Role of endogenous substance P in stress-induced activation of mesocortical dopamine neurones

The dopamine (DA) innervation to the forebrain arises from subpopulations of midbrain DA neurones broadly classified as nigrostriatal, mesolimbic and mesocortical¹. Significant differences in the autoregulatory mechanisms and neuronal inputs of these DA pathways may account for their differences in physiological and pharmacological responsiveness². For example, foot-shock stress can activate rat mesocortical DA cells but does not alter nigrostriatal DA turnover^3-5, while also decreasing substance P (SP) concentrations in the midbrain interpeduncular nucleus and in the adjacent ventral tegmental area (VTA), but not in the substantia nigra (SN)⁶. This suggested that the activation of the SP input to the VTA⁶ may mediate activation of certain DA systems by footshock stress (Fig. 1); behavioural studies also had suggested an excitatory effect of SP on DA cells in the VTA⁷. SP antagonists now available are neurotoxic⁸ and of questionable efficacy⁹, we therefore used monoclonal antibody against SP. Antibody microinjected into the VTA prevented normal footshock-induced activation of mesocortical DA neurones, suggesting mediation by SP input to the VTA. The in vivo application of antibodies may prove valuable in studies of neuropeptides in the central nervous system (CNS).