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1.
Neurosci Biobehav Rev ; 155: 105456, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37926241

RESUMO

As a major regulator of dopamine (DA), DA autoreceptors (DAARs) exert substantial influence over DA-mediated behaviors. This paper reviews the physiological and behavioral impact of DAARs. Individual differences in DAAR functioning influences temperamental traits such as novelty responsivity and impulsivity, both of which are associated with vulnerability to addictive behavior in animal models and a broad array of externalizing behaviors in humans. DAARs additionally impact the response to psychostimulants and other drugs of abuse. Human PET studies of D2-like receptors in the midbrain provide evidence for parallels to the animal literature. These data lead to the proposal that weak DAAR regulation is a risk factor for addiction and externalizing problems. The review highlights the potential to build translational models of the functional role of DAARs in behavior. It also draws attention to key limitations in the current literature that would need to be addressed to further advance a weak DAAR regulation model of addiction and externalizing risk.


Assuntos
Autorreceptores , Dopamina , Animais , Humanos , Autorreceptores/metabolismo , Receptores de Dopamina D2 , Temperamento , Mesencéfalo
2.
Ann Intern Med ; 176(5): 676-684, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37155992

RESUMO

BACKGROUND: Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. PURPOSE: To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. DATA SOURCES: MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. STUDY SELECTION: Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. DATA EXTRACTION: Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. DATA SYNTHESIS: Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. LIMITATIONS: There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. CONCLUSION: Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol. PRIMARY FUNDING SOURCE: None.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Apneia Obstrutiva do Sono , Promotores da Vigília , Humanos , Autorreceptores , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Distúrbios do Sono por Sonolência Excessiva/etiologia , Modafinila/efeitos adversos , Metanálise em Rede , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/tratamento farmacológico , Promotores da Vigília/efeitos adversos
3.
Cells ; 11(19)2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36230998

RESUMO

The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [3H]D-aspartate ([3H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT2A heteroreceptors with MDL11,939 (1 µM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 µM). 5-HT2A receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1-10 µM) mimics the 5-HT2A agonist (±) DOI and inhibits the KCl-evoked [3H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT2A proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 µM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT2A and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT2A metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens.


Assuntos
Clozapina , Receptores de Glutamato Metabotrópico , Trazodona , Animais , Autorreceptores/metabolismo , Clozapina/farmacologia , Ácido D-Aspártico/farmacologia , Exocitose/fisiologia , Ácido Glutâmico/metabolismo , Ketanserina/farmacologia , Córtex Pré-Frontal/metabolismo , Ratos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Serotonina , Trazodona/farmacologia
4.
Int J Mol Sci ; 23(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36232321

RESUMO

Alcohol use disorder (AUD) is characterized by escalating alcohol consumption, preoccupation with alcohol, and continued alcohol consumption despite adverse consequences. Dopamine has been implicated in neural and behavioral processes involved in reward and reinforcement and is a critical neurotransmitter in AUD. Clinical and preclinical research has shown that long-term ethanol exposure can alter dopamine release, though most of this work has focused on nucleus accumbens (NAc). Like the NAc, the dorsal striatum (DS) is implicated in neural and behavioral processes in AUD. However, little work has examined chronic ethanol effects on DS dopamine dynamics. Therefore, we examined the effect of ethanol consumption and withdrawal on dopamine release and its presynaptic regulation with fast-scan cyclic voltammetry in C57BL/6J mice. We found that one month of ethanol consumption did not alter maximal dopamine release or dopamine tissue content. However, we did find that D2 dopamine autoreceptors were sensitized. We also found a decrease in cholinergic control of dopamine release via ß2-containing nAChRs on dopamine axons. Interestingly, both effects were reversed following withdrawal, raising the possibility that some of the neuroadaptations in AUD might be reversible in abstinence. Altogether, this work elucidates some of the chronic alcohol-induced neurobiological dysfunctions in the dopamine system.


Assuntos
Autorreceptores , Dopamina , Consumo de Bebidas Alcoólicas , Animais , Colinérgicos/farmacologia , Dopamina/farmacologia , Etanol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens
5.
Mol Psychiatry ; 27(11): 4599-4610, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36195637

RESUMO

Alcohol-use-disorders are chronic relapsing illnesses, often co-morbid with anxiety. We have previously shown using the "drinking-in-the-dark" model in mice that the stimulation of the serotonin receptor 1A (5-HT1A) reduces ethanol binge-drinking behaviour and withdrawal-induced anxiety. The 5-HT1A receptor is located either on Raphe neurons as autoreceptors, or on target neurons as heteroreceptors. By combining a pharmacological approach with biased agonists targeting the 5-HT1A auto- or heteroreceptor and a chemogenetic approach (DREADDs), here we identified that ethanol-binge drinking behaviour is dependent on 5-HT1A autoreceptors and 5-HT neuronal function, with a transition from DRN-dependent regulation of short-term (6 weeks) ethanol intake, to MRN-dependent regulation after longer ethanol exposure (12 weeks). We further identified a serotonergic microcircuit (5-HTMRN→DG) originating from the MRN and projecting to the dentate gyrus (DG) of the hippocampus, that is specifically affected by, and modulates long-term ethanol consumption. The present study indicates that targeting Raphe nuclei 5-HT1A autoreceptors with agonists might represent an innovative pharmacotherapeutic strategy to combat alcohol abuse.


Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo , Serotonina , Animais , Camundongos , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/metabolismo , Autorreceptores/fisiologia , Etanol/metabolismo , Etanol/farmacologia , Núcleos da Rafe , Receptor 5-HT1A de Serotonina , Serotonina/metabolismo
6.
Neuropharmacology ; 220: 109258, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36116534

RESUMO

Adrenergic receptors (AR) in the ventral tegmental area (VTA) modulate local neuronal activity and, as a consequence, dopamine (DA) release in the mesolimbic forebrain. Such modulation has functional significance: intra-VTA blockade of α1-AR attenuates behavioral responses to salient environmental stimuli in rat models of drug seeking and conditioned fear as well as phasic DA release in the nucleus accumbens (NAc). In contrast, α2-AR in the VTA has been suggested to act primarily as autoreceptors, limiting local noradrenergic input. The regulation of noradrenaline efflux by α2-AR could be of clinical interest, as α2-AR agonists are proposed as promising pharmacological tools in the treatment of PTSD and substance use disorder. Thus, the aim of our study was to determine the subtype-specificity of α2-ARs in the VTA capable of modulating phasic DA release. We used fast scan cyclic voltammetry (FSCV) in anaesthetized male rats to measure DA release in the NAc after combined electrical stimulation and infusion of selected α2-AR antagonists into the VTA. Intra-VTA microinfusion of idazoxan - a non-subtype-specific α2-AR antagonist, as well as BRL-44408 - a selective α2A-AR antagonist, attenuated electrically-evoked DA in the NAc. In contrast, local administration of JP-1302 or imiloxan (α2B- and α2C-AR antagonists, respectively) had no effect. The effect of BRL-44408 on DA release was attenuated by intra-VTA DA D2 antagonist (raclopride) pre-administration. Finally, we confirmed the presence of α2A-AR protein in the VTA using western blotting. In conclusion, these data specify α2A-, but not α2B- or α2C-AR as the receptor subtype controlling NA release in the VTA.


Assuntos
Núcleo Accumbens , Área Tegmentar Ventral , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Autorreceptores/metabolismo , Dopamina/metabolismo , Idazoxano/farmacologia , Masculino , Norepinefrina/metabolismo , Racloprida/farmacologia , Ratos , Receptores Adrenérgicos alfa 1/metabolismo
7.
Cell Rep ; 40(13): 111431, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36170827

RESUMO

The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show, by application of several super-resolution microscopy techniques to cultured neurons and mouse striatal slices, that the DA transporter (DAT), a key protein in varicosities of dopaminergic neurons, exists in the membrane in dynamic equilibrium between an inward-facing nanodomain-localized and outward-facing unclustered configuration. The balance between these configurations is inversely regulated by excitatory drive and DA D2 autoreceptor activation in a manner dependent on Ca2+ influx via N-type voltage-gated Ca2+ channels. The DAT nanodomains contain tens of transporters molecules and overlap with nanodomains of PIP2 (phosphatidylinositol-4,5-bisphosphate) but show little overlap with D2 autoreceptor, syntaxin-1, and clathrin nanodomains. The data reveal a mechanism for rapid alterations of nanoscopic DAT distribution and show a striking link of this to the conformational state of the transporter.


Assuntos
Autorreceptores , Proteínas da Membrana Plasmática de Transporte de Dopamina , Animais , Autorreceptores/metabolismo , Clatrina/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Camundongos , Fosfatidilinositóis/metabolismo , Proteínas Qa-SNARE/metabolismo
8.
ACS Chem Neurosci ; 13(19): 2863-2873, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36099546

RESUMO

Zebrafish (Danio rerio) are ideal model organisms for investigating nervous system function, both in health and disease. Nevertheless, functional characteristics of dopamine (DA) release and uptake regulation are still not well-understood in zebrafish. In this study, we assessed D3 autoreceptor function in the telencephalon of whole zebrafish brains ex vivo by measuring the electrically stimulated DA release ([DA]max) and uptake at carbon fiber microelectrodes with fast-scan cyclic voltammetry. Treatment with pramipexole and 7-OH-DPAT, selective D3 autoreceptor agonists, sharply decreased [DA]max. Conversely, SB277011A, a selective D3 antagonist, nearly doubled [DA]max and decreased k, the first-order rate constant for the DA uptake, to about 20% of its original value. Treatment with desipramine, a selective norepinephrine transporter blocker, failed to increase current, suggesting that our electrochemical signal arises solely from the release of DA. Furthermore, blockage of DA uptake with nomifensine-reversed 7-OH-DPAT induced decreases in [DA]max. Collectively, our data show that, as in mammals, D3 autoreceptors regulate DA release, likely by inhibiting uptake. The results of this study are useful in the further development of zebrafish as a model organism for DA-related neurological disorders such as Parkinson's disease, schizophrenia, and drug addiction.


Assuntos
Autorreceptores , Peixe-Zebra , Animais , Autorreceptores/metabolismo , Encéfalo/metabolismo , Fibra de Carbono , Desipramina , Dopamina , Estimulação Elétrica , Mamíferos/metabolismo , Nomifensina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Pramipexol , Receptores de Dopamina D2/metabolismo , Tetra-Hidronaftalenos , Peixe-Zebra/metabolismo
9.
Exp Brain Res ; 240(10): 2803-2815, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36057752

RESUMO

In humans, social isolation is a known risk factor for disorders such as substance use disorder and depression. In rodents, social isolation is a commonly used environmental manipulation that increases the occurrence of behaviors related to these disorders. Age is thought to influence the effects of social isolation, but this predictive relationship is not well-understood. The present study aimed to determine the effects of social isolation on mesolimbic dopamine release at different developmental age points in mice. The experimental ages and their corresponding comparison to human age stages are as follows: 1 month = adolescence, 4 months = mature adulthood, 12 months = middle adulthood, and 18 months = older adult. Mice were socially isolated for 6 weeks during these developmental stages, then in vivo fixed potential amperometry with recording electrodes in the nucleus accumbens was used to measure stimulation-evoked dopamine release, the synaptic half-life of dopamine, dopamine autoreceptor functioning, and the dopaminergic response to cocaine. Isolation altered dopamine functioning in an age-dependent manner. Specifically, isolation increased dopamine release in the adult ages, but not adolescence, potentially due to increased inhibitory effects of dopamine autoreceptors following adolescent social isolation. Regarding the cocaine challenge, isolation increased dopaminergic responses to cocaine in adolescent mice, but not the adult mice. These findings have implications for clinical and experimental settings. Elucidating the relationship between age, social isolation, and neurochemical changes associated with substance use disorder and depression may lead to improvements in preventing and treating these disorders.


Assuntos
Cocaína , Transtornos Relacionados ao Uso de Substâncias , Animais , Autorreceptores , Cocaína/farmacologia , Dopamina , Camundongos , Isolamento Social
10.
Curr Top Behav Neurosci ; 59: 169-191, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35704272

RESUMO

Substance use disorders are a leading cause of morbidity and mortality, and available pharmacological treatments are of modest efficacy. Histamine is a biogenic amine with four types of receptors. The histamine H3 receptor (H3R) is an autoreceptor and also an heteroreceptor. H3Rs are highly expressed in the basal ganglia, hippocampus and cortex, and regulate a number of neurotransmitters including acetylcholine, norepinephrine, GABA and dopamine. Its function and localization suggest that the H3R may be relevant to a number of psychiatric disorders and could represent a potential therapeutic target for substance use disorders. The purpose of the present review is to summarize preclinical studies investigating the effects of H3R agonists and antagonists on animal models of alcohol, nicotine and psychostimulant use. At present, the effects of H3R antagonists such as thioperamide, pitolisant or ciproxifan have been investigated in drug-induced locomotion, conditioned place preference, drug self-administration, reinstatement, sensitization and drug discrimination. For alcohol and nicotine, the effects of H3R ligands on two-bottle choice and memory tasks, respectively, have also been investigated. The results of these studies are inconsistent. For alcohol, H3R antagonists generally decreased the reward-related properties of ethanol, which suggests that H3R antagonists may be effective as a treatment option for alcohol use disorder. However, the effects of H3R antagonists on nicotine and psychostimulant motivation and reward are less clear. H3R antagonists potentiated the abuse-related properties of nicotine, but only a handful of studies have been conducted. For psychostimulants, evidence is mixed and suggests that more research is needed to establish whether H3R antagonists are a viable therapeutic option. The fact that different drugs of abuse have different brain targets may explain the differential effects of H3R ligands.


Assuntos
Estimulantes do Sistema Nervoso Central , Antagonistas dos Receptores Histamínicos H3 , Receptores Histamínicos H3 , Transtornos Relacionados ao Uso de Substâncias , Acetilcolina , Animais , Autorreceptores , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina , Etanol/farmacologia , Histamina , Antagonistas dos Receptores Histamínicos H3/farmacologia , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Ligantes , Nicotina , Norepinefrina , Receptores Histamínicos H3/fisiologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Ácido gama-Aminobutírico
11.
Mol Cell Neurosci ; 120: 103719, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35283305

RESUMO

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.


Assuntos
Aminopiridinas , Autorreceptores , Hipocampo , Plasticidade Neuronal , Reconhecimento Fisiológico de Modelo , Piperidinas , Pirimidinas , Receptor 5-HT1A de Serotonina , Reconhecimento Psicológico , Agonistas do Receptor 5-HT1 de Serotonina , Aminopiridinas/farmacologia , Animais , Autorreceptores/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/fisiologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico
12.
JAMA Psychiatry ; 79(4): 300-312, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35171215

RESUMO

IMPORTANCE: Combining antidepressants is frequently done in the treatment of acute depression, but studies have yielded conflicting results. OBJECTIVE: To conduct a systematic review and meta-analysis assessing efficacy and tolerability of combination therapy. Combinations using presynaptic α2-autoreceptor antagonists or bupropion were investigated separately. DATA SOURCES: MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were systematically searched from each database inception through January 2020. STUDY SELECTION: Randomized clinical trials (RCTs) comparing combinations of antidepressants with antidepressant monotherapy in adult patients with acute depression were included. DATA EXTRACTION AND SYNTHESIS: Following guidelines from Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and recommendations from the Cochrane Handbook, 2 reviewers independently performed a literature search, study selection, data extraction, and evaluation of risk of bias. Data were pooled in random-effects analyses. MAIN OUTCOMES AND MEASURES: Primary outcome was efficacy measured as standardized mean difference (SMD); secondary outcomes were response, remission, change from baseline in rating scale scores, number of dropouts, and number of dropouts due to adverse events. RESULTS: Thirty-nine RCTs including 6751 patients were eligible. Combination treatment was statistically significantly associated with superior treatment outcomes relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44). Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Bupropion combinations were not superior to monotherapy (SMD = 0.10; 95% CI, -0.07 to 0.27). Numbers of dropouts and dropouts due to adverse events did not differ between treatments. Studies were heterogeneous, and there was indication of publication bias (Egger test result was positive; P = .007, df = 36), but results remained robust across prespecified secondary outcomes and sensitivity and subgroup analyses, including analyses restricted to studies with low risk of bias. CONCLUSIONS AND RELEVANCE: In this meta-analysis of RCTs comparing combinations of antidepressants with antidepressant monotherapy, combining antidepressants was associated with superior treatment outcomes but not with more patients dropping out of treatment. Combinations using an antagonist of presynaptic α2-autoreceptors may be preferable and may be applied as a first-line treatment in severe cases of depression and for patients considered nonresponders.


Assuntos
Bupropiona , Depressão , Adulto , Antidepressivos/uso terapêutico , Autorreceptores , Bupropiona/uso terapêutico , Depressão/tratamento farmacológico , Quimioterapia Combinada , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Biomed Pharmacother ; 148: 112699, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35152045

RESUMO

The rise in obesity prevalence has been linked to overconsumption of high-sugar containing food and beverages. Recent evidence suggests that chronic sucrose consumption leads to changes in serotonergic neuroplasticity within the neural circuits involved in feeding control. Although there is a relationship between serotonin signalling in the brain and diet-induced obesity, the specific serotonin (5-HT) receptors or pathways involved remain unknown. The 5-HT1A receptor subtype plays a role in regulating mood, anxiety, and appetite, and has been associated with reversing addiction to substances of abuse. However, the respective role of 5-HT1A auto- vs heteroreceptors in sucrose consumption has not been examined. Mice were given controlled access to either 5%, 10% or 25% w/v sucrose, or water as a control, for 12 weeks using the well-established "drinking in the dark" protocol (n = 6-8 mice per group). Ligands selectively targeting 5-HT1A auto- and/or heteroreceptors (NLX-112, unbiased 5-HT1A receptor agonist; NLX-101, preferential heteroreceptor agonist; F13714, preferential autoreceptor agonist) were administered i.p. acutely after 6 and 12 weeks of sucrose consumption. The specific involvement of 5-HT1A receptors in these effects was verified by blockade with the selective 5-HT1A receptors antagonist WAY-100,635. The specific subpopulation of 5-HT1A receptors involved in sucrose consumption was dependent on the concentration of sucrose solution and the duration of exposure to sucrose (6 weeks vs 12 weeks). Long-term sucrose consumption leads to accentuated 5-HT1A autoreceptor function. Thus, targeting 5-HT1A autoreceptors might represent an effective therapeutic strategy to combat the rise in obesity resulting from the overconsumption of high-sugar diet.


Assuntos
Serotonina , Sacarose , Animais , Autorreceptores/metabolismo , Encéfalo/metabolismo , Camundongos , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia
14.
Brain ; 145(10): 3488-3499, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34951464

RESUMO

Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson's disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson's disease population. Here, we applied 18F-fallypride PET studies to assess striatal and extrastriatal D2-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson's disease patients with impulsive-compulsive behaviours would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D2 autoreceptors would underlie this response. Twenty patients with Parkinson's disease (mean age = 64.1 ± 5.8 years) both with (n = 10) and without (n = 10) impulsive-compulsive behaviours, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an OFF dopamine state. All completed PET imaging with 18F-fallypride, a high-affinity D2-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise and region of interest analyses revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum correlated positively with patient-reported participation in reward-based behaviours, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson's disease Rating Scale. In participants without impulsive-compulsive behaviours, baseline midbrain D2 receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviours. These findings emphasize that reward-based behaviours in Parkinson's disease are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviours.


Assuntos
Doença de Parkinson , Estriado Ventral , Idoso , Humanos , Pessoa de Meia-Idade , Anfetamina/uso terapêutico , Autorreceptores , Dextroanfetamina/farmacologia , Dopamina , Comportamento Impulsivo/fisiologia , Ligantes , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Receptores de Dopamina D2/metabolismo , Método Simples-Cego , Estriado Ventral/diagnóstico por imagem
15.
Brain Struct Funct ; 227(3): 925-941, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34854963

RESUMO

G-protein-coupled D2 autoreceptors expressed on dopamine neurons (D2Rs) inhibit transmitter release and cell firing at axonal endings and somatodendritic compartments. Mechanistic details of somatodendritic dopamine release remain unresolved, partly due to insufficient information on the subcellular distribution of D2Rs. Previous studies localizing D2Rs have been hindered by a dearth of antibodies validated for specificity in D2R knockout animals and have been limited by the small sampling areas imaged by electron microscopy. This study utilized sub-diffraction fluorescence microscopy and electron microscopy to examine D2 receptors in a superecliptic pHlourin GFP (SEP) epitope-tagged D2 receptor knockin mouse. Incubating live slices with an anti-SEP antibody achieved the selective labeling of plasma membrane-associated receptors for immunofluorescent imaging over a large area of the substantia nigra pars compacta (SNc). SEP-D2Rs appeared as puncta-like structures along the surface of dendrites and soma of dopamine neurons visualized by antibodies to tyrosine hydroxylase (TH). TH-associated SEP-D2Rs displayed a cell surface density of 0.66 puncta/µm2, which corresponds to an average frequency of 1 punctum every 1.50 µm. Separate ultrastructural experiments using silver-enhanced immunogold revealed that membrane-bound particles represented 28% of total D2Rs in putative dopamine cells within the SNc. Structures immediately adjacent to dendritic membrane gold particles were unmyelinated axons or axon varicosities (40%), astrocytes (19%), other dendrites (7%), or profiles unidentified (34%) in single sections. Some apposed profiles also expressed D2Rs. Fluorescent and ultrastructural analyses also provided the first visualization of membrane D2Rs at the axon initial segment, a compartment critical for action potential generation. The punctate appearance of anti-SEP staining indicates there is a population of D2Rs organized in discrete signaling sites along the plasma membrane, and for the first time, a quantitative estimate of spatial frequency is provided.


Assuntos
Receptores de Dopamina D2/metabolismo , Substância Negra , Animais , Autorreceptores/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Camundongos , Receptores de Dopamina D2/análise , Substância Negra/metabolismo
16.
Prog Brain Res ; 261: 3-39, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33785133

RESUMO

The serotonergic system of the central nervous system (CNS) has been implicated in a broad range of physiological functions and behaviors, such as cognition, mood, social interaction, sexual behavior, feeding behavior, sleep-wake cycle and thermoregulation. Serotonin (5-hydroxytryptamine, 5-HT) establishes a plethora of interactions with neurochemical systems in the CNS via its numerous 5-HT receptors and autoreceptors. The facets of this control are multiple if we consider the molecular actors playing a role in the autoregulation of 5-HT neuron activity including the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B, 5-HT7 receptors as well as the serotonin transporter. Moreover, extrinsic loops involving other neurotransmitters giving the other 5-HT receptors the possibility to impact 5-HT neuron activity. Grasping the complexity of these interactions is essential for the development of a variety of therapeutic strategies for cognitive defects and mood disorders. Presently we can illustrate the plurality of the mechanisms and only conceive that these 5-HT controls are likely not uniform in terms of regional and neuronal distribution. Our understanding of the specific expression patterns of these receptors on specific circuits and neuronal populations are progressing and will expand our comprehension of the function and interaction of these receptors with other chemical systems. Thus, the development of new approaches profiling the expression of 5-HT receptors and autoreceptors should reveal additional facets of the 5-HT controls of neurochemical systems in the CNS.


Assuntos
Serotonina/metabolismo , Autorreceptores , Humanos , Neurotransmissores , Receptores de Serotonina
17.
Int J Neuropsychopharmacol ; 24(3): 239-251, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33151278

RESUMO

BACKGROUND: Impulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated. METHODS: We evaluated a large cohort (n = 49) of Roman high- and low-avoidance rats using single photon emission computed tomography to concurrently measure in vivo striatal D2/3 receptor (D2/3R) availability and amphetamine (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the DA-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex vivo autoradiography in the same animals. RESULTS: We replicated a robust inverse relationship between impulsivity, as measured with the 5-choice serial reaction time task, and D2/3R availability in ventral striatum and extended this relationship to D2/3R levels measured in dorsal striatum. Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in dorsal striatum and ventral striatum. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high-impulsive/novelty-preferring Roman high-avoidance animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release. CONCLUSIONS: Impulsivity and novelty preference are related but mediated by overlapping, yet dissociable, DA-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype.


Assuntos
Dopamina/metabolismo , Comportamento Exploratório/fisiologia , Comportamento Impulsivo/fisiologia , Neostriado/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Estriado Ventral/metabolismo , Anfetamina/farmacologia , Animais , Autorreceptores/efeitos dos fármacos , Autorreceptores/metabolismo , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Dopaminérgicos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Neostriado/efeitos dos fármacos , Ratos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Tomografia Computadorizada de Emissão de Fóton Único , Estriado Ventral/efeitos dos fármacos
18.
BMC Neurosci ; 21(1): 40, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967609

RESUMO

BACKGROUND: Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding involves genomics, neurochemistry, electrophysiology, and behavior. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders. This paper presents a new deterministic model of serotonin metabolism and a new systems population model that takes into account the large variation in enzyme and transporter expression levels, tryptophan input, and autoreceptor function. RESULTS: We discuss the steady state of the model and the steady state distribution of extracellular serotonin under different hypotheses on the autoreceptors and we show the effect of tryptophan input on the steady state and the effect of meals. We use the deterministic model to interpret experimental data on the responses in the hippocampus of male and female mice, and to illustrate the short-time dynamics of the autoreceptors. We show there are likely two reuptake mechanisms for serotonin and that the autoreceptors have long-lasting influence and compare our results to measurements of serotonin dynamics in the substantia nigra pars reticulata. We also show how histamine affects serotonin dynamics. We examine experimental data that show very variable response curves in populations of mice and ask how much variation in parameters in the model is necessary to produce the observed variation in the data. Finally, we show how the systems population model can potentially be used to investigate specific biological and clinical questions. CONCLUSIONS: We have shown that our new models can be used to investigate the effects of tryptophan input and meals and the behavior of experimental response curves in different brain nuclei. The systems population model incorporates individual variation and can be used to investigate clinical questions and the variation in drug efficacy. The codes for both the deterministic model and the systems population model are available from the authors and can be used by other researchers to investigate the serotonergic system.


Assuntos
Autorreceptores/fisiologia , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Algoritmos , Animais , Feminino , Histamina/farmacologia , Masculino , Refeições , Camundongos , Modelos Neurológicos , Modelos Teóricos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Caracteres Sexuais , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Triptofano/farmacologia , Triptofano Hidroxilase/metabolismo
19.
Pharmacol Ther ; 213: 107583, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32473160

RESUMO

Dopamine D2 autoreceptors (D2ARs), located in somatodendritic and axon terminal compartments of dopamine (DA) neurons, function to provide a negative feedback regulatory control on DA neuron firing, DA synthesis, reuptake and release. Dysregulation of D2AR-mediated DA signaling is implicated in vulnerability to substance use disorder (SUD). Due to the extreme low abundance of D2ARs compared to postsynaptic D2 receptors (D2PRs) and the lack of experimental tools to differentiate the signaling of D2ARs from D2PRs, the regulation of D2ARs by drugs of abuse is poorly understood. The recent availability of conditional D2AR knockout mice and newly developed virus-mediated gene delivery approaches have provided means to specifically study the function of D2ARs at the molecular, cellular and behavioral levels. There is a growing revelation of novel mechanisms and new proteins that mediate D2AR activity, suggesting that D2ARs act cooperatively with an array of membrane and intracellular proteins to tightly control DA transmission. This review highlights D2AR-interacting partners including transporters, G-protein-coupled receptors, ion channels, intracellular signaling modulators, and protein kinases. The complexity of the D2AR interaction network illustrates the functional divergence of D2ARs. Pharmacological targeting of multiple D2AR-interacting partners may be more effective to restore disrupted DA homeostasis by drugs of abuse.


Assuntos
Autorreceptores/metabolismo , Receptores de Dopamina D2/metabolismo , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Humanos , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo
20.
Behav Brain Res ; 389: 112618, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360167

RESUMO

Dorsal raphe (DR) and median raphe (MR) 5-HT neurons are two distinct sub-systems known to be regulated by 5-HT1A and 5-HT1B auto-receptors. Whether the auto-receptors in each sub-system are functionally altered in depressive-like state remains unknown. The present study is aimed to study a specific circuit (DR-ventral hippocampus and MR-dorsal hippocampus) within each sub-system to investigate changes in receptor sensitivity in the pathogenesis of depression. A mouse model of depression was developed through the social defeat paradigm, and was then treated with fluoxetine (FLX). 5-HT1A auto-receptor in the neuronal cell body (DR or MR) and 5-HT1B auto-receptor in the axonal terminal (ventral or dorsal hippocampus) were directly targeted by local perfusion of antagonists (5-HT1A: WAY100635; 5-HT1B: GR127935) through reverse microdialysis. Time courses of dialysate 5-HT measured at the axonal terminal were subsequently determined for each circuit. At baseline, 5-HT1A and 5-HT1B antagonists dose-dependently increased dialysate 5-HT, with sub-circuit specificity. In the depressive-like state, greater increases in dialysate 5-HT were observed only in the DR-ventral hippocampus circuit following local delivery of both antagonists, which were then fully restored following the FLX treatment. In contrast, no changes were observed in the MR-dorsal hippocampus circuit. Our results demonstrate differential changes in sensitivities of 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus and MR-dorsal hippocampus circuits. 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus circuit are sensitized in the depressive-like state. Taken together, these results suggest that the DR sub-system maybe the neural substrate mediating depressive phenotypes.


Assuntos
Autorreceptores/metabolismo , Depressão/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Animais , Masculino , Camundongos Endogâmicos C57BL , Microdiálise , Vias Neurais/metabolismo , Comportamento Social
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