Guy Debonnel

Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors

We have shown previously that low doses of selective sigma (sigma)- receptor ligands potentiate the excitatory response of pyramidal neurons to NMDA in the CA3 region of the dorsal hippocampus in the rat. Because progesterone competitively displaces the binding of the ligand N-[3H]allyl-normetazocine (SKF-10,047), the present studies were undertaken to determine in vivo the effect of neuroactive steroids on NMDA-induced excitation of rat CA3 pyramidal neurons. Low doses of dehydroepiandrosterone (DHEA) potentiated the NMDA response selectively and dose-dependently. The effect of DHEA was reversed by the selective sigma antagonist N-dipropyl-2-(4-methoxy-3- (2-phenylethoxy)phenyl)- ethylamine monohydrochloride (NE-100) and by haloperidol, but not by spiperone. Progesterone had no effect by itself but reversed, at low doses, the potentiation of the NMDA response induced by DHEA as well as those induced by nonsteroidal sigma ligands. Neither pregnenolone nor pregnenolone sulfate had any effect on the NMDA response--nor did they antagonize the potentiation of the NMDA response induced by DHEA and by nonsteroidal sigma ligands. A pertussis toxin pretreatment, which inactivates Gi/o-proteins, abolished the potentiating effects of DHEA. Ovariectomy enhanced the potentiation of the NMDA response by the nonsteroidal sigma ligand di(2-tolyl)guanidine (DTG). There was a reciprocal occlusion of the effects of DHEA and DTG; DTG did not potentiate the NMDA response further after DHEA, and DHEA did not do so after DTG. These results suggest that some neuroactive steroids modulate the NMDA response via sigma receptors.

Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype

Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1–deficient (Kcnk2−/−) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.

Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

N-methyl-D-aspartate-induced neuronal activation is selectively modulated by σ receptors

Abstract The effects of two high-affinity σ ligands, DTG (1,3-di(2-tolyl)guanidine) and haloperidol, on the activation of dorsal hippocampus pyramidal neurons induced by microiontopheretic application of N-methyl-D-aspartate (NMDA) were assessed electrophysiologically. Low doses of DTG (0.5–3 μg/kg i.v.) potentiated the NMDA response. This effect of DTG was blocked by haloperidol (10 μg/kg i.v.), but not by spiperone, a potent dopamine antagonist with low affinity for σ receptors. These results suggest that σ receptors modulate the NMDA-induced neuronal activation.

A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression.

OBJECT Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression. METHODS Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50). RESULTS Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery. CONCLUSIONS Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB1 receptors (CB1Rs). The action of CB1R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood. In this study, we demonstrated that, at low doses, the CB1R agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST). This effect is CB1R dependent because it was blocked by the CB1R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB1R-dependent mechanism. Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB1R-independent mechanism. The CB1R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB1R-dependent antidepressant-like effect in the FST. These results demonstrate that CB1R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.

Effect of Vagus Nerve Stimulation on Serotonergic and Noradrenergic Transmission

Vagus nerve stimulation (VNS) is an antiepileptic treatment, which has recently shown promise as an antidepressant. Yet, its antidepressant mechanisms of action are unknown. Serotonergic [5-hydroxytryptamine (5-HT, serotonin)] and noradrenergic [norepinephrine (NE)] systems are involved in the pathophysiology of depression and in the mechanisms of action of antidepressants. The present study analyzes 5-HT and NE neuronal firing rates in their brainstem nuclei: the dorsal raphe nucleus (DRN) and locus coeruleus (LC), respectively. The basal firing rates in the DRN and LC were significantly increased after long-term treatments with VNS. After short-term VNS treatments, firing rates were significantly higher for LC (at 1 h and 3 days). As changes in their firing rate may have been due to altered autoreceptor sensitivities, the responses of autoreceptors to the acute administration of their respective agonists were assessed. However, no significant difference was seen in the DRN. No significant differences in dose response curves for 5-HT1A somatodendritic and α2-adrenergic autoreceptors were noticed between long-term VNS and controls. VNS appears to have a novel mechanism of antidepressant action, enabling its effectiveness in treatment-resistant depression. LC firing rates significantly increase earlier than the DRN basal firing. As the LC has an excitatory influence on DRN, it is possible that the increased DRN firing rate is secondary to an initial increased LC firing rate from VNS.

Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters.

In vitro radioligand binding studies were carried out in rat brain membranes to assess the affinity of various reuptake inhibitors for the serotonin (5-hydroxytryptamine, 5-HT) and the norepinephrine transporters using the selective ligands [3H]cyanoimipramine and [3H]nisoxetine, respectively. The selective 5-HT reuptake inhibitors paroxetine, indalpine and fluvoxamine displayed a high affinity for the 5-HT transporter, whereas the norepinephrine reuptake inhibitor desipramine had a high affinity for the norepinephrine transporter. Duloxetine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed a high affinity for both the 5-HT and the norepinephrine transporters. Interestingly, venlafaxine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed only a moderate affinity for the 5-HT transporter (Ki = 74 nM) and a very low affinity for the norepinephrine transporter (Ki = 1.26 microM). The relatively low affinities of venlafaxine contrast with its potent in vivo 5-HT and norepinephrine reuptake blocking properties. These results raise the possibility that the in vivo effects on the 5-HT and norepinephrine reuptake observed with venlafaxine may not be mediated solely by its binding to the [3H]cyanoimipramine and [3H]nisoxetine binding sites.

Mirtazapine and paroxetine in major depression: A comparison of monotherapy versus their combination from treatment initiation

This double-blind study compared initial combination therapy against monotherapy using two antidepressant drugs with complementary mechanisms of action on the serotonin (5-HT) and norepinephrine (NE) systems. Sixty one adult patients with a DSM-IV diagnosis of unipolar depression were randomized to receive mirtazapine (30 mg/day), paroxetine (20 mg/day), or the combination of both drugs for 6 weeks. Response at week 4 was defined as a 30% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS), and at week 6 as a 50% reduction in the MADRS. Remission was defined as a reduction in the MADRS score to 10 points or less. After 4 weeks, non-responders in the monotherapy groups had their medication dose increased by 50%. After 6 weeks, non-responders on monotherapy had the second trial drug added to their current regimen. Non-responders on combination therapy had the dosage of both drugs increased by 50%. There was a significantly greater decrease in MADRS scores in the combination group compared to the monotherapy groups at days 28, 35 and 42, with a 10 point difference separating the combination from the monotherapies at day 42. Remission rates at week 6 were 19% on mirtazapine, 26% on paroxetine, and 43% on the combination. Fifteen patients in the mirtazapine arm and 10 in the paroxetine arm who did not respond had the other drug added to their current regimen, and 5 on the combination had an increase in dose of both drugs secondary to non-response. Of these 30 patients, approximately 50% went on to achieve remission in the subsequent 2 weeks. These results indicate that the combined use of two antidepressants was well tolerated and produced a greater improvement than monotherapy.

Assessment of the Serotonin and Norepinephrine Reuptake Blocking Properties of Duloxetine in Healthy Subjects

Duloxetine is a dual inhibitor of norepinephrine (NE) and serotonin (5-HT) uptake. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant. The aim of this study was to assess the effects of duloxetine on the 5-HT and NE reuptake processes in healthy human volunteers. Twenty-seven healthy young males without a history of psychiatric disorder were randomly assigned to four groups, each group receiving one of the following daily drug regimens: placebo, clomipramine (a potent 5-HT/NE reuptake blocker) 100 mg/day, duloxetine 20 mg/day, or duloxetine 60 mg/day. In order to assess the NE reuptake process, the pressor response to intravenous tyramine (4 and 6 mg) was measured. Determination of the whole blood 5-HT content was used to evaluate the 5-HT reuptake blockade. These measurements were performed at baseline and repeated after 7 and 14 days of drug intake. Both duloxetine, at doses of 20 to 60 mg/day, and clomipramine significantly interfered with the 5-HT reuptake process, as demonstrated by marked decreases in blood 5-HT concentrations. However, the same doses of duloxetine, unlike clomipramine, failed to impede the usual increase in blood pressure that follows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, having no clear effect on the NE reuptake process. Nevertheless, given that the highest dose of duloxetine increased supine systolic blood pressure, it is possible that it represents the threshold regimen for NE reuptake inhibition.