Project 6C: Stress Neuropeptide Pathways of Methamphetamine-Induced Behavioral Adaptation

Andrey Ryabinin, Ph.D., Principal Investigator

Stress-related corticotropin-releasing factor (CRF) and vasopressin (AVP) peptides are heavily implicated in psychostimulant-induced behaviors relevant to methamphetamine (MA) addiction. CRF and AVP peptides target several receptors and the CRF-binding protein. In addition, the CRF system include three CRF-related endogenous ligands (urocortins; Ucns) that compete with CRF at multiple binding sites.

Previous work from our laboratory has found a specific role for the CRF type-2 receptor (CRF2), but not the CRF type-1 receptor (CRF1), in acute MA-induced locomotor activity. Our brain-mapping analyses identified the basolateral and central amygdala (BLA, CeA) as candidate loci for the CRF2-dependent behavioral response to MA, supporting the well-documented involvement of amygdalar CRF systems in addiction.

However, these studies argued against a role for the endogenous ligands CRF and urocortin-1 (Ucn1), and instead implicated the CRF2-selective endogenous ligand Ucn3. The findings on the importance of CRF2 were unexpected given that CRF1, but not CRF2, can drive the hypothalamic-pituitary-adrenal (HPA)-axis, and that HPA-axis activation is essential for a multitude of behavioral adaptations relevant to MA addiction.

Because the AVP type-1b receptor (V1b) can also directly activate the HPA-axis, we hypothesize that Ucn3 acting on CRF2 receptors and AVP acting on V1a receptors are involved in the mechanisms underlying MA-induced activation of stress systems and associated behaviors.

To test this hypothesis, we will perform a series of experiments addressing the following two specific aims (SAs): SA1. Using selective pharmacology, investigate the impact of AVP-V1b receptor signaling on acute MA-induced locomotor activity and repeated MA-induced sensitization of locomotor activity; SA2.

Using a genetic knockout model, investigate the role of Ucn3 in the dose-response of MA-induced locomotor activity, and identify Ucn3-dependent neural patterns of MA-induced transcriptional activity by implementing immediate early gene brain mapping techniques.