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.
Footnotes
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Send reprint requests to: Bryan K. Tolliver, Ph.D., Department of Psychiatry, University of California, San Francisco/SFVAMC #127, 4150 Clement St., San Francisco, CA 94121. E-mail tollivr{at}itsa.ucsf.edu
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↵1 This work was supported by U.S. Public Health Service Award DA-07376 (S.P.B.) and National Research Service Award DA-05715 (B.K.T.).
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↵2 Present address: Department of Psychiatry, University of Cincinnati, P.O. Box 670559, 231 Bethesda Ave., Cincinnati OH 45267.
- Abbreviations:
- AC
- adenylate cyclase
- AMPH
- amphetamine
- CTX
- cholera toxin
- GABA
- γ-aminobutyric acid
- PKA
- protein kinase A
- Rp-cAMPS
- Rp-adenosine-3′,5′-cyclic monophosphothioate triethylamine
- Sp-cAMPS
- Sp-adenosine-3′,5′-cyclic monophosphothioate triethylamine
- IPSP
- inhibitory postsynaptic potential
- SQ 22
- 536, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine
- VTA
- ventral tegmental area
- Received August 4, 1998.
- Accepted October 26, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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Necessary Role for Ventral Tegmental Area Adenylate Cyclase and Protein Kinase A in Induction of Behavioral Sensitization to Intraventral Tegmental Area Amphetamine
