Dopamine receptor turnover rates in rat striatum are age-dependent.

Abstract

The time course of recovery of [3H~spiperone binding in the rat striatum after a single injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) shows that a slower rate of regeneration/turnover of D-2 dopamine receptors occurs in mid-lifemature versus young male rats. This slower receptor recovery reflects relatively slower rates of both receptor synthesis and degradation. Studies using cycloheximide indicate that protein synthesis plays a significant role in the reappearance of[FH]spiperone-binding sites. Other experiments indicate that chronic reserpine treatment, which produces dopamine receptor up regulation, also produces accelerated receptor recovery after EEDQ blockade. An age-related decline in dopamine receptor turnover, if present in humans and progressive into senescence, could be responsible for the increased risk of developing Parkinson disease and drug-induced parkinsonian-like extrapyramidal side effects with age. On the other hand, the more rapid receptor turnover rates seen in young rats may be a biochemical feature related to plasticity in the striatum during development.Age-related differences in therapeutic dosages and extrapyramidal side effects have been reported for the clinical use of antipsychotic drugs (1, 2). Since these agents are hypothesized to exert their therapeutic as well as extrapyramidal side effects by blocking dopamine receptors in the brain, one might expect the regulation of functional levels or other properties of these dopamine receptors to exhibit age-dependent differences. Indeed, dopamine receptor levels in rat striatum have been observed to increase over the first month postnatally (3), and age-correlated losses of dopaminergic receptor-binding activity and function have been noted in humans and rodents (for review, see refs. 2 and 4). In aged rodents relative deficits in the ability of dopamine receptors to exhibit up regulation in response to chronic dopamine receptor antagonist (antipsychotic) drug treatments have been described (5), although other researchers have not observed such aging-related deficits in dopamine receptor up regulation when more robust (lesion-induced) decreases in agonist input were used (6-9).Aging-related deficits in the ability of 83-adrenergic receptor to exhibit up regulation have also been described (10-12).A recent report described aging-related decreases in the regeneration of visceral beta-adrenergic receptors after their irreversible blockade (13), thus suggesting one possible mechanism for the observed age-related deficits in receptor up regulation. A vehicle and decapitated at various times. For time-course experiments, rats were sacrificed at the same time of day 6, 28-30, 52-54, 100-102, 148-150, and 172-174 hr after injection with either EEDQ or vehicle. Their brains were rapidly removed and placed in ice-cold saline, and their striata were dissected and stored frozen at -70'C for up to 6 days. An EEDQ dose of 8 mg/kg was chosen because it produced near maximal receptor blockade ...

The partial dopamine D2-like receptor agonist terguride functions as an agonist in preweanling rats after a 5-day reserpine regimen

“…Although not examined in the present study, repeated reserpine treatment does cause D 2 -like receptor upregulation in adult rats (Burt et al 1977;Leff et al 1984); therefore, the present data are consistent with either a "conformational change" or "receptor reserve" explanation of partial agonist functioning.…”

On Distributions of Physiological and Anatomical Variables in Pathological Conditions: Dopamine D2 Receptors in Schizophrenia and Their Occupancies after Drug Treatment

“…The above predictions are in accordance with the observation that dopamine turnover is not increased in the brains of schizophrenics and is possibly decreased (Leff et al, 1984) Furthermore, if there are too few dapamine D2 receptors, the combined effects of neuroleptic blockade and receptor upregulation are unlikely to result in an effective D2 dopamine occupancy in the normal range. The idea that schizophrenia may be accompanied by too few or too many D2 receptors is in the spirit of the recently described picture where too much or too little D l activation can result in impaired cognitive performance (Desimone, 1995).…”

“…If B,cax is the average dopamine D2 receptor density for normals, then the average occupancy, or concentration of receptor-dopamine complexes is To take into account the changes in dopamine receptor density due to degradation and synthesis, we use a model previously used for acetylcholine receptors (Fambrough et al, 1977) and dopamine receptors by Leff et al (1984). Letting R(t) now standfor the density of receptors at time t, this quantity is given by the solution of the differential equation where a is the degradation rate and P i s rate of synthesis, assumed constant.…”

“…It is well known that dopamine receptor populations are labile in both their properties and number densities with ongoing synthesis and degradation (Leff et al, 1984;Hess and Creese, 1987;Crammer and Heine, 1991). In particular, after chronic application of many dopamine antagonists there is a proliferation and increase in the density of D2 receptors (Leff et al, 1984;Seeman and Grigoriadis, 1987;Cooper et a]., 1991; Buckland et al, 1992). Furthermore, Knable et al (1996) demonstrated that both normals and schizophrenics had elevated Dl levels in prefrontal and cingulate cortices after the administration of neuroleptics.…”

In vitro and in vivo characterization of 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-isothiocyano)phenyl-l,4-dihydropyridine as a Ca2+ channel antagonist

“…Times for 50% recovery of binding sites were between 35 and 50 h and these were approximately doubled in the presence of cycloheximide. These times are in good accord with those determined for a number of plasmalemmal receptors including a, -adrenoceptors (23-33 h; Sladeczek and Bockaert 1982;Mauger et al 1982 tion rates of 0.02-0.03 h-' and production rates of 1.7-3.2 fmol-mg protein-' -h-I have been reported for a -adrenoceptors and dopamine receptors (Mauger et al 1982;Sladeczek and Bockaert 1982;Leff et al 1984) which also concur with those obtained for nitrendipine binding sites (Table 2). Administration of cycloheximide reduced approximately equally the rates of binding site appearance and degradation.…”