RESUMO
Dopamine can modulate long-term episodic memory. Its potential role on the generation of false memories, however, is less well known. In a randomized, double-blind, placebo-controlled experiment, 24 young healthy volunteers ingested a 4-mg oral dose of haloperidol, a dopamine D2 -receptor antagonist, or placebo, before taking part in a recognition memory task. Haloperidol was active during both study and test phases of the experiment. Participants in the haloperidol group produced more false recognition responses than those in the placebo group, despite similar levels of correct recognition. These findings show that dopamine blockade in healthy volunteers can specifically increase false recognition memory.
Assuntos
Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Memória/efeitos dos fármacos , Estimulação Luminosa/métodos , Reconhecimento Psicológico/efeitos dos fármacos , Repressão Psicológica , Adulto , Antipsicóticos/farmacologia , Método Duplo-Cego , Feminino , Voluntários Saudáveis/psicologia , Humanos , Masculino , Memória/fisiologia , Reconhecimento Psicológico/fisiologia , Adulto JovemRESUMO
As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11 C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11 C]Ro15-4513 total distribution volume (VT ) in the right hippocampus in the GD group compared with HV. We found higher levels of the 'Negative Urgency' construct of impulsivity in GD, and these were positively associated with higher [11 C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11 C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.
Assuntos
Comportamento Aditivo/metabolismo , Comportamento Aditivo/fisiopatologia , Encéfalo/fisiopatologia , Jogo de Azar/metabolismo , Jogo de Azar/fisiopatologia , Comportamento Impulsivo/fisiologia , Receptores de GABA-A/metabolismo , Adulto , Azidas , Benzodiazepinas , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodosRESUMO
OBJECTIVE: Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression. METHODS: PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)." RESULTS: Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress. CONCLUSION: Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.
Assuntos
Amantadina/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Animais , Monoaminas Biogênicas , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , HumanosRESUMO
OBJECTIVE: To assess through a systematic review of the literature if the practice of splitting tablets containing psychoactive/psychotropic medications for medical or economic reasons would result in the expected doses. DATA SOURCES: A MEDLINE and PsycInfo comprehensive search of English-language publications from January 1999 to December 2015 was conducted using the terms describing tablet splitting (tablet splitting, split tablets, tablet subdivision, divided tablets, and half tablets) and psychoactive substances (psychoactive medicines, psychotropic medicines, antidepressants, anxiolytics, anticonvulsants, antipsychotics, and antiparkinsonian agents). An additional supplementary search included the references from the articles found. STUDY SELECTION/DATA EXTRACTION: Studies were included if splitting content was directly related to psychoactive medications and examined the effect of tablet splitting on drug uniformity, weight uniformity, and adherence of psychoactive drugs. Articles were systematically reviewed and examined regarding the study design, methodology, and results of the study. A total of 125 articles were screened, and 13 were selected. RESULTS: Tablet splitting implications are extensive, yet substantial deviations from the ideal weight, potency, and dose uniformity are more prone to be important to patient safety. The uneven division of tablets might result in the administration of different doses than what was prescribed, causing under- or overdosing, which might be relevant depending on the drug. In 55% of the cases, splitting psychoactive drugs was satisfactory. CONCLUSIONS: It cannot be generalized that splitting psychoactive drugs compromises dose accuracy, thus tablet splitting might still be employed in cases in which the advantages outweigh the disadvantages. It is recommended that alternatives be adopted to prevent the disadvantages related to tablet splitting.
Assuntos
Psicotrópicos/administração & dosagem , Humanos , Psicotrópicos/efeitos adversos , Psicotrópicos/economia , ComprimidosRESUMO
Recent data have shown an association between polyunsaturated fatty acid and depression. This study examined the effect of the supplementation with n-6 fatty acid on the behavior of rats treated with imipramine and submitted to the Forced Swimming Test (FST). Non-supplemented imipramine-treated rats presented a significant reduction of immobility time in the FST whereas n-6 fatty acid-supplemented rats showed a significantly higher immobility time. Imipramine significantly increased norepinephrine plasma concentrations in the two groups. These results show that the diet supplemented with n-6 fatty acid altered the behavior of the animals in the FST, inhibiting the imipramine effect.
Assuntos
Antidepressivos Tricíclicos/farmacologia , Depressão/tratamento farmacológico , Ácidos Graxos Ômega-6/farmacologia , Imipramina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Catecolaminas/sangue , Cromatografia Líquida de Alta Pressão , Depressão/psicologia , Dieta , Eletroquímica , Masculino , Óleos de Plantas/química , Primula/química , Ratos , Ratos Wistar , Serotonina/sangue , Natação/psicologiaRESUMO
Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [(11)C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [(11)C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [(11)C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [(11)C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.
Assuntos
Anfetamina/administração & dosagem , Analgésicos Opioides/metabolismo , Estimulantes do Sistema Nervoso Central/administração & dosagem , Jogo de Azar/diagnóstico por imagem , Jogo de Azar/metabolismo , Administração Oral , Adulto , Anfetamina/sangue , Analgésicos Opioides/farmacocinética , Análise de Variância , Isótopos de Carbono/farmacocinética , Estimulantes do Sistema Nervoso Central/sangue , Feminino , Fentanila/análogos & derivados , Fentanila/farmacocinética , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de PósitronsRESUMO
INTRODUCTION: Certain features of event-related potentials (ERPs), electroencephalographic (EEG), and behavioural measures vary with differing states of alertness and/or sedation. PURPOSE: This study was conducted to investigate changes in several measures usually viewed as reflecting states of sedation/sleepiness associated with the use of a range of doses of the hypnotic benzodiazepine (BZD) flunitrazepam (FNZ). METHODS: This was a double blind, independent group design study of the effects of acute oral doses of FNZ in young healthy volunteers. Forty-eight subjects were randomly allocated to one of four groups-FNZ (0.6, 0.8, and 1.0 mg) and placebo (PLAC)-and tested prior to treatment and then in a posttreatment session close to the theoretical peak plasma concentration. ERP latencies and amplitudes were measured at midfrontal (Fz), midcentral (Cz), and midparietal (Pz) using a standard auditory oddball paradigm. EEG changes were assessed at Pz. Behavioural measures included the digit-symbol substitution test (DSST), a cancellation task (CT), and subjective ratings of alertness and attentiveness by the subjects (SUB) and the experimenter (EXP). RESULTS: FNZ led to psychomotor impairments and decreased alertness and attention; these effects were consistent with previous findings. A progressive, dose-related increase in P3 latency occurred in Fz, Cz, and Pz, and there was an increase in N1 (Fz, Cz) and N2 (Fz). N2-P3 amplitude decreased in Fz. EEG power bands beta 1 increased for the two highest doses, but no significant differences were noted in theta, delta, and alpha bands. P3 latencies, experimenter-rated levels of alertness, and DSST scores differentiated all three doses of FNZ from PLAC. CONCLUSION: The most sensitive measures used were P3 latencies of the ERPs (which varied with FNZ dose), DSST, and the experimenter-rated levels of alertness. However, we found no evidence for the assumption that one single phenomenon was reflected in all measures and different mechanisms were probably involved. Further experiments will be needed for more in-depth probing of the finer mechanisms underlying sedation/sleepiness and how they affect behavioural and eletrophysiological measures of the central nervous system (CNS) function.
Assuntos
Eletroencefalografia/efeitos dos fármacos , Potenciais Evocados Auditivos/efeitos dos fármacos , Flunitrazepam/farmacologia , Hipnóticos e Sedativos/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Adolescente , Adulto , Análise de Variância , Atenção/efeitos dos fármacos , Atenção/fisiologia , Método Duplo-Cego , Eletroencefalografia/estatística & dados numéricos , Potenciais Evocados Auditivos/fisiologia , Feminino , Humanos , Masculino , Psicometria , Estatísticas não ParamétricasRESUMO
Objective: Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression. Methods: PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)." Results: Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress. Conclusion: Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.
Assuntos
Humanos , Animais , Amantadina/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Antidepressivos/uso terapêutico , Monoaminas Biogênicas , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de MedicamentosRESUMO
Obstructive sleep apnea (OSA) is a multifactorial sleep disorder associated with an increased risk of cardiovascular mortality and morbidity. Several mechanisms have been proposed to explain the association between OSA and cardiovascular dysfunction. One of the proposed mechanisms is an inflammatory response to OSA mediated by tumor necrosis factor (TNF-α). Patients with OSA have higher plasma, serum, and intracellular levels of TNF-α, which may be reduced after apnea treatment with continuous positive airway pressure (CPAP). Because TNF-α plays an important role in OSA related cardiovascular morbidity, the present review aims to identify other preventive measures, in addition to CPAP, that may minimize the inflammatory process in OSA and consequently the risk of premature death due to cardiovascular dysfunction. Thus, we hypothesized that a nutritional immunology profile, i.e., supplementation with omega-3 fatty acids, may be valuable for individuals with OSA.
RESUMO
It is well-known that cocaine dependence is a public health issue, and several studies stress the need to look for new and more effective treatments. Although the mesolimbic dopamine (DA) system, which originates in the ventral tegmental area (VTA) and projects to several forebrain structures, is known to be critically involved in the neurobiology of cocaine dependence, acetylcholine (ACh) has also been shown to play an important role in cocaine dependence via its action on this reward system. ACh is also important in the formation of hippocampal memory associated with appetitive behavior. Thus, the aim of this study was to evaluate the effect of biperiden, an ACh antagonist with high affinity for muscarinic M1 type receptors, on the acquisition of cocaine-conditioned place preference (CPP) in mice. The cocaine and biperiden were dissolved in sterile saline and were administered intraperitoneally at a dose of 10mg/kg. The conditioning regime was 8 days long, and the cholinergic antagonist was given immediately at the end of each conditioning session. The test for CPP occurred 24h after the last session. The results showed that animals treated with biperiden spent significantly less time in the cocaine-paired compartment than did the ones treated with saline. This finding represents a reduction in the consolidation of cocaine-induced CPP. One hypothesis that could explain this outcome focuses on the action of cholinergic antagonists on the consolidation of contextual memories. The amnesic effect of M1 antagonists on aversive tasks and on morphine CPP has been demonstrated when administered before the training or the conditioning session. The present study highlights the possibility of impairment in the acquisition of an appetitive memory, even when the cholinergic drug is administered after the conditioning session. This protocol also rejects the possibility of performance disturbance and suggests a possible pharmacological tool in the treatment of cocaine dependence.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Biperideno/farmacologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Memória/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/antagonistas & inibidores , Animais , Condicionamento Operante/efeitos dos fármacos , Masculino , CamundongosRESUMO
Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Aprendizagem por Associação/efeitos dos fármacos , Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Receptores de Dopamina D1/agonistasRESUMO
Cocaine addiction is a public health issue in many countries, stressing the need for more effective treatments. As all drugs of abuse, cocaine acts on the brain reward system, increasing dopamine (DA) levels. Other neurotransmitters such as acetylcholine (ACh) are involved in the mechanisms underlying the development and the maintenance of cocaine addiction. ACh plays an important role in learning and memory processes and also regulates DA in some specific regions of the central nervous system. The present study investigated the effects of biperiden, a muscarinic cholinergic (mACh) antagonist in two animal models: conditioned place preference (CPP) and behavioral sensitization. Male C57BL/6J mice were used in both studies. The CPP protocol was unbiased and carried out in three phases: habituation, conditioning and testing. For conditioning, cocaine was injected at a dose of 10mg/kg in eight 15 min-sessions. The treatment with biperiden (doses of 0.1, 1 and 10 mg/kg) was made 30 min prior to the testing session. For behavioral sensitization development, cocaine was administered at the dose of 10 mg/kg for 10 days. After sensitization, two challenges were performed: saline and cocaine (5 mg/kg). Biperiden (10 mg/kg) was administered 30 min before the cocaine challenge. At the dose of 10 mg/kg, biperiden blocked the cocaine-CPP expression, suggesting an effect on conditioned memory retrieval. However, the same dose potentiated the expression of behavioral sensitization, suggesting an increase in DA release, probably in the NAc. Biperiden, as other mACh antagonists, may be a promising drug for the pharmacologic treatment of cocaine addiction.