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National Institute on Drug Abuse

1 Z01 DA000009-22 BNRB
Cardiovascular Changes Induced By Drugs of Abuse

Lead Investigator: Charles W. Schindler, PhD (PP, NIDA)
PI/SOR: Steven R Goldberg, PhD (PP, NIDA)
Lab staff: Sergi Ferre, M.D., Ph.D (PP, NIDA)
Eric B Thorndike (PP, NIDA)
Extramural Collaborators: Srihari R. Tella, PhD (Office of Diversion Control, Drug Enforcement Administration)
 from October 01, 2006 to September 30, 2007
Human subject research: Neither Human Subjects nor Human Tissues
Total Staff Years:0.8
Keywords:cocaine, adenosine, cardiovascular, blood pressure, heart rate, ECG, squirrel monkey, rat
Goals and Objectives:Most abused drugs also have effects on the cardiovascular system. These effects can range from the prominent effects of the psychomotor stimulants cocaine and methamphetamine to the much smaller effects of caffeine. These effects are typically studied in the absence of ongoing behavior, although we have shown that cardiovascular effects can also be apparent even during drug self-administration. These cardiovascular “side effects” may play a role in the total behavioral process, and they are particularly important in predicting the safety of any proposed treatment medication. It is inevitable that any treatment drug will also be used in combination with the abused drug in individuals that relapse to drug use. Therefore, the goal of this research is to determine the pharmacological mechanisms by which abused drugs produce cardiovascular effects and to determine the interactions between abused drugs and potential treatment medications on these cardiovascular effects.
Summary:Research over the past year has continued to focus 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. We have previously shown that adenosine A2A agonists can increase heart rate in rats, an effect that appears to be medicated by CNS adenosine receptors. The site of action for this effect has been hypothesized to be the nucleus tractus solitarius (NTS). To investigate this possibility further, we have implanted microdialysis probes in the NTS and administered the adenosine agonist CGS 21680. CGS 21680 produced an increase in the level of glutamate in the NTS, while the adenosine A2A antagonist MSX-3 produced a decrease of glutatmate, suggesting a tonic level of control by adenosine. The combination of CGS 21680 and MSX-3 produced no change in glutatmate. When CGS 21680 was injected into the NTS on a single side, no change in cardiovascular parameters were noted. It is likely that bilateral injections will be required to observed a cardiovascular effect.

Kappa agonists have been proposed as treatments for psychostimulant abuse. Completed studies in squirrel monkeys implanted with arterial catheters have shown that 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.
Publications generated by this research:
  1. Schindler CW, Graczyk Z, Gilman JP, Negus SS, Bergman J, Mello NK, Goldberg SR (2007) Effects of kappa opioid agonists alone and in combination with cocaine on heart rate and blood pressure in conscious squirrel monkeys. Eur J Pharmacol, in press (e-pub ahead of print).

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