The decarboxylation product of arginine, agmatine, has effectively reduced or prevented opioid-induced tolerance and dependence when given either systemically (intraperitoneally or subcutaneously) or centrally (intrathecally or intracerebroventricularly). Systemically administered agmatine also reduces the escalation phase of intravenous fentanyl self-administration in rats. The present study assessed whether centrally (intracerebroventricular, i.c.v.) delivered agmatine could prevent the development of fentanyl self-administration in mice. Mice were trained to respond under a fixed-ratio 1 (FR1) schedule for either fentanyl (0.7 μg/70 μl, p.o.) or food reinforcement. Agmatine (10 nmol/5 μl), injected i.c.v. 12-14 h before the first session and every other evening (12-14 h before session) for 2 weeks, completely attenuated oral fentanyl self-administration (but not food-maintained responding) compared to saline-injected controls. When agmatine was administered after fentanyl self-administration had been established (day 8) it had no attenuating effects on bar pressing. This dose of agmatine does not decrease locomotor activity as assessed by rotarod. The present findings significantly extend the previous observation that agmatine prevents opioid-maintained behavior to a chronic model of oral fentanyl self-administration as well as identifying a supraspinal site of action for agmatine inhibition of drug addiction.
Bibliographical noteFunding Information:
The authors appreciate the contributions of Dr. Andrew M. Morgan for assisting in establishing the experimental protocols in our laboratory and of Dr. Marilyn Carroll for useful discussion on experimental design. These studies were made possible by the generous support of the National Institute on Drug Abuse (NIDA) in the form of a K01 award (DA-00509) and an R21 CEBRA (DA-15387) award made to C.A.F. An NRSA pre-doctoral fellowship (F31 DA021054) supports C.L.W.