Abstract
Smoking cessation leads to a dysphoric state and this increases the risk for relapse. Animal studies indicate that the dysphoric state associated with nicotine withdrawal is at least partly mediated by an increase in corticotropin-releasing factor (CRF) release in the central nucleus of the amygdala (CeA). In the present study, we investigated whether a sustained overexpression of CRF in the CeA affects the dysphoric-like state associated with nicotine withdrawal. To study brain reward function, rats were prepared with intracranial self-stimulation (ICSS) electrodes in the medial forebrain bundle. An adeno-associated virus (AAV, pseudotype 2/5) was used to overexpress CRF or green fluorescent protein (GFP, control) in the CeA and minipumps were used to induce nicotine dependence. The AAV2/5-CRF vector induced a 40% increase in CRF protein and mRNA levels in the CeA. Administration of the nicotinic receptor antagonist mecamylamine (precipitated withdrawal) or nicotine pump removal (spontaneous withdrawal) led to elevations in ICSS thresholds. Elevations in ICSS thresholds are indicative of a dysphoric-like state. The overexpression of CRF did not affect baseline ICSS thresholds but diminished the elevations in ICSS thresholds associated with precipitated and spontaneous nicotine withdrawal. The real-time reverse transcriptase (RT)–PCR analysis showed that the overexpression of CRF led to a decrease in CRF1 mRNA levels and an increase in CRF2 mRNA levels in the CeA. In conclusion, the overexpression of CRF in the CeA diminishes the dysphoric-like state associated with nicotine withdrawal and this might be driven by neuroadaptive changes in CRF1 and CRF2 receptor gene expression.
Highlights
Tobacco addiction is characterized by a loss of control over smoking, withdrawal symptoms, and relapse.[1,2,3] Smoking cessation leads to dysphoria and increased anxiety and these negative affective symptoms provide a powerful incentive for the continuation of smoking.[4,5,6,7] Animal studies suggest that the activation of brain stress systems contributes to the negative affective state associated with nicotine withdrawal.[6]Corticotropin-releasing factor (CRF) was first isolated from the hypothalamus and shown to regulate hypothalamic-pituitaryadrenal axis activity.[8]
Corticotropin-releasing factor mediates its effects on emotional states via the activation of CRF1 and CRF2 receptors
We showed that blockade of CRF1 receptors in the whole brain or in the central nucleus of the amygdala (CeA) diminishes the dysphoric-like state associated with precipitated nicotine withdrawal.[23,24]
Summary
Tobacco addiction is characterized by a loss of control over smoking, withdrawal symptoms, and relapse.[1,2,3] Smoking cessation leads to dysphoria and increased anxiety and these negative affective symptoms provide a powerful incentive for the continuation of smoking.[4,5,6,7] Animal studies suggest that the activation of brain stress systems contributes to the negative affective state associated with nicotine withdrawal.[6]. It is interesting to note that recent studies have shown that a brief period of lentiviral-mediated CRF overexpression increases stress-induced anxiety-like behavior whereas prolonged overexpression of CRF dramatically decreases stress-induced anxietylike behavior in mice.[25,26] This suggests that chronic overexpression of CRF may lead to the adaptations that diminish the effects of CRF. The sections were incubated increase in CRF levels in the CeA affects brain reward function in with antibodies, mounted on slides, and examined with a confocal drug naïve rats and nicotine-withdrawing rats. These studies investigated the effects of chronic adeno-associated virus (AAV2/5)-mediated overexpression of CRF in the CeA on baseline intracranial self-stimulation (ICSS) thresholds (28 days) and ICSS thresholds during precipitated and spontaneous nicotine withdrawal. The blots were incubated with CRF antibodies and visualized on film (see Supplementary Methods).[27,28] overexpression of CRF might affect nicotine withdrawal
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