Prevention and reversal of dopamine receptor supersensitivity by cyclo(leucyl-glycyl) (CLG): biphasic dose-response curves.

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/day) induced a behavioral supersensitivity (stereotypic sniffing) to dopamine (DA) agonists (apomorphine) and upregulation (increased Bmax for sulpiride-inhibitable [3H]spiroperidol binding) of striatal and limbic D2 DA receptors (DAr). Coadministration of cyclo(leucyl-glycyl) (CLG; 8mg/kg, SC; every third day, every other day, but not every day) with HAL attenuated the behavioral supersensitivity. D2-DAr binding assays showed 1) that CLG-induced changes in Bmax parallel these behavioral changes and 2) that the biphasic CLG dose-response curve may involve CLG failure at high cumulative doses to lower Bmax. CLG also reversed an already established D2 DAr supersensitivity/upregulation (i.e., when CLG was injected daily for four days after the withdrawal of HAL). CLG alone did not alter behavior or binding. CLG's ability to both prevent and reverse D2 DAr upregulation/supersensitivity in animal models suggests that CLG may be useful, within a therapeutic window, in clinical disorders that are thought to involve upregulated DAr (e.g., tardive dyskinesia, L-DOPA-induced dyskinesias, and schizophrenia).

Alterations in striatal neurotrophic activity induced by dopaminergic drugs.

The administration of dopaminergic drugs induces a variety of compensatory responses ostensibly designed to reinstate normal dopamine (DA) tone. We have hypothesized that drug-induced alterations in striatal-derived neurotrophic activity contributes to these compensatory processes. This phenomenon has been studied by examining the growth of mesencephalic cultures incubated with cell-free extracts of striatal tissue taken from patients or rats treated with various drugs. Our results reveal that reducing striatal DA tone by administering the DA antagonist haloperidol, the DA neurotoxin 6-hydroxydopamine, or as occurs naturally in Parkinson's disease, increases striatal trophic activity. Conversely, increasing striatal DA tone by administering the indirect DA agonists amphetamine or levodopa reduces trophic activity in the striatum. Kainic acid lesions of the striatum similarly reduce this trophic activity. The implications of these drug-induced alterations in trophic activity are discussed and reviewed.

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.

Neurochemical basis for the absence of overt "stereotyped" behaviors in rats with up-regulated striatal D2 dopamine receptors.

Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.