Intra-VTA adenosine A1 receptor activation blocks morphine stimulation of motor behavior and cortical and limbic Fos immunoreactivity.
Drugs of abuse produce psychomotor stimulation as one of their characteristic behavioral effects. Single administration of opiates stimulates motor activity via effects on gamma-aminobutyric acid (GABA) and dopamine transmission in the ventral tegmental area (VTA). Adenosine A(1) receptor agonists inhibit VTA GABAergic and dopaminergic transmission and are predicted to alter the behavioral effects of opiates. This study examined the effects of intra-VTA administration of selective adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) and antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) on morphine-induced motor stimulation in C57BL/6 mice. It also examined the effects of CPA on morphine's activation of VTA neurons projecting to limbic and cortical regions including the nucleus accumbens (NAc), anterior cingulate cortex (ACg) and prelimbic cortex (PrL) via quantitation of immediate-early gene c-Fos protein in these regions. Mice received subcutaneous morphine and intra-VTA administration of CPA and then automated motor activity was measured. Morphine treatment induced both motor activity and Fos immunoreactivity in the NAc, ACg and PrL suggesting that behavioral stimulation is produced by neural activation in these regions. Intra-VTA CPA administration produced a dose-dependent inhibition of morphine-induced motor stimulation and blocked c-Fos induction in all three regions. Intra-VTA CPT treatment had no effects on motor activity or on morphine-induced motor stimulation. VTA adenosine A(1) agonist inhibition of morphine's effects on motor activity and of neural activation of VTA projections suggests that these neurons and their regulation are critical to morphine's stimulant effects. Adenosine A(1) receptor agonists and purinergic modulators may represent useful treatment approaches for blocking the behavioral effects of opiates.
Kaplan
Gary B
GB
Mental Health Service, VA Boston Healthcare System, Boston, MA 02130, USA. Gary.Kaplan@va.gov
Leite-Morris
Kimberly A
KA
Klufas
Michael A
MA
Fan
Wenying
W
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D008032:Limbic System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000276:immunology / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D058907:Adenosine A1 Receptor Agonists; D015415:Biomarkers; D016760:Proto-Oncogene Proteins c-fos; C053907:8-cyclopentyl-1,3-dimethylxanthine; C048599:N(6)-cyclopentyladenosine; D009020:Morphine; D013806:Theophylline; D000241:Adenosine