Relevance of norepinephrine-dopamine interactions in the treatment of major depressive disorder

Abstract

Central dopaminergic and noradrenergic systems play essential roles in controlling several forebrain functions. Consequently, perturbations of these neurotransmissions may contribute to the pathophysiology of neuropsychiatric disorders. For many years, there was a focus on the serotonin (5-HT) system because of the efficacy of selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants in the treatment of major depressive disorder (MDD). Given the interconnectivity within the monoaminergic network, any action on one system may reverberate in the other systems. Analysis of this network and its dysfunctions suggests that drugs with selective or multiple modes of action on dopamine (DA) and norepinephrine (NE) may have robust therapeutic effects. This review focuses on NE-DA interactions as demonstrated in electrophysiological and neurochemical studies, as well as on the mechanisms of action of agents with either selective or dual actions on DA and NE. Understanding the mode of action of drugs targeting these catecholaminergic neurotransmitters can improve their utilization in monotherapy and in combination with other compounds particularly the SSRIs. The elucidation of such relationships can help design new treatment strategies for MDD, especially treatment-resistant depression.

Figure 1

Schematic representation of the reciprocal interaction between serotonin (5‐HT) neurons in the dorsal raphe nucleus, norepinephrine (NE) neurons in the locus coeruleus and dopamine (DA) neurons in the ventral tegmental area. It also shows the nature of modulation of different neurotransmitters on diverse classes of auto‐ and heteroreceptors. (+) signs indicate an agonism or stimulatory effect and (–) signs indicate an antagonism or an inhibitory effect.

Figure 2

Illustration of the conversion of DA to NE by β‐hydroxylase. Note that the difference between these two molecules resides only in one hydroxy group, thus imparting these two transmitters with only small differential three‐dimentional configurations.

Figure 3

Effect of single‐ and dual‐acting catecholaminergic reuptake inhibitors on escitalopram‐induced decrease in DRN 5‐HT neuronal activity. (A, B): Examples of integrated firing histograms showing the effects of cumulative intravenous doses of escitalopram on the spontaneous activity of DRN 5‐HT neurons in presence of vehicle (A), or of the DA/NE reuptake inhibitor nomifensine (5 mg/kg; iv; B). The arrows indicate the compounds administered and the time at which the injection of the specified doses was completed. The escitalopram‐induced inhibition of firing rate was reversed with the 5‐HT_1A receptor antagonist WAY100635. (C) Symbols represent the mean (± SEM) of percent of baseline firing rate of DRN 5‐HT neurons observed at each dose of escitalopram after the administration of vehicle; GBR 12909, reboxetine and nomifensine. These means were calculated on the 60 second‐period preceding each drug administration. ***P < 0.001. Statistical significance was taken as P < 0.05.

Figure 4

Diagrams of DA neurons representing their response and adaptations to the activation of D₂ receptor by the D_2/3 receptor agonist pramipexole or the inhibition of the NE and DA transporters with nomifensine. The spikes on the axon represent the firing activity of DA neurons. The dots around the DA neurons represent DA molecules. These neurons have D_2/3 autoreceptors that inhibit firing and release when activated by an excess amount of DA. The effects of DA on postsynaptic neurons are mediated by several subtypes of DA receptors.

Figure 5

Assessment of the sensitivity of the VTA DA D_2/3 autoreceptor: Integrated firing rate histogram illustrating the effect of apomorphine administration on VTA DA firing activity in controls and rats treated with pramipexole for 14 days. The apomorphine‐induced inhibition of firing rate was reversed with the D₂ receptor antagonist haloperidol. Note that the inhibitory effect of apomorphine in control rats is dampened in rats treated with pramipexole, indicating a desensitization of D_2/3 receptors.

Figure 6

Diagrams of NE neurons representing their response and adaptations to the inhibition of the NE and DA transporters with nomifensine or release of DA and NE by bupropion. The spikes on the axons represent the firing activity of NE neurons. The dots around NE neuron represent NE molecules. These neurons have α₂ autoreceptors that inhibit firing and release when activated by an excess amount of NE. The effects of NE on postsynaptic neurons are mediated by several subtypes of α‐ and β ‐adrenergic receptors. NRI, norepinephrine reuptake inhibitor.

Figure 7

(A) The upper panel represents the integrated histogram of the firing activity of a LC NE neuron (lower panel) that was inhibited by the selective α₂‐adrenoceptor agonist clonidine and reversed by the selective α₂‐adrenoceptor receptor antagonist idazoxan. (B) Integrated histogram of the firing activity of a LC NE neuron (lower panel) illustrating the decreased responsiveness to three consecutive intravenous injections of clonidine in a rat treated with bupropion for 14 days, thus indicating a desensitization of α₂‐autoreceptors.