Association of Changes in Norepinephrine and Serotonin Transporter Expression with the Long-Term Behavioral Effects of Antidepressant Drugs

Zhao, Zhihong; Zhang, Han‐Ting; Bootzin, Elianna; Millan, Mark J.; O'Donnell, James M.

doi:10.1038/npp.2008.183

Cited by 50 publications

(31 citation statements)

References 87 publications

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“…We find that despite less density of neurons, the transporter binding per neuron is still low, emphasizing the deficient serotonin input to PFC. Our results are consistent with a report of serotonin axonal loss in PFC (Austin et al , 2002) and less serotonin release per terminal and compensatory accelerated internalization of the transporter (Lau et al , 2008; Parsey et al , 2006b; Zhao et al , 2009). Fewer SERT-labeled axons or terminals could be the result of fewer axons or conceivably to reduced trafficking of the SERT from the soma to the terminal, and the present study cannot distinguish between these possibilities.…”

Section: Discussionsupporting

confidence: 93%

Neuron density and serotonin receptor binding in prefrontal cortex in suicide

Underwood¹,

Kassir²,

Bakalian³

et al. 2011

Int. J. Neuropsychopharm.

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Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and SERT, 5-HT1A and 5-HT2A binding in matched suicides and controls. Suicides and normal controls (N=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal (BA9) and ventral (BA47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density. Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for the serotonin transporter in BA47 but not in BA9; the 5-HT1A binding index was higher in BA9 but not in BA47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA47 but not BA9, while 5-HT1A binding was higher in BA9 but not BA47. SERT binding negatively correlated with 5-HT1A binding in BA47 in suicides. Neuron density decreased with age. 5-HT1A binding index was higher in females than males. We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor upregulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation.

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Section: Discussionsupporting

confidence: 93%

Neuron density and serotonin receptor binding in prefrontal cortex in suicide

Underwood¹,

Kassir²,

Bakalian³

et al. 2011

Int. J. Neuropsychopharm.

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“…This would suggest again that DSP4 is having a localized effect on noradrenergic terminals. Zhao et al, (2009) also demonstrated that changes in NET binding sites can occur with chronic antidepressant treatment, without an accompanying change in NET mRNA, supporting the possibility of a local effect on NET binding sites at terminal regions.…”

Section: Discussionmentioning

confidence: 68%

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat

et al. 2010

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Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days, 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha1-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in α2-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a LOSS of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD.

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“…Differences may be due to different ethnic populations or sample selection (our patients were chosen due to unsuccessful antidepressant treatment). It is notable that our patient population represents the most severe endpoint of depression, and long-lasting anti-depressive treatments may have had an impact on mRNA expression of both NET and 5-HTTLPR [32].…”

Section: Discussionmentioning

confidence: 99%