, 1999; Vazdarjanova &

, 1999; Vazdarjanova & see more McGaugh, 1999; LaLumiere et al., 2003; Berlau & McGaugh, 2006), and thus reductions in the region have wider implications for associative learning in general, and not just reward-based learning. Here we demonstrate that there are large reductions in rates of glucose utilization in the dorsal raphe and

locus coeruleus following withdrawal from cocaine self-administration. Our previous study, which investigated the effect of cocaine self-administration while cocaine was still on board, found no differences in functional activity in the locus coeruleus and actually higher levels of metabolism in the dorsal raphe, compared with controls (Macey et al., 2004). Because these areas are cell body nuclei for monoamine projections that are widespread throughout the brain, these data demonstrate that cocaine self-administration affects a broad expanse of the brain, certainly well beyond the dopamine system that is typically investigated. Our data of alterations of functional activity in the dorsal raphe are particularly intriguing, as the 5-HT system has been shown to

play a role in locomotor activity. Specifically, 5-HT levels have been shown to be inversely related to vertical activity (Brookshire & Jones, 2009); thus, it is tempting to speculate that reduced serotonergic activity (as indicated by the lower levels of functional activity in the dorsal raphe) may have had direct behavioral consequences (increased vertical activity Ixazomib in vitro at baseline). In addition, if the alterations in raphe activity that we see in rodents Phosphoprotein phosphatase are also present in human users, they may account for the sleep disturbances

that are often reported by addicts following cocaine misuse during the first 3 weeks of abstinence (Morgan & Malison, 2007; Schierenbeck et al., 2008). Also, dysfunction of both the dorsal raphe and the locus coeruleus has been directly related to anxiety and depression during acute (1 week) and long-term (6 weeks) withdrawal (Graeff et al., 1996; Weiss et al., 2001; Carrasco & Van de Kar, 2003; Itoi & Sugimoto, 2010). Furthermore, the locus coeruleus system has been shown to mediate shifts in attention, and thus, in addition to stress and anxiety, these reductions could have effects on basic attention, which could in turn lead to additional learning and memory deficits (Rajkowski et al., 1994; Aston-Jones et al., 1999; Usher et al., 1999). These functional alterations could be due to the ability of cocaine to inhibit both the norepinephrine and the serotonin transporters (Rothman & Baumann, 2003), and therefore the changes during withdrawal may be compensatory effects due to the sustained elevated levels of these transmitters during cocaine self-administration.

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