POSTNATAL ONTOGENY OF GABA(B) BINDING IN RAT-BRAIN

The postnatal development of GABA(B) binding sites in rat brain was studied by quantitative receptor autoradiography using [H-3]GABA under selective conditions. Binding levels peak at regionally specific times during the first three weeks of life and then decline to adult levels. GABA(B) 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 GABA(B) 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 GABA(B) 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 GABA(B) binding extensively in both postnatal day 7 and adult brain. The non-competitive antagonist zinc also inhibited GABA(B) 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 GABA(B) binding reflects changes in binding site density rather than modulation of binding site affinity. While immature GABA(B) 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 GABA(B) binding sites in immature brain may have a distinct pharmacological profile. Our data suggest significant regional and pharmacological changes in GABA(B) binding during development. The implications of these findings are discussed with regards to a possible role of GABA(B) receptors in the development of the central nervous system.