Tolerance to cocaine in brain stimulation reward following continuous cocaine infusions.
This study examined tolerance to cocaine's threshold-lowering effect in brain stimulation reward (BSR) following continuous cocaine infusions and secondly, used the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) to determine NO's involvement in the development of cocaine tolerance. Animals were continuously infused with saline or cocaine (30 mg/kg per day) via osmotic minipump for 14 days and injected daily with saline or L-NAME (30 mg/kg, i.p.) following BSR testing. Saline-treated animals continuously infused with saline showed stable BSR thresholds across the 14-day infusion period. Saline-treated animals continuously infused with cocaine showed markedly lowered BSR thresholds on Day 1 followed by a progressive increase in BSR thresholds across the infusion period - indicating the development of tolerance. L-NAME-treated animals continuously infused with cocaine showed stimulation thresholds that were not significantly different from saline-treated animals continuously infused with cocaine. A cocaine challenge injection (10 mg/kg, i.p.) administered 3 and again at 10 days following minipump removal revealed that saline-treated animals continuously infused with saline showed lowered BSR thresholds. Saline-treated animals continuously infused with cocaine displayed lowered BSR thresholds that were not significantly different from saline-infused animals. L-NAME treated animals continuously infused with cocaine showed higher BSR thresholds to a challenge 3 days following pump removal. However, stimulation thresholds for this group failed to reach statistical significance on both days (i.e., Days 3 and 10) following pump removal. Results showed that animals continuously infused with cocaine develop robust tolerance to cocaine's threshold-lowering effect during the 14-day infusion period. Tolerance to cocaine's threshold-lowering effect was short-lived and dissipated soon after minipump removal. L-NAME treatment failed to significantly alter the development of tolerance to cocaine's threshold-lowering suggesting that NO does not have a primary role in the development of cocaine tolerance.
Addiction Research Unit, Department of Psychology, State University of New York at Buffalo, Buffalo New York 14260-4110. Electronic address: C.Pudiak@yahoo.com.
Cindy M
CM
Pudiak
Addiction Research Unit, Department of Psychology, State University of New York at Buffalo, Buffalo New York 14260-4110.
Rhonda
R
KuoLee
Addiction Research Unit, Department of Psychology, State University of New York at Buffalo, Buffalo New York 14260-4110.
Michael A
MA
Bozarth
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D004361:Drug Tolerance / Q000502:physiology; D007260:Infusion Pumps; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects* / Q000502:physiology
D003042:Cocaine
Brain stimulation reward; Continuous cocaine; L-NAME; Nitric oxide; Psychomotor stimulants; Tolerance