CHOLINERGIC CONTRIBUTIONS TO EMOTION REGULATION

Abstract

Theories based on clinical and neuroanatomical studies implicate the muscarinic cholinergic system in normal and pathological emotion regulation. Emotional and sensory experiences can be induced with intravenous administration of the local anesthetic procaine hydrochloride, which selectively activates limbic regions in humans and animals. Procaine has a high affinity for muscarinic cholinergic receptors in vitro. This research tests three hypotheses: (1) procaine binds to muscarinic receptors in vivo; (2) procaine alters functional connectivity among cholinergic brain regions and their targets; and (3) procaine-induced emotions are related to core cholinergic regions. In Experiment I, anesthetized rhesus monkeys underwent positron emission tomography (PET) studies before and after administration of six doses of procaine on separate days using a radioligand with preferential binding to muscarinic M2 receptors ([18F]FP-TZTP). Procaine blocked [18F]FP-TZTP in a dose-response fashion uniformly across the brain, while significantly increasing tracer flow in limbic compared with non-limbic regions.

In Experiment II, behavioral and physiological measures were assessed at baseline and following procaine in 32 healthy controls and 15 patients with bipolar disorder undergoing [15O] PET yielding regional cerebral blood flow (rCBF). Procaine selectively increased rCBF in anterior paralimbic regions in healthy controls, but to a lesser degree in patients. Regions connected via cholinergic pathways showed significantly different functional connectivity in both groups with procaine, however, prefrontal regions showed differential functional connectivity with cholinergic brain regions in patients compared with controls. Changes in activity of cholinergic regions explained the variance in anxiety ratings in an opposite manner in each group, and in euphoria ratings only in patients. In conclusion, procaine binds directly with muscarinic receptors in vivo while selectively increasing limbic activity in anesthetized monkeys. Two key findings herein procaine-induced alterations in functional connectivity of core cholinergic regions in humans, and the association of core cholinergic regional activity with emotional experience support theories implicating cholinergic contributions to emotion regulation. Decreased anterior paralimbic activity and altered functional connectivity of cholinergic regions in patients with bipolar illness compared with controls revealed by procaine offers additional insight into the regional neurobiology of the disease, and may ultimately be targeted in therapeutic approaches to bipolar disorder.