Immunohistochemical studies of the localization of neurons containing the enzyme that synthesizes dopamine, GABA, or gamma-hydroxybutyrate in the ratsubstantia nigra and striatum

gamma-Hydroxybutyrate (GHB) is an endogenous metabolite of gamma-aminobutyr ic acid (GABA), which is synthesized in the neuronal compartment of the cen tral nervous system. This substance possesses several properties that suppo rt its role as a neurotransmitter/ neuromodulator in brain. In particular, it is synthesized by a specific pathway that transforms GABA into succinic semialdehyde via GABA-T activity; then succinic semialdehyde is converted i nto GHB by a specific succinic semialdehyde reductase (SSR). The last enzym e is considered as a marker for neurons that synthesize GHB. This compound binds in brain to receptors whose distribution, ontogenesis, kinetics, and pharmacology are specific. Endogenous GHB, but also GHB exogenously adminis tered to rats, participate in the regulation of dopaminergic activity of th e nigrostriatal pathway. To investigate the distribution of GHB neurons in this pathway and the anatomic relationships between dopaminergic and GHB ne urons, immunocytochemical identification of dopamine, GABA, and GHB neurons was carried out in the substantia nigra and striatum of the rat. The follo wing markers for these neurons were used: anti-tyrosine hydroxylase (TH) an tibodies for dopamine neurons, antiglutamate decarboxylase (GAD) antibodies for GABA neurons, and anti-succinic semialdehyde reductase (SSR) antibodie s for GHB neurons. GABA neurons were studied because GAD and SSR co-exist f requently in the same neuron, and GABA alone also exerts its own regulatory effects on dopaminergic neurons. This study reveals the co-existence of GA D/SSR and GAD/SSR/TH in numerous neurons of the substantia nigra. However, some neurons appear to be only GAD or SSR positive. Tn the striatum, TH-pos itive terminals surround many GHB neurons. GAD innervation is abundant in c lose contact with unlabeled neurons in the caudate-putamen, whereas distinc t SSR-positive punctuates are also present. The existence of SSR-reactive s ynapses and neurons was confirmed in the striatum at the electron microscop ic level. On the basis of these results, a clear anatomo-functional relatio nship between GHB and dopamine networks cannot be defined; however, we prop ose the modulation by GHB of striatal intrinsic neurons that could then int erfere with the presynaptic control of dopaminergic activity. J. Comp. Neur ol. 426:549-560, 2000. (C) 2000 Wiley-Liss, Inc.