Dopamine and adrenergic receptor complexes form under a circadian-regulated cycle and directly modulate melatonin synthesis and release from the pineal gland.

Polymorphic variants of the dopamine D4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here we show that whereas the most frequent 4-repeat (D4.4) and the 2-repeat (D4.2) variants form functional heteromers with the short isoform of the dopamine D2 receptor (D2S), the 7-repeat risk allele (D4.7) does not. D2 receptor activation in the D2S-D4 receptor heteromer potentiates D4 receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D4.7 or in the striatum of knock-in mutant mice carrying the 7 repeats of the human D4.7 in the third intracellular loop of the D4 receptor. In the striatum D4 receptors are localized in cortico-striatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D2S receptors. This interaction shows the same qualitative characteristics than the D2S-D4 receptor heteromer-mediated MAPK signaling and D2S receptor activation potentiates D4 receptor-mediated inibition of striatal glutamate release. It is therefore postulated that dysfunctional D2S-D4.7 heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD.

The indoloquinolizidine-peptide 28 [(3S,12bR)-N-((S)-1-((S)-1-((S)- 2,3,4,6,7,12, 12b-octahydroindolo[2,3-a]The negative allosteric modulation was also found when agonist binding to D 1 receptors was assayed. Indoloquinolizidinepeptide 28 was a weak ago-allosteric modulator but markedly led to a decreased potency without decreasing the maximum partial/ full agonist-mediated effect on cAMP levels. Compounds able to decrease the potency while preserving the efficacy of D 1 receptor agonists are promising for exploration in psychotic pathologies.