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.

Figure 1

Schematic depicting how differential trafficking of CRF₁ and CRF₂ results in different physiological and behavioral responses. Ovals represent DRN neurons, blue symbols are CRF₁ and red symbols are CRF₂. In the unstressed state approximately 50% of CRF₁ receptors are on plasma membrane, whereas 10% of CRF₂ are on plasma membrane. In this state, CRF acts at CRF₁ receptors to inhibit the DRN-5-HT system. This is associated with active coping. With repeated stress, the receptors are trafficked in opposing directions. Particularly, CRF₂ is recruited to the plasma membrane. The result is that CRF can interact with CRF₂ receptors and the neuronal response switches from inhibition to excitation. This is associated with passive coping behavior.

Figure 2

Effects of intra-DRN administration of CRF receptor agonists and antagonists on behavior in the forced swim test and defensive burying. A1–4. Effects of agents on the incidence of immobility in 3 5-min epochs during forced swim. A1. The lower dose of CRF (3 ng, n=8), but not higher dose (10 ng, n=8) decreases the incidence of immobility. For ACSF n=10. A two-way ANOVA revealed a statistically significant effect of drug (F(2,77)=8.5, p<0.001) and time (F(2,77)=57, p<0.001) and no interaction. A2. Urocortin 2 (30 ng, n=7) did not change the incidence of immobility compared to ACSF injection (n=8). A3. Urocortin 2 (100 ng, n=10) did not change the incidence of immobility compared to ACSF injection (n=9). A4. Injection of the selective CRF2 antagonist, antisauvagine-30 (50 ng, n=9) decreased the incidence of immobility compared to ACSF injection (n=10). A two way ANOVA revealed an effect of drug treatment (F(1,59)=6.4, p=0.01) and time (F(2,59)=57, p<0.001) and no interaction. B. Effects of intra-DRN CRF (3 ng, n=13) or urocortin 2 (30 ng, n=9) on the latency to bury and the duration of burying in the defensive burying test. The matched ACSF groups are n=13 and n=8 for CRF and urocortin 2, respectively. *p<0.05, **p=0.01, Student’s t-test.