Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems.

Vagus nerve stimulation (VNS) is an adjunctive treatment for resistant epilepsy and depression. Electrophysiological recordings in the rat brain have already shown that chronic VNS increases norepinephrine (NE) neuronal firing activity and, subsequently, that of serotonin (5-HT) neurons through an activation of their excitatory α1-adrenoceptors. Long-term VNS was shown to increase the tonic activation of post-synaptic 5-HT1A receptors in the hippocampus. This study was aimed at examining the effect of VNS on extracellular 5-HT, NE and dopamine (DA) levels in different brain areas using in vivo microdialysis, on NE transmission in the hippocampus, and DA neuronal firing activity using electrophysiology. Rats were implanted with a VNS device and stimulated for 14 d with standard parameters used in treatment-resistant depression (0.25 mA, 20 Hz, 500 µs, 30 s on-5 min off). The results of the present study revealed that 2-wk VNS significantly increased extracellular NE levels in the prefrontal cortex and the hippocampus and enhanced the tonic activation of post-synaptic α2-adrenoceptors on pyramidal neurons. The electrophysiological experiments revealed a significant decrease in ventral tegmental area DA neuronal firing rate after long-term VNS; extracellular DA levels were nevertheless increased in the prefrontal cortex and nucleus accumbens. Chronic VNS significantly increased extracellular 5-HT levels in the dorsal raphe but not in the hippocampus and prefrontal cortex. In conclusion, the effect of VNS in increasing the transmission of monoaminergic systems targeted in the treatment of resistant depression should be involved, at least in part, in its antidepressant properties observed in patients not responding to many antidepressant strategies.

Serotonin(4) (5-HT(4)) 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.

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.

Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation.

BACKGROUND: Vagus nerve stimulation (VNS) is a recent intervention for treatment-resistant depression. Electrophysiological recordings in the rat brain showed that VNS increases the firing rate of norepinephrine (NE) neurons after 1 day of stimulation and that of serotonin (5-HT) neurons after 14 days. This study was conducted to further characterize these effects. METHODS: We implanted rats with a VNS electrode and stimulator. We used the selective noradrenergic toxin DSP-4 to lesion NE neurons of the locus coeruleus. We recorded dorsal raphe 5-HT neurons under chloral hydrate anesthesia. We recorded hippocampus CA(3) pyramidal neurons using 5-barreled iontophoretic pipettes. RESULTS: Analysis of a previously published data set revealed that VNS increased not only the spontaneous firing rates of NE neurons, but also the percentage of neurons firing in bursts. The enhancement of the 5-HT neuron firing rate by VNS was abolished by lesioning NE neurons. We found that VNS increased the degree of activation of postsynaptic alpha(1)-adrenoceptors on 5-HT neurons, probably through an increased release of endogenous NE. The tonic activation of postsynaptic 5-HT(1A) receptors in the hippocampus was enhanced after 14 days of VNS, as with other antidepressant treatments. LIMITATIONS: Our study limitations include the fact that we turned off the stimulator during the electrophysiological recordings, which likely decreased the vagal tone to the brain. Also, we obtained the data while the animals were under anesthesia, therefore studies need to be carried out in unanesthetized rats to ascertain whether the anesthetic agent influenced the changes observed between control rats and those treated with VNS. CONCLUSION: Vagus nerve stimulation initially increases the firing activity and pattern of NE neurons and subsequently those of 5-HT neurons, presumably as a cascade effect via alpha(1)-postsynaptic adrenoceptors. To date, VNS appears to be a unique antidepressant treatment increasing 5-HT transmission and enhancing the firing activity of NE neurons. These effects could contribute to the effectiveness of VNS in treatment-resistant depression.

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.

An index of 5-HT synthesis changes during early antidepressant treatment: alpha-[11C]methyl-L-tryptophan PET study.

The antidepressant selective serotonin transporter inhibitors (SSRIs) are clinically active after a delay of several weeks. Indeed, the rapid increase of serotonin (5-HT) caused by SSRIs, stimulates the 5-HT(1A) autoreceptors, which exert a negative feedback on the 5-HT neurotransmission. Only when autoreceptors are desensitized, can SSRIs exert their therapeutic activity. The 5-HT(1A) receptor antagonist pindolol has been used to accelerate the clinical effects of antidepressant by preventing the negative feedback. Using the alpha-[(11)C]methyl-L-tryptophan/positron emission tomography (PET), the goal of the present double-blind, randomized study was to compare the changes in alpha-[(11)C]methyl-L-tryptophan trapping, an index of serotonin synthesis, in patients suffering from unipolar depression treated with the SSRI citalopram (20 mg/day) plus placebo versus patients treated with citalopram plus pindol (7.5 mg/day). PET and Hamilton depression rating scale (HDRS-17) were performed at baseline, and after 10 and 24 days of antidepressant treatment. Results show that the combination citalopram plus pindol, compared to citalopram alone shows a more rapid and greater increase of an index of 5-HT synthesis in prefrontal cortex (BA 9). This research is the first human PET study demonstrating that, after 24 days, the combination SSRIs plus pindolol produces a greater increase of the metabolism of serotonin in the prefrontal cortex, an area associated to depressive symptoms.

Chronic buspirone treatment normalizes open field behavior in olfactory bulbectomized rats: assessment with a quantitative autoradiographic evaluation of the 5-HT1A binding sites.

The olfactory bulbectomized (OBX) rat model of depression has been widely used in studies on the behavioral and neurochemical aspects of human depression. The objective of the present investigation was to assess open field (OF) activity and the brain regional 5-HT(1A) receptor densities of the sham operated (SHX) and OBX rats treated with saline (SHX-SAL, OBX-SAL), and either 10 mg/(kg day) (SHX-B10, OBX-B10) or 20 mg/(kg day) (SHX-B20, OBX-B20) of buspirone for 14 days, delivered by a subcutaneous osmotic minipump. Adult Sprague-Dawley rats were used for this experiment. The surgery was performed on the first day of the experiment and the rats were randomly assigned to either the SHX or OBX groups. The results of the OF tests were organized in eight groups. Following 14 days of treatment and the final OF tests, the rats were sacrificed and the brains were used for 5-HT(1A) receptor autoradiography using [(3)H]8-OH-DPAT. The data showed that the OF activities, 14 days following surgery, in the OBX rats were significantly elevated when compared to the SHX rats. In the OBX rats, only the 14-day treatment with 20mg/(kgday) of buspirone normalized the elevated OF activity, the same dose shown previously to be needed for the normalization of the regional 5-HT synthesis. A significant reduction in the number of 5-HT(1A) receptor sites was found in most brain regions in the OBX rats when compared to the SHX rats. Data also show that the regional density of the 5-HT(1A) receptors in OBX-SAL treated rats is lower than that of the SHX-SAL rats. The 14-day treatment with either 10 or 20 mg/(kg day) of buspirone reduced the 5-HT(1A) receptors in most brain regions of the SHX rats, without an obvious dose-dependent effect of the buspirone. The comparison between the OBX-B20 and control (SHX-B20) rats suggests that the buspirone treatment resulted in a regional balance in the 5-HT(1A) sites. A dose dependent reduction in the density of 5-HT(1A) sites was observed in the sham rats, but the buspirone treatment had very little effect on the density of the 5-HT(1A) receptors in the OBX rats. From these observations, we conclude that the antidepressant effects of buspirone in the OBX rat model of depression are likely mediated through the fine tuning of the regional imbalance of 5-HT(1A) receptors with even increases of about 20% in some limbic regions. The data suggest that the neurochemical effects of antidepressants should be studied in animal models of depression rather than in normal rats.

Effects of OPC-14523, a combined sigma and 5-HT1a ligand, on pre- and post-synaptic 5-HT1a receptors.

OPC-14523 (OPC) is a novel compound with high affinity for sigma and 5-HT1A receptors that shows 'antidepressant-like' effects in animal models of depression. We have previously demonstrated that OPC produces an increase in 5-HT neurotransmission and a decreased response of 5-HT neurons to the acute administration of paroxetine in the DRN, an effect that appears to be mediated by OPC's 5-HT1A receptor affinity. The current study sets out to investigate more specifically the effects of OPC on 5-HT1A pre- and post-synaptic receptors, to assess whether it acts as an agonist or antagonist. Using an electrophysiological model of in vivo extracellular recordings in anaesthetized rats, the effects of OPC was assessed on pre-synaptic DRN 5-HT1A autoreceptors and post-synaptically on hippocampal 5-HT1A receptors of CA3 pyramidal neurons. OPC applied by microiontophoresis, produced a significant decrease in the firing activity of 5-HT neurons of the DRN and of quisqualate-activated CA3 pyramidal neurons of the dorsal hippocampus. The effects of OPC on 5-HT1A receptors were significantly reduced by the co-application of the 5-HT1A antagonist WAY-100635. In addition, the effects of OPC were not blocked by the injection of the sigma antagonists NE-100 or haloperidol. Therefore, OPC is acting as an agonist on both pre- and post-synaptic 5-HT1A receptors. The current findings combined with previous data on OPC suggest a pharmacological profile that warrants further investigation.

Effects of the 5-HT7 receptor antagonist SB-269970 on rat hormonal and temperature responses to the 5-HT1A/7 receptor agonist 8-OH-DPAT.

The physiological function of 5-HT(7) receptors is not yet fully determined. This study was designed to characterize the involvement of 5-HT(7) receptor in rat body temperature regulation and in adrenocorticotropic hormone (ACTH) and corticosterone secretion. In the first part of our study, acute administration of SB-269970 (0.1-1 mg/kg, i.p.), a potent and selective 5-HT(7) receptors antagonist, dose-dependently prevented 5-HT(1A/7) receptor agonist 8-OH-DPAT (0.1 mg/kg, s.c.)-induced hypothermia and when the 5-HT(1A) receptor antagonist WAY-100,635 was co-injected with SB-269970, a reduction of the latter hypothermia was obtained in an additive manner. In contrast, 1 mg/kg (i.p.) of SB-269970 failed to prevent 8-OH-DPAT (0.5 mg/kg, s.c.)-induced increase of ACTH and corticosterone plasma levels. In conclusion, the present results unveil an additive effect of both 5-HT(1A) and 5-HT(7) receptors in core body temperature regulation.

Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: viral transfections, subacute and chronic treatments with 5-HT4 agonists.

BACKGROUND: We recently identified a facilitory control exerted by serotonin4 (5-HT4) receptors on the in vivo firing activity of dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons. However, these findings were based on acute administrations of 5-HT4 receptor agonists and antagonists, which were active only in a subpopulation of 5-HT neurons. We had no evidence that this influence was significant when considering the entire DRN, nor if it was persistent after chronic treatments. In addition, the poor distribution of 5-HT4 receptors within the DRN raised the question of the neuroanatomical bases underlying this control. METHODS AND RESULTS: Here we show that the subacute intraperitoneal (IP) injection of the 5-HT4 receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before the beginning of recordings augment the mean firing rate of DRN neurons by 40% and 66%, respectively. These increases remain stable when the compounds are administered continuously during 3 and 21 days; the effects of the 3-day treatment are blocked by the 5-HT4 receptor antagonist GR 125487 (1000 microg/kg, intravenous [i.v.]). In addition, stereotaxic microinjections of herpes simplex viruses, transformed to overexpress 5-HT4 receptors, increase DRN 5-HT neuronal mean activity when performed in the medial prefrontal cortex (mPFC) but not in the striatum or in the hippocampus. CONCLUSIONS: This finding suggests the existence of a 5-HT(4)-dependent activation of DRN that may involve the mPFC, unveiling the 5-HT4 receptor as a putative player in the physiopathology of several disorders related to central 5-HT dysfunction.

Chronic administration of citalopram in olfactory bulbectomy rats restores brain 5-HT synthesis rates: an autoradiographic study.

RATIONALE: The olfactory bulbectomized (OBX) rat model is widely accepted as an animal model of depression with a proposed serotonergic imbalance in the brain. OBJECTIVE: To study the effects of chronic administration of citalopram on serotonin (5-HT) synthesis rates. METHOD: Serotonin synthesis was evaluated using the alpha-[(14)C]methyl-L: -tryptophan (alpha-MTrp) autoradiographic method in OBX rats. Citalopram was administered continuously (10 mg kg(-1) day(-1)) for 14 days using a subcutaneous osmotic minipump. RESULTS: The OBX rats treated with citalopram (OBX-CTP) have the same 5-HT synthesis rates as the sham-operated rats treated with citalopram (Sham-CTP). The OBX-CTP rats, relative to the OBX rats treated with saline (OBX-SAL), showed a reduction in the majority of the terminal brain structures, suggesting a normalization of 5-HT synthesis in the OBX-CTP rats following treatment. The OBX-SAL rats have significantly greater synthesis than the Sham-SAL rats in a majority of the terminal structures, but lower rates in the dorsal raphe. A few structures in the OBX-CTP group have lower synthesis than in the Sham-SAL group (e.g., dorsal raphe, hippocampus, amygdala). The data suggest that receptors in some brain areas are likely still responsive to the elevated levels of the extracellular 5-HT produced by citalopram. CONCLUSION: There is no significant global or individual structure difference in the synthesis between the Sham-CTP and OBX-CTP groups. The similarity in the synthesis between the OBX-CTP, Sham-CTP and Sham-SAL groups is likely a result of changes in the sensitivity of the receptors through which 5-HT synthesis is controlled. Because of some of the differences in the synthesis between the Sham-CTP and Sham-SAL groups, the data suggest that receptors throughout the brain are not fully desensitized.

Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression.

CONTEXT: The serotonin hypothesis of depression invokes a relative or absolute deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the brain pathways mediating the expression of mood (ie, the limbic cortex) is a plausible candidate mechanism. OBJECTIVES: To measure and compare, using the alpha-[(11)C]methyl-l-tryptophan/positron emission tomography method, the brain trapping constant of alpha-[(11)C]methyl-l-tryptophan (K*, milliliters per gram per minute), an index of serotonin synthesis, in brain areas involved in the regulation of mood in patients with major depression (MD) and age- and sex-matched controls. DESIGN: Between-group comparison. SETTING: Department of Psychiatry and Montreal Neurological Institute, McGill University. PARTICIPANTS: Seventeen medication-free outpatients with a current episode of MD (9 women: mean +/- SD age, 41 +/- 11 years; 8 men: mean +/- SD age, 41 +/- 11 years) and 17 controls (9 women: mean +/- SD age, 37 +/- 15 years; 8 men: mean +/- SD age, 32.5 +/- 9.9 years). Main Outcome Measure Normalized K*, normalized to the global mean, was measured in the dorsolateral prefrontal, anterior cingulate, and mesial temporal cortices; the thalamus; and the caudate nucleus. RESULTS: Compared with age- and sex-matched controls, normalized K* was significantly decreased bilaterally in female patients with MD in the anterior cingulate cortex, in the left anterior cingulate cortex in male patients with MD, and in the left mesial temporal cortex in male and female patients with MD (P<.001 for all). Exploratory analyses identified additional patient-control differences for normalized K* (eg, inferior frontal gyrus and superior parietal lobule), most of which, once corrected for 38 multiple comparisons, lost their significance. Morphometric measurements of the cingulate cortex divisions confirmed that the reduction of normalized K* in depressed patients was not attributable to a reduction in gray matter volume. Normalized K* in the anterior cingulate cortex did not correlate with ratings of depression severity collected at the time of scan. CONCLUSIONS: Reduction of normalized K*, an index of serotonin synthesis, in parts of the limbic and paralimbic cortices may contribute to the biochemical alterations associated with MD.

Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part II. Regulatory mechanisms.

In the companion paper, we showed that the spontaneous firing activity of DRN 5-HT neurons is significantly higher in male (M) than in freely cycling female (CF) rats. Moreover, during pregnancy, it increased in parallel to circulating levels of progesterone, peaking at day 17 of pregnancy (P17). In this second part, we assessed the role of three regulatory mechanisms potentially involved in these modifications of the 5-HT neurons firing activity. During pregnancy, the ED(50) for the response to LSD was decreased by about 70%, indicating a partial desensitization of 5-HT(1A) autoreceptors, which is consistent with the 5-HT neurons higher firing activity. The GABAergic tonic inhibition of 5-HT neurons was assessed using the responses to GABA, bicuculline and isoniazid. Together, they indicate a lower GABAergic tonic inhibition in males and P17 as compared to CF, which is in agreement with their greater 5-HT neurons firing rate. Finally, the efficacy of the long feedback loop, involving postsynaptic 5-HT(1A) receptors, did not seem affected by gender, ovariectomy or pregnancy since the response to systemic 8-OH-DPAT was similar. These results constitute strong evidence of mechanisms by which gender and hormonal fluctuations can modulate the 5-HT neurons function and influence vulnerability to mood disorders.

Effects of quetiapine and olanzapine in patients with psychosis and violent behavior: a pilot randomized, open-label, comparative study.

OBJECTIVE: Patients suffering from psychosis are more likely than the general population to commit aggressive acts, but the therapeutics of aggressive behavior are still a matter of debate. METHODS: This pilot randomized, open-label study compared the efficacy of quetiapine versus olanzapine in reducing impulsive and aggressive behaviors (primary endpoints) and psychotic symptoms (secondary endpoints) from baseline to days 1, 7, 14, 28, 42, 56, and 70, in 15 violent schizophrenic patients hospitalized in a maximum-security psychiatric hospital. RESULTS: Quetiapine (525±45 mg) and olanzapine (18.5±4.8 mg) were both efficacious in reducing Impulsivity Rating Scale from baseline to day 70. In addition, both treatments reduced the Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale, and Clinical Global Impression Scale scores at day 70 compared to baseline, and no differences were observed between treatments. Moreover, quetiapine, but not olanzapine, yielded an improvement of depressive symptoms in the items "depression" in Brief Psychiatric Rating Scale and "blunted affect" in Positive and Negative Syndrome Scale. Modified Overt Aggression Scale scores were also decreased from baseline to the endpoint, but due to the limited number of patients, it was not possible to detect a significant difference. CONCLUSION: In this pilot study, quetiapine and olanzapine equally decreased impulsive and psychotic symptoms after 8 weeks of treatment. Double-blind, large studies are needed to confirm the validity of these two treatments in highly aggressive and violent schizophrenic patients.

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.

Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat.

BACKGROUND: We have recently reported that serotonin(4) (5-HT(4)) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants. METHODOLOGY/PRINCIPAL FINDINGS: We found that, in acute conditions, the 5-HT(4) agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4) agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT(1A) receptors, that was two to three times stronger when the 5-HT(4) agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound. CONCLUSIONS/SIGNIFICANCE: These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4) agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

Optimization of vagus nerve stimulation parameters using the firing activity of serotonin neurons in the rat dorsal raphe.

Vagus nerve stimulation (VNS) is a recently approved adjunctive intervention for treatment-resistant depression. This therapy enhances the firing rate of rat norepinephrine neurons after 1 h and that of serotonin (5-HT) neurons only after 14 days. Various stimulation parameters were thus tested on their capacity to enhance 5-HT neuronal firing because of the delayed action of VNS on the 5-HT system and its important role in the antidepressant response. Rats were implanted with a stimulator and treated for 14 days, each group of rats having only one stimulation parameter modified from the standard ones (0.25 mA, 20 Hz, 500 micros, 30 s ON/5 min OFF). Electrophysiological recordings showed that the usual parameters utilized in depressed patients, with the exception of current intensity, produced an optimal activation of 5-HT neurons. Excessive enhancement of the charge delivered to the nerve can lead to a loss of VNS effect on 5-HT neuronal firing.

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.

Further evidence for an antidepressant potential of the selective sigma1 agonist SA 4503: electrophysiological, morphological and behavioural studies.

In this study, we evaluated the ability of the selective sigma1 agonist SA 4503 to produce changes in brain function, similar to those elicited by classical antidepressants. We focused more specifically on the influence of SA 4503 on central serotonergic (5-HT) transmission, and on hippocampal cell proliferation. A 2-d continuous treatment with SA 4503 (1-40 mg/kg.d) increased 5-HT neuron firing rate in a dose-dependent, bell-shaped manner, with a culminating effect of +90% at 10 mg/kg.d. The same dose induced the appearance of a 5-HT1A receptor-mediated inhibitory tonus on hippocampal pyramidal neurons, as revealed by intravenous injections of the selective 5-HT1A antagonist WAY 100635. Moreover, continuous administration of SA 4503 (3 and 10 mg/kg.d, 3 d) dose-dependently enhanced the number of bromodeoxyuridine-positive cells in the subgranular zone of the hippocampus (+48% and +94%, respectively), thus indicating an increased cell proliferation. Finally, a single administration of SA 4503 (3 and 10 mg/kg i.p.) increased the time spent swimming in the forced swimming test. Together, these results provide both functional and behavioural evidence that this compound has an important antidepressant potential. Further, the fact that the functional changes occurred within a short time-frame (2-3 d) suggest that this antidepressant potential might have a rapid onset of action.

Effects of different doses of venlafaxine on serotonin and norepinephrine reuptake in healthy volunteers.

Venlafaxine is generally considered to be a dual 5-HT and NE reuptake inhibitor when it is used at doses above 75 mg/d in humans. While its 5-HT reuptake-inhibiting property has been demonstrated, some controversy still exists regarding the doses of venlafaxine required to inhibit NE reuptake. Healthy male volunteers received, on a double-blind basis, paroxetine (20 mg/d), desipramine (100 mg/d), nefazodone (300 mg/d), or venlafaxine (150 or 300 mg/d) in the last 5 d of a 7-d period of administration. Inhibition of 5-HT reuptake was estimated by determining the degree of depletion of whole-blood 5-HT, while that of NE was assessed by measuring the attenuation of the systolic blood pressure increases produced by intravenous injections of tyramine. Paroxetine, both regimens of venlafaxine, and to a lesser extent desipramine significantly decreased whole-blood 5-HT content. Nefazodone failed to produce any significant change. Desipramine abolished the tyramine pressor response, whereas all other drug regimens left this parameter unaltered. Venlafaxine and paroxetine acted as potent 5-HT reuptake inhibitors in the present study. In contrast, neither the moderate nor the high dose of venlafaxine displayed any significant inhibiting activity in this model assessing NE reuptake in peripheral NE terminals. The validity of the model was confirmed by the potent inhibitory action of desipramine on NE reuptake. While the reasons for this unexpected lack of action remain unclear, venlafaxine appeared to be an effective NE reuptake agent in depressed patients using the same approach.