Pharmacology of central octopaminergic and muscarinic pathways in Drosophila melanogaster larvae: Assessing the target potential of GPCRs

Abstract

G-Protein-Coupled Receptors (GPCRs) are an underdeveloped target in the search for agrochemicals with octopamine receptors, a GPCR, being the target of a single insecticide/acaricide class (formamidines). The evolution of insecticide resistance has resulted in the need to identify new or underutilized targets for the development of agrochemicals, with the goal of controlling arthropod pests that affect agriculture or human and animal health. The insect cholinergic system has been a fruitful target for the development of insecticides/acaricides viz. acetylcholinesterase inhibitors and agonists/modulators of the nicotinic acetylcholine receptor. However, the muscarinic acetylcholine receptors (mAChRs), which are GPCRs, have not been successfully developed as a target for agrochemicals. Others have recently identified three subtypes of insect mAChRs in Drosophila melanogaster, and extracellular recordings from transected D. melanogaster larval central nervous system (CNS) were performed to investigate the electrogenesis of the octopaminergic and muscarinic systems. Octopamine (10 μM) resulted in a sustained neuroexcitation during a 30 min exposure, and neuroexcitation after 21 min was blocked by octopamine receptor antagonist, phentolamine (100 μM). Exposure of this preparation to the non-selective mAChR agonist, pilocarpine (10 μM), resulted in a biphasic response, characterized by neuroexcitation followed by a decrease in the CNS firing rate below initial control levels. This biphasic effect was antagonized by the classical mAChR antagonist atropine (10 μM). It was also found that atropine (10 μM) blocked octopamine's sustained neuroexcitation, indicating the possibility of cross-talk between these two GPCR pathways.