ALTERATION OF D-1 AND D-2 DOPAMINERGIC RECEPTOR KINETICS IN SPECIFIC RAT-BRAIN REGIONS FOLLOWING REPEATED ADMINISTRATION OF OPIATES

The present study was conducted to investigate the effects of repeated administration of opiates on the binding characteristics of D-1 and D-2 dopamine receptors in specific rat brain regions. Male Sprague-Dawley rats (150-175 g) were adapted for 1 week under controlled conditions (22 +/- 1 degrees C, 40% relative humidity, 12h light:12h dark illumination cycle). After the adaptation period, rats were randomly assigned into six groups (n = 15/group) for two sets of experiments; one for D-1 and the other for D-2 receptor binding evaluation. In each set, group 1 served as saline control, group 2 was treated with morphine(1 mg/kg/day for 7 days) and group 3 was treated with naloxone (2 mg/kg/day for 7 days). Following the third day of morphine injection, rats showed restlessness, hyperactivity, increased urination, diarrhea, lacrimation, irritability and squealing on touch, head and body shakes and salivation just prior to morphine dosage. These observed signs are typical for morphine withdrawal. One hour after the last injection, rats were sacrificed by decapitation, brains were removed and kept at -70 degrees C. The frozen brains were further dissected into cortex (CTX), hypothalamus (HYPO), hippocampus (HIPP) and midbrain (MID), pooled (5/pool), homogenized and used for radioreceptor assays. For DI binding study, H-3-SCH-23390 was used as ligand and for D-2 receptor binding H-3-YM-09151-2 was employed. Following repeated morphine or naloxone treatment, B-max values for H-3-SCH-23390 binding to membranes of HYPO and MID were increased and decreased, respectively, whereas K-d values were significantly decreased in both HYPO and MID of morphine and naloxone-treated animals. In rat brain CTX, both morphine and naloxone decreased K-d and B-max values of H-3-SCH-23390 binding, however the decrease in B-max values noted after morphine administration was not statistically significant. Decrease in both B-max and K-d values of dopamine D-1 receptors were observed after naloxone but not morphine treatment in HIPP. Morphine administration increased the density of D-2 receptors in HIPP and MID and decreased the affinity of H-3-YM-09151-2 binding in CTX, HIPP and MID. Naloxone treatment resulted in increased number of H-3-YM-09151-2 binding sites in CTX, HYPO and HIPP. While naloxone treatment increased K-d values of H-3-YM-09151-2 in HYPO and HIPP, it decreased these values in CTX and MID. It is concluded that repeated intermittent treatment with opiates induces alterations in D-1 and D-2 dopamine receptors binding properties and that these changes are regionally specific. Our findings may in part explain some pharmacological and behavioral effects of repeated administration of opiates and shed some light on the neurochemical alterations associated with opiate withdrawal since the changes in dopaminergic receptor binding observed with morphine treatment were accompanied by typical morphine withdrawal symptoms.