The notion that l/l smokers use nicotine to compensate for serotonergic and deficits is supported by the hypothesized interplay between nicotine and serotonin in the regulation of emotion. Nicotine may stimulate serotonin (5-HT) release at high doses (Ho & Tyndale, 2007; Mihailescu, Palomero-Rivero, Meade-Huerta, Maza-Flores, & Drucker-Colin, 1998; Ribeiro, Bettiker, Bogdanov, & Wurtman, 1993) and its withdrawal may decrease 5-HT in limbic and forebrain structures, possibly by increasing the inhibitory influence of 5- HT1-A autoreceptors within the raphe nuclei (Kenny & Markou, 2001). In fact, drugs that increase serotonin by inhibiting the action of 5-HT1A receptors block the increased startle response in animals undergoing nicotine withdrawal (Rasmussen, Kallman, & Helton, 1997). This loss of serotonergic stimulation could lead to an increase in emotional reactivity during nicotine withdrawal. Inhibiting the reuptake of serotonin also rapidly reverses the elevation in brain-stimulation reward thresholds observed in rats undergoing nicotine withdrawal (Harrison, Liem, & Markou, 2001). Balfour (Balfour & Ridley, 2000) has suggested, however, that nicotine may ultimately decrease 5-HT in the hippocampus (possibly by increasing 5-HT1A receptors), an action that could be interpreted
