Nicotine withdrawal syndrome: behavioural distress and selective up-regulation of the cyclic AMP pathway in the amygdala.
Nicotine addiction is a major public health issue. The use of laboratory animal models is a crucial tool in research aiming at understanding the pathophysiological mechanisms of nicotine dependence and at proposing new therapies. In rodents, cessation of nicotine exposure or administration of the nicotinic antagonist mecamylamine induces a nicotine withdrawal syndrome. Antagonist-precipitated withdrawal from other abused drugs such as opiates or cannabinoids has been associated with region-specific modifications of the activity of the cyclic AMP pathway. Here we show that mecamylamine-precipitated nicotine withdrawal in the rat is characterized by an increase in thigmotaxis (time spent in the periphery of an open field) that may be indicative of behavioural distress and can be associated with a selective up-regulation of adenylyl cyclase activity in the amygdala, a region implicated in the regulation of negative affect in response to aversive stimuli, including withdrawal. Adenylyl cyclase activity that is increased during precipitated nicotine withdrawal is stimulated by calcium/calmodulin, as is also the case for opioid and cannabinoid abstinence. This suggests that directly or indirectly mediated increases in the activity of the cyclic AMP pathway could constitute a possible common molecular mechanism underlying neuroadaptive changes following abstinence from different abused drugs.
Tzavara
Eleni T
ET
Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN 46285-0510, USA.
Monory
Krisztina
K
Hanoune
Jacques
J
Nomikos
George G
GG
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D005731:Ganglionic Stimulants / Q000009:adverse effects; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000009:adverse effects; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013315:Stress, Psychological / Q000139:chemically induced* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000523:psychology; D015854:Up-Regulation
D005731:Ganglionic Stimulants; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D008464:Mecamylamine; D009538:Nicotine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases