Role of synaptic integration of dopaminergic and cholinergic transmissions in basal ganglia function

Abstract

Our studies concern the mechanisms of synaptic transmission and integration in the basal ganglia network, using immunotoxin-mediated cell targeting. We generated transgenic mice that expressed the human interleukin-2 receptor (hIL-2R)/GFP fusion protein under the control of the mGluR2 promoter. The immunotoxin that was composed of the monoclonal hIL-2R antibody fused to bacterial toxin was injected into the striatum. Immunotoxin injection selectively eliminated cholinergic interneurons in the basal ganglia network. Unilateral ablation of cholinergic neurons caused an acute abnormal turning and showed a gradual recovery thereafter. This recovery was incomplete and displayed abnormal turning by excess stimulation and inhibition of dopamine. In the acute phase, the reduction of basal ganglia acetylcholine resulted in a predominant action of dopamine. D1 and D2 dopamine receptors were then down-regulated, thus relieving dopamine overactions and compensating acetylcholine-depleted synaptic perturbation. However, this compensation was still defective in responding to excess stimulation and inhibition of dopamine. Therefore, the acetylcholine-dopamine interaction is concertedly and adaptively regulated in basal ganglia function. We also investigated the role of acetylcholine in the nucleus accumbens by bilaterally ablating cholinergic neurons from the nucleus accumbens. Bilateral cholinergic cell elimination markedly enhanced reinforcement and addiction of cocaine and morphine. Acetylcholine in the nucleus accumbens is critical in controlling neural plasticity associated with abuse of drugs.