Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction

Abstract

Addiction and stress are linked at multiple levels. Drug abuse is often initiated as a maladaptive mechanism for coping with stress. It is maintained in part by negative reinforcement to prevent the aversive consequences of stress associated with abstinence. Finally, stress is a major factor leading to relapse in subjects in which drug seeking behavior has extinguished. These associations imply overlapping or converging neural circuits and substrates that underlie the processes of addiction and the expression of the stress response. Here we discuss the major brain serotonin (5-HT) system, the dorsal raphe nucleus (DRN)-5-HT system as a point of convergence that links these processes and how the stress-related neuropeptide, corticotropin-releasing factor (CRF) directs this by a bimodal regulation of DRN neuronal activity. The review begins by describing a structural basis for CRF regulation of the DRN-5-HT system. This is followed by a review of the effects of CRF and stress on DRN function based on electrophysiological and microdialysis studies. The concept that multiple CRF receptor subtypes in the DRN facilitate distinct coping behaviors is reviewed with recent evidence for a unique cellular mechanism by which stress history can determine the type of coping behavior. Finally, work on CRF regulation of the DRN-5-HT system is integrated with literature on the role of 5-HT-dopamine interactions in addiction.

Prefrontal/Amygdalar System Determines Stress Coping Behavior Through 5-HT/GABA Connection

“…On the basis of results from experiment 1 showing a prefrontal 5-HT-amygdalar GABA circuitry in response to stress, it was investigated if this system is involved also in controlling coping behavior in the FST. First, the effect of bilateral prefrontal selective 5-HT depletion in mpFC and L-allylglycine (1 mM) bilateral infusion in BLA were assessed on behavioral outcomes in the FST, a well-known experimental condition commonly used to investigate stress-related behavior and to model depressive-like behavior in rodents (Porsolt et al, 1977;Valentino et al, 2010;Ebner et al, 2005). Selective bilateral 5-HT depletion in mpFC (Sham group (n ¼ 8) 293.18±6.6 s, 5-HT-depleted group (n ¼ 8) 122.19 ± 13.3 s, F 1.14 ¼ 132.2, Po0.01) or bilateral BLA L-allylglycine infusion (bilateral BLA CSF (n ¼ 6) 307.5±16.1 s, bilateral BLA L-allylglycine group (n ¼ 7) 135.2 ± 8.6 s, F 1.11 ¼ 95.79, Po0.01) significantly reduced immobility.…”

Individual Differences and Social Influences on the Neurobehavioral Pharmacology of Abused Drugs

“…5-HT systems also are linked to maternal separationinduced changes in sensitivity to stress and abused drugs Valentino et al, 2010). In rats, maternal separation decreases 5-HT functioning in amygdala, including reduced 5-HT levels, 5-HT1A autoreceptors, and 5-HT transporters (Vicentic et al, 2006;Oreland et al, 2009).…”

The Neurokinin-1 Receptor in Addictive Processes

“…NK1R antagonists can prevent immobilization stress-induced dopamine release in the prefrontal cortex (Hutson et al, 2004;Renoldi and Invernizzi, 2006), which is of particular interest for the NK1R's targeted role in stress-elicited drug seeking (see later discussion). The effect of the NK1R on monoamine signaling is a major mechanistic area of overlap with the functions of CRH receptors, which can influence the activity of the monoaminergic systems (Dunn et al, 2004;Valentino and Commons, 2005;Valentino et al, 2010).…”