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

In the present study, we investigated the effects of selective activation o r inhibition of ventral tegmental area (VTA) adenylate cyclase (AC) and pro tein kinase A (PKA) on long-term sensitization induced by repeated intra-VT A 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 s timulation 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 i nduced by repeated i.p. AMPH. Persistent activation of AC by intra-VTA chol era toxin (500 ng/side) modestly increased acute locomotion and induced a r obust 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 triethyl ami ne (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 in tra-VTA AMPH but had no effect on sensitization induced by repeated i.p. AM PH. Intra-VTA microinjection of the selective PKA activator Sp-adenosine-3' ,5'-cyclic monophosphothioate triethylamine (Sp-cAMPS; 25-100 nmol/side) do se-dependently stimulated acute locomotion and exerted synergistic effects on locomotor activity when coinfused into the VTA with AMPH but had no dete ctable effect on acute i.p. AMPH-induced locomotion. Repeated intra-VTA Sp- cAMPS did not induce sensitization to AMPH challenge but potentiated the se nsitization induced by repeated i.p. AMPH. These results suggest that VTA c AMP signal transduction is necessary for the induction of persistent sensit ization to intra-VTA amphetamine and that peripheral and intra-VTA AMPH may not induce behavioral sensitization by identical mechanisms.