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The postnatal development of GABAB binding sites in rat brain was studied by quantitative receptor autoradiography using [3H]GABA under selective conditions. Binding levels peak at regionally specific times during the first three weeks of life and then decline to adult levels. GABAB binding peaked in the globus pallidus, vestibular and spinal trigeminal nuclei, and the CA3 region of the hippocampus at postnatal day 3; in the striatum, nucleus accumbens, inferior olive, septum, dentate gyrus and CA1 region of the hippocampus at postnatal day 7; in the neocortex and thalamus at postnatal day 14; and in the medial geniculate at postnatal day 21. Following these regionally specific peaks, binding decreased to postnatal day 28 levels. Further significant decreases in binding were observed in all regions examined between postnatal day 28 and adulthood. Comparisons of binding site pharmacology reveal equipotent displacement of GABAB binding by several competitive agonists and antagonists in postnatal day 7 and adult rat brain, indicating that immature and adult binding sites have similar pharmacological properties with regard to these compounds. The GABAB receptor antagonist CGP 54626A, however, inhibited binding more potently in the postnatal day 7 thalamus and neocortex than in these areas in the adult brain. The guanyl nucleotide analogue guanosine 5'-O-(3-thiotriphasphate) inhibited GABAB binding extensively in both postnatal day 7 and adult brain. The non-competitive antagonist zinc also inhibited GABAB binding at both ages and was more potent in postnatal day 7 brain than in adult brain. Saturation analyses reveal two binding sites with similar affinities in both immature and adult rat brain, indicating that postnatal modulation of GABAB binding reflects changes in binding site density rather than modulation of binding site affinity. While immature GABAB binding sites share most pharmacological characteristics with adult binding sites and appear to be coupled to G-proteins at an early age, their interactions with zinc and CGP 54626A suggest that GABAB binding sites in immature brain may have a distinct pharmacological profile. Our data suggest significant regional and pharmacological changes in GABAB binding during development. The implications of these findings are discussed with regards to a possible role of GABAB receptors in the development of the central nervous system.

Quantitative receptor autoradiography using [3H]GABA under selective conditions was used to characterize the pharmacology, distribution, cellular localization, and development of GABAB binding sites in rodent cerebellum. Pharmacologic analysis of [3H]GABA binding showed that drugs active at GABAB receptors displaced [3H]GABA with the following order of potency: 3-aminopropylphosphonous acid > CGP 35348 = 2-hydroxysaclofen > phaclofen. GTP-gamma-S and GDP-beta-S also diminished potently [3H]GABA binding in a dose-dependent manner. The pattern of [3H]GABA binding to GABAB binding sites was systematically mapped throughout the rat cerebellum. GABAB binding was greatest in the molecular layer and a pattern of parasagittal zonation was observed in the molecular layer of lobules VII-X in adult rats. The cellular localization of GABAB binding was investigated using lesion techniques. Neither methyl azoxymethanol lesions of cerebellar granule cells nor 3-acetylpyridine lesions of climbing fibers resulted in a decrease in [3H]GABA binding. Homozygote stumbler mutant mice, deficient in Purkinje cell dendrites, had a significant decrease in [3H]GABA binding in the molecular layer. These results suggest that the majority of cerebellar molecular layer GABAB binding sites detected by [3H]GABA autoradiography are located on Purkinje cell dendrites. Examination of [3H]GABA binding to GABAB binding sites during development revealed that binding in the molecular layer peaks between postnatal day 14 and postnatal day 28 and then decreases to adult levels. Transient expression of high levels of GABAB binding was observed in the deep cerebellar nuclei, peaking at postnatal day 3 and decreasing to adult levels by postnatal day 21. Our investigation of GABAB pharmacology yielded data in agreement with previously reported results. We have described a parasagittal pattern of GABAB binding in the cerebellar molecular layer and assigned the majority of cerebellar GABAB binding sites to Purkinje cell dendrites. Finally, development studies reveal transient peaks in GABAB binding in the cerebellar molecular layer and deep cerebellar nuclei.

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