Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats.

Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used self-administration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE self-administration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers.

Nicotine modulation of adolescent dopamine receptor signaling and hypothalamic peptide response.

Adolescence is a sensitive developmental period for limbic and dopamine systems that coincides with the typical age for onset of tobacco use. We have previously shown that a 4-day, low-dose nicotine (0.06 mg/kg) pretreatment enhances locomotor and penile response to the D2-like agonist, quinpirole (0.4 mg/kg), in adolescent but not adult rats. The present study is designed to determine mechanisms underlying this effect. Nicotine enhancement of adolescent quinpirole-induced locomotion was mediated by D2 receptors (D2Rs) since it was blocked by the D2R antagonist, L-741,626, but not by the D3R and D4R antagonists, NGB 2904 and L-745,870. Enhancement of quinpirole-induced erectile response was blocked by both L-741,626 and NGB 2904, indicating involvement of D3Rs. Whereas D2R binding was unaffected by adolescent nicotine pretreatment, effector coupling in the striatum was increased, as determined by GTPγS binding. Nicotine pretreatment enhanced quinpirole-induced c-fos mRNA expression in the hypothalamic paraventricular and supraoptic nuclei in adolescents only. Adolescent nicotine pretreatment enhanced c-fos mRNA expression in corticotropin releasing factor (CRF) cells of the paraventricular nucleus, and enhancement of penile erection was blocked by the CRF-1 receptor antagonist, CP 376,396. These findings suggest that adolescent dopamine and CRF systems are vulnerable to alteration by nicotine. This is the first evidence for a role of CRF in adolescent erectile response.

Age-dependent alterations in reward-seeking behavior after brief nicotine exposure.

RATIONALE: Adolescence is a developmental period that coincides with the onset of tobacco use. Teen smokers are also more likely to abuse other drugs compared to nonsmokers. Previous studies with rats have shown that low-dose nicotine pretreatment enhances initial acquisition of cocaine self-administration when given during early adolescence, but not at later ages. The aim of the present study was to determine whether these nicotine pretreatment effects extend to extinction and reinstatement of reward-seeking behavior. METHODS: Adolescent [postnatal day (P)28] and adult rats (P86) were pretreated for 4 days with nicotine (60 µg/kg, i.v.) or saline. Following pretreatment, rats were allowed to nose poke for cocaine (500 µg/kg/infusion) or sucrose pellets for at least 12 days or until meeting acquisition criterion. Responding was then extinguished for at least 7 days or until extinction criterion was met. The following day, the rats were reinstated with either a priming injection of cocaine (10 mg/kg, i.p.) or sucrose pellets. RESULTS: Nicotine markedly enhanced extinction of cocaine self-administration in adolescent rats, but not adults. Pretreatment also enhanced the acquisition of cocaine self-administration in adolescents, while reducing discrimination for the reinforced hole in adults. There were no pretreatment or age effects on cocaine-induced reinstatement. In contrast, nicotine induced only minor enhancement of sucrose-taking behavior in adolescents, with no significant impact on extinction or reinstatement at either age. CONCLUSIONS: Nicotine pretreatment affects reward-related behavior in both an age- and reward-dependent manner. These findings show that brief nicotine exposure during early adolescence enhances drug-related learning.

Nicotinic receptors in addiction pathways.

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that consist of pentameric combinations of α and ß subunits. These receptors are widely distributed throughout the brain and are highly expressed in addiction circuitry. The role of nAChRs in regulating neuronal activity and motivated behavior is complex and varies both in and among brain regions. The rich diversity of central nAChRs has hampered the characterization of their structure and function with use of classic pharmacological techniques. However, recent molecular approaches using null mutant mice with specific regional lentiviral re-expression, in combination with neuroanatomical and electrophysiological techniques, have allowed the elucidation of the influence of different nAChR types on neuronal circuit activity and behavior. This review will address the influence of nAChRs on limbic dopamine circuitry and the medial habenula-interpeduncular nucleus complex, which are critical mediators of reinforced behavior. Characterization of the mechanisms underlying regulation of addiction pathways by endogenous cholinergic transmission and by nicotine may lead to the identification of new therapeutic targets for treating tobacco dependence and other addictions.