood pressure and heart rate were recorded for 1 hour. We have recently confirmed that the heart rate increasing effects of adenosine A2A agonists are mediated in the central nervous system while other effects of adenosine A2A and A1 agonists are mediated in the periphery. These experiments involved both peripheral and central administration of drug and pretreatment with ganglionic blockers. We are currently investigating the central locus of the adensosine A2A mediated increase in heart rate. In particular, we are investigating the role of the hindbrain cardiovascular control regions in this effect. Additional studies are focusing on the effects of adenosine agonists and antagonist following chronic caffeine treatment. Here we have found that chronic caffeine produces rapid and near complete tolerance to the locomotor activating effects of caffeine, but does not alter the cardiovascular effects of either adenosine A1 or A2A subtype specific receptor agonists or antagonists. This result provides additional support for our previous conclusion that the behavioral and cardiovascular effects of adenosine are mediated via different mechanisms. Kappa agonists have been proposed as treatments for psychostimulant abuse. In squirrel monkeys implanted with arterial catheters kappa agonists produce large increases in heart rate. This is due to both the central effects of these drugs as shown in studies with ganglionic blockers and peripheral effects as a peripherally active kappa agonist also increases heart rate. The effects of the kappa agonists can be blocked by the opioid antagonist naltrexone, implicating the involvement of kappa opioid receptors. When given in combination with cocaine kappa agonists do not potentiate the effects of cocaine. Thus kappa agonists can be used safely in the treatment psychostimulant abuse.