Chronic Nicotine Consumption and Withdrawal Regulate Melanocortin Receptor, CRF, and CRF Receptor mRNA Levels in the Rat Brain.

Alterations in the various neuropeptide systems in the mesocorticolimbic circuitry have been implicated in negative effects associated with drug withdrawal. The corticotropin-releasing factor (CRF) and α-melanocyte-stimulating hormone are two peptides that may be involved. This study investigated the regulatory effects of chronic nicotine exposure and withdrawal on the mRNA levels of melanocortin receptors (MC3R, MC4R), CRF, and CRF receptors (CRFR1 and CRFR2) expressed in the mesocorticolimbic system. Rats were given drinking water with nicotine or without nicotine (control group) for 12 weeks, after which they continued receiving nicotine (chronic exposure) or were withdrawn from nicotine for 24 or 48 h. The animals were decapitated following behavioral testing for withdrawal signs. Quantitative real-time PCR analysis demonstrated that nicotine exposure (with or without withdrawal) increased levels of CRF and CRFR1 mRNA in the amygdala, CRF mRNA in the medial prefrontal cortex, and CRFR1 mRNA in the septum. Nicotine withdrawal also enhanced MC3R and MC4R mRNA levels in different brain regions, while chronic nicotine exposure was associated with increased MC4R mRNA levels in the nucleus accumbens. These results suggest that chronic nicotine exposure and withdrawal regulate CRF and melanocortin signaling in the mesocorticolimbic system, possibly contributing to negative affective state and nicotine addiction.

Decreased anxiety-like behavior in a selectively bred high nicotine-preferring rat line.

Genetic vulnerability contributes significantly to the individual variability observed in nicotine dependence. Selective breeding for sensitivity to a particular effect of abused drugs has produced rodent lines useful for studying genetic vulnerability to drug addiction. Previous research showed that anxiety-related personality traits are associated with nicotine dependence. Therefore, we examined the differences in anxiety-like behavior between a high nicotine-preferring rat line and their controls. At the beginning of the study, all rats, naïve to any drug, were exposed sequentially to open field arena, marble-burying and elevated plus-maze paradigms. In the second step, all rats received nicotine in drinking water for 7 weeks. Behavioral tests were rerun on the final 2 weeks of chronic nicotine treatment. Elevated plus-maze testings under basal condition and during chronic nicotine treatment showed that the time spent on the open arms, preference for being in the open arms, and the latency to enter the closed arms were higher, whereas open arm avoidance index was lower in nicotine-preferring rats compared to the controls. In the open field test, nicotine-preferring rats spent longer time in the central zone and excreted less fecal pellets; they buried less marbles in the marble-burying test. These findings indicate a lower level of anxiety-like behavior in nicotine-preferring rat line under basal conditions and during chronic nicotine treatment. We conclude that lower anxiety level in nicotine-preferring rat line is consistent with novelty-seeking personality type and may increase vulnerability to nicotine dependence in this rat line.

Chronic oral nicotine administration and withdrawal regulate the expression of neuropeptide Y and its receptors in the mesocorticolimbic system.

Neuropeptide Y (NPY) and its receptors are involved in the regulation of mood, stress, and anxiety. In parallel, NPY signaling may play a vital role in the negative affective state induced by drug withdrawal. This study examined the changes in the transcript levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system during chronic nicotine exposure and withdrawal. Rats were administered with nicotine (initial dose: 25 µg/ml, maintenance dose: 50 µg/ml, free base) in drinking water for 12 weeks. Control group received only tap water. In the final week of the study, some of the nicotine-treated animals continued to receive nicotine (0-W), whereas some were withdrawn for either 24 (24-W) or 48 (48-W) h. All animals were decapitated after the evaluation of somatic signs (frequency of gasps, eye blinks, ptosis, shakes, teeth chatter) and the duration of locomotor activity and immobility. mRNA levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system were measured by quantitative real-time PCR (qRT-PCR). Results showed that nicotine withdrawal increased overall somatic signs. Moreover, chronic nicotine treatment increased the duration of locomotor activity, whereas withdrawal increased the duration of immobility. qRT-PCR analysis revealed that chronic nicotine treatment increased NPY mRNA levels in the hippocampus. On the other hand, 24- and 48-h withdrawals increased NPY mRNA levels in the amygdala and medial prefrontal cortex (mPFC), Y1 and Y2 mRNA levels in the nucleus accumbens and mPFC, and Y5 mRNA levels in the mPFC. These findings suggest that nicotine withdrawal enhances NPY signaling in the mesocorticolimbic system, which could be an important mechanism involved in regulating the negative affective state triggered during nicotine withdrawal.