Necessary role for ventral tegmental area adenylate cyclase and protein kinase A in induction of behavioral sensitization to intraventral tegmental area amphetamine

Abstract

In the present study, we investigated the effects of selective activation or inhibition of ventral tegmental area (VTA) adenylate cyclase (AC) and protein kinase A (PKA) on long-term sensitization induced by repeated intra-VTA or peripheral amphetamine (AMPH). Selective inhibition of AC by SQ 22,536 (9-(tetrahydro-2-furanyl)-9H-purin-6-amine; 100 nmol/side bilateral into VTA) had no effect on acute basal locomotion but attenuated the locomotor stimulation induced by acute i.p. AMPH (1.5 mg/kg). Coinjection of SQ 22,536 (100 nmol/side) fully blocked the sensitization induced by repeated intra-VTA AMPH (15 nmol/side) but had no detectable effect on the sensitization induced by repeated i. p. AMPH. Persistent activation of AC by intra-VTA cholera toxin (500 ng/side) modestly increased acute locomotion and induced a robust sensitization to i.p. AMPH challenge 10 days after the last of three repeated VTA microinjections. Selective inhibition of PKA by Rp-adenosine-3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS; 25 nmol/side) had no effect on acute basal or AMPH-stimulated locomotion. Coinjection of Rp-cAMPS (25 nmol/side) fully blocked the sensitization induced by repeated intra-VTA AMPH but had no effect on sensitization induced by repeated i.p. AMPH. Intra-VTA microinjection of the selective PKA activator Sp-adenosine-3',5'-cyclic monophosphothioate triethylamine (Sp-cAMPS; 25-100 nmol/side) dose-dependently stimulated acute locomotion and exerted synergistic effects on locomotor activity when coinfused into the VTA with AMPH but had no detectable effect on acute i.p. AMPH-induced locomotion. Repeated intra-VTA Sp-cAMPS did not induce sensitization to AMPH challenge but potentiated the sensitization induced by repeated i.p. AMPH. These results suggest that VTA cAMP signal transduction is necessary for the induction of persistent sensitization to intra-VTA amphetamine and that peripheral and intra-VTA AMPH may not induce behavioral sensitization by identical mechanisms.