The Impact of Removal of Ovarian Hormones on Cholinergic Muscarinic Receptors: Examining Prepulse Inhibition and Receptor Binding

Abstract

Ovarian hormones, such as estrogens and progesterone, are known to exert beneficial effects on cognition and some psychiatric disorders. The basis of these effects is not fully understood, but may involve altered cholinergic neurotransmission. This study aimed to investigate how a lack of ovarian hormones would impact muscarinic receptor-induced deficits in prepulse inhibition (PPI) and muscarinic receptor density in several brain regions. Adult female rats were either ovariectomized, to remove the source of ovarian hormones, or left intact (sham-operated). PPI is a measure of sensorimotor gating that is typically impaired in schizophrenia patients, and similar deficits can be induced in rats by administering scopolamine, a muscarinic receptor antagonist. Our results revealed no significant effects of ovariectomy on PPI after saline or scopolamine treatment. Autoradiography was performed to measure cholinergic muscarinic receptor binding density using [ 3 H]-pirenzepine, [ 3 H]-AF-DX, and [ 3 H]-4-DAMP, to label M 1 , M 2 /M 4 , and M 3 receptors, respectively. We examined the amygdala, caudate putamen, dorsal hippocampus, motor cortex, retrosplenial cortex, and ventromedial hypothalamus. There were no significant group differences in any region for any muscarinic receptor type. These results suggest that removing peripheral ovarian hormones does not influence the cholinergic muscarinic receptor system in the context of PPI or receptor binding density.Brain Sci. 2020, 10, 106 2 of 12 onset of schizophrenia in men [5]; the latter phenomenon is consistent across cultures and independent of the diagnostic classification system used [6][7][8]. There is also evidence to suggest that the impact of ovarian hormones on the symptoms of schizophrenia varies across the reproductive lifespan of women, which is underscored by changing levels of hormones, including the main ovarian hormones, estrogen and progesterone [8][9][10]. Overall, these factors lead to a less severe course of illness, milder symptoms, and superior treatment outcomes in women.Cholinergic signaling plays a crucial role in multiple cognitive processes, including learning, memory, and sensory perception [11]. Converging lines of evidence have implicated muscarinic cholinergic signaling in the pathophysiology of schizophrenia. In patients with schizophrenia, in vivo muscarinic receptor availability was reduced [12,13], and postmortem radioligand binding studies using [ 3 H]-pirenzepine, which label muscarinic M 1 and M 4 receptors, have indicated that the densities of these receptors were decreased in the prefrontal cortex, anterior cingulate cortex, hippocampus, and caudate putamen of schizophrenia patients [14][15][16][17][18]. Notably, decreased levels of both M 1 mRNA levels [17,19,20] and M 1 receptor protein, but not M 2 , M 3 , or M 4 receptor protein [17,21], were observed in the dorsolateral prefrontal cortex and superior prefrontal gyrus from people with schizophrenia. These data suggest that low levels of cortical M 1 receptors are a significant c...

The effects of galangin in prepulse inhibition test and experimental schizophrenia models

“…It was reported that muscarinic receptor antagonists disrupted PPI (Ch'ng et al, 2020). Jones et al reported that the muscarinic acetylcholine M 1 /M 4 receptor agonist xanomeline improved apomorphine-induced PPI disruption in rats and suggested an interaction between cholinergic and dopaminergic systems in the regulation of PPI.…”

Modulation of Muscarinic Signalling in the Central Nervous System by Steroid Hormones and Neurosteroids

“…Experimental studies in ovariectomized rats suggested that estrogen level affects mAChRs expression in the cerebral cortex [64], medial basal hypothalamus [67,68], and hippocampus [69][70][71]. Interestingly, a recent study did not find any changes in the density of mAChRs in the brain of ovariectomized rats [72].…”

Clinical Effectiveness of Muscarinic Receptor-Targeted Interventions in Neuropsychiatric Disorders: A Systematic Review

“…Studies employing receptor-specific antibodies, in situ hybridisation, and tomographic imaging revealed a region-specific negative correlation between muscarinic receptor availability and symptoms of schizophrenia [ 40 , 41 ]. Notably, scopolamine (non-selective muscarinic receptor antagonist) induces psychotic-like symptoms, referred to as "anti-muscarinic syndrome" [ 42 , 43 ]. Based on available evidence from tomographic imaging and post mortem studies, it was proposed that combined agonism of M 1 and M 4 receptors may be more efficacious given that a subgroup of people with schizophrenia also showed M 1 muscarinic receptor deficiency, known as muscarinic receptor deficit schizophrenia (MRDS) [ 44 ].…”