Involvement of prolactin and somatostatin in depression and the mechanism of action of antidepressant drugs

Neuropeptides have been implicated in the physiology and pathophysiology of stress responses and therefore may play an important role in the pathogenesis of affective disorders such as Major Depression Disorder (MDD). The data presented in this mini-review demonstrate the role of prolactin (PRL) and somatostatin (STT) in the pathology and pharmacotherapy of MDD, focusing particularly on the response to antidepressant treatment, and compare the available data with the results obtained in our laboratory using the well-validated chronic mild stress (CMS) animal model of MDD.Despite the availability of many pharmacological therapies for depression, ca. 35% patients remain treatment resistant. This clinical situation is also true for rats subjected to CMS; some animals do not respond to antidepressant therapy and are considered treatment resistant. The most interesting results presented in this mini-review concern the changes in PRL and SST receptors in the brains of rats subjected to the full CMS procedure and IMI treatment and demonstrate the role of these receptors in the mechanisms of antidepressant action.The possible interaction between SST and PRL, the involvement of the D₂ dopamine receptor, and their direct protein-protein interactions are also discussed, with the conclusion that these two neurohormones play an important role in the mechanism of resilience after stress as well as in the mechanism of action of antidepressant drugs.     

Possible involvement of the dopaminergic system in the mode of action of the potential antidepressant trazium esilate

Trazium esilate (EGYT-3615) is structurally an as-triazino isoquinolinium salt which showed considerable activity in pharmacological tests characteristic for antidepressants (antagonism of tetrabenazine, potentiation of yohimbine, behavioral despair). The compound exhibited minimal sedative effect. Some findings suggest that it influences the central dopaminergic system. The drug potentiated actions of amphetamine such as stereotypy and hypermotility. It differentially blocked the hypothermic and the stereotypy inducing action of apomorphine. Trazium esilate also inhibited the cataleptic state provoked by bulbocapnine in mice. In higher dose it decreased the plasma prolactin level in rats. The compound potentiated the effect of norepinephrine on isolated vas deferens of the rat. Trazium esilate is a weak displacer on a1-, a2- and D2-receptors, however, it induced a2-receptor desenzitization after repeated treatment. It had no influence on rat brain cortical noradrenaline and striatal dopamine release evoked by high K+ concentration, but it increased the spontaneous dopamine outflow in rat striatum. The compound also elevated the striatal dopamine and DOPAC levels both after acute and chronic treatment.     

Potential roles of NCAM/PSA-NCAM proteins in depression and the mechanism of action of antidepressant drugs

Recently, it has been proposed that abnormalities in neuronal structural plasticity may underlie the pathogenesis of major depression, resulting in changes in the volume of specific brain regions, including the hippocampus (HIP), the prefrontal cortex (PC), and the amygdala (AMY), as well as the morphology of individual neurons in these brain regions. In the present survey, we compile the data regarding the involvement of the neural cell adhesion molecule (NCAM) protein and its polysialylated form (PSA-NCAM) in the pathogenesis of depression and the mechanism of action of antidepressant drugs (ADDs). Elevated expression of PSA-NCAM may reflect neuroplastic changes, whereas decreased expression implies a rigidification of neuronal morphology and an impedance of dynamic changes in synaptic structure. Special emphasis is placed on the clinical data, genetic models, and the effects of ADDs on NCAM/PSA-NCAM expression in the brain regions in which these proteins are constitutively expressed and neurogenesis is not a major factor; this emphasis is necessary to prevent cell proliferation and neurogenesis from obscuring the issue of brain plasticity.     

Acute and chronic effects of the atypical antidepressant,mianserin on brain noradrenergic neurons

Corticotropin-releasing factor (CRF), which may serve as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), has been postulated to be hypersecreted in depression. The present study was designed to test the hypothesis that antidepressants interfere with CRF putative neurotransmission in the LC. The acute and chronic effects of the atypical antidepressant mianserin on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by a stressor which requires endogenous CRF, and LC activation by ICV CRF were characterized in halothane-anesthetized rats. Acute IV administration of mianserin (0.0001–1.0 mg/kg) increased LC spontaneous discharge and decreased LC discharge evoked by repeated sciatic nerve stimulation in a dose-dependent manner. Additionally, mianserin (0.1 mg/kg) inhibited LC activation by hemodynamic stress (IV infusion of nitroprusside) and by ICV administration of CRF (3.0 µg). In rats chronically administered mianserin LC spontaneous and sensory-evoked discharge rates, and LC activation by CRF were similar to those of untreated rats or rats chronically administered saline. Moreover, acute IV administration of mianserin (0.1 mg/kg) to rats chronically treated with mianserin was less effective in altering LC spontaneous and sensory-evoked discharge. In contrast, LC activation by hemodynamic stress was still greatly attenuated in rats chronically administered mianserin. This is similar to the previously reported effect produced by chronic administration of the antidepressant, desmethylimipramine. The present results demonstrate that acute administration of low doses of mianserin attenuates LC activation by a variety of stimuli and suggest that tolerance developes with chronic administration to some of the effects of mianserin on LC discharge characteristics. The finding that LC activation by hemodynamic stress, which requires endogenous CRF, is attenuated after chronic mianserin administration suggests that interference with putative CRF neurotransmission in the LC may be an important common mode of antidepressant action.This work was supported by U.S.P.H.S. Grants MH42796, MH40008, MH00840, and a NARSAD award to A.L.C.     

Overuse of antidepressant drugs for the treatment of depression

The problem of under-diagnosis and under-treatment of depression has been identified as a major public health issue and measures have been taken to increase the recognition of depression and its treatment with antidepressants. The possibility of harm from the overuse of antidepressants has attracted far less attention. This review sets out evidence to show that inappropriate use of antidepressants (i.e. outside clinical indications, in excessive doses and for prolonged periods) constitutes a concerning public health problem. Antidepressant prescribing increased by between 4- and 10-fold in various age groups and countries in the last decade of the 20th century. The population of severely depressed patients (in whom antidepressants are accepted to be an effective treatment) who are not receiving antidepressants is probably much smaller than the population receiving these drugs inappropriately. We sound a note of caution for depression awareness campaigns. These apparently well-reasoned responses to the perceived under-recognition of depression can exacerbate over-prescribing. Unless prescribing patterns change, any benefits from increasing access to antidepressants for those with severe depression will be accompanied by significant harms due to inappropriate prescribing in conditions, such as mild depression, where antidepressants are not indicated.     

Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons

Atomoxetine (ATM) is a potent norepinephrine (NE) uptake inhibitor and increases both NE and dopamine synaptic levels in prefrontal cortex, where it is thought to exert its beneficial effects on attention and impulsivity. At the behavioral level, ATM has been shown to cause improvements on the measures of executive functions, such as response inhibition, working memory and attentional set shifting across different species. However, the exact mechanism of action for ATM's effects on cognition is still not clear. One possible target for the cognitive enhancing effects of ATM is the noradrenergic locus coeruleus (LC), the only source of NE to key forebrain areas such as cerebral cortex and hippocampus. Although it is known that ATM increases NE availability overall by blocking reuptake of NE, the effects of this agent on impulse activity of LC neurons have not been reported. Here, the effect of ATM (0.1-1?mg/kg, ip) on NE-LC neurons was investigated by recording extracellular activity of LC neurons in isoflurane-anesthetized rats. ATM caused a significant decrease of the tonic activity of LC single-units, although leaving intact the sensory-evoked excitatory component of LC phasic response. Moreover, the magnitude of the inhibitory component of LC response to paw stimulation was increased after 1?mg/kg of ATM and its duration was prolonged at 0.3?mg/kg. Together, these effects of ATM produced an increase in the phasic-to-tonic ratio of LC phasic response to sensory stimulation. ATM also modulated the average sensory-evoked local field potential (LFP) and spike-field coherence in LC depending on the dose tested. The lower dose (0.1?mg/kg) significantly decreased early positive and negative components of the sensory-evoked LFP response. Higher doses (0.3-1?mg/kg) initially increased and then decreased the amplitude of components of the evoked fields, whereas the spike-field coherence was enhanced by 1?mg/kg ATM across frequency bands. Finally, coherence between LC fields and EEG signals was generally increased by 1?mg/kg ATM, whereas 0.1 and 0.3?mg/kg respectively decreased and increased coherence values in specific frequency bands. Taken together these results suggest that ATM effects on LC neuronal activity are dose-dependent, with different doses affecting different aspects of LC firing. This modulation of activity of LC-NE neurons may play a role in the cognitive effects of ATM. This article is part of a Special Issue entitled 'Cognitive Enhancers'.     

Effect of vinpocetine on noradrenergic neurons in rat locus coeruleus

Conventional extracellular single unit recordings were used to investigate the effect of vinpocetine on locus coeruleus noradrenergic neurons in chloral hydrate-anesthetized rats. Vinpocetine produced a significant and dose-dependent increase in the firing rate of locus coeruleus neurons (ED30 = 0.75 mg/kg i.v.) up to 1 mg/kg i.v., followed by a complete blockade of spiking activity at doses higher than this. The effective dose range was in very good agreement with the dose range corresponding to the memory-enhancing effects of the compound. Our results supplied direct electrophysiological evidence that vinpocetine increases the activity of ascending noradrenergic pathways. This effect can be related to the cognitive-enhancing characteristics of the compound.     

抗抑郁药物的作用机理与研究进展

本文通过查阅国内外有关文献,对抗抑郁症药物的作用机理与研究进展进行阐述,为抗抑郁药物的进一步研究提供参考。     

Effect of various antidepressant drugs on the spontaneous firing rate of locus coeruleus and dorsal raphe neurons of the rat.

The spontaneous firing rate of the noradrenergic neurons of the locus coeruleus and of the serotonergic neurons of the dorsal raphe was recorded with extracellular microelectrodes in chloral hydrate-anesthetized rats. A quantitative comparison of the effect of five tricyclic antidepressants, of tranylcypromine and of mianserin on the spontaneous activity of these two types of cells was performed. All drugs tested, except mianserin reduced the frequency of discharge of the noradrenergic neurons. Intravenous perfusion of the drugs allowed the doses required for inhibition of firing to 50% of the baseline rate (ID50) to be determined. Secondary aminated antidepressants (desipramine and nortriptyline) were more potent inhibitors than their tertiary aminated analogues (imipramine, chlorimipramine and amitriptyline). All drugs tested, except desipramine decreased the rate of firing of the serotonergic cells. In this case, the tertiary aminated antidepressants were much more potent than their secondary analogues. Mianserin was only active at very high doses. These results are in good agreement with the relative potencies of the tricyclic antidepressants for blocking the uptake of noradrenaline and serotonin into central and peripheral neurons.     

Possible involvement of noradrenergic descending pain-modulating pathways in the mode of antinociceptive action of flupirtine, a novel non-opioid analgesic

These experimental studies were conducted to obtain information about the antinociceptive action of flupirtine within the central nervous system. Flupirtine dose-dependently increased pain threshold in the electrostimulated pain test in mice. Its antinociceptive activity was attenuated by simultaneous administration of the noradrenergic alpha 1/alpha 2-antagonist yohimbine and alpha 2-antagonist idazoxane. By contrast, the analgesia induced by codeine or morphine was not influenced by alpha 2-adrenergic antagonists at all. A striking resemblance could be observed in the pharmaco-EEG of freely moving rats treated with clonidine and flupirtine, respectively. The present results are consistent with the hypothesis that the noradrenergic descending pain-modulating system might be involved in the antinociceptive mode of action of flupirtine.     

Reduced sensitivity of neurons to noradrenamine after chronic treatment with antidepressant drugs

The sensitivity of cingulate cortical neurons to microiontophoretically administered noradrenaline (NE) and GABA was investigated in groups of rats treated either chronically or acutely with various antidepressant drugs or with the tricyclic antiepileptic carbamazepine. The chronically treated animals received one daily intraperitoneal injection of either desipramine (10 mg/kg), clomipramine (10 mg/kg), maprotiline (25 mg/kg), tranylcypromine (1 mg/kg) or carbamazepine (30 mg/kg p.o) for 4 weeks. The acutely treated rats received one daily injection of the vehicle for 4 weeks, followed by one single injection of one of the five drugs 24 h before the experiment. NE and γ-aminobutyric acid (GABA) were administered microiontophoretically during periods of 60 sec with various ejection currents. In chronically treated rats a statistically significant reduction in the sensitivity of cortical cells to NE was observed with all four antidepressants. However, in rats treated chronically with carbamazepine, no desensitisation was observed.Desensitization to NE following chronic treatment with desipramine developed within the first 10 days of treatment. Following a ten-day treatment, there was a 33 percent and by the end of the fourth week a 43 percent reduction in sensitivity to NE. The sensitivity of these cingulate neurons to GABA was unchanged after chronic treatment with the antidepressant drugs. In conclusion, the present study demonstrates that chronic treatment with antidepressant drugs leads to a postsynaptic subsensitivity of cortical neurons to NE.     

The influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice: Possible implications for the actions of antidepressant drugs

This study has investigated the influence of central noradrenergic function on 5-HT₂-mediated head-twitch responses in mice. Central injection of low doses of the α₁-adrenoceptor agonists phenylephrine or methoxamine, or peripheral administration of the antagonist prazosin had no effect on the head-twitches induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). High doses of both α₁-adrenoceptor agonists and antagonists markedly inhibited this response. Head-twitches induced by 5-MeODMT were potently inhibited by low doses of the α₂-adrenoceptor agonist clonidine, and potentiated by the antagonists idazoxan and yohimbine. Clonidine also potently inhibited this response when produced by 5-hydroxytryptophan (5-HTP) and carbidopa. The action of the β-adrenoceptor agonist clenbuterol on head-twitches was paradoxical, this drug enhancing the responses to precursor loading (5-HTP/carbidopa) but inhibiting those induced by direct agonists (5-MeODMT, quipazine). Lesioning noradrenergic neurons by central injection of 6-hydroxydopamine (6-OHDA) or peripheral administration of DSP-4 resulted in enhanced head-twitch behaviour. 6-Hydroxydopamine lesioning did not alter the inhibition of head-twitch responses by clonidine but prevented their enhancement following withdrawal from repeated desmethylimipramine (DMI) administration. It is therefore suggested that head-twitch behaviour may be under tonic control by a population of α₂-adrenoceptors which are not on presynaptic noradrenergic terminals, but are postsynaptic and located “down-stream” of the 5-HT₂ receptor. In addition, the enhancement of this behaviour produced by withdrawal from repeated DMI administration probably also resulted from alterations in central noradrenergic function.