SYNAPTIC STRUCTURE AND CONNECTIVITY OF SEROTONIN TERMINALS IN THE VENTRAL TEGMENTAL AREA - POTENTIAL SITES FOR MODULATION OF MESOLIMBIC DOPAMINE NEURONS

Microinfusion of serotonin (5-hydroxytryptamine; 5-HT) into the ventra l tegmental area enhances the release of dopamine in the nucleus accum bens, a major target of midbrain dopamine neurons. We examined the syn aptic basis for 5-HT modulation of neurons in the ventral tegmental ar ea which either (i) project to the nucleus accumbens or (ii) contain t he catecholamine synthesizing enzyme tyrosine hydroxylase, a marker of dopamine neurons in this brain region. In the first study, immunopero xidase labeling of 5-HT in the ventral tegmental area was combined wit h retrograde transport of gold particles following unilateral injectio ns of the tracer into the nucleus accumbens of adult rats. The gold pa rticles had been previously coupled to wheat germ agglutinin conjugate d to inactive horseradish peroxidase. Gold particles were enlarged for visualization using a silver enhancement procedure. By brightfield mi croscopy, retrogradely labeled neurons contained black punctate granul es within their perikarya and proximal processes. The labeled cells we re scattered ipsilateral to the injection within the paranigral and pa rabrachial subdivisions of the Ventral tegmental area. Both regions al so contained 5-HT immunoreactive varicosities. By electron microscopy, irrespective of the ventral tegmental subdivision, 5-HT labeling was seen primarily in unmyelinated axons and axon terminals. The terminals contained small, clear and large dense core vesicles and ranged from 0.3 mu m to 1.4 mu m in cross-sectional diameter. 22% (n = 250) of the axon terminals containing 5-HT immunoreactivity formed synaptic conta cts with neurons containing the retrograde label. Of these 5-HT termin als, 16% formed asymmetric type contacts and 6% formed symmetric junct ions on the retrogradely labeled neurons. The remaining 5-HT terminals were either apposed to (but lacked recognized synapses on) perikarya and large dendrites containing the retrogradely transported protein-go ld tracer or contacted unlabeled neurons. In the second set of experim ents combining immunoperoxidase of 5-HT and immunogold silver for tyro sine hydroxylase, 32% (n = 250) of the 5-HT-Iabeled terminals formed s ynaptic junctions with perikarya or dendrites containing tyrosine hydr oxylase immunoreactivity. Of these 5-HT terminals, 23% formed asymmetr ic type junctions. The remainder were either symmetric or lacked recog nized membrane densities. The prominence of asymmetric junctions forme d by 5-HT-labeled terminals on neurons projecting to the nucleus accum bens and those containing tyrosine hydroxylase in the ventral tegmenta l area suggests a cellular basis for serotonergic excitation of mesoac cumbens dopamine neurons. Additionally, the multiplicity of junctions formed by 5-HT terminals on targets with or without retrograde labelin g or tyrosine hydroxylase immunoreactivity is consistent with known di verse physiological actions of 5-HT in the ventral tegmental area.