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1.
Proc Natl Acad Sci U S A ; 116(51): 25968-25973, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31776253

RESUMO

Evidence shows that the neurotransmitter dopamine mediates the rewarding effects of nicotine and other drugs of abuse, while nondopaminergic neural substrates mediate the negative motivational effects. ß2* nicotinic acetylcholine receptors (nAChR) are necessary and sufficient for the experience of both nicotine reward and aversion in an intra-VTA (ventral tegmental area) self-administration paradigm. We selectively reexpressed ß2* nAChRs in VTA dopamine or VTA γ-amino-butyric acid (GABA) neurons in ß2-/- mice to double-dissociate the aversive and rewarding conditioned responses to nicotine in nondependent mice, revealing that ß2* nAChRs on VTA dopamine neurons mediate nicotine's conditioned aversive effects, while ß2* nAChRs on VTA GABA neurons mediate the conditioned rewarding effects in place-conditioning paradigms. These results stand in contrast to a purely dopaminergic reward theory, leading to a better understanding of the neurobiology of nicotine motivation and possibly to improved therapeutic treatments for smoking cessation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Dopamina/farmacologia , Nicotina/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Ácido gama-Aminobutírico/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Agonistas de Dopamina , Flupentixol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Motivação/efeitos dos fármacos , Recompensa
2.
PLoS Genet ; 15(8): e1008331, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412019

RESUMO

Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the serious lepidopteran agricultural pest Helicoverpa armigera as a model, we revealed that 20-hydroxyecdysone (20E) binds to the dopamine receptor (DopEcR), a G protein-coupled receptor, to stop larval feeding and promote pupation. DopEcR was expressed in various tissues and its level increased during metamorphic molting under 20E regulation. The 20E titer was low during larval feeding stages and high during wandering stages. By contrast, the dopamine (DA) titer was high during larval feeding stages and low during the wandering stages. Injection of 20E or blocking dopamine receptors using the inhibitor flupentixol decreased larval food consumption and body weight. Knockdown of DopEcR repressed larval feeding, growth, and pupation. 20E, via DopEcR, promoted apoptosis; and DA, via DopEcR, induced cell proliferation. 20E opposed DA function by repressing DA-induced cell proliferation and AKT phosphorylation. 20E, via DopEcR, induced gene expression and a rapid increase in intracellular calcium ions and cAMP. 20E induced the interaction of DopEcR with G proteins αs and αq. 20E, via DopEcR, induced protein phosphorylation and binding of the EcRB1-USP1 transcription complex to the ecdysone response element. DopEcR could bind 20E inside the cell membrane or after being isolated from the cell membrane. Mutation of DopEcR decreased 20E binding levels and related cellular responses. 20E competed with DA to bind to DopEcR. The results of the present study suggested that 20E, via binding to DopEcR, arrests larval feeding and promotes pupation.


Assuntos
Ecdisterona/metabolismo , Proteínas de Insetos/metabolismo , Mariposas/fisiologia , Receptores Dopaminérgicos/metabolismo , Animais , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Flupentixol/farmacologia , Técnicas de Silenciamento de Genes , Proteínas de Insetos/genética , Larva/efeitos dos fármacos , Larva/fisiologia , Muda/efeitos dos fármacos , Muda/fisiologia , Mariposas/efeitos dos fármacos , Interferência de RNA , Receptores Dopaminérgicos/genética , Células Sf9
3.
Int J Biol Sci ; 15(7): 1523-1532, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337981

RESUMO

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is hyperactivated in lung cancer and regulates a broad range of cellular processes, including proliferation, survival, angiogenesis, and metastasis. Thus PI3K is considered a promising target for therapy. To date, PI3K inhibitors have not been approved for lung cancer. Recent studies showed that the antipsychotic agent flupentixol induced apoptosis of lung cancer cell, however the anti-tumor mechanism of flupentixol remains unclear. Methods: (1) The idock software simulated the molecular docking between the PI3Kα protein and flupentixol. (2) Inhibition of PI3Kα by the flupentixol was examined by in vitro kinase assays. (3) The cytotoxicity of flupentixol on the NSCLC cell lines was tested by MTT assays. (4) We treated A549 and H661 cells with flupentixol and then measured the percentage of apoptotic cells by the Annexin V/PI analysis. (5) We investigated the effect of flupentixol on the expression of critical PI3K/AKT signaling pathway proteins, further analyzed on the cleavage of PARP and caspase-3 by Western blotting. (6) BALB/C nude mice were subcutaneously injected with A549 cells to evaluate the effect of flupentixol on the growth of lung carcinoma. Results: Structural analysis of the predicted binding conformation suggested that flupentixol docks to the ATP binding pocket of PI3Kα. Kinase assays demonstrate that flupentixol indeed inhibited the PI3Kα kinase activity. Flupentixol exhibited cytotoxicity in lung cancer cell lines A549 and H661 in a dose- and time-dependent manner. Furthermore, flupentixol more strongly inhibited the phosphorylation of AKT (T308 and S473) and the expression of its downstream target gene Bcl-2 than two known PI3K inhibitors (BYL719 and BKM120). Flupentixol induced apoptosis as measured by PARP and caspase-3 cleavage. Finally, flupentixol significantly suppressed A549 xenograft growth in BALB/C nude mice. Conclusions: Flupentixol could be docked to the PI3Kα protein and specifically inhibit the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo. As an old drug, flupentixol is a new PI3K inhibitor that may be used for the treatment of lung cancers.


Assuntos
Antineoplásicos/farmacologia , Antipsicóticos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Flupentixol/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Software
4.
J Neurosci ; 39(9): 1744-1754, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30617206

RESUMO

The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control over drug seeking progressively devolves to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms. The causal importance of this functional recruitment of aDLS in the switch from controlled to compulsive drug use in vulnerable individuals remains to be established. Here we tested the hypothesis that individual differences in the susceptibility to aDLS dopamine-dependent control over alcohol seeking predicts and underlies the development of compulsive alcohol seeking. Male alcohol-preferring rats, the alcohol-preferring phenotype of which was confirmed in an intermittent two-bottle choice procedure, were implanted bilaterally with cannulae above the aDLS and trained instrumentally on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed compulsive seeking behavior. The susceptibility to aDLS dopamine control over behavior was investigated before and after the development of compulsivity by measuring the extent to which bilateral aDLS infusions of the dopamine receptor antagonist α-flupenthixol (0, 5, 10, and 15 µg/side) decreased alcohol seeking at different stages of training, as follows: (1) after acquisition of instrumental taking responses for alcohol; (2) after alcohol-seeking behavior was well established; and (3) after the development of punishment-resistant alcohol seeking. Only alcohol-seeking, not alcohol-taking, responses became dependent on aDLS dopamine. Further, marked individual differences in the susceptibility of alcohol seeking to aDLS dopamine receptor blockade actually predicted the vulnerability to develop compulsive alcohol seeking, but only in subjects dependent on aDLS dopamine-dependent control.SIGNIFICANCE STATEMENT Over the course of addictive drug exposure, there is a transition in the control over drug seeking from ventral to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms, but it is unclear whether this is causally involved in the development of compulsive drug seeking. We tested the hypothesis that individual differences in the reliance of alcohol seeking on aDLS dopamine predicts and underlies the emergence of compulsive alcohol seeking. We identified individual differences in the reliance of well established alcohol seeking, but not taking behavior, on aDLS mechanisms and also showed that this predicted the subsequent development of compulsive alcohol-seeking behavior. Thus, those individuals in whom alcohol seeking depended on aDLS mechanisms were vulnerable subsequently to display compulsivity.


Assuntos
Alcoolismo/fisiopatologia , Comportamento Compulsivo/fisiopatologia , Corpo Estriado/fisiopatologia , Comportamento de Procura de Droga , Alcoolismo/metabolismo , Animais , Comportamento Compulsivo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Masculino , Ratos , Recompensa
5.
Neuropharmacology ; 131: 154-165, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29225042

RESUMO

Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within meso-corticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During a 10-14 day period of abstinence from cocaine, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, rapidly reverses and depotentiates enhanced AMPAR signaling. To understand how re-exposure to cocaine alters AMPAR synaptic transmission, we investigated the roles of dopamine and endocannabinoid (eCB) signaling in modifying synaptic strength in the NAc shell. Using patch-clamp recordings from NAc slices prepared after 10-14 days of abstinence from repeated cocaine, we found that AMPAR-mediated depotentiation is rapidly induced in the NAc shell within 20 min of cocaine re-exposure ex vivo, and persists for up to five days before synapses return to levels of potentiation observed during abstinence. In cocaine-treated animals, global dopamine receptor activation was both necessary and sufficient for the cocaine-evoked depotentiation of AMPAR synaptic function. Additionally, we identified that CB1 receptors are engaged by endogenous endocannabinoids (eCBs) during re-exposure to cocaine ex vivo. Overall, these results indicate the central role that dopamine and eCB signaling mechanisms play in modulating cocaine-induced AMPAR plasticity in the NAc shell.


Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Endocanabinoides/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Flupentixol/farmacologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Morfolinas/farmacologia , Naftalenos/farmacologia , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Pirazóis/farmacologia , Rimonabanto
6.
Schizophr Bull ; 44(6): 1381-1387, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29272458

RESUMO

Very little is known about the comparative long-term effectiveness of novel antipsychotics in relapse prevention, especially in first-episode schizophrenia. Nationwide data from Finnish health care registers were gathered prospectively for all persons with periods of inpatient care due to schizophrenia in Finland during 1972-2014. Altogether 62250 persons were included in the prevalent cohort, and 8719 in the incident (first-episode schizophrenia) cohort. The follow-up for antipsychotic use started at 1996 for the prevalent cohort, and at the first discharge from inpatient care for the incident cases. Within-individual Cox regression models for risk of psychiatric and all-cause hospitalization were constructed to compare risk during antipsychotic use and no use using individual as his/her own control to eliminate selection bias. With follow-up time up to 20 years (median = 14.1, interquartile range = 6.9-20.0), 59% of the prevalent cohort were readmitted to psychiatric inpatient care. Olanzapine long-acting injection (LAI; adjusted hazard ratio = 0.46, 95% confidence interval = 0.36-0.61), clozapine (0.51, 0.49-0.53), and paliperidone LAI (0.51, 0.40-0.66) were associated with the lowest risk of psychiatric rehospitalization in the prevalent cohort. Among first-episode patients, the lowest risks were observed for flupentixol LAI (0.24, 0.12-0.49), olanzapine LAI (0.26, 0.16-0.44), and perphenazine LAI (0.39, 0.31-0.50). Clozapine and LAIs were associated with the lowest risk of all-cause hospitalization in both cohorts. Clozapine and LAIs are the most effective treatments in preventing psychiatric and all-cause hospitalization among chronic and first-episode patients with schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Olanzapina/farmacologia , Readmissão do Paciente/estatística & dados numéricos , Esquizofrenia/tratamento farmacológico , Prevenção Secundária/estatística & dados numéricos , Adulto , Idoso , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Feminino , Finlândia/epidemiologia , Flupentixol/farmacologia , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Olanzapina/administração & dosagem , Palmitato de Paliperidona/farmacologia , Perfenazina/farmacologia , Prevalência , Esquizofrenia/epidemiologia , Adulto Jovem
7.
Br J Cancer ; 117(4): 513-524, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28697173

RESUMO

BACKGROUND: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis. METHODS: Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome dose-limiting CNS-associated side effects of certain FIASMAs. RESULTS: Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects. CONCLUSIONS: This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.


Assuntos
Antidepressivos Tricíclicos/farmacologia , Antipsicóticos/farmacologia , Colesterol/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Perfenazina/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Antidepressivos Tricíclicos/uso terapêutico , Antipsicóticos/administração & dosagem , Autofagia/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Sobrevivência Celular/efeitos dos fármacos , Desipramina/farmacologia , Desipramina/uso terapêutico , Endocitose/efeitos dos fármacos , Endossomos/metabolismo , Feminino , Flupentixol/farmacologia , Flupentixol/uso terapêutico , Flufenazina/farmacologia , Flufenazina/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HCT116 , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Concentração Inibidora 50 , Lipossomos , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Células MCF-7 , Melanoma/genética , Camundongos , Nortriptilina/farmacologia , Nortriptilina/uso terapêutico , Perfenazina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingomielina Fosfodiesterase/genética , Proteína X Associada a bcl-2/metabolismo
8.
Psychol Med ; 47(12): 2187-2196, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28347393

RESUMO

BACKGROUND: Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported. METHODS: We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naïve patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment-related adverse-events (extrapyramidal symptoms and weight gain). RESULTS: Excessive cortical volume reductions were observed in patients [-4.6 (6.6)%] v. controls [-1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis. CONCLUSIONS: Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Córtex Cerebral , Flupentixol/análogos & derivados , Substância Cinzenta , Transtornos Psicóticos , Esquizofrenia , Substância Branca , Adulto , Antipsicóticos/administração & dosagem , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Preparações de Ação Retardada , Feminino , Flupentixol/administração & dosagem , Flupentixol/farmacologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacos , Substância Branca/patologia , Adulto Jovem
9.
Eur J Neurosci ; 45(1): 147-158, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27521051

RESUMO

Dopaminergic neurotransmission in the striatum has been widely implicated in the reinforcing properties of substances of abuse. However, the striatum is functionally heterogeneous, and previous work has mostly focused on psychostimulant drugs. Therefore, we investigated how dopamine within striatal subregions modulates alcohol-directed behaviour in rats. We assessed the effects of infusion of the dopamine receptor antagonist alpha-flupenthixol into the shell and core of the nucleus accumbens (NAcc) and the dorsolateral striatum (DLS) on responding for alcohol under fixed ratio 1 (FR1) and progressive ratio (PR) schedules of reinforcement. Bilateral infusion of alpha-flupenthixol into the NAcc shell reduced responding for alcohol under both the FR1 (15 µg/side) and the PR schedule (3.75-15 µg/side) of reinforcement. Infusion of alpha-flupenthixol into the NAcc core (7.5-15 µg/side) also decreased responding for alcohol under both schedules. By contrast, alpha-flupenthixol infusion into the DLS did not affect FR1 responding, but reduced responding under the PR schedule (15 µg/side). The decreases in responding were related to earlier termination of responding during the session, whereas the onset and rate of responding remained largely unaffected. Together, these data suggest that dopamine in the NAcc shell is involved in the incentive motivation for alcohol, whereas DLS dopamine comes into play when obtaining alcohol requires high levels of effort. In contrast, NAcc core dopamine appears to play a more general role in alcohol reinforcement. In conclusion, dopaminergic neurotransmission acts in concert in subregions of the striatum to modulate different aspects of alcohol-directed behaviour.


Assuntos
Corpo Estriado/fisiologia , Reforço Psicológico , Transmissão Sináptica , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacos
10.
Addict Biol ; 22(5): 1218-1231, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27230434

RESUMO

Functional connections between the basolateral amygdala (BLA) and nucleus accumbens (NAc) are involved critically in opiate-reward processing. In the BLA, inhibitory GABAergic substrates are inhibited by cannabinoid CB1 receptor (CB1R) activation and can modulate BLA projections to various limbic regions, including the NAc. However, the potential role of CB1R transmission in the regulation of opiate-related memory formation via the BLA → NAc circuit is not understood. Using an unbiased conditioned place preference paradigm in rats, we examined the effects of intra-BLA CB1R modulation by either direct pharmacological activation or blockade of CB1R transmission. We report that intra-BLA CB1R activation switches normally rewarding effects of morphine into strongly aversive effects. In contrast, CB1R blockade strongly potentiates normally subreward threshold effects of morphine. Next, using targeted microinfusions of an NMDA receptor antagonist to either the core or shell (NASh) subdivisions of the NAc, we found that selective blockade of NMDA transmission in the NA shell, but not core, prevented both intra-BLA CB1 blockade-mediated opiate reward potentiation and CB1 activation-mediated aversion effects. Finally, using multi-unit, in vivo electrophysiological recordings in the NASh, we report that the ability of intra-BLA CB1R modulation to control opiate reward salience and motivational valence is associated with distinct reward or aversion neuronal activity patterns and bi-directional regulation of intra-NASh fast-spiking interneurons versus medium spiny neurons. These findings identify a unique mechanism whereby bi-directional BLA CB1R transmission can regulate opiate-related motivational processing and control affective states through functional modulation of mesolimbic neuronal activity.


Assuntos
Analgésicos Opioides/farmacologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Morfina/farmacologia , Núcleo Accumbens/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiologia , Comportamento Animal , Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Condicionamento Clássico , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Masculino , Morfolinas/farmacologia , Motivação , Naftalenos/farmacologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Recompensa , Transdução de Sinais
11.
Behav Brain Res ; 314: 1-5, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27478141

RESUMO

Dopamine's (DA) role in reward-processing is currently discussed as either providing a teaching signal to guide learning or mediating the transfer of incentive salience (i.e. motivational aspects) from unconditioned stimuli (US) to conditioned stimuli (CS). We used a Pavlovian conditioned approach (PCA) procedure to further investigate DAs contribution to these processes. Experiment 1 assessed the acquisition of PCA to a manipulable lever cue for 7days under DA-blockade with Flupenthixol (FLU; 225µg/kg) or Saline (SAL) treatment, followed by 6-days off-drug testing. FLU decreased the number of conditioned responses (CR) during the treatment phase, but cessation of treatment resulted in an immediate increase in CR to levels comparable to SAL controls; notably, CR in FLU-treated rats were restricted to goal tracking behaviour. During continued off-drug testing, rats from the FLU group developed sign tracking with a similar temporal pattern as controls. In experiment 2, acquisition of PCA to a non-manipulable auditory cue was investigated. FLU reduced the number of CR during treatment, and removing DA antagonism resulted in a similar rapid increase of CR as seen in experiment 1. These data complement other reports by demonstrating that, independently from the physical properties of the CS, DA is not required for learning predictive aspects of a CS-US relationship but for the development of behaviour (namely sign tracking) which is based on the motivational aspects of a CS-US relationship.


Assuntos
Condicionamento Clássico/fisiologia , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Aprendizagem/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Viés , Sinais (Psicologia) , Dopamina/metabolismo , Aprendizagem/fisiologia , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Recompensa
12.
Chem Phys Lipids ; 198: 61-71, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27282777

RESUMO

Cis-(Z)-flupentixol dihydrochloride (FLU), a thioxanthene drug, is used in therapy of schizophrenia as well as in anxiolytic and depressive disorders. Since the action mechanism of FLU is not completely understood, the main objective of present study is to provide a detailed evaluation of flupentixol-phospholipid membrane interactions at molecular level. FLU-dipalmitoylphosphatidylcholine (DPPC) interactions in presence and absence of cholesterol (CHO) were investigated as a function of temperature. The changes in upper part of membrane were more pronounced than those in central part of membrane, as indicated by EPR and FTIR. FLU was proposed to incorporate into phospholipid membranes with its triple ring parallel to head group and its chain toward alkyl chain of phospholipids. According to DSC results, the incorporation of 10 mol% FLU into DPPC caused a shoulder in transition peak, suggesting the occurence of a phase separation, and formation of this new phase is still observable in presence of CHO. It is well known that, structure and dynamics of lipids have significant influence on the function of membrane bound proteins, and consecutively their actions. Based upon these, it was proposed that FLU may modify membrane associated receptors and transport proteins, which would form the basis of its clinical efficiency.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Colesterol/farmacologia , Flupentixol/farmacologia , Interações Medicamentosas , Flupentixol/química , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Temperatura
13.
Behav Brain Res ; 310: 42-50, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27155504

RESUMO

Cocaine has long been known to produce an initial "high" followed by an aversive/anxiogenic "crash". While much is known about the neurobiology of cocaine's positive/rewarding effects, the mechanisms that give rise to the drug's negative/anxiogenic actions remain unclear. Recent research has implicated the lateral habenula (LHb) in the encoding of aversive events including the anxiogenic response to cocaine. Of particular interest in this regard are the reciprocal connections between the LHb and the ventral tegmental area (VTA). VTA-DA neurons innervate different subsets of LHb cells that in turn feedback upon and modulate VTA neuronal activity. Here we examined the impact of D2 receptor activation and inhibition on the anxiogenic response to cocaine using a runway model of self-administration that is sensitive to the dual and opposing effects of the drug. Male rats ran a straight alley for IV cocaine (1.0mg/kg) following bilateral intra-LHb infusions of the D2 receptor antagonist, cis-flupenthixol (0, 7.5 or 15µg/side) or the D2 agonist, sumanirole (0, 5 or 10µg/side). Vehicle-pretreated controls developed approach-avoidance conflict behaviors about goal-box entry reflective of the dual positive and negative effects of cocaine. These behaviors were significantly diminished during LHb-D2 receptor antagonism and increased by the LHb D2 receptor agonist. These results demonstrate that activity at the D2 receptor in the lateral habenula serves to modulate the anxiogenic response to cocaine.


Assuntos
Ansiedade/induzido quimicamente , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Habenula/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Benzimidazóis/farmacologia , Cateteres de Demora , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Conflito Psicológico , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Habenula/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos Sprague-Dawley , Receptores de Dopamina D2/agonistas , Autoadministração
14.
Eur J Pharmacol ; 779: 31-7, 2016 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-26945819

RESUMO

The thioxanthene antipsychotic drugs chlorprothixene and flupentixol have anti-inflammatory and antioxidant properties. The reactive oxygen species produced by NADPH oxidase during microglia-mediated inflammatory responses cause neuronal damage, thereby contributing to various neurodegenerative diseases. Voltage-gated proton channels sustain the NADPH oxidase activity, and inhibition of the channels' activity reduces the production of reactive oxygen species. Herein, the effects of chlorprothixene and flupentixol on proton currents were investigated in BV2 microglial cells using the whole-cell patch-clamp method. Both drugs inhibited the proton currents in a concentration-dependent manner (IC50=1.7µM and 6.6µM, respectively). Chlorprothixene at 3µM slightly shifted the activation voltage toward depolarization. Both the activation and the deactivation kinetics of the proton currents were slowed by chlorprothixene 1.2- and 3.5-fold, respectively. Thus, the inhibition of proton currents may be partly responsible for the antioxidant effects of thioxanthene antipsychotic drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Clorprotixeno/farmacologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Flupentixol/farmacologia , Microglia/efeitos dos fármacos , Prótons , Potenciais de Ação/efeitos dos fármacos , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Cinética , Camundongos , Microglia/citologia
15.
Neuropsychopharmacology ; 41(3): 858-68, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26174597

RESUMO

Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.


Assuntos
Dopamina/metabolismo , Motivação/fisiologia , Norepinefrina/metabolismo , Comportamento Social , Inibidores da Captação Adrenérgica/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Cloridrato de Atomoxetina/farmacologia , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Flupentixol/farmacologia , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Masculino , Metilfenidato/farmacologia , Motivação/efeitos dos fármacos , Testes Neuropsicológicos , Piperazinas/farmacologia , Distribuição Aleatória , Ratos Wistar , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Dopaminérgicos/metabolismo
16.
Neuropeptides ; 53: 19-27, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26329764

RESUMO

It has been shown that dopamine antagonists suppress the ghrelin-induced increased motivation to work for food. The aim of this study was to investigate the influence of the dopamine antagonist flupentixol on ghrelin-induced food intake. Ad libitum fed male Sprague-Dawley (SD) rats were injected intraperitoneally (ip) with vehicle plus vehicle, vehicle plus ghrelin (13 µg/kg), 0.25mg/kg or 0.5mg/kg flupentixol plus ghrelin, or 0.25mg/kg or 0.5 mg/kg flupentixol plus vehicle. In a second experiment, intracerebroventricularly (icv) cannulated rats received an ip injection of vehicle (0.15M NaCl) or flupentixol (0.25mg/kg) and 20 min later an icv injection of vehicle or ghrelin (1 µg/rat). Both experiments were performed twice: first, rats were offered only standard chow, while in the second experiment they could choose between standard chow and a palatable/preferred chow. Cumulative light phase food intake was assessed for 7h. Ip as well as icv injected ghrelin reliably increased intake of standard chow. Flupentixol did not affect ghrelin-induced intake of standard chow. Ip injected ghrelin failed to increase the intake of palatable chow, whereas icv injected ghrelin did. This effect was not blocked by ip flupentixol. In summary, ip administered ghrelin did not increase the intake of chow the rats preferred; whereas icv injected ghrelin further stimulated the intake of preferred chow suggesting a direct central mediation of this effect. Our results show that the dopamine antagonist flupentixol does not influence ghrelin-induced feeding in our choice paradigm.


Assuntos
Antagonistas de Dopamina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Flupentixol/farmacologia , Grelina/antagonistas & inibidores , Animais , Antagonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Flupentixol/administração & dosagem , Preferências Alimentares , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Periodicidade , Ratos , Ratos Sprague-Dawley
17.
Brain Res ; 1614: 86-93, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-25911581

RESUMO

The laterodorsal tegmental nucleus (LDTg) importantly contributes to regulating firing activity of midbrain dopamine neurons and forebrain dopamine levels. Whether excitation of LDTg afferents to the ventral tegmental area (VTA) can reinforce operant behavior in rats is not known. Rats received adeno-associated viral vectors encoding channelrhodopsin2 (ChR2) and EYFP or EYFP only into the LDTg and were implanted with bilateral optic probes aimed at the VTA. LDTg ChR2-infected rats, but not LDTg EYFP-infected rats acquired lever pressing to obtain photostimulation into the VTA. During reversal testing, where contingencies between response levers were reversed, LDTg ChR2-infected rats learned to press the alternate, now reinforced, lever within one session. Following pretreatment with the broad-spectrum dopamine receptor blocker flupenthixol LDTg ChR2-infected rats initiated lever-pressing with normal latencies and lever-pressed normally for the first ten minutes of the session. Lever-pressing rates were strongly reduced thereafter. These results provide further support for an important role of LDTg inputs to the VTA in appetitively motivated behaviors.


Assuntos
Axônios/fisiologia , Condicionamento Operante/fisiologia , Optogenética , Reforço Psicológico , Área Tegmentar Ventral/citologia , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Channelrhodopsins , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Ratos , Ratos Long-Evans , Fatores de Tempo , Transdução Genética
18.
Psychopharmacology (Berl) ; 232(15): 2697-709, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25791190

RESUMO

RATIONALE: Successive negative contrast (SNC) describes a change in the behaviour of an animal following a downshift in the quantitative or qualitative value of an expected reward. This behavioural response has been hypothesised to be linked to affective state, with negative states associated with larger and/or prolonged shifts in behaviour. OBJECTIVE: This study has investigated whether different psychopharmacological treatments have dissociable actions on the SNC effect in rats and related these findings to their actions on different neurotransmitter systems and affective state. METHODS: Animals were trained to perform a nose-poke response to obtain a high-value food reward (four pellets). SNC was quantified during devalue sessions in which the reward was reduced to one pellet. Using a within-subject study design, the effects of acute treatment with anxiolytic, anxiogenic, antidepressant and dopaminergic drugs were investigated during both baseline (four pellets) or devalue sessions (one pellet). RESULTS: The indirect dopamine agonist, amphetamine, attenuated the SNC effect whilst the D1/D2 antagonist, alpha-flupenthixol, potentiated it. The antidepressant citalopram, anxiolytic buspirone and anxiogenic FG7142 had no specific effects on SNC, although FG7142 induced general impairments at higher doses. The α2-adrenoceptor antagonist, yohimbine, increased premature responding but had no specific effect on SNC. Results for the anxiolytic diazepam were mixed with one group showing an attenuation of the SNC effect whilst the other showed no effect. CONCLUSIONS: These data suggest that the SNC effect is mediated, at least in part, by dopamine signalling. The SNC effect may also be attenuated by benzodiazepine anxiolytics.


Assuntos
Anfetamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Dopaminérgicos/farmacologia , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Recompensa , Animais , Ansiolíticos/farmacologia , Buspirona/farmacologia , Carbolinas/farmacologia , Citalopram/farmacologia , Diazepam , Emoções/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Masculino , Ratos , Agonistas do Receptor de Serotonina/farmacologia , Inibidores de Captação de Serotonina/farmacologia
19.
Behav Brain Res ; 286: 22-8, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25721736

RESUMO

Conditioned defeat (CD) is a behavioral response that occurs in Syrian hamsters after they experience social defeat. Subsequently, defeated hamsters no longer produce territorial aggression but instead exhibit heightened levels of avoidance and submission, even when confronted with a smaller, non-aggressive intruder. Dopamine in the nucleus accumbens is hypothesized to act as a signal of salience for both rewarding and aversive stimuli to promote memory formation and appropriate behavioral responses to significant events. The purpose of the present study was to test the hypothesis that dopamine in the nucleus accumbens modulates the acquisition and expression of behavioral responses to social defeat. In Experiment 1, bilateral infusion of the non-specific D1/D2 receptor antagonist cis(z)flupenthixol (3.75 µg/150 nl saline) into the nucleus accumbens 5 min prior to defeat training significantly reduced submissive and defensive behavior expressed 24h later in response to a non-aggressive intruder. In Experiment 2, infusion of 3.75 µg cis-(Z)-flupenthixol 5 min before conditioned defeat testing with a non-aggressive intruder significantly increased aggressive behavior in drug-infused subjects. In Experiment 3, we found that the effect of cis-(Z)-flupenthixol on aggression was specific to defeated animals as infusion of drug into the nucleus accumbens of non-defeated animals did not significantly alter their behavior in response to a non-aggressive intruder. These data demonstrate that dopamine in the nucleus accumbens modulates both acquisition and expression of social stress-induced behavioral changes and suggest that the nucleus accumbens plays an important role in the suppression of aggression that is observed after social defeat.


Assuntos
Dominação-Subordinação , Memória/fisiologia , Núcleo Accumbens/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Agressão/efeitos dos fármacos , Agressão/fisiologia , Animais , Cateteres de Demora , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Medo/efeitos dos fármacos , Medo/fisiologia , Flupentixol/farmacologia , Masculino , Memória/efeitos dos fármacos , Mesocricetus , Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/antagonistas & inibidores
20.
Behav Pharmacol ; 26(1-2): 193-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25325288

RESUMO

The reinforcing and addictive properties of cocaine are thought to rely on the dopaminergic innervation of the striatum. The ventromedial [i.e. nucleus accumbens shell (NAcc) shell] and dorsolateral [dorsolateral striatum (DLS)] regions of the striatum are serially connected, and it is thought that slowly developing neuroadaptations are responsible for the recruitment of the DLS in mediating habitual drug use after extended drug experience. Remarkably, we have recently shown that the DLS is also involved in cocaine self-administration after limited use, to modulate the reinforcing properties of the drug, a function usually ascribed to the NAcc shell. Here, we investigated whether the involvement of the DLS in cocaine reinforcement requires dopaminergic activity within the NAcc shell, by performing a pharmacological disconnection study. We infused the dopamine receptor antagonist α-flupenthixol unilaterally into the NAcc shell and infused this same antagonist into the contralateral DLS, thereby disrupting dopaminergic interconnectivity within the striatum. We show that this disconnection results in increased responding for cocaine under a fixed ratio-1 schedule of reinforcement in rats with limited cocaine experience. These data suggest that a functional dopaminergic interaction between the NAcc shell and the DLS mediates cocaine reinforcement during the early stages of drug use.


Assuntos
Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Animais , Corpo Estriado/metabolismo , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Masculino , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Esquema de Reforço , Reforço Psicológico
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