Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

Abstract

Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabeling for NET and colocalization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 days, 15 mg/kg/day), NET-immunoreactive (-ir) axons were significantly less likely to colocalize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI and vehicle treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labeling. Our findings encourage consideration of possible postranslational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance.

The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

“…Noradrenaline plays an important role in modulating the behavioral response to stress, and it is of note that various stress treatments increase noradrenaline release 12 and sensitization 58 , 59 within the mPFC. Importantly, TH is found within noradrenergic terminals in the PFC, 60 , 61 and selective noradrenaline reuptake inhibitors (but not selective serotonin reuptake inhibitors) reduce Fos-like immunoreactivity in the mPFC following testing on the FST. 62 As hyporeactivity of the mPFC in response to stress may provide a foundation for stress-related behavioral traits, 63 it would be of interest to consider measurements of catecholamine activity within the mPFC of hBDNF Val66Met mice, both at baseline and following stress, in future studies.…”

Ultrastructural evidence for synaptic contacts between cortical noradrenergic afferents and endocannabinoid-synthesizing post-synaptic neurons

“…In order to circumvent this caveat, we use a very small amount of Triton X-100 at 0.01% following the procedures reported by Farb and colleagues (Farb et al, 2010). Additionally, we also used an antibody directed against NET as an additional marker of noradrenergic axon terminals that is more readily detectable using electron microscopic analysis (Kravetz et al, 2013; Erickson et al, 2011). …”

Light and electron microscopic analysis of enkephalin-like immunoreactivity in the basolateral amygdala, including evidence for convergence of enkephalin-containing axon terminals and norepinephrine transporter-containing axon terminals onto common targets

“…The specificity of this antibody has been demonstrated by absence of staining in NET knock out animals and following preadsorption with the antigenic peptide (Matthies et al, 2009). It has been used to localize noradrenergic terminals in both light and electron microscopic studies (Matthies et al, 2009; Erickson et al, 2011). …”