Dopaminergic projections from the VTA substantially contribute to the mesohabenular pathway in the rat

Recent evidence suggests that the lateral habenular complex (LHb) is a source of negative reward signals in midbrain dopaminergic neurons. LHb activity, in turn, is modulated by locally released dopamine, which is largely derived from the ventral tegmental area (VTA) via the mesohabenular pathway. Unfortunately, the presumed importance of this modulation has not been appreciated so far, as its intensity had been largely underestimated in previous reports. Consequently, the present study used contemporary techniques to reexamine the origin of dopaminergic fibers to the LHb. For this purpose, the retrograde tract-tracer gold-coupled wheatgerm agglutinin was injected into the LHb of fourteen rats. Four of these animals providing the most representative information were selected for detailed analysis. In total, 343 retrogradely labeled neurons were detected in the VTAs of these animals. By far most of them were found in the anterior VTA, accumulating in its ventral paramedian fields. About 47% (162) of retrogradely labeled cells displayed tyrosine hydroxylase immunoreactivity, suggesting that almost half of the mesohabenular neurons are dopaminergic. In addition, our data suggest that also incerto-hypothalamic and periventricular neurons contribute dopaminergic terminals to the LHb. The majority of LHb neurons, however, does not project to the origin of the mesohabenular pathway in the anterior VTA. Consequently, there might be no closed VTA-LHb-VTA loop. Instead, our data are in line with the idea that the anterior VTA via its projection to the medial part of the LHb may modulate the information flow from the limbic forebrain to monoaminergic midbrain nuclei.