Subject(s)
Brain/physiology , Cocaine-Related Disorders/psychology , Cocaine/pharmacology , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Tobacco Use Disorder/psychology , Animals , Dose-Response Relationship, Drug , Rats , Receptor, Metabotropic Glutamate 5 , RewardABSTRACT
Nicotinic acetylcholine receptor (nAChR) antagonists have been shown previously to decrease nicotine self-administration and precipitate elevations in brain reward thresholds and somatic signs of withdrawal in animals chronically exposed to nicotine. Both the positive-reinforcing effects of acute nicotine and the negative effects of nicotine withdrawal have been hypothesized to contribute to the development and maintenance of nicotine dependence. The aim of the present study was to use methyllycaconitine (MLA), an alpha 7 nAChR antagonist, to investigate the role of alpha 7 receptors in the reinforcing effects of nicotine and nicotine withdrawal. MLA was administered to animals allowed to self-administer nicotine intravenously, and also to animals that had been prepared with nicotine-containing osmotic mini-pumps and trained on a brain stimulation reward procedure. The results indicated that pretreatment with the highest doses of MLA used (3.9 and 7.8 mg/kg) significantly reduced nicotine self-administration at two doses of self-administered nicotine (0.03 and 0.06 mg/kg/infusion). Nevertheless, MLA administration, at all doses tested, had no effect on brain reward thresholds or the number of somatic signs of withdrawal observed in rats chronically exposed to either nicotine or saline. In conclusion, the alpha 7 nAChR subtype appears to play a significant role in the reinforcing effects of acute nicotine administered intravenously, but not in nicotine dependence, as reflected in the lack of precipitation of the nicotine withdrawal syndrome in nicotine-treated animals.
Subject(s)
Aconitine/analogs & derivatives , Aconitine/therapeutic use , Nicotinic Antagonists/therapeutic use , Tobacco Use Disorder/drug therapy , Aconitine/pharmacology , Animals , Behavior, Animal , Brain/drug effects , Disease Models, Animal , Electric Stimulation , Electrodes, Implanted , Male , Nicotine/adverse effects , Nicotinic Antagonists/administration & dosage , Nicotinic Antagonists/pharmacology , Rats , Rats, Wistar , Reward , Self Administration , Substance Withdrawal Syndrome/diagnosis , Substance Withdrawal Syndrome/etiologyABSTRACT
RATIONALE: The study of the effects of repeated amphetamine administration and withdrawal on brain reward function has relevance to both amphetamine dependence and non-drug-induced depressions. OBJECTIVES: The purpose of this study was to investigate the effects of continuous amphetamine administration and withdrawal on brain stimulation reward thresholds, and the changes that occur with repeated amphetamine exposures. METHODS: Rats were prepared with bipolar electrodes in the lateral hypothalamus and trained in a discrete-trial reward threshold procedure. Then, rats underwent two separate periods of amphetamine administration via subcutaneous osmotic mini-pumps. RESULTS: Continuous amphetamine administration was associated with lowering in brain reward thresholds and decreases in response latencies, while withdrawal was associated with threshold elevations. These effects changed with subsequent amphetamine administration and withdrawal. CONCLUSIONS: The results of this study indicated that with the amphetamine administration regime used here, rats developed increased sensitivity to the effects of acute amphetamine administration and tolerance to the effects of amphetamine withdrawal.
