# Direct Facilitatory Role of Paragigantocellularis Neurons in Opiate Withdrawal-Induced Hyperactivity of Rat Locus Coeruleus Neurons: An In Vitro Study

## TL;DR

This study shows that neurons in the paragigantocellularis nucleus directly increase activity in locus coeruleus neurons during opiate withdrawal.

## Contribution

A new brain slice preparation enables direct evidence of PGi's facilitatory role in LC hyperactivity during opiate withdrawal.

## Key findings

- LC neurons with intact PGi inputs show significantly higher spontaneous discharge rates.
- PGi input increases the frequency of excitatory post-synaptic currents in LC neurons.
- Resting membrane potential of LC neurons is more depolarized with PGi input.

## Abstract

Studies have shown that following opiate withdrawal, the spontaneous discharge rate of locus coeruleus (LC) neurons remarkably increases. Combination of intrinsic mechanisms with extrinsic excitatory modulations mediates the withdrawal-induced hyperactivity of LC neurons. The nucleus paragigantocellularis (PGi) provides the main excitatory inputs to LC and plays a pivotal role in opiate withdrawal. In the present study the direct facilitatory role of PGi on opiate withdrawal-induced hyperactivity of LC neurons was investigated using a newly developed brain slice, containing both LC and PGi. HRP retrograde neuronal tracing was used to verify the existence of both LC and PGi neurons in the developed slice. The spontaneous discharge rate (SDR), resting membrane potential (RMP) and spontaneous excitatory post-synaptic currents (sEPSCs) were recorded in LC neurons using whole cell patch clamp recording. Results showed that the net SDR and the net RMP of LC neurons in slices containing both LC and PGi neurons are significantly higher than slices lacking intact (uncut) PGi inputs. Also, the frequency of sEPSCs in those LC neurons receiving PGi inputs significantly increased compared to the slices containing no intact PGi inputs. Altogether, our results propose that increase in PGi-mediated excitatory transmission might facilitate the opiate withdrawal-induced hyperactivity of LC neurons.