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1.
Eur Rev Med Pharmacol Sci ; 28(4): 1356-1365, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38436168

RESUMO

OBJECTIVE: Aripiprazole, risperidone, atomoxetine, and methylphenidate are drugs commonly prescribed for many psychiatric conditions and can be used alone or in combination in children and adolescents. This study aimed to investigate comparatively the possible genotoxic effects or genoprotective potentials of these drugs on human lymphocytes and HepG2 cells. MATERIALS AND METHODS: Cytotoxicity analysis was performed with the cell viability test on human lymphocytes and HepG2 cells, and half-maximal inhibitory concentration (IC50) values of the drugs were determined, and three different doses (» IC50, ½ IC50, and IC50) were applied for genetic analysis. For the determined doses, cells with and without DNA damage were examined by comet analysis. RESULTS: In lymphocytes, aripiprazole and risperidone increased DNA damage at moderate and maximum doses, whereas atomoxetine increased DNA damage only at the maximum dose. In HepG2 cells, risperidone reduced DNA damage at all doses, while atomoxetine increased DNA damage at all doses. On the other hand, in the DNA-damaged cells induced by hydrogen peroxide (H2O2), DNA damage decreased at all concentrations of all drugs in both lymphocytes and HepG2 cells. CONCLUSIONS: As a result, the genotoxicity of the drugs was found to be dose-dependent, and all drugs showed a genoprotective effect on DNA-damaged cells.


Assuntos
Antipsicóticos , Metilfenidato , Adolescente , Criança , Humanos , Antipsicóticos/farmacologia , Risperidona/farmacologia , Aripiprazol , Cloridrato de Atomoxetina/farmacologia , Metilfenidato/toxicidade , Células Hep G2 , Peróxido de Hidrogênio , Dano ao DNA , Linfócitos , DNA
2.
Cogn Affect Behav Neurosci ; 24(2): 351-367, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38253774

RESUMO

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.


Assuntos
Anfetamina , Cloridrato de Atomoxetina , Atenção , Estimulantes do Sistema Nervoso Central , Ketamina , Metilfenidato , Nicotina , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cloridrato de Atomoxetina/farmacologia , Cloridrato de Atomoxetina/administração & dosagem , Atenção/efeitos dos fármacos , Atenção/fisiologia , Masculino , Ratos , Metilfenidato/farmacologia , Metilfenidato/administração & dosagem , Nicotina/farmacologia , Nicotina/administração & dosagem , Anfetamina/farmacologia , Anfetamina/administração & dosagem , Ketamina/farmacologia , Ketamina/administração & dosagem , Estimulação Luminosa/métodos , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/administração & dosagem , Aprendizagem Seriada/efeitos dos fármacos , Aprendizagem Seriada/fisiologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia , Ratos Sprague-Dawley
3.
Cell Biochem Biophys ; 81(1): 105-115, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36346546

RESUMO

Atomoxetine (ATX) is a presynaptic norepinephrine transporter (NET) inhibitor widely prescribed for attention-deficit/hyperactivity disorder (ADHD) due to its low abuse potential and absence of psychostimulant effects. While NET inhibition is implicated in the clinical response, several additional pharmacoactivities may contribute to clinical efficacy or unwanted side effects. We recently reported that ATX can dose-dependently alter mitochondrial function and cellular redox status. Here, we assessed potential alterations in mitochondrial biogenesis, mitochondrial dynamics and cellular antioxidant capacity following high- and low-dose ATX treatment of differentiated human neuroblastoma cells. Human SH-SY5Y neuroblastoma cells were treated with ATX (1, 5, 10, 20 and 50 µM) for 7 days under differentiation culture conditions. Changes in the expression levels of protein markers for mitochondrial biogenesis, fusion and fission as well as of antioxidant proteins were analysed by Western blot. High-dose ATX (50 µM) reduced while low-dose ATX (10 µM) increased mitochondrial biogenesis as evidenced by parallel changes in SDHA, COX-I, PGC1α and TFAM expression. High-dose ATX also reduced mitochondrial fusion as evidenced by OPA1 and MFN2 downregulation, and mitochondrial fission as indicated by DRP1 and Fis1 downregulation. In contrast, ATX did not alter expression of the antioxidant enzymes SOD1 and catalase, the phase II transcription factor Nfr2, or the Nfr2-regulated antioxidant enzyme NQO1. Clinical responses and side effects of ATX may be mediated by dose-dependent modulation of mitochondrial biogenesis and dynamics as well as NET inhibition.


Assuntos
Antioxidantes , Neuroblastoma , Humanos , Cloridrato de Atomoxetina/farmacologia , Antioxidantes/farmacologia , Biogênese de Organelas , Neurônios
4.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36142172

RESUMO

Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of osterix (OSX), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Nootrópicos , Adulto , Cloridrato de Atomoxetina/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Diferenciação Celular , Estimulantes do Sistema Nervoso Central/farmacologia , Criança , Guanfacina/farmacologia , Humanos , Ligantes , Metilfenidato/uso terapêutico , Modafinila/farmacologia , Modafinila/uso terapêutico , Nootrópicos/uso terapêutico , Osteoprotegerina/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B
5.
Physiol Behav ; 249: 113767, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35245527

RESUMO

Metabolic conditions like diabetes, is a major risk factor for the development of dementia of vascular origin. This study investigates the efficacy of atomoxetine (ATX) and N-acetylcysteine (NAC) in streptozotocin (STZ) diabetes induced vascular endothelium dysfunction and related dementia. Single dose STZ (50 mg/kg i.p) was administered to Albino Wistar rats (male, 200-250 g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests (ASST) were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-α, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE and histopathological changes were also assessed. Atomoxetine - ATX (2 mg kg-1/ 4 mg kg-1) and N-acetylcysteine- NAC (250 mg kg-1/ 500 mg kg-1) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg kg-1) was used as a positive control. STZ administered rats showed increase in serum glucose levels and decrease in body weight. Rats administered with STZ also showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress, inflammation, AChE activity and histopathological changes. Administration of ATX and NAC in two different doses as well as in combination, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, biochemical parameters and histopathological changes. Co-treatment of ATX and NAC was better in comparison to the doses when given alone. Hence, STZ administration caused diabetes induced dementia of vascular origin which was attenuated by the administration of ATX and NAC. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced dementia of vascular origin conditions.


Assuntos
Demência Vascular , Diabetes Mellitus Experimental , Acetilcolinesterase/metabolismo , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Cloridrato de Atomoxetina/farmacologia , Cloridrato de Atomoxetina/uso terapêutico , Peso Corporal , Encéfalo/metabolismo , Demência Vascular/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Masculino , Aprendizagem em Labirinto , Estresse Oxidativo , Ratos , Estreptozocina/toxicidade
6.
Neuropharmacology ; 187: 108494, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33587920

RESUMO

Although attention-deficit/hyperactivity disorder (ADHD) is widely studied, problems regarding the adverse effect risks and non-responder problems still need to be addressed. Combination pharmacotherapy using standard dose regimens of existing medication is currently being practiced mainly to augment the therapeutic efficacy of each drug. The idea of combining different pharmacotherapies with different molecular targets to alleviate the symptoms of ADHD and its comorbidities requires scientific evidence, necessitating the investigation of their therapeutic efficacy and the mechanisms underlying the professed synergistic effects. Here, we injected male ICR mice with MK-801 to induce ADHD behavioral condition. We then modeled a "combined drug" using sub-optimal doses of methylphenidate, atomoxetine, and fluoxetine and investigated the combined treatment effects in MK-801-treated mice. No sub-optimal dose monotherapy alleviated ADHD behavioral condition in MK-801-treated mice. However, treatment with the combined drug attenuated the impaired behavior of MK-801-treated animals. Growth impediment, sleep disturbances, or risk of substance abuse were not observed in mice treated subchronically with the combined drugs. Finally, we observed that the combined ADHD drug rescued alterations in p-AKT and p-ERK1/2 levels in the prefrontal cortex and hippocampus, respectively, of MK-801-treated mice. Our results provide experimental evidence of a possible new pharmacotherapy option in ameliorating the ADHD behavioral condition without the expected adverse effects. The detailed mechanism of action underlying the synergistic therapeutic efficacy and reduced adverse reaction by combinatorial drug treatment should be investigated further in future studies.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Cloridrato de Atomoxetina/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Fluoxetina/farmacologia , Metilfenidato/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Sinergismo Farmacológico , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/toxicidade , Crescimento e Desenvolvimento/efeitos dos fármacos , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Teste de Campo Aberto , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sono/efeitos dos fármacos
7.
Vet Med Sci ; 6(4): 1017-1024, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32342640

RESUMO

Atomoxetine (ATX) is a noradrenaline reuptake inhibitor used to treat Attention deficit hyperactive disorder (ADHD), or improve cognition in normal subjects. Cancer patients treated with systemic adjuvant chemotherapy have described experiencing deterioration in cognition. Doxorubicin (DOX, Adriamycin) is one of the anthracycline families used in chemotherapy, which has a deteriorating effect on both cognition and proliferation. The cognitive effects of ATX require inputs from the hippocampus. The aim of this study was to examine spatial memory and proliferation in the subgranular zone (SGZ) of the DG in adult Lister Hooded rats treated either alone or with a combination of Atomoxetine (30 mg kg-1  day-1 , six i.p. doses, one injection every other day) and Doxorubicin (DOX) ( 2 mg kg-1  day-1 , six i.p. doses, one injection every other day). Spatial memory was tested using the Novel location recognition (NLR) test, and proliferation of hippocampal cells was quantified using immunohistochemistry for the proliferative marker Ki67. Results showed that ATX treatment has improved the NLR task and increased cell proliferation in the SGZ of the DG, compared with saline-treated controls. Animals treated with DOX only showed deficits in NLR task, and co-administration of ATX along with DOX did not improve their performance. DOX chemotherapy caused a significant reduction in the number of proliferating cells in the SGZ of the DG compared with saline-treated controls. This reduction was reversed by co-administration of ATX. The above findings suggest that DOX can negatively affect both cell proliferation and memory and ATX co-administration improves proliferation, but not memory in the adult male rat hippocampus.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antibióticos Antineoplásicos/efeitos adversos , Cloridrato de Atomoxetina/farmacologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Masculino , Neoplasias/tratamento farmacológico , Distribuição Aleatória , Ratos
8.
Behav Brain Res ; 378: 112266, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31580915

RESUMO

Psychostimulants are highly effective cognitive-enhancing therapeutics yet have a significant potential for abuse and addiction. While psychostimulants likely exert their rewarding and addictive properties through dopamine transporter (DAT) inhibition, the mechanisms of their procognitive effects are less certain. By one prevalent view, psychostimulants exert their procognitive effects exclusively through norepinephrine transporter (NET) inhibition, however increasing evidence suggests that DAT also plays a critical role in their cognitive-enhancing properties, including long-term memory enhancement. The present experiments test the hypothesis that combined strong NET and weak DAT inhibition will mimic the fear memory-enhancing but not the addiction-related effects of psychostimulants in mice. We examined the effects of the high affinity NET inhibitors atomoxetine or nisoxetine and the low affinity DAT inhibitor bupropion, either alone or in combination, on short- and long-term memory of Pavlovian fear conditioning. We also examined the addiction-related effects of combined strong NET and weak DAT inhibition using conditioned place preference and a locomotor activity test. While atomoxetine or nisoxetine alone enhanced short-term fear memory, the addition of bupropion was required to significantly enhance long-term fear memory. Additionally, combined atomoxetine and bupropion did not produce substantial motor stimulation or place preference. These findings suggest that combining strong NET and weak DAT inhibition could lead to the development of a highly effective cognitive enhancer that lacks the potential for addiction.


Assuntos
Cloridrato de Atomoxetina/farmacologia , Comportamento Animal/efeitos dos fármacos , Bupropiona/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Medo/efeitos dos fármacos , Fluoxetina/análogos & derivados , Memória de Longo Prazo/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Nootrópicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Animais , Cloridrato de Atomoxetina/administração & dosagem , Bupropiona/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Quimioterapia Combinada , Feminino , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Captação de Neurotransmissores/administração & dosagem , Nootrópicos/administração & dosagem
9.
Eur Neuropsychopharmacol ; 29(2): 235-246, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30552041

RESUMO

The nicotinic acetylcholine receptor (nAChR) agonist nicotine and the noradrenaline transporter inhibitor atomoxetine are widely studied substances due to their propensity to alleviate cognitive deficits in psychiatric and neurological patients and their beneficial effects on some aspects of cognitive functions in healthy individuals. However, despite growing evidence of acetylcholine-noradrenaline interactions, there are only very few direct comparisons of the two substances. Here, we investigated the effects of nicotine and atomoxetine on response inhibition in the stop-signal task and we characterised the neural correlates of these effects using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 3T. Nicotine (7 mg dermal patch) and atomoxetine (60 mg per os) were applied to N = 26 young, healthy adults in a double-blind, placebo-controlled, cross-over, within-subjects design. BOLD images were collected during a stop-signal task that controlled for infrequency of stop trials. There were no drug effects on behavioural performance or subjective state measures. However, there was a pronounced upregulation of activation in bilateral prefrontal and left parietal cortex following nicotine during successful compared to unsuccessful stop trials. The effect of nicotine on BOLD during failed stop trials was correlated across individuals with a measure of trait impulsivity. Atomoxetine, however, had no discernible effects on BOLD. We conclude that nicotine effects on brain function during inhibitory control are most pronounced in individuals with higher levels of impulsivity. This finding is compatible with previous evidence of nicotine effects on stop-signal task performance in highly impulsive individuals and implicates the nAChR in the neural basis of impulsivity.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Cloridrato de Atomoxetina/farmacologia , Encéfalo/efeitos dos fármacos , Inibição Psicológica , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Administração Cutânea , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Oxigênio/sangue , Tempo de Reação/efeitos dos fármacos , Escala Visual Analógica , Adulto Jovem
10.
Br J Psychiatry ; 212(4): 234-238, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29501070

RESUMO

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) increases the risk of suicidal behaviours through psychiatric comorbidities; however, a significant direct association has not been observed between ADHD and suicide attempts. Aims To evaluate the risk of suicide attempt in adolescents and young adults with ADHD. METHOD: Using a nationwide, population-based insurance claims database, this longitudinal cohort study enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009. Any suicide attempt was identified from enrolment to 31 December 2011. The association between ADHD medications and the likelihood of suicide attempt was assessed. RESULTS: ADHD was an independent risk factor for any suicide attempt (hazard ratio = 3.84, 95% CI = 3.19-4.62) and repeated suicide attempts (hazard ratio = 6.52, 95% CI = 4.46-9.53). Subgroup analyses of men, women, adolescents and young adults demonstrated the same trend. Methylphenidate or atomoxetine treatment did not increase the risk of suicide attempt or repeated suicide attempts. Long-term methylphenidate treatment was associated with a significantly decreased risk of repeated suicide attempts in men (hazard ratio = 0.46, 95% CI = 0.22-0.97). CONCLUSION: ADHD was a risk factor for suicide attempt and a stronger predictor of repeated suicide attempts, independent of comorbidities. Further investigation is warranted to explore the mechanism underlying the association between ADHD and suicidal behaviours. Declaration of interest None.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Tentativa de Suicídio/estatística & dados numéricos , Adolescente , Adulto , Cloridrato de Atomoxetina/farmacologia , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Metilfenidato/farmacologia , Programas Nacionais de Saúde/estatística & dados numéricos , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
11.
Psychopharmacology (Berl) ; 233(15-16): 2999-3008, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27325394

RESUMO

RATIONALE: Impulsive choice, or an inability to delay immediate gratification, has been strongly linked to the development and persistence of drug abuse. Indeed, delaying drug use itself may underlie drug addiction and relapse. Thus, employing treatments that are efficacious in reducing impulsive choice (atomoxetine; ATO) or drug-seeking behavior (progesterone; PRO) may be an effective means of treating drug addiction. OBJECTIVE: The current study assessed sex differences in the effects of PRO, ATO, and their combination in a delay discounting paradigm for cocaine and for sucrose pellets. METHOD: Male and female rats chose between a small-immediate or a large-delayed (0, 7.5, 15, 30, 60 s) outcome in an impulsive choice procedure for sucrose pellets (1 vs. 3 pellets) or for iv cocaine infusions (0.3 vs. 0.9 mg/kg). Following baseline assessment of impulsive choice, rats received daily treatment of vehicle (VEH), PRO (0.5 mg/kg), ATO (1.5 mg/kg), or a combination (PRO + ATO) until a second assessment of impulsive choice was determined. RESULTS: Compared to the VEH group, females were less impulsive for cocaine following PRO or the PRO + ATO combined treatment, whereas males were less impulsive for cocaine following ATO. No treatment effects were observed on impulsive choice for sucrose pellets. CONCLUSIONS: The present results indicate that impulsive choice for cocaine is reduced by PRO in females and by ATO in males. These findings suggest both treatments may be an effective intervention in treating cocaine abuse, but that their effectiveness differs by sex.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Cloridrato de Atomoxetina/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Cocaína/administração & dosagem , Desvalorização pelo Atraso/efeitos dos fármacos , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento Impulsivo/efeitos dos fármacos , Progesterona/farmacologia , Progestinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Feminino , Masculino , Ratos , Fatores Sexuais , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem
12.
Pharmacol Biochem Behav ; 145: 17-23, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27003832

RESUMO

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.


Assuntos
Cloridrato de Atomoxetina/farmacologia , Cloridrato de Atomoxetina/uso terapêutico , Cocaína , Comportamento de Procura de Droga/efeitos dos fármacos , Progesterona/farmacologia , Progesterona/uso terapêutico , Caracteres Sexuais , Animais , Cafeína/antagonistas & inibidores , Cafeína/farmacologia , Cocaína/administração & dosagem , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Interações Medicamentosas , Extinção Psicológica/efeitos dos fármacos , Feminino , Masculino , Ratos , Autoadministração
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