Serotonergic regulation of neuronal excitability in the prefrontal cortex

The cerebral cortex receives a dense serotonergic innervation originating predominantly from the dorsal raphe nucleus. This innervation regulates cortical functioning by activating multiple serotonin receptors that are differentially expressed by pyramidal cells and interneurons. Electrophysiological studies in the prefrontal cortex indicate that receptors of the 5-HT_1A and 5-HT_2A subtypes are the main serotonin receptors regulating membrane excitability in pyramidal cells. Most pyramidal cells in layer V coexpress 5-HT_1A and 5-HT_2A receptors that together regulate how these neurons encode excitatory input into neuronal firing. In contrast, a subset of large pyramidal cells of deep layer V appears to express exclusively 5-HT_2A receptors that depolarize and excite these cells. Serotonin also depolarizes and excites at least two classes of GABAergic interneurons by acting on 5-HT₃ and 5-HT_2A receptors. The differential expression of serotonin receptors in different pyramidal cells and interneurons is consistent with a growing appreciation of the anatomical, molecular and functional heterogeneity of pyramidal cells and interneurons of the cerebral cortex. These findings begin to lay the ground for a cellular-level understanding of the serotonergic regulation of the prefrontal cortex.     

Effect of atypical antipsychotic drugs on 5-HT2 receptors in the rat orbito-frontal cortex: an in vivo electrophysiological study

Low doses of the atypical antipsychotic drug risperidone are effective in patients with obsessive compulsive disorder (OCD) not responding to serotonin (5-HT) reuptake inhibitors, although higher doses have been reported to induce OCD symptoms in psychotic patients. Since such atypical antipsychotics exert, in addition to dopamine, 5-HT₂ receptor antagonistic properties, it was deemed essential to investigate the electrophysiological effect of these agents on 5-HT₂ receptors in the rat orbito-frontal cortex (OFc), a brain region implicated in OCD. Microiontophoretic application of the GABA_A receptor antagonist bicuculline had no effect on the suppressant effect of neuronal activity in the OFc induced by microiontophoretic application of the preferential 5-HT_2A and 5-HT_2C receptor agonists (+)-1-(4-iodo-2, 5-dimethoxyphenyl)-2-aminopropane (DOI) and m-chlorophenyl-piperazine (mCPP), respectively, but it antagonized the effect of GABA on the same neurons. These results indicate a lack of involvement of GABA interneurons in the suppressant effect of DOI and mCPP. While the 5-HT₂ receptor antagonist ritanserin (2 mg/kg, IV) attenuated the inhibitory effect of DOI and mCPP in the medial prefrontal cortex (mPFc), the inhibition was unaffected in the OFc. In the mPFc, the effect of DOI and mCPP was blocked by both clozapine (1.0 and 10 mg/kg, IV) and risperidone (0.1 and 1.0 mg/kg, IV). In the OFc, only the suppressant effect of mCPP was attenuated by both doses of clozapine but only by the high dose of risperidone. These results suggest that the 5-HT₂ response in the OFc is more akin to the 5-HT_2C subtype and that the deleterious effect sometimes observed with high doses of risperidone and clozapine may be due to a decrease in 5-HT neurotransmission. In contrast, the beneficial effect of low doses of risperidone may be due, in part, to the antagonism of dopamine receptors. Received: 22 June 1998/Final version: 8 October 1998     

Local 5HT3 receptors mediate fluoxetine but not desipramine-induced increase of extracellular dopamine in the prefrontal cortex

Fluoxetine and desipramine, two antidepressants that block selectively the serotonin and the noradrenaline carrier, increase extracellular dopamine concentrations in the prefrontal cortex of freely-moving rats. This effect is calcium dependent and is prevented, in the case of fluoxetine but not desipramine, by systemic pretreatment with low doses or by low concentrations in the dialyzing Ringer of the potent 5-HT₃ antagonist ICS 205930. Fluoxetine, but not desipramine, increases extracellular serotonin concentrations in the prefrontal cortex. The results indicate that selective serotonin reuptake blockers increase extracellular dopamine in the prefrontal cortex by stimulating local 5-HT₃ receptors.     

Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies

Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the blockade of serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline transporters. These drugs show slow onset of clinical action and limited efficacy, partly due to the activation of physiological negative feed-back mechanisms operating through autoreceptors (5-HT_1A, 5-HT_1B, α₂-adrenoceptors) and postsynaptic receptors (e.g., 5-HT₃). As a result, clinically-relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei but not in forebrain, as indicated by rodent microdialysis studies and by PET-scan studies in primate/human brain. The prevention of these self-inhibitory mechanisms by antagonists of the above receptors augments preclinical and clinical antidepressant effects. Hence, the mixed ß-adrenoceptor/5-HT_1A antagonist pindolol accelerated, and in some cases enhanced, the clinical action of selective serotonin reuptake inhibitors (SSRI). This strategy has been incorporated into two new multi-target antidepressant drugs, vilazodone and vortioxetine, which combine 5-HT reuptake inhibition and partial agonism at 5-HT_1A receptors. Vortioxetine shows also high affinity for other 5-HT receptors, including excitatory 5-HT₃ receptors located in cortical and hippocampal GABA interneurons. 5-HT₃ receptor blockade by vortioxetine enhances pyramidal neuron activity in prefrontal cortex as well as cortical and hippocampal 5-HT release. It is still too soon to know whether these new antidepressants will represent a real advance over existing drugs in the real world. However, their development opened the way to future antidepressant drugs based on the prevention of local and distal self-inhibitory mechanisms attenuating monoamine activity.     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.     

The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat.

Dopaminergic axons innervating the prefrontal cortex (PFC) target both pyramidal cells and GABAergic interneurons. Many of these dopamine (DA) axons in the rat coexpress the peptide neurotransmitter neurotensin. Previous electrophysiological data have suggested that neurotensin activates GABAergic interneurons in the PFC. Activation of D2-like DA receptors increases extracellular GABA levels in the PFC, as opposed to the striatum, where D2 receptor activation inhibits GABAergic neurons. Because activation of presynaptic D2 release-modulating autoreceptors in the PFC suppresses DA release but increases release of the cotransmitter neurotensin, D2 agonists may enhance the activity of GABAergic interneurons via release of neurotensin. In order to determine if neurotensin can activate GABAergic interneurons, we treated rats with the peptide neurotensin agonist, PD149163, and examined Fos expression in PFC neurons. Systemic administration of PD149163 increased overall Fos expression in the PFC, but not in the dorsal striatum. PD149163 induced Fos in PFC interneurons, as defined by the presence of calcium-binding proteins, and in pyramidal cells. Pretreatment with the high-affinity neurotensin antagonist, SR48692, blocked neurotensin agonist-induced Fos expression. These data suggest that neurotensin activates interneurons in the PFC of the rat.     

Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

Blonanserin differs from currently used serotonin 5-HT_2A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D_2/3 receptors than for serotonin 5-HT_2A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT_2A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr¹⁹⁷ and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser⁸⁹⁷ by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser⁸⁹⁶ by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT_2A receptors in the mPFC.     

Dopamine Modulation of GABAergic Function Enables Network Stability and Input Selectivity for Sustaining Working Memory in a Computational Model of the Prefrontal Cortex

Dopamine modulation of GABAergic transmission in the prefrontal cortex (PFC) is thought to be critical for sustaining cognitive processes such as working memory and decision-making. Here, we developed a neurocomputational model of the PFC that includes physiological features of the facilitatory action of dopamine on fast-spiking interneurons to assess how a GABAergic dysregulation impacts on the prefrontal network stability and working memory. We found that a particular non-linear relationship between dopamine transmission and GABA function is required to enable input selectivity in the PFC for the formation and retention of working memory. Either degradation of the dopamine signal or the GABAergic function is sufficient to elicit hyperexcitability in pyramidal neurons and working memory impairments. The simulations also revealed an inverted U-shape relationship between working memory and dopamine, a function that is maintained even at high levels of GABA degradation. In fact, the working memory deficits resulting from reduced GABAergic transmission can be rescued by increasing dopamine tone and vice versa. We also examined the role of this dopamine–GABA interaction for the termination of working memory and found that the extent of GABAergic excitation needed to reset the PFC network begins to occur when the activity of fast-spiking interneurons surpasses 40 Hz. Together, these results indicate that the capability of the PFC to sustain working memory and network stability depends on a robust interplay of compensatory mechanisms between dopamine tone and the activity of local GABAergic interneurons.     

Role of 5-HT1A receptors in the modulation of stress-induced lactate metabolism in the medial prefrontal cortex and basolateral amygdala

Rationale Lactate has been shown to play a significant role in energy metabolism and reflect neural activity in the brain.Objectives Using in vivo microdialysis technique, we measured extracellular lactate concentrations in the medial prefrontal cortex (mPFC) and the basolateral amygdaloid (BLA) nucleus of rats under electric foot shock stress. Moreover, to examine the role of serotonin (5-HT)_1A receptors in brain energy metabolism in response to stressors, we attempted to determine whether the stress-induced changes of extracellular lactate levels in the mPFC and BLA are attenuated by tandospirone, a partial agonist at 5-HT_1A receptors, or perospirone, a novel atypical antipsychotic with a 5-HT_1A receptor partial agonist and 5-HT_2A/dopamine-D₂ antagonist property.Results Foot shock stress led to an increase in extracellular lactate concentrations both in the mPFC and BLA. Tandospirone (2 mg/kg) attenuated the foot shock stress-induced increase of extracellular lactate concentrations in both of the brain regions, which was blocked by pretreatment with WAY-100635, a selective 5-HT_1A antagonist. On the other hand, perospirone (0.3 mg/kg) attenuated the increment of extracellular lactate concentrations in the mPFC and BLA, which was unaltered by pretreatment with WAY-100635.Conclusions These results indicate that the foot shock stress-induced increase in lactate metabolism is partly regulated by 5-HT_1A receptors both in cortical and limbic regions.     

Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved

Rationale  Second-generation antipsychotics have some beneficial effect on cognition. Recent studies, furthermore, indicate differential effects of second-generation antipsychotics on impairment in executive cognitive function. Objective  We evaluated the effect of the second-generation antipsychotic drug, sertindole, on extracellular levels of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in the rat medial prefrontal cortex (mPFC). Risperidone was studied for comparison. Moreover, selective serotonin 5-HT_2A, 5-HT_2C, and 5-HT₆ receptor antagonists were used, given alone and in combination with the preferential DA D₂ receptor antagonist, haloperidol, to further clarify the action of the two drugs. Materials and methods  Rats were treated acutely with vehicle or drugs, and extracellular levels of neurotransmitters were assessed by microdialysis in freely moving animals. Results  Sertindole and risperidone significantly increased extracellular levels of DA. Haloperidol; the 5-HT_2A receptor antagonist, M100907; the 5-HT_2C receptor antagonist, SB242084; and the 5-HT₆ receptor antagonist, GSK-742457, induced minor increases in levels of DA, but the three latter compounds raised the DA levels notably in combination with haloperidol. Sertindole and risperidone significantly increased the extracellular levels of ACh but only sertindole raised the extracellular levels of Glu. The selective 5-HT₆ receptor antagonist, SB-271046, significantly increased the extracellular levels of Glu. Conclusion  Sertindole and risperidone markedly increased extracellular levels of DA in mPFC. The built-in 5-HT_2A/5-HT_2C/D₂ receptor antagonism of the two drugs might be involved in this action. Both drugs increased the extracellular levels of ACh but only sertindole enhanced Glu levels. The high affinity of sertindole for the 5-HT₆ receptor compared to risperidone may differentiate sertindole from risperidone.     

MS-377, a novel selective sigma(1) receptor ligand, reverses phencyclidine-induced release of dopamine and serotonin in rat brain

A novel selective sigma(1) receptor ligand, (R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377), inhibits phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP)-induced behaviors in animal models. In this study, we measured extracellular dopamine and serotonin levels in the rat brain after treatment with MS-377 alone, using in vivo microdialysis. We also examined the effects of MS-377 on extracellular dopamine and serotonin levels in the rat medial prefrontal cortex after treatment with PCP. MS-377 itself had no significant effects on dopamine release in the striatum (10 mg/kg, p.o.) nor on dopamine or serotonin release in the medial prefrontal cortex (1 and 10 mg/kg, p.o.). PCP (3 mg/kg, i.p.) markedly increased dopamine and serotonin release in the medial prefrontal cortex. MS-377 (1 mg/kg, p.o.), when administered 60 min prior to PCP, significantly attenuated this effect of PCP. These results suggest that the inhibitory effects of MS-377 on PCP-induced behaviors are partly mediated by inhibition of the increase in dopamine and serotonin release in the rat medial prefrontal cortex caused by PCP.     

Asenapine elevates cortical dopamine,noradrenaline and serotonin release. Evidence for activation of cortical and subcortical dopamine systems by different mechanisms

Rationale  Asenapine, a psychopharmacologic agent developed for schizophrenia and bipolar disorder, has higher affinity for 5-HT_2A/C,6,7 and α₂ adrenergic receptors than for D₂ receptors. Asenapine exhibits potent antipsychotic-like effects without inducing catalepsy, increases cortical and subcortical dopamine release, and facilitates cortical glutamatergic transmission in rats. In this study, we further analyzed the effects of asenapine on dopaminergic, noradrenergic, and serotonergic systems in the rat brain. Materials and methods  We studied the effects of asenapine on (1) dopaminergic neurons in the ventral tegmental area (VTA) and noradrenergic neurons in the locus coeruleus using in vivo single cell recording, (2) release of dopamine and noradrenaline (medial prefrontal cortex), serotonin (frontal cortex), and dopamine (nucleus accumbens), using in vivo microdialysis. Results  Systemic asenapine increased dopaminergic (0.001–0.2 mg/kg, i.v.) and noradrenergic (0.025–0.05 mg/kg i.v.) neuronal firing, and asenapine (0.1–0.2 mg/kg, s.c) increased cortical noradrenaline and serotonin output. Local asenapine administration increased all three monoamines in the cortex but did not affect accumbal dopamine output. Intra-VTA tetrodotoxin perfusion blocked asenapine-induced accumbal but not cortical dopamine outflow. Conclusion  Asenapine at doses associated with antipsychotic activity enhanced cortical monoamine efflux. Whereas the asenapine-induced dopamine increase in nucleus accumbens is dependent on activation of dopaminergic neurons in the VTA, the increase of cortical dopamine outflow involves largely a local action at nerve terminals. Our data provide further insight on the pharmacologic characteristics of asenapine that may have bearing on its clinical efficacy in the treatment of schizophrenia and bipolar disorder.     

Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectively in the mesolimbic dopaminergic system

The atypical profile of clozapine and some other new atypical antipsychotic drugs has been attributed to a relatively selective effect on the mesolimbic dopaminergic system, as well as to their potent serotonin 5-HT₂ receptor antagonism and high ratio of 5-HT₂ to dopamine D₂ receptor affinities. It is unclear, however, how concurrent 5-HT₂ and D₂ receptor antagonism specifically affects the mesoaccumbens and the mesocortical dopaminergic systems.The present study examined the effect of pretreatment with the 5-HT₂ receptor antagonist, ritanserin, on changes in midbrain dopamine neuronal activity as well as in forebrain, extracellular concentrations of dopamine, induced by relatively low doses of the D₂ receptor antagonist raclopride, utilizing in vivo extracellular single cell recording techniques and voltammetry in anesthetized rats, as well as microdialysis in freely moving rats. Raclopride alone (10–2560 g/kg, i.v.) induced a dose-dependent increase in three parameters of neuronal activity, i.e. burst firing, firing rate and variation coefficient, of midbrain DA neurons. This effect of raclopride was more pronounced in cells of the ventral tegmental area than in cells of the substantia nigra-zona compacta. Ritanserin alone (1.0 mg/kg, i.v.) also increased all three parameters of neuronal activity in dopamine cells of the ventral tegmental area, but only firing rate in the cells of the substantia nigra. Ritanserin pretreatment (30 min) significantly enhanced the stimulatory effects of low doses of raclopride (10–20 g/kg) on burst firing in dopamine neurons, preferentially in the ventral tegmental area. Raclopride alone (50 g/kg, s.c.) increased extracellular concentrations of dopamine in the medial prefrontal cortex and the dorsolateral striatum by 75 and 110%, respectively, as measured by microdialysis. Ritanserin alone (1.5 mg/kg, s.c.) did not significantly affect cortical and striatal extracellular dopamine concentrations; however, pretreatment (40 min) with ritanserin elevated the raclopride-induced increase of dopamine concentrations in the medial prefrontal cortex to about 250%, but failed to affect the action of raclopride on striatal dopamine levels. Raclopride alone (10 and 320 g/kg, i.v.) dose-dependently increased extracellular concentrations of dopamine in the nucleus accumbens and the dorsolateral striatum to about 500%, as determined by voltammetry. Ritanserin alone (1.0 mg/kg, i.v.) did not significantly affect the voltammetric dopamine signal in the nucleus accumbens or the dorsolateral striatum; however, ritanserin pretreatment (30 min) enhanced the raclopride-induced increase in accumbal but not striatal dopamine concentrations to about 1600%. The stimulatory effect of the combined ritanserin plus raclopride treatment on neuronal activity and DA release was more pronounced in the mesolimbic than the nigrostriatal dopaminergic system.The present data indicate that concurrent 5-HT₂ and D₂ receptor antagonism selectively affects the activity of the mesolimbic dopaminergic system. These findings provide an experimental basis for the notion that combined 5-HT₂ and D₂ receptor antagonism may underlie the limbic mode of action of at least some atypical antipsychotic drugs and consequently contribute to their unique therapeutic effects.     

A combination of mirtazapine and milnacipran augments the extracellular levels of monoamines in the rat brain

Mirtazapine, an antidepressant, antagonizes α(2)-adrenergic autoreceptors and heteroreceptors, which leads to enhanced noradrenergic and serotonergic transmission without inhibiting monoamine transporters. Using a microdialysis technique, we investigated whether co-administration of mirtazapine and a serotonin noradrenaline reuptake inhibitor (SNRI), milnacipran, augments the effects of each drug on the extracellular levels of monoamines by pharmacological synergy. Mirtazapine increased the extracellular levels of noradrenaline and serotonin in the dorsal hippocampus. In contrast, it increased the levels of noradrenaline and dopamine without changing serotonin levels in the prefrontal cortex. Milnacipran increased the levels of all monoamines evaluated in both areas, and the combined treatment with mirtazapine augmented these changes. The combined treatment with idazoxan, an α(2) adrenoceptor antagonist, and milnacipran also increased all monoamine levels in the prefrontal cortex. Ketanserin, a serotonin 5-HT(2A) receptor antagonist, showed no effect in combination with milnacipran, while SB242084, a 5-HT(2C) receptor antagonist, augmented the effects of milnacipran on the levels of serotonin and dopamine in the prefrontal cortex. These results suggest that combined treatment with mirtazapine and milnacipran augments the extracellular levels of noradrenaline, serotonin and dopamine through the blockade of α(2) adrenoceptors without regional specificity, whereas mirtazapine enhances serotonergic transmission in a region-specific manner. 5-HT(2C) receptor antagonism may also partly contribute to the amplification effects of mirtazapine on serotonin and dopamine levels. These neurochemical changes could play a role in reported advantageous clinical effects in patients treated with an SNRI and mirtazapine.     

Functional mechanism of ASP5736, a selective serotonin 5-HT5A receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia

The 5-HT_5A receptor is arguably the least understood 5-HT receptor. Despite widespread expression in human and rodent brains it lacks specific ligands. Our previous results suggest that 5-HT_5A receptor antagonists may be effective against cognitive impairment in schizophrenia. In this study, using behavioral, immunohistochemical, electrophysiological and microdialysis techniques, we examined the mechanism by which ASP5736, a novel and selective 5-HT_5A receptor antagonist, exerts a positive effect in animal models of cognitive impairment. We first confirmed the effect of ASP5736 on cognitive deficits in rats treated subchronically with phencyclidine hydrochloride (PCP) using an attentional set shifting task. Subsequently, we identified 5-HT_5A receptors in dopaminergic (DAergic) neurons and parvalbumin (PV)-positive interneurons in the ventral tegmental area (VTA) and in PV-positive interneurons in the medial prefrontal cortex (mPFC). Burst firing of the DAergic cells in the parabrachial pigmental nucleus (PBP) in the VTA, which predominantly project to the mPFC, was significantly enhanced by treatment with ASP5736. In contrast, ASP5736 exerted no significant effect on either the firing rate or burst firing in the DA cells in the paranigral nucleus (PN), that project to the nucleus accumbens (N. Acc.). ASP5736 increased the release of DA and gamma-aminobutyric acid (GABA) in the mPFC of subchronically PCP-treated rats. These results support our hypothesis that ASP5736 might block the inhibitory 5-HT_5A receptors on DAergic neurons in the VTA that project to the mPFC, and interneurons in the mPFC, and thereby improve cognitive impairment by preferentially enhancing DAergic and GABAergic neurons in the mPFC.     

Effects of imipramine on raphe nuclei and prefrontal cortex extracellular serotonin levels in the rat

 The effect of acute administrations of three doses of imipramine (1, 5 and 10 mg/kg SC), a widely used tricyclic antidepressant, on extracellular levels of serotonin (5-HT) has been studied by intracerebral microdialysis in raphe nuclei and prefrontal cortex of conscious rats. Imipramine 1 mg/kg SC did not change extracellular 5-HT in either raphe nuclei and prefrontal cortex. However, with the dose of 5 mg/kg SC imipramine induced in raphe nuclei, a brief increase of extracellular 5-HT followed by a lowering (55–65% basal release) of the neurotransmitter. The same dose of imipramine decreased (60–70% of basal value) extracellular 5-HT in prefrontal cortex. Imipramine 10 mg/kg SC significantly increased 5-HT levels in both raphe nuclei (190 ± 20% above basal value) and prefrontal cortex (280 ± 15% above basal value). Pretreatment with (-)pindolol (5 mg/kg SC), a non-selective 5-HT_1A subtype receptor antagonist, 30 min before imipramine 5 mg/kg, modified the effect of the antidepressant: an increase, instead of a decrease, on prefrontal cortex dialysate 5-HT was observed. (-)Pindolol (10 mg/kg SC) increased extracellular 5-HT in both raphe nuclei (155 ± 20% above basal value) and prefrontal cortex (160 ± 8% above basal value). These data show that acute administration of imipramine modifies extracellular 5-HT at the level of the raphe nuclei and prefrontal cortex. 5-HT_1A autoreceptors in the raphe nuclei, which this study suggests to be tonically active, may be stimulated after systemic administration of high doses of imipramine. Received: 10 April 1997 / Final version: 30 June 1997     

Activation of metabotropic glutamate 2/3 receptors attenuates methamphetamine-induced hyperlocomotion and increase in prefrontal serotonergic neurotransmission

Rationale

Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induced hyperlocomotion. The mechanism for the antipsychotic effect of mGlu2/3 receptor agonists was studied in a hypoglutamatergic model, but not a hyperdopaminergic model.

Objectives

To study the mechanism for the antipsychotic effect of the agonist in the hyperdopaminergic model, this study examined the effects of the selective mGlu2/3 receptor agonist MGS0028 on methamphetamine-induced hyperlocomotion and the increases in extracellular levels of serotonin, dopamine, noradrenaline, and glutamate in the prefrontal cortex and nucleus accumbens of mice.

Results

Systemic administration of MGS0028 attenuated methamphetamine-induced hyperlocomotion in a dose-dependent manner. Microdialysis studies showed that MGS0028 significantly inhibited methamphetamine-induced increases in the extracellular serotonin, but not dopamine and noradrenaline, levels in the prefrontal cortex, and it did not affect methamphetamine-induced increases in the extracellular amine levels in the nucleus accumbens. Methamphetamine did not affect the glutamate release in the prefrontal cortex and nucleus accumbens. Local application of MGS0028 into the prefrontal cortex also attenuated methamphetamine-induced hyperlocomotion and increases in the extracellular serotonin levels in the prefrontal cortex. Moreover, MGS0028 did not affect methamphetamine-induced hyperlocomotion in the mice pretreated with p-chlorophenylalanine, a serotonin synthesis inhibitor.

Conclusions

Activation of prefrontal mGlu2/3 receptors inhibits the psychomotor stimulant effect of methamphetamine in mice, and the prefrontal serotonergic system may be involved in this effect. The finding provides evidence that prefrontal mGlu2/3 receptors are functionally coupled with the serotonergic system.     

Measuring GABAergic Inhibitory Activity with TMS-EEG and Its Potential Clinical Application for Chronic Pain

Chronic pain is debilitating disorder in which the underlying pathophysiology is still unknown. Impaired cortical inhibition is one mechanism that is associated with chronic pain. Cortical inhibition refers to a neurophysiological process in which gamma-aminobutyric acid (GABA) inhibitory interneurons selectively attenuate the activity of pyramidal neurons in the cortex. Previous studies have capitalized on the ability of transcranial magnetic stimulation (TMS) to index cortical inhibition by stimulating the motor cortex and measuring the resulting peripheral motor evoked potentials with electromyography. Chronic pain has been shown to induce changes in cortical inhibition within the motor cortex using TMS. Electroencephalography (EEG) studies also demonstrate that gamma (30–50 Hz) oscillations in the prefrontal and somatosensory cortex are associated with the experience of pain. As gamma oscillations are mediated by GABA, the combination of TMS with EEG allows for the examination of the relationship between cortical inhibition, gamma and chronic pain. In this paper, we summarize the evidence of impaired GABAergic and gamma oscillations in chronic pain patients. We then demonstrate TMS-EEG as a reliable method in which to record cortical inhibition directly from the prefrontal cortex to examine the modulatory effect of GABA_B receptor inhibition on cortical oscillations. Finally, the modulation of GABA and gamma oscillations with repetitive TMS will be suggested as the possible mechanism through which rTMS exerts its therapeutic effects in the treatment of pain. The aim of this paper, therefore, is to present the TMS-EEG as a potential method through which to better classify, diagnose and treat chronic pain.     

GABA, but not opioids, mediates the anti-hyperalgesic effects of 5-HT(7) receptor activation in rats suffering from neuropathic pain

Among receptors mediating serotonin actions in pain control, the 5-HT₇R is of special interest because it is expressed by primary afferent fibers and intrinsic GABAergic and opioidergic interneurons within the spinal dorsal horn. Herein, we investigated whether GABA and/or opioids contribute to 5-HT₇R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT₇R agonists (AS-19, MSD-5a, E-55888) was found to markedly reduce mechanical and thermal hyperalgesia in rats with unilateral constriction injury to the sciatic nerve (CCI-SN). In contrast, mechanical hypersensitivity caused by unilateral constriction injury to the infraorbital nerve was essentially unaffected by these ligands. Further characterization of the anti-hyperalgesic effect of 5-HT₇R activation by the selective agonist E-55888 showed that it was associated with a decrease in IL-1ß mRNA overexpression in ipsilateral L4–L6 dorsal root ganglia and lumbar dorsal horn in CCI-SN rats. In addition, E-55888 diminished CCI-SN-associated increase in c-Fos immunolabeling in superficial laminae of the lumbar dorsal horn and the locus coeruleus, but increased c-Fos immunolabeling in the nucleus tractus solitarius and the parabrachial area in both control and CCI-SN rats. When injected intrathecally (i.t.), bicuculline (3 μg i.t.), but neither phaclofen (5 μg i.t.) nor naloxone (10 μg i.t.), significantly reduced the anti-hyperalgesic effects of 5-HT₇R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT₇R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT₇R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supraspinal mechanisms might also be involved.     

Combination of escitalopram and a 5-HT(₁A) receptor antagonist selectively decreases the extracellular levels of dopamine in the nucleus accumbens relative to striatum through 5-HT(₂C) receptor stimulation; suggestive of antipsychotic potential

Serotonin 5-HT_2C receptors are widely distributed throughout the brain located on GABAergic interneurons and afferent neurons in the ventral tegmental area and substantia nigra. Consequently, activation of this receptor modulates the dopaminergic neurotransmission. The antipsychotic potential of the combined treatment with escitalopram, in therapeutic relevant doses, and the 5-HT_1A receptor antagonist, WAY-100635, has been evaluated by assessment of conditioned avoidance (CAR) behaviour and the use of microdialysis in freely moving rats. The combined treatment was found to decrease both CAR behaviour without affecting escape failures and the basal extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) acutely without affecting DA levels in the striatum, suggesting an antipsychotic-like effect with mesolimbic selectivity. The escitalopram/WAY-100635-induced changes in CAR behaviour and DA were prevented by pretreatment with the 5-HT_2C receptor antagonist, SB242084, indicating that the effects are mediated by stimulation of the 5-HT_2C receptor. Thus, indirect activation of the 5-HT_2C receptor may induce antipsychotic-like effects. The observations on DA levels were in line with the findings made with the selective 5-HT_2C receptor agonist, vabicaserin, which was also shown to produce a mesolimbic selective decrease in DA levels in the present study. In addition, it was demonstrated that escitalopram, in combination with the partial 5-HT_1A agonist, (-)-pindolol, decreased basal DA levels in the NAc. A potential therapeutic effect could readily be assessed, since both escitalopram and (-)-pindolol are already on the market.