Dopamine receptors mediate differential morphological effects on cerebral cortical neurons in vitro

A morphogenic role of neurotransmitters during cellular differentiation in vitro has been demonstrated in recent years. Using in situ hybridization, we confirm the presence of the D1 receptor at E16 and show additionally that the transcript is relatively widespread and present in both proliferative and differentiating areas of the cerebral wall. Because DA receptor expression precedes the arrival of presynaptic terminals during forebrain development, we examined the role of DA in cerebral cortical neuron differentiation in vitro, using immunohistochemical markers of dendrites, microtubule-associated-membrane protein 2 (MAP2) and axons, neurofilament protein (NF-H). Neurite length, cell size, and cell viability in response to D1 and D2 receptor agonists SKF38393 and quinpirole, respectively, and to DA were analyzed in neurons obtained from embryonic (E) day 16 rats. We have shown that 1) paradoxically, DA at different concentrations can either stimulate or inhibit neurite outgrowth; 2) there is a bimodal pattern of DA-induced axonal outgrowth, i.e., at low and high doses; 3) D2 receptor activation induces neurite outgrowth while D1 receptor activation is inhibitory; 4) D2-mediated neurite elongation is preferentially axonal while D1 receptor activation reduces both axonal and dendritic outgrowth; 5) low doses of DA promote the expression of cytoskeletal components of axonal maturation; and 6) D1 receptor activation decreases neuronal size. We suggest that DA may influence cellular differentiation and circuitry formation early in development of the cerebral cortex through receptor-mediated effects on process outgrowth, which could lead to effects on circuit formation.