Increase In D2 Receptor Density Research Articles

Early-life risperidone alters locomotor responses to apomorphine and quinpirole in adulthood

An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0 mg/kg) or vehicle from postnatal day 14–42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3 mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.

Interactions between D1 and D2 dopamine receptor family agonists and antagonists: the effects of chronic exposure on behavior and receptor binding in rats and their clinical implications.

Functional interactions between dopamine receptor subtypes may affect behavioral and biochemical responses which serve as models for neuropsychiatric illnesses and the clinical effects of drug therapy. We evaluated the effects of chronic exposure to the selective D1 receptor antagonist SCH 23390, and the selective D2 receptor antagonist metoclopramide, on spontaneous and drug-induced behavior and receptor density in rats, and then determined how these effects would be modified by concurrent administration of antagonists or agonists [SKF 38393, LY 171555 (quinpirole)] selective for the complementary receptor subtype. Administered alone, both the D1 and D2 antagonists had acute cataleptic effects to which animals became tolerant following chronic treatment, but the selective antagonists had opposing effects on spontaneous locomotor activity. Both antagonists produced equivalent, supersensitive behavioral responses to apomorphine, and resulted in an increase in D2 receptor density. Coadministration of the D1 and D2 antagonists had a synergistic effect on catalepsy, attenuated the effects on spontaneous locomotor activity observed with either drug alone, and had an additive effect on both apomorphine-induced stereotypic behavior and D2 receptor proliferation. On the other hand, when either selective antagonist was combined with the agonist selective for the complementary receptor subtype, both D2 receptor proliferation and behavioral supersensitivity were completely blocked. Combined antagonist-agonist treatments had opposing effects on the development of tolerance to antagonist-induced catalepsy. D2 - but not D1 - receptor densities were correlated with animals' behavioral responses to apomorphine. There results support and extend the notion that complex functional interactions between D1 and D2 receptor families occur within the central nervous system, and suggest that novel effects might be derived from combined administration of receptor selective agonists and antagonists.

Olfactory deprivation increases dopamine D2 receptor density in the rat olfactory bulb

Unilateral olfactory deprivation during postnatal development results in significant anatomical and neurochemical changes in the deprived olfactory bulb. Perhaps the most dramatic neurochemical change is the loss of dopaminergic expression by neurons of the glomerular region. We describe here the effects of early olfactory deprivation on other elements of the bulb dopaminergic system, namely the dopamine receptors of the olfactory bulb. Rat pups had a single naris occluded on postnatal day 2 (PN2). On PN20 or PN60, animals were sacrificed and the bulbs were examined for catecholamine levels or D2 and D1 dopamine receptor binding. Receptor densities were quantified by in vitro autoradiography using the tritiated antagonists spiperone (D2) and SCH23390 (D1). Dopamine uptake sites were similarly examined using tritiated mazindol. No significant specific labeling of D1 or mazindol sites was observed in the olfactory bulbs of control or experimental animals at either age. Normal animals displayed prominent labeling of D2 sites in the glomerular and nerve layers. After 60 days of deprivation, deprived bulbs exhibited an average increase in D2 receptor density of 32%. As determined by Scatchard analysis, the mean values for Kd and Bmax were 0.134 nM and 293 fmol/mg protein in normal bulbs, and 0.136 nM and 403 fmol/mg protein in deprived bulbs. The results suggest that, as in the neostriatum, dopamine depletion in the olfactory bulb leads to an upregulation of D2 receptor sites. This change may represent an attempt by the system to adapt neurochemically to reduced dopaminergic activity and thereby maintain bulb function.