Received for publication May 18, 2009.
Revised June 18, 2009.
Accepted for publication June 23, 2009.

Up-regulation of AGS3 during morphine withdrawal promotes cAMP superactivation via adenylyl cyclase 5 and 7 in rat nucleus accumbens/striatal neurons

Abstract

Effective medical treatment of opiate addiction is limited by a high relapse rate in abstinent addicts. Opiate withdrawal causes cAMP superactivation, but the underlying molecular mechanisms are not clear. Recent evidence implicates an activator of G-protein signaling 3 (AGS3) in opiate addiction. Previously, we found that during a 10 min activation of opioid receptors, AGS3 binds G_i-GDP to promote free G stimulation of adenylyl cyclase (AC) 2 and 4, and/or inactivate G_i inhibitory function, thereby transiently enhancing cAMP-dependent protein kinase A (PKA) activity. In contrast, we report here that in NAc/striatal neurons morphine withdrawal induces cAMP superactivation which requires up-regulation of AGS3. cAMP increases as a function of withdrawal time, by approximately 20% at 10 min and 75% at 5 h. However, cAMP superactivation does not require G. Instead, adenosine A2A receptor activation of G_s/olf appears to initiate cAMP superactivation and promote AGS3 up-regulation. Elevated AGS3 binds to G_i to prevent its inhibition on AC activation. Moreover, withdrawal-induced increases in cAMP/PKA activate PLC and protein kinase C (PKC) to further stimulate AC5 and AC7, causing cAMP superactivation. Our findings identify a critical role of AC 5 and 7 and A2A receptors for up-regulation of AGS3 in morphine withdrawal-induced cAMP superactivation.

Key words: Adenosine, Adenylyl cyclases, cAMP, Protein Kinase A, Protein Kinase C, Opioids