Dopamine depletion produces augmented behavioral responses to a mu-, but not a delta-opioid receptor agonist in the nucleus accumbens: lack of a role for receptor upregulation.
Microinjection of either mu- or delta-opioid agonists into the nucleus accumbens produces an increased locomotor activity, and when the dopaminergic innervation of the nucleus accumbens is bilaterally lesioned, the locomotor response to the microinjection of mixed mu- and delta-opioid agonists is augmented. To determine whether the lesion-induced augmentation to opioids is specific to mu- or delta-opioid receptor activation, dopamine innervation of the nucleus accumbens was lesioned with 6-hydroxydopamine (6-OHDA), and the motor stimulant response to intra-accumbens microinjection of the selective mu-opioid agonist, Tyr-D-Ala-Gly-mePhe-Gly-OH (DAMGO), was compared to that of the delta-opioid agonist, [D-penicillamine2,5]-enkephalin (DPDPE). The lesions caused a 95% depletion of tissue dopamine levels in the nucleus accumbens of the DAMGO-injected rats compared to sham-lesioned rats. Horizontal and vertical photocell counts were significantly increased in response to DAMGO in 6-OHDA-lesioned compared to the sham-lesioned rats. This behavioral augmentation was dose dependent and blocked by naloxone. In rats with similar accumbal dopamine depletions (94%), the locomotor response to DPDPE was not enhanced. The augmentation in the behavioral response to DAMGO was not associated with a change in the Bmax or Kd of [125I]DAMGO binding in nucleus accumbens homogenates from lesioned rats. Likewise, using quantitative receptor autoradiography, no difference between 6-OHDA- and sham-lesioned rats was observed in [125I]DAMGO or [125I]DPDPE binding. Therefore, the augmented behavioral response to opioids in the nucleus accumbens following dopamine depletion relies predominately on mu-opioid receptor stimulation. However, this augmentation is not mediated by an alteration in the number or affinity of these receptors.
Churchill
L
L
Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman 99164-6520.
Kalivas
P W
PW
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D007457:Iodine Radioisotopes; D008297:Male; D008845:Microinjections; D009294:Narcotics / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D015854:Up-Regulation / Q000187:drug effects*
D015306:Biogenic Monoamines; D004745:Enkephalins; D007457:Iodine Radioisotopes; D009294:Narcotics; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004298:Dopamine