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Background and Purpose: The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective.Experimental Approach: We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430).Key Results: DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects.Conclusions and Implications: DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT1A autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT1A receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT1A autoreceptors. However, it is unclear whether 5-HT1A receptor antagonists not discriminating between pre- and post-synaptic 5-HT1A receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT1A receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT1A receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT1A receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT1A receptor antagonist. However, blockade of post-synaptic 5- HT1A receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function. [ABSTRACT FROM AUTHOR]

Background and Purpose: F15599, a novel 5-hydroxytryptamine (5-HT)(1A) receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT(1A) heteroreceptors.Experimental Approach: In vivo single unit and local field potential recordings and microdialysis in the rat.Key Results: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 microg x kg(-1) i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 microg x kg(-1) i.v.). Both effects were reversed by the 5-HT(1A) antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (approximately 1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT(1A) receptors) with an ED(50) of 30 microg x kg(-1) i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT(1A) autoreceptor activation) with an ED(50) of 240 microg x kg(-1) i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (+/-)WAY100635.Conclusions and Implications: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT(1A) receptors in PFC rather than somatodendritic 5-HT(1A) autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT(1A) receptor agonists, which preferentially activate somatodendritic 5-HT(1A) autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT2 receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. Method: To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). Results: The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Conclusion: Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors. [ABSTRACT FROM AUTHOR]

The dual-specificity tyrosine-phosphorylated and regulated kinase 1A ( DYRK1A) gene encodes a protein kinase known to play a critical role in neurodevelopment. Mice with one functional copy of Dyrk1A (Dyrk1A+/−) display a marked hypoactivity and altered gait dynamics in basal conditions and in novel environments. Dopamine (DA) is a key neurotransmitter in motor behavior and genetic deletion of certain genes directly related to the dopaminergic system has a strong impact on motor activity. We have studied the effects of reduced Dyrk1A expression on the function of the nigrostriatal dopaminergic system. To characterize the dopaminergic system in DYRK1A+/− mice, we have used behavioral, pharmacological, histological, neurochemical and neuroimaging (microPET) techniques in a multidisciplinary approach. Dyrk1A+/− mice exhibited decreased striatal DA levels, reduced number of DA neurons in the substantia nigra pars compacta, as well as altered behavioral responses to dopaminergic agents. Moreover, microdialysis experiments revealed attenuated striatal DA release and positron emission tomography scan display reduced forebrain activation when challenged with amphetamine, in Dyrk1A+/− compared with wild-type mice. These data indicate that Dyrk1A is essential for a proper function of nigrostriatal dopaminergic neurons and suggest that Dyrk1A+/− mice can be used to study the pathogenesis of motor disorders involving dopaminergic dysfunction. [ABSTRACT FROM AUTHOR]

The release of 5-HT in terminal areas of the rodent brain is regulated by 5-HT[sub 1B] receptors. Here we examined the role of 5-HT[sub 1B] receptors in the control of 5-HT output and firing in the dorsal raphe nucleus (DR), median raphe nucleus (MnR) and forebrain of the rat in vivo. The local perfusion (30–300 µm) of the selective 5-HT[sub 1B] receptor agonist CP-93,129 to freely moving rats decreased 5-HT release in the DR and more markedly in the MnR. Likewise, 300 µm CP-93,129 reduced 5-HT output in substantia nigra pars reticulata, ventral pallidum, lateral habenula and the suprachiasmatic nucleus. The effect of CP-93,129 was prevented by SB-224289, but not by WAY-100635, selective 5-HT[sub 1B] and 5-HT[sub 1A] receptor antagonists, respectively. SB-224289 did not alter dialysate 5-HT in any raphe nuclei. The intravenous administration of the brain-penetrant selective 5-HT[sub 1B] receptor agonist CP-94,253 (0.5–2.0 mg/kg) to anesthetized rats decreased dialysate 5-HT in dorsal hippocampus and globus pallidus, increased it in MnR and left it unaltered in the DR and medial prefrontal cortex. SB-224289, at a dose known to block 5-HT[sub 1B] autoreceptor-mediated effects (5 mg/kg), did not prevent the effect of CP-94,253 on MnR 5-HT. The intravenous administration of CP-94,253 (0.05–1.6 mg/kg) to anesthetized rats increased the firing rate of MnR, but not DR-5-HT neurons. The local perfusion of CP-94,253 in the MnR showed a biphasic effect, with 5-HT reductions at 0.3–3 µm and increase at 300 µm. These results suggest that 5-HT cell firing and release in midbrain raphe nuclei (particularly in the MnR) are under control of 5-HT[sub 1B] receptors. The activation of 5-HT[sub 1B] autoreceptors (possibly located on 5-HT nerve endings and/or varicosities within DR and MnR) reduces 5-HT release. The effects of higher concentrations of 5-HT[sub 1B] receptor agonists seem more compatible with the activation of 5-HT[sub 1B] heteroreceptors on inhibitory neurons. [ABSTRACT FROM AUTHOR]

Abstract: Single treatment with the serotonin (5-hydroxytryptamine)5-HT[sub 1A] receptor agonists8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and alnespirone(S-20499) reduces the extracellular 5-HT concentration (5-HT[sub ext]) inthe rat midbrain and forebrain. Given the therapeutic potential of selective5-HT[sub 1A] agonists in the treatment of affective disorders, we haveexamined the changes in 5-HT[sub 1A] receptors induced by 2-week minipumpadministration of alnespirone (0.3 and 3 mg/kg/day) and 8-OH-DPAT (0.1 and 0.3mg/kg/day). The treatment with alnespirone did not modify baseline5-HT[sub ext] but significantly attenuated the ability of 0.3 mg/kg s.c.alnespirone to reduce 5-HT[sub ext] in the dorsal raphe nucleus (DRN) andfrontal cortex. In contrast, the ability of 8-OH-DPAT (0.025 and 0.1 mg/kgs.c.) to reduce 5-HT[sub ext] in both areas was unchanged by 8-OH-DPATpretreatment. Autoradiographic analysis revealed a significant reduction of[[sup 3]H]8-OH-DPAT and [[sup 3]H]WAY-100635 {[sup 3]H-labeledN-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide· 3HCl} binding to somatodendritic 5-HT[sub 1A] receptors (but notto postsynaptic 5-HT[sub 1A] receptors) of rats pretreated withalnespirone but not with 8-OH-DPAT. In situ hybridization analysis revealed nochange of the density of the mRNA encoding the 5-HT[sub 1A] receptors inthe DRN after either treatment. These data indicate that continuous treatmentfor 2 weeks with alnespirone, but not with 8-OH-DPAT, causes a functionaldesensitization of somatodendritic 5-HT[sub 1A] receptors controlling5-HT release in the DRN and frontal cortex. [ABSTRACT FROM AUTHOR]

The dual-specificity tyrosine-phosphorylated and regulated kinase 1A ( DYRK1A) gene encodes a protein kinase known to play a critical role in neurodevelopment. Mice with one functional copy of Dyrk1A (Dyrk1A+/−) display a marked hypoactivity and altered gait dynamics in basal conditions and in novel environments. Dopamine (DA) is a key neurotransmitter in motor behavior and genetic deletion of certain genes directly related to the dopaminergic system has a strong impact on motor activity. We have studied the effects of reduced Dyrk1A expression on the function of the nigrostriatal dopaminergic system. To characterize the dopaminergic system in DYRK1A+/− mice, we have used behavioral, pharmacological, histological, neurochemical and neuroimaging (microPET) techniques in a multidisciplinary approach. Dyrk1A+/− mice exhibited decreased striatal DA levels, reduced number of DA neurons in the substantia nigra pars compacta, as well as altered behavioral responses to dopaminergic agents. Moreover, microdialysis experiments revealed attenuated striatal DA release and positron emission tomography scan display reduced forebrain activation when challenged with amphetamine, in Dyrk1A+/− compared with wild-type mice. These data indicate that Dyrk1A is essential for a proper function of nigrostriatal dopaminergic neurons and suggest that Dyrk1A+/− mice can be used to study the pathogenesis of motor disorders involving dopaminergic dysfunction. [ABSTRACT FROM AUTHOR]

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

In the rat, postsynaptic 5-hydroxytryptamine2A receptors medial prefrontal cortex control the activity of the serotonergic system through changes in the activity of pyramidal neurons projecting to the dorsal raphe nucleus. Here we extend these observations to mouse brain. The prefrontal cortex expresses abundant 5- hydroxytryptamine2A receptors, as assessed by immunohistochemistry, Western blots and in situ hybridization procedures. The application of the 5-hydroxytryptamine2A/2C agonist DOI (100 microm) by reverse dialysis in the medial prefrontal cortex doubled the local release of 5-hydroxytryptamine. This effect was reversed by coperfusion of tetrodotoxin, and by the selective 5-hydroxytryptamine2A receptor antagonist M100907, but not by the 5-hydroxytryptamine2C antagonist SB-242084. The effect of DOI was also reversed by prazosin (alpha1-adrenoceptor antagonist), BAY x 3702 (5-hydroxytryptamine1A receptor agonist), NBQX (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate/kainic acid antagonist) and 1S,3S-ACPD (mGluR II/III agonist), but not by dizocilpine (N-methyl-d-aspartate antagonist). alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate mimicked the 5-hydroxytryptamine elevation produced by DOI, an effect also reversed by BAY x 3702. Likewise, the coperfusion of classical (chlorpromazine, haloperidol) and atypical antipsychotic drugs (clozapine, olanzapine) fully reversed the 5-hydroxytryptamine elevation induced by DOI. These observations suggest that DOI increases 5-hydroxytryptamine release in the mouse medial prefrontal cortex through the activation of local 5-hydroxytryptamine2A receptors by an impulse-dependent mechanism that involves/requires the activation of local alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate receptors. This effect is reversed by ligands of receptors present in the medial prefrontal cortex, possibly in pyramidal neurons, which are involved in the action of antipsychotic drugs. In particular, the reversal by classical antipsychotics may involve blockade of alpha1-adrenoceptors, whereas that of atypical antipsychotics may involve 5-hydroxytryptamine2A receptors and alpha1-adrenoceptors.

In this study we investigated, using in vivo microdialysis and single unit recordings, the role of serotonin4 (5-HT4) receptors in the control of nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity. In freely moving rats, the 5-HT4 antagonist GR 125487 (1 mg/kg, i.p.), without effect on its own, significantly reduced the enhancement of striatal DA outflow induced by 0.01 (-35%) and 0.1 (-66%), but not 1 mg/kg, s.c. haloperidol (HAL). Intrastriatal infusion of GR 125487 (1 microM) had no influence on basal DA outflow, but attenuated (-49%) the effect of 0.01 mg/kg HAL. Systemic administration of GR 125487 modified neither basal nor 0.01 mg/kg HAL-stimulated accumbal DA outflow. In halothane-anaesthetized rats, 1 or 10 mg/kg GR 125487, without effect by itself, failed to modify the changes in accumbal and striatal DA outflow elicited by electrical stimulation (300 microA, 1 ms, 20 Hz, 15 min) of the dorsal raphe nucleus. Finally, GR 125487 (444 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra or the ventral tegmental area, reduced HAL-stimulated (1--300 microg/kg, i.v.) impulse flow of nigrostriatal DA neurons only. These results indicate that 5-HT4 receptors exert a facilitatory control on both striatal DA release and nigral DA neuron impulse flow only when nigrostriatal DA transmission is under activated conditions. Furthermore, they indicate that the striatum constitutes a major site for the expression of the control exerted by 5-HT4 receptors on DA release. In contrast, 5-HT4 receptors have no influence on mesoaccumbal DA activity in either basal or activated conditions.

The present study was conducted in order to examine the influence of catecholaminergic afferents on the release of serotonin in the median raphe nucleus in vivo. To this aim, selective dopamine D1 and D2, and alpha1- and alpha2-adrenergic agonists and antagonists were administered locally (1, 10 and 100 microM) through a dialysis probe implanted in the median raphe nucleus of freely moving rats. The D1 and D2 agonists, (+/-)-1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF-38393) and quinpirole, respectively, and the D1 and D2 antagonists, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH-23390) and raclopride, respectively, did not alter the release of serotonin in the median raphe nucleus. The alpha1-adrenoceptor agonist phenylephrine did not modify the release of serotonin in this nucleus, although an increased release was observed when the more potent alpha1-adrenoceptor agonist cirazoline was used. In contrast, the alpha1-adrenoceptor antagonist prazosin reduced the release of 5-hydroxytryptamine (5-HT) in a concentration-dependent manner. The release of 5-HT was also reduced by the alpha2-adrenoceptor agonist clonidine and increased by the alpha2-adrenoceptor antagonist 2-methoxy-idazoxan (RX821002). These results indicate that the release of serotonin in the median raphe nucleus does not appear to be regulated by dopaminergic afferents through the activation of dopamine D1 or D2 receptors. On the contrary, it is suggested that endogenous noradrenaline exerts a direct tonic stimulatory control on the release of serotonin through alpha1-adrenoceptors, and an indirect tonic inhibitory influence through alpha2-adrenoceptors located probably in noradrenergic nerve terminals within the median raphe nucleus.

We assessed the role of glial cells in the uptake of serotonin (5-hydroxytryptamine, 5-HT). Primary cultures of rat and mouse cortical astrocytes took up and deaminated 5-HT. The antidepressants citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine and sertraline inhibited this process. The presence of the mRNAs for the 5-HT transporter and monoamine oxidase-A (MOA-A) was established in cultured astrocytes and in adult rat brain areas with (midbrain and brainstem) and without (frontal cortex) serotonergic cell bodies after reverse transcription-polymerase chain reaction and hybridization with probes complementary to the cloned neuronal 5-HT transporter and MAO-A. To examine in vivo the role of astrocytes in the elimination of 5-HT from the extracellular brain space, 5-HT was perfused through dialysis probes implanted in the frontal cortex of conscious rats and its concentration was measured at the probe outlet. Tissue 5-HT recovery was dose-dependently inhibited by the concurrent perfusion of citalopram, fluoxetine and paroxetine, showing that it essentially measured uptake through the high-affinity 5-HT transporter. Rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT; 88% reduction of tissue 5-HT) displayed tissue 5-HT recovery slightly higher than sham-operated rats (55 +/- 2 vs. 46 +/- 3%, P < 0.001), a finding perhaps attributable to the astrogliosis induced by 5,7-DHT denervation. Rats lesioned with 6-hydroxydopamine showed tissue 5-HT uptake similar to controls, suggesting negligible reuptake of 5-HT by catecholaminergic terminals. These results are consistent with the presence of a glial component of 5-HT uptake in the rodent brain, sensitive to antidepressants, which takes place through a 5-HT transporter very similar or identical to that present in neurons.