Sensitization to psychostimulants and stress after injection of pertussis toxin into the A10 dopamine region.
An augmentation of psychostimulant-induced motor activity, termed sensitization, occurs with daily treatment and can last for months or years. At least in part, sensitization results from a long-term change in mesocorticolimbic dopamine transmission and may involve a disinhibition of dopamine neurons. Dopamine D2 autoreceptors and gamma-aminobutyric acidB (GABAB) receptors provide tonic inhibition to dopamine neurons via a G protein-mediated increase in K+ efflux. To evaluate the role of these inhibitory mechanisms in sensitization, pertussis toxin (PTX) was injected into the A10 dopamine region to uncouple the receptors via ADP-ribosylation of G proteins. In this study we demonstrated a significant augmentation in cocaine-stimulated motor activity, at doses greater than 3.0 mg/kg, 14 days after intra-A10 injection of PTX. Also, amphetamine-, but not morphine- or caffeine-stimulated motor activity was significantly augmented 2 weeks after PTX pretreatment. In vivo microdialysis revealed an augmentation of cocaine-induced increases in extracellular dopamine in the nucleus accumbens 14 days after PTX pretreatment. Pretreatment in the A10 region with the GABAB agonist baclofen, blocked cocaine-stimulated motor activity in control animals, but not in PTX-pretreated animals, indicating that the PTX treatment had uncoupled the GABAB receptor. Footshock stress activates mesocortical dopamine transmission, and postmortem tissue levels of dihydroxyphenylacetic acid and homovanillic acid in the prefrontal cortex were increased in PTX-pretreated animals. We hypothesize that the sensitized responses to cocaine, amphetamine and stress produced by PTX results from a decrease in dopamine D2 and GABAB-mediated inhibitory control of A10 dopamine neurons.
Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman.
J D
JD
Steketee
P W
PW
Kalivas
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology; D003956:Dialysis / Q000379:methods; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D013312:Stress, Physiological / Q000139:chemically induced*; D010566:Virulence Factors, Bordetella / Q000009:adverse effects* / Q000494:pharmacology
D010566:Virulence Factors, Bordetella; D002110:Caffeine; D000244:Adenosine Diphosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D001418:Baclofen; D003042:Cocaine; D004298:Dopamine