Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex

Devoto, Paola; Flore, Giovanna; Pira, Luigi; Longu, Giorgio; Gessa, Gian Luigi

doi:10.1016/j.ejphar.2004.01.018

Cited by 81 publications

(51 citation statements)

References 26 publications

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“…Patients were randomly assigned to 4 weeks' treatment with mirtazapine or venlafaxine. Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) with a profile of a2-, 5-HT2A-, 5-HT2B-, 5-HT3-and histamine 1-(H1-) receptor antagonism (Haddjeri et al, 1996;De Boer et al, 1994;De Boer, 1996;Devoto et al, 2004). The primary effect of venlafaxine, which is a serotonin and noradrenalin reuptake inhibitor (SNRI), is to elevate extracellular serotonin (5-HT) and noradrenalin levels by inhibiting their reuptake to pre-synaptic sites.…”

Section: Participantsmentioning

confidence: 99%

Brain activation predicts treatment improvement in patients with major depressive disorder

Samson

Meisenzahl

Scheuerecker

et al. 2011

Journal of Psychiatric Research

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a b s t r a c tMajor depressive disorder (MDD) is associated with alterations in brain function that might be useful for therapy evaluation. The current study aimed to identify predictors for therapy improvement and to track functional brain changes during therapy. Twenty-one drug-free patients with MDD underwent functional MRI twice during performance of an emotional perception task: once before and once after 4 weeks of antidepressant treatment (mirtazapine or venlafaxine). Twelve healthy controls were investigated once with the same methods. A significant difference between groups was a relative greater activation of the right dorsolateral prefrontal cortex (dlPFC) in the patients vs. controls. Before treatment, patients responding better to pharmacological treatment showed greater activation in the dorsomedial PFC (dmPFC), posterior cingulate cortex (pCC) and superior frontal gyrus (SFG) when viewing of negative emotional pictures was compared with the resting condition. Activations in the caudate nucleus and insula contrasted for emotional compared to neutral stimuli were also associated with successful treatment. Responders had also significantly higher levels of activation, compared to non-responders, in a range of other brain regions. Brain activation related to treatment success might be related to altered self-referential processes and a differential response to external emotional stimuli, suggesting differences in the processing of emotionally salient stimuli between those who are likely to respond to pharmacological treatment and those who will not. The present investigation suggests the pCC, dmPFC, SFG, caudate nucleus and insula may have a key role as a biological marker for treatment response and predictor for therapeutic success.

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Section: Participantsmentioning

confidence: 99%

Brain activation predicts treatment improvement in patients with major depressive disorder

Samson

Meisenzahl

Scheuerecker

et al. 2011

Journal of Psychiatric Research

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“…This is consistent with previous data showing that DA has a greater affinity for the NET than the DA transporter (DAT) itself (Giros et al, 1994) and that DA reuptake by NE terminals occurs in brain regions in which DAT expression is minimal (e.g., the frontal cortex), intermediate, or maximal (e.g., nucleus accumbens shell and the bed nucleus, respectively) (Bymaster et al, 2002;Morón et al, 2002;Carboni and Silvagni, 2004). Recent experiments have proposed that DA may be coreleased with NE from noradrenergic terminals in several cortical areas (Devoto et al, 2004). Although it is not clear whether this feature might be related to a previous nonspecific uptake of DA by NE terminals, it is proposed here that DA is taken up by the NET in the hippocampus (Fig.…”

Section: Downloaded Frommentioning

confidence: 99%

Cross-Talk between Dopaminergic and Noradrenergic Systems in the Rat Ventral Tegmental Area, Locus Ceruleus, and Dorsal Hippocampus

Guiard

Mansari²,

Blier³

2008

Mol Pharmacol

132

114

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A decreased central dopaminergic and/or noradrenergic transmission is believed to be involved in the pathophysiology of depression. It is known that dopamine (DA) neurons in the ventral tegmental area (VTA) and norepinephrine (NE) neurons in the locus ceruleus (LC) are autoregulated by somatodendritic D 2 -like and ␣ 2 -adrenoceptors, respectively. Complementing these autoreceptor-mediated inhibitory feedbacks, anatomical and functional studies have established a role for noradrenergic inputs in regulating dopaminergic activity, and reciprocally. In the present study, a microiontophoretic approach was used to characterize the postsynaptic catecholamine heteroreceptors involved in such regulations. In the VTA, the application of DA and NE significantly reduced the firing activity of DA neurons. In addition to a role for D 2 -like receptors in the inhibitory effects of both catecholamines, it was demonstrated that the ␣ 2 -adrenoceptor antagonist idazoxan dampened the DA-and NE-induced attenuations of DA neuronal activity, indicating that both of these receptors are involved in the responsiveness of VTA DA neurons to catecholamines. In the LC, the effectiveness of iontophoretically applied NE and DA to suppress NE neuronal firing was blocked by idazoxan but not by the D 2 -like receptor antagonist raclopride, which suggested that only ␣ 2 -adrenoceptors were involved. In the dorsal hippocampus, a forebrain region having a sparse dopaminergic innervation but receiving a dense noradrenergic input, the suppressant effects of DA and NE on pyramidal neurons were attenuated by idazoxan but not by raclopride. The suppressant effect of DA was prolonged by administration of the selective NE reuptake inhibitor desipramine and, to lesser extent, of the selective DA reuptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)-piperazine (GBR12909), suggesting that both the NE and DA transporters were involved in DA uptake in the hippocampus. These findings might help in designing new antidepressant strategies aimed at enhancing DA and NE neurotransmission.The catecholamines neurotransmitters dopamine (DA) and norepinephrine (NE) are believed to be involved in psychiatric disorders, and a better knowledge of the reciprocal interactions between these two systems should improve our understanding of the pathophysiology and treatment of mood disorders. Anatomical evidence indicates that noradrenergic neurons of the locus ceruleus (LC) send projections to the ventral tegmental area (VTA) in the vicinity of DA neuron cell bodies (Simon et al., 1979). Several subtypes of ␣-adrenergic receptors have been identified in the VTA (Lee et al., 1998), raising the possibility that NE inputs play a role in modulating DA neuronal activity. Consistent with this assumption, it was recently demonstrated that a selective lesion of LC NE neurons increases the mean firing activity of DA neurons by 70% and their burst activity by almost 50%, thus revealing a net inhibitory effect of NE in the VTA (Guiard et al., 2008). In con...

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“…The lack of substitution with yohimbine is of particular note in view of its modest 5-HT 1A agonist properties (Winter and Rabin 1993;Millan et al 2000b). Blockade of inhibitory α 2 -autoreceptors/heteroceptors facilitates noradrenergic (and dopaminergic) transmission, contributing to antidepressant actions and favoring arousal and motor activation (Millan et al 2000a;Devoto et al 2004;Invernizzi and Garattini 2004). Accordingly, α 2 -AR blockade may explain the lack of decrease in response rates during "mirtazapine" training and testing sessions in countering its histamine H 1 receptor-mediated sedative actions (Szegedi and Schwertfeger 2005;Schmid et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The facilitatory influence of mirtazapine upon ascending dopaminergic and adrenergic pathways provides a functional substrate for its beneficial influence in depressed states and can be attributed to antagonism of 5-HT 2C receptors and α 2(A) -adrenoceptors (ARs) which exert a tonic, inhibitory influence upon dopaminergic and adrenergic projections (Millan et al 2000a;Di Matteo et al 2002;Devoto et al 2004;Invernizzi and Garattini 2004;Dekeyne et al 2008). Blockade of 5-HT 2C receptors improves anxious states and exerts a favorable influence on sexual function and sleep architecture which are perturbed in depressive states (Davis and Wilde 1996;Kent 2000;Anttila and Leinonen 2001;Millan 2006;Dekeyne et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Discriminative stimulus properties of the “atypical” antidepressant, mirtazapine, in rats: a pharmacological characterization

Dekeyne

Millan

2008

Psychopharmacology

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Rationale Though interoceptive properties of antidepressants have been described, discriminative stimulus (DS) properties of mirtazapine, which does not affect monoamine reuptake, remain uncharacterized. Objectives The objectives of the study are to train rats to recognize a mirtazapine DS, then perform substitution studies with other antidepressants and drugs acting at sites occupied by mirtazapine. Materials and methods Using a two-lever, fixed-ratio 10 schedule, rats were trained to discriminate mirtazapine (2.5 mg/kg, i.p.) from saline. Results Sessions, 63± 8, were necessary to reach the criterion for 14 rats that all subsequently recognized (100%) mirtazapine at the training dose. Mirtazapine blocks serotonin (5-HT) 2C receptors, and the 5-HT 2C antagonists, SB242,084, SB243,213 and S32006, revealed dosedependent and full (≥80%) substitution at doses of 2.5, 2.5, and 0.63 mg/kg, respectively. By contrast, the 5-HT 2A antagonists, MDL100,907 and SR46349-B, the 5-HT 2B antagonist, SB204,741, and the 5-HT 3 antagonist, ondansetron, showed no significant substitution. Though mirtazapine indirectly recruits 5-HT 1A receptors, the 5-HT 1A agonists, buspirone and 8-OH-DPAT, did not substitute. Mirtazapine blocks α 2 -adrenoceptors, but several α 2 -adrenoceptor antagonists (yohimbine, RX821,002 and atipamezole) failed to substitute. Despite blockade by mirtazapine of histamine H 1 receptors, no substitution was seen with the selective H 1 antagonist, pyrilamine. Finally, the selective noradrenaline reuptake inhibitor, reboxetine (0.16), fully substituted for mirtazapine, whereas the 5-HT/noradrenaline reuptake inhibitors, duloxetine and S33005, several 5-HT reuptake inhibitors (citalopram, fluvoxamine, and paroxetine) and the dopamine reuptake inhibitors, bupropion and GBR12,935, did not substitute. Conclusion Mirtazapine elicits a DS in rats for which selective antagonists at 5-HT 2C receptors display dosedependent substitution, whereas drugs acting at other sites recognized by mirtazapine are ineffective.

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Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex

Cited by 81 publications

References 26 publications

Brain activation predicts treatment improvement in patients with major depressive disorder

Brain activation predicts treatment improvement in patients with major depressive disorder

Cross-Talk between Dopaminergic and Noradrenergic Systems in the Rat Ventral Tegmental Area, Locus Ceruleus, and Dorsal Hippocampus

Discriminative stimulus properties of the “atypical” antidepressant, mirtazapine, in rats: a pharmacological characterization

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