Resumen de Modulation of physiological responses of dopamine d2 receptors by class c gpcr in rat brain striatal slices
Abstract Dopamine receptors play a key role in motor activity and goal-directed behaviors and are relevant for the treatment of diverse disorders, including schizophrenia and Parkinson’s disease. G protein-coupled receptors are known to form homo- and heterodimers at the plasma membrane, but the function of such receptor oligomers is relatively unknown. Here we hypothesized that heteromerization between D2 receptors and other receptors would alter responses to D2 agonists, which we measured with a sensitive radioisotopic methodology assessing D2 autoreceptor-mediated inhibition of rat brain dopamine synthesis. The inhibitory effect of D2 receptor full agonist quinpirole could not be modified with mGlu5 receptor negative allosteric modulators MTEP or fenobam or with the GABAB antagonist CGP55845. In contrast, fenobam and MTEP, but not the GABAB antagonist CGP55845, blocked the effect elicited by D2 receptor partial agonists, either aripiprazole or (-) PPP. On other hand mGlu5 positive allosteric modulator CDPPB could not impair the inhibition of dopamine synthesis caused by the D2 partial agonist aripiprazole, although the AgoPAM VU0360172 abolished this inhibition. The simplest explanation for this crosstalk between D2 and mGlu5 receptors in the regulation of dopamine synthesis is a membrane interaction or heteromerization that has already been described in other cell types. Presynaptic co-localization of mGlu5 receptor immunoreactivity with tyrosine hydroxylase was observed in dopaminergic terminals in striatum and nucleus accumbens and also in dopaminergic cell bodies in ventral tegmental area (VTA) and substantia nigra. Moreover, we also detected the same co-localization of mGlu5 receptor and tyrosine hydroxylase in human caudate nucleus. Of note the membrane interaction between D2 and mGlu5 receptors appears to affect only responses to D2 partial agonists, but not full agonists. These results could be relevant for the treatment of neuropsychiatric disorders, where D2 receptors are important targets of pharmacotherapy.
