Disruption of G(i/o) protein signaling in the nucleus accumbens results in a D1 dopamine receptor-mediated hyperactivity.
Intra-accumbens infusion of pertussis toxin (PTX) results in a progressive and persistent locomotor hyperactivity and sensitizes rats to the locomotor-activating effects of cocaine. The present study further defined the hyperactivity resulting from inactivation of accumbens Gi/Go proteins and tested the hypothesis that PTX-induced hyperactivity is mediated by dopamine D1 receptors. PTX (0.15 microg/side) infused bilaterally into the nucleus accumbens of rats resulted in a progressive increase in locomotor activity that peaked at 218% of preinjection activity levels 15 days after injection and persisted for greater than 5 weeks postinjection. Administration of the D1 receptor antagonist SCH23390 16 and 23 days after PTX injections dose dependently attenuated PTX-induced hyperactivity. D1 receptor blockade did not significantly alter activity in sham-injected animals. These findings support the hypothesis that the hyperactivity resulting from PTX-mediated inactivation of G(i/o) proteins reflects increased nucleus accumbens D1 receptor activation and suggest that striatal D1 receptors are important mediators of activity-related behavior, such as cocaine-induced hyperactivity.
Schroeder
Joseph A
JA
Department of Pharmacology, Temple University School of Medicine, 3420 N Broad Street MRB321, Philadelphia, PA 19140, USA. jschroed@astro.temple.edu
Hummel
Michele
M
Unterwald
Ellen M
EM
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006948:Hyperkinesis / Q000139:chemically induced* / Q000523:psychology; D007267:Injections; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go