Long-lasting dopamine receptor up-regulation in amphetamine-treated rats following amphetamine neurotoxicity.
Amphetamine (A) (9.2 mg/kg, IP), in combination with iprindole (I) (10.0 mg/kg, IP), caused long-lasting dopamine (DA) depletions in striatum (-49%, 4 weeks) but not in nucleus accumbens following one A/I injection. Striatal DA had recovered by 4 months. DA receptors (DAr) were up-regulated: 1) behavioral responses to a DA receptor agonist (apomorphine) were significantly elevated. These included apomorphine-induced locomotor activity (+103% and +160%, on weeks 3 and 10) and apomorphine-induced stereotypy (day 10). 2) Bmax for [3H]spiroperidol binding to striatal D2 DAr (12 weeks) increased (+53%, week 12). Injection of the DAr neuromodulator cyclo(leucyl-glycyl) (8 mg/kg/day x 4 days, SC) reversed the Bmax increase. Thus toxicity (DA depletion) following high-dose amphetamine appears to induce compensatory changes in DAr. This DAr upregulation may explain the lack of abnormal movements despite enduring DA depletion. Additionally, the A/I paradigm as an animal model of long-lasting DAr up-regulation, could be used to screen neuromodulatory agents, like CLG, that might treat disorders (e.g., tardive dyskinesia and schizophrenia) thought to involve up-regulated DAr.
Fields
J Z
JZ
Research Service, Hines V. A. Hospital, IL 60141.
Wichlinski
L
L
Drucker
G E
GE
Engh
K
K
Gordon
J H
JH
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000633:toxicity*; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism; D007488:Iprindole / Q000633:toxicity; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
D009479:Neuropeptides; D010456:Peptides, Cyclic; D011954:Receptors, Dopamine; C021166:cyclo(leucylglycine); D007488:Iprindole; D001058:Apomorphine; D003913:Dextroamphetamine; D004298:Dopamine