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.
Highlights
Locus coeruleus (LC) nucleus, which is bilaterally located on the floor of the fourth ventricle, is the largest cluster of noradrenergic neurons in brain stem [1,2]
In all forms of slices, there were no significant differences among the spontaneous discharge rate (SDR) of LC neurons
The effect of naloxone was tested in all cells of this group, where no significant change was observed in resting membrane potential (RMP) as well as in SDR (Fig 2A–2C)
Summary
Locus coeruleus (LC) nucleus, which is bilaterally located on the floor of the fourth ventricle, is the largest cluster of noradrenergic neurons in brain stem [1,2]. This region expresses a high density of opioid receptors and because of its relatively homogenous structure, serves as a good model for studying opiate actions [3]. Different in vivo and in vitro investigations have shown that acute morphine administration decreases LC neuronal activity, whereas these neurons undergo significant tolerance to opiate effects during chronic opiate exposure [4]. Following opiate withdrawal, the spontaneous firing rate of LC neurons increases dramatically above the normal level [5,6]
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