The striatum is a major component of the basal ganglia, through which cortical input is integrated and focused to particular brain regions involved in motor planning and motor memory. Striatal activity is strongly modulated by nigrostriatal dopamine (DA) input. Both major striatal efferent pathways projecting to the globus pallidus (GP) and substantia nigra pars reticulata (SNr) use gamma-aminobutyric acid (GABA) as their neurotransmitter. Adenosine is a ubiquitous neuromodulator, but the observations that high affinity A(2a) adenosine receptors in striatum are associated exclusively with striatopallidal neurons and that D2 DA and A(2a) receptors have opposing actions in the striatum suggest that adenosine may play a unique role in the basal ganglia. The overall hypothesis being tested is that an important mechanism by which DA and adenosine regulate synaptic transmission in basal ganglia is modulation of stimulation-evoked release of DA and GABA. The primary test system to be used in these experiments will be electrically-stimulated release of endogenous DA or GABA from rat brain slices. The first set of experiments will address whether in the striatum """"""""postsynaptic"""""""" D2 receptors that modulate the GABA release can be differentiated, particularly with respect to coupling mechanisms and/or drug-induced regulation, from presynaptic D2 autoreceptors that modulate DA release. Schild analysis, sensitivity to tetrodotoxin, coupling to G proteins and K+ channels and regulation induced by subchronic administration of neuroleptics will be determined. The second set of experiments will determine the pharmacological profile of adenosine receptor subtypes that modulate GABA release in striatum. The potential antagonism between A(2a) and D2 receptor agonists will also be explored. The third set of experiments will investigate whether there is a regional specificity in the modulation of GABA release by D1 and D2 DA receptors, as well as A1 and A2a adenosine receptors, in micropunches of GP, SNr and striatum. Initially, the importance of autoinhibition of GABA release via GABA-B receptors will be evaluated. Next, the pharmacological profiles, putative enabling effects of D1 receptors on D2 receptor- mediated activity and interactions between A2a and D2 receptors will be explored in these same brain regions. Striatal ibotenic acid lesions will be used to determine whether or not a particular modulatory action in GP or SNr is selectively attenuated following degeneration of the striatopallidal and striatonigral pathways. Additionally, whole-cell patch-clamp and conventional intracellular recording in slices containing both striatum and GP will be used to further define the locus, of the modulatory drug, actions in the striatopallidal pathway. These experiments will determine whether different DA and adenosine receptor subtypes are involved in the modulation of GABA release GP and SNr and whether the same relationship exists in striatum. Understanding the basic biology of the two major striatal efferent pathways may suggest new pharmacological strategies for independently manipulating their function, which, could prove useful in the treatment of movement disorders such as Parkinson's disease and Huntington's disease.
