Inhibition of monoamine oxidase isoforms modulates nicotine withdrawal syndrome in the rat.

AIMS: There have been many reports of monoamine oxidase (MAO) inhibition by non-nicotine ingredients in tobacco smoke, persisting for days after smoking cessation. This study determined the effect of inhibiting MAO and its isoforms on nicotine withdrawal syndrome. MAIN METHODS: Rats were rendered nicotine-dependent by seven days of subcutaneous (s.c.) 9 mg/kg/day infusion of nicotine bitartrate. Twenty-two hours after termination of infusion, they were observed over 20 min for somatically expressed nicotine withdrawal signs. Three hours before observation, rats were injected intraperitoneally (i.p.) with 4 mg/kg each of the MAO A antagonist clorgyline and the MAO B antagonist deprenyl, or with saline alone. A similar experiment was performed with non-dependent, saline-infused rats. Another experiment compared nicotine-dependent rats that received injections of either saline or 4 mg/kg clorgyline alone. A further experiment compared rats receiving either saline or 4 mg/kg deprenyl alone. KEY FINDINGS: Combined treatment with both MAO inhibitors markedly and significantly exacerbated somatically expressed nicotine withdrawal signs in nicotine infused rats, while having no significant effects in saline-infused rats. Rats injected s.c. with 4 mg/kg clorgyline alone had significantly more withdrawal signs than saline-injected rats, while deprenyl-injected rats had significantly fewer signs than saline controls. Assays confirmed that clorgyline thoroughly reduced MAO A enzymatic activity and deprenyl thoroughly reduced MAO B activity. SIGNIFICANCE: The results suggest that inhibition of MAO A may contribute to the intensity of withdrawal syndrome in smoking cessation.

Nociceptin/orphanin FQ (N/OFQ) induces a quasi-morphine abstinence syndrome in the rat.

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide that exerts antiopiate effects under some circumstances, and there is evidence that it contributes to opiate tolerance. This raises the question, might N/OFQ also contribute to opiate dependence and abstinence? Twenty-two male Sprague-Dawley rats were cannulated in the third ventricle and challenged 7 days later by third ventricle injection of 50, 200 or 1,000 ng N/OFQ or saline alone. Each rat was observed under "blind" conditions for 30 min beginning 15 min after onset of the third ventricle injection. There was a significant positive linear trend of signs as a function of N/OFQ dose. Subjects receiving saline had 18.0+/-2.0 (mean+/-SEM) overall abstinence-like signs, whereas subjects receiving 50, 200 or 1000 ng N/OFQ had 35.2+/-3.6, 49.8+/-2.6 and 63.5+/-9.7 signs, respectively. In 16 additional rats, abstinence-like signs induced by 1000 ng N/OFQ were significantly attenuated by low SC doses of morphine or clonidine. These results raise the possibility that N/OFQ might contribute to opiate dependence and subsequent abstinence syndrome. On the other hand, N/OFQ over a wide dose range induced abstinence signs with similar potency in morphine dependent and non-dependent rats.

A rodent model of cocaine abstinence syndrome.

This study introduces a rat model of cocaine abstinence syndrome based on quantitation of spontaneously emitted behaviors following termination of continuous drug exposure (analogous to established methods of assessing morphine and nicotine abstinence). Groups of eight male S-D rats were infused SC for 7 days via an osmotic minipump with saline alone or with 40 or 60 mg/kg/day cocaine HCl. Pumps were removed and rats were observed at 12, 24, 36, and 48 h postremoval. Each 15-min observation employed a checklist of abstinence signs including ptosis, chews, teeth chatters, gasps, writhes, seminal ejaculations, head shakes, and tremors. The high infusion rate group displayed significantly more signs than the low infusion rate group, which in turn, displayed significantly more signs than the saline group. Cocaine injection significantly reduced signs by 83.3%, while saline injection reduced them by only 4.9%. In another experiment, rats infused with 60 mg/kg/day showed significantly more signs 36 h postinfusion than before infusion, during infusion and 84 h postinfusion. Finally, 6.5 days of infusion resulted in significantly more abstinence signs than did 1.5 days of infusion. This rapid and simple model quantitated cocaine abstinence syndrome in a manner that was cocaine-reversible and related to the rate and duration of drug infusion.

Nitric oxide synthesis inhibition attenuates behavioral actions of neuropeptide FF.

Neuropeptide FF (NPFF) has certain antiopiate actions and may play a role in opiate tolerance and dependence. Third ventricle injection of 10 micrograms NPFF induces a quasimorphine abstinence syndrome in opiate-naive rats. Nitric oxide synthesis may also contribute to opiate tolerance and dependence. The present study tests the hypothesis that NPFF acts through stimulation of nitric oxide synthase (NOS). Third ventricular injection of 10 micrograms NPFF precipitated an average of 46 abstinence-like signs during a 20-min observation. Pretreatment (30 min earlier) with 7.5 or 15 mg/kg s.c. of the NOS inhibitor nitro-L-arginine (L-NNA) resulted in a significant and dose-dependent alleviation of NPFF-induced abstinence-like signs. The anti-NPFF activity of 15 mg/kg L-NNA was blocked by 750 mg/kg L-arginine, but not by the same amount of D-arginine, indicating that L-NNA attenuates NPFF activity through a stereospecific inhibition of NOS.