|Neuropharmacology. 2015 Mar 31;95:206-214. |
|Agonist and antagonist effects of cytisine in vivo.[Pubmed: 25839895]|
|Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4β2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including Cytisine.
METHODS AND RESULTS:
The present study aimed to characterize behavioral effects of Cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not Cytisine (0.3-3 mg/kg), lowered ICSS thresholds and Cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not Cytisine (0.3-3 mg/kg), stimulated locomotor activity and Cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not Cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), Cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline.
Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although Cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects.
|J Pharmacol Exp Ther. 2009 Apr;329(1):377-86 |
|Cytisine-based nicotinic partial agonists as novel antidepressant compounds.[Pubmed: 19164465]|
|Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that Cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models.
METHODS AND RESULTS:
We tested Cytisine and two derivatives, 5-bromo-Cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-Cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by Cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly.
These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.