Temporal development of behavioral impairments in rats following locus coeruleus lesion induced by 6-hydroxydopamine: Involvement of β3-adrenergic receptors. (June 2019)

• Record Type: Journal Article
• Authors: Sampaio, Tuane Bazanella; Soares de Souza, Bruna; Roversi, Katiane; Schuh, Tayná; Poli, Anicleto; Takahashi, Reinaldo Naoto; Prediger, Rui Daniel
• Is Part Of: Neuropharmacology. Volume 151(2019)
• Page Start: 98
• Page End: 111
• Publication Date: 2019-06
• Subjects: 6-OHDA -- Locus coeruleus -- Apoptosis -- Olfaction -- Depression -- Memory; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.04.006
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Noradrenergic degeneration in the locus coeruleus (LC) seems a convergent neuropathological marker of different neurodegenerative diseases. Herein, we investigated the temporal development of apoptotic signaling activation in the LC, noradrenergic dysfunction and behavioral impairments in rats following the noradrenergic lesion of the LC. For this purpose, the dopamine reuptake inhibitor nomifensine was administered 1 h before the stereotaxic bilateral injections of 6-hydroxydopamine (6-OHDA; 5, 10 or 20 μg/hem) into the LC. The behavioral and neurochemical analyses were performed at 7, 21 and 42 days after 6-OHDA injections. All doses of 6-OHDA induced neuronal death in LC, but only the highest dose (20 μg/hem) disrupted the motor function. 6-OHDA (5 μg/hem) injection induced short-term memory deficits in all periods, olfactory discrimination and long-term memory impairments at 7 days, and depressive-like behaviors at 21 and 42 days after injection. Moreover, 6-OHDA infusion increased Bax/Bcl2 ratio and caspase 3 levels, and decreased the dopamine β-hydroxylase immunocontent in the LC. Noradrenergic neurotransmission dysfunction was observed in the LC, olfactory bulb, prefrontal cortex, hippocampus and striatum. The intranasal (i.n.) noradrenaline (NA) infusion restored the impairments in the olfactory discrimination, short-term memory and depressive-like behavior of 6-OHDA-lesioned rats. In addition, these effects were blocked by the prior i.n. infusion of the β3 -adrenergic receptor antagonist SR59230A. These findings indicate that the 6-OHDA injection into the LC induced the apoptosis signaling activation, noradrenergic neurotransmission dysfunction and behavioral impairments that were restored via β3 -adrenergic receptors activation mediated by the i.n. NA administration. Highlights: 6-OHDA injection into locus coeruleus (LC) induced time-dependent olfactory, cognitive and emotional impairments in rats. 6-OHDA infusion increased Bax/Bcl2 ratio and caspase 3 levels, and decreased the dopamine β-hydroxylase in the LC. 6-OHDA infusion decreased noradrenergic transmission in the LC, olfactory bulb, prefrontal cortex, hippocampus and striatum. Intranasal noradrenaline administration improved 6-OHDA-induced behavioral changes via activation of β3 -adrenergic receptors.