Preoccupation/Anticipation Stage

Neuroanatomical Substrates of Nicotine "Craving"

A human neurological study of individuals with stroke-induced destruction of the insula cortex revealed that in the group who smoked prior to stroke stopped smoking abruptly following damage to the insula. Preclinical studies have subsequently shown that destruction of the insula blocks the cue-induced reinstatement of nicotine seeking in mice and rats that have been trained to intravenously self-administer nicotine and then subjected to extinction. Deep-brain stimulation of the insula has similar effects. Another likely driving force for craving is the nucleus accumbens. In a rat study, 2 weeks after nicotine self-administration, activated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and NMDA receptors and a reduction of glutamate transporters were observed in the nucleus accumbens. Cues paired with nicotine elicited glutamate release. The blockade of NMDA receptors blocked cue-induced reinstatement (Table 7.5). Notably, this pattern of low basal glutamate tone (decreased glutamate transporters) in the nucleus accumbens but the phasic release of glutamate in the presence of nicotine cues is identical to observations of protracted cocaine abstinence.

TABLE 7.5

Neuropharmacological Agents that Block Nicotine-, Cue, and Stress-Induced Reinstatement in Rodents that Have Been Trained to Intravenously Self-Administer Nicotine and then Subjected to Extinction

Nicotine-induced reinstatement

Dopamine D4 receptor antagonist
_-type peroxisome proliferator-activated receptor agonist

Cue-induced reinstatement

noncompetitive nicotinic receptor antagonist (mecamylamine)
_4_2 nicotinic receptor partial agonist (varenicline)
GABA agonist (GABA transaminase inhibitor)
GABAB receptor agonist
dopamine D1, D2, D3, and D4 receptor antagonists
dopamine D2 receptor partial agonist
cannabinoid CB1 receptor antagonist
anandamide transporter inhibitor
opioid receptor antagonist (naltrexone)
metabotropic glutamate 5 receptor antagonist
metabotropic glutamate 2/3 receptor antagonist
metabotropic glutamate 1 receptor antagonist
NMDA subunit antagonist
cystine-glutamate antiporter system agonist (N-acetylcysteine)
glutamate modulator (acamprosate)
_1 adrenergic receptor antagonist
_ adrenergic receptor antagonist
serotonin 5-HT2C receptor antagonist
serotonin 5-HT6 receptor antagonist
T-type calcium channel antagonist

Stress-induced reinstatement

CRF receptor antagonist
_2 adrenergic receptor agonist (clonidine)
_ opioid receptor antagonist

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