AMPHETAMINE-INDUCED PREPRODYNORPHIN MESSENGER-RNA EXPRESSION AND KAPPA-OPIOID RECEPTOR-BINDING IN BASAL GANGLIA OF ADULT-RATS AFTER PRENATAL EXPOSURE TO DIAZEPAM

In order to obtain information on the functional state of basal gangli a following prenatal benzodiazepine exposure, preprodynorphin mRNA exp ression and kappa-opoid receptors were studied in offspring of timed-p regnant Long Evens rats treated with diazepam (1.25 mg/k/day) on gesta tional days 14 to 20. Preprodynorphin mRNA was localized by in situ hy bridization using a P-33-labeled oligonucleotide. Relative optical den sity (ROD) was quantified by image analysis in four quadrants of cauda te putamen, in nucleus accumbens and olfactory tubercle of adult male rats. Six hours after functional challenge by injection of D-amphetami ne (8 mg/kg s.c.), prenatally vehicle-exposed rats exhibited increased preprodynorphin mRNA (ROD) levels in caudate putamen (dorsolateral 18 1%, dorsomedial 150%, ventrolateral 153%, ventromedial 140% of control ), nucleus accumbens (142%) and olfactory tubercle (213%), Prenatal di azepam exposure attenuated the effect of amphetamine in all regions; s tatistically significant differences between ROD levels of prenatally vehicle/adult amphetamine-treated and prenatally diazepam/adult amphet amine-treated groups were seen in ventrolateral caudate putamen, nucle us accumbens and olfactory tubercle. Baseline levels and topographical distribution of preprodynorphin mRNA remained unchanged, kappa-Opioid receptor binding was analyzed in membrane fractions from nucleus accu mbens + olfactory tubercle. caudate putamen, and midbrain of male and female offspring using [H-3]U69593. B-max was reduced in nucleus accum bens + olfactory tubercle, but not in caudate putamen or midbrain of a dult, prenatally diazepam-exposed male offspring. This effect was not vet seen at. earlier postnatal stages (14 and 28 days), and was also a bsent in females. These data indicate that prenatal exposure to diazep am results in a delayed change in the functional state of dynorphin-co ntaining neurons in several parts of the basal ganglia of adult male o ffspring. The decreased responsiveness to enhanced dopaminergic transm ission may impair the function of basal ganglia circuitry.