Description:

The Department of Neuroscience welcomes Dr. Julia Lemos, Assistant Professor, with University of Minnesota to the 2021/2022 seminar series.

Abstract

Dopamine (DA) transmission in the nucleus accumbens (NAc) is a driving force for many important behaviors involving motivation and reward-seeking. Furthermore, DA dysregulation in the NAc is associated with a plethora of disorders that include attention deficit hyperactivity disorder, Parkinson’s disease, and mood disorders. It has been demonstrated that acetylcholine can both trigger and modulate dopamine transmission under certain conditions. However, despite knowledge that the M5 receptor is the only muscarinic receptor subtype with detectable mRNA in the dopaminergic neurons of the midbrain, there has been a paucity of information on its function in relation to DA modulation in the nucleus accumbens and DA-dependent behavior. We conducted fast scan cyclic voltammetry experiments in an ex vivo coronal slice preparation to assess M5-dependent modulation of dopamine transmission in the NAc core. Here we show that under pharmacologic conditions that isolate electrical stimulation of dopamine fibers (in DhβE, 1 µM), the non-selective agonist, oxotemorine-M (Oxo-M, 10 µM) can potentiate the peak amplitude of DA transients. Using a genetic deletion strategy, we confirmed that this effect was dependent on M5 receptors. Compared to M5+/+ littermates, Oxo-M did not potentiate DA transmission and instead there was a small but significant depression in peak dopamine transients. We went on to conduct a full concentration response curve in both male and female mice. We also showed that M5-depednent potentiation of DA neurotransmission shows stress sensitivity. Finally, we found that M5 -/- mice had a sex-dependent selective deficit in exploratory behaviors under certain conditions. This indicates that the “anxiety-like” deficit may be selective to some contexts, but not others. These findings suggest that the M5 receptor is a promising therapeutic target for DA-dependent mood disorders. Our future aims are to further explore the effects of stress on ACh-DA interactions, as well as research the use of positive allosteric modulators (PAMs) and their ability to rescue the effects of stress and potentiate DA transmission in the midbrain.