RESUMO
Assessing the role of cannabinoid (CB) receptors in behavior is relevant given the trend toward the legalization of medicinal and recreational marijuana. The present research aims at bridging a gap in our understanding of CB-receptor function in animal models of frustrative nonreward. These experiments were designed to (1) determine the effects of chronic administration of the nonselective CB1-receptor agonist WIN 55,212-2 (WIN) on reward downshift in rats and (2) determine whether the effects of chronic WIN were reducible to acute effects. In Experiment 1, chronic WIN (7 daily injections, 10 mg/kg, ip) accelerated the recovery of consummatory behavior after a 32-to-4% sucrose downshift relative to vehicle controls. In addition, chronic WIN eliminated the preference for an unshifted lever when the other lever was subject to a 12-to-2 pellet downshift in free-choice trials, but only in animals with previous experience with a sucrose downshift. In Experiment 2, acute WIN (1 mg/kg, ip) reduced consummatory behavior, but did not affect recovery from a 32-to-4% sucrose downshift. The antagonist SR 141716A (3 mg/kg, ip) also failed to interfere with recovery after the sucrose downshift. In Experiment 3, acute WIN administration (1 mg/kg, ip) did not affect free-choice behavior after a pellet downshift, although it reduced lever pressing and increased magazine entries relative to vehicle controls. The effects of chronic WIN on frustrative nonreward were not reducible to acute effects of the drug. Chronic WIN treatment in rats, like chronic marijuana use in humans, seems to increase resistance to the effects of frustrative nonreward.
Assuntos
Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Comportamento Consumatório/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Receptores de Canabinoides/metabolismo , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Recompensa , Rimonabanto/farmacologia , Sacarose/farmacologiaRESUMO
Nicotinamide (NAM) alters behavior in C. elegans and Drosophila, serving as an agonist of TRPV channels affecting sensory neurons and mimicking the mode of action of insecticides used to control phloem-feeding insects. The impact of NAM on green peach aphid (Myzus persicae) behaviors was assessed in artificial diet assays and foliar applications to Arabidopsis plants. Aphids feeding on artificial diets supplemented with NAM impaired stylet movement causing feeding interruptions and ultimately starvation and death. Aphid feeding behaviors were negatively impacted on NAM sprayed plants at concentrations as low as 2.5 mM leading to increased mortality. In choice assays with NAM sprayed leaves aphids showed clear preference for untreated control leaves. NAM is an intermediate in the NAD salvage pathway that should accumulate in nicotinamidase (nic) mutants. LC-MS analysis showed NAM accumulates 60-fold in nic-1-1 Arabidopsis mutants as compared with Col-0. Aphid reproductive potential was significantly decreased on nic-1-1 mutant plants, resulting in a smaller colony size and arrested population development. The results support the hypothesis that dietary NAM causes behavioral changes in aphids, including altered feeding, reduced reproduction, and increased mortality. NAM is thought to bind to TRPV channels causing overstimulation of sensory neurons in the aphid feeding apparatus.
Assuntos
Afídeos/fisiologia , Fertilidade/efeitos dos fármacos , Niacinamida/farmacologia , Animais , Afídeos/efeitos dos fármacos , Arabidopsis/parasitologia , Proteínas de Arabidopsis/genética , Comportamento de Escolha/efeitos dos fármacos , Dieta , Comportamento Alimentar/efeitos dos fármacos , Interações Hospedeiro-Parasita/efeitos dos fármacos , Mutação/genética , Análise de SobrevidaRESUMO
RATIONALE: Chronic administration of D2/3 receptor agonists ropinirole or pramipexole can increase the choice of uncertain rewards in rats, theoretically approximating iatrogenic gambling disorder (iGD). OBJECTIVES: We aimed to assess the effect of chronic ropinirole in animal models that attempt to capture critical aspects of commercial gambling, including the risk of losing rather than failing to gain, and the use of win-paired sensory stimuli heavily featured in electronic gambling machines (EGMs). METHODS: Male Long-Evans rats learned the rat gambling task (rGT; n = 24), in which animals sample between four options that differ in the magnitude and probability of rewards and time-out punishments. In the cued rGT (n = 40), reward-concurrent audiovisual cues were added that scaled in complexity with win size. Rats were then implanted with an osmotic pump delivering ropinirole (5 mg/kg/day) or saline for 28 days. RESULTS: Chronic ropinirole did not unequivocally increase preference for more uncertain outcomes in either the cued or uncued rGT. Ropinirole transiently increased premature responses, a measure of motor impulsivity, and this change was larger and more long-lasting in the cued task. CONCLUSIONS: These data suggest that explicitly signaling loss prevents the increase in preference for uncertain rewards caused by D2/3 receptor agonists observed previously. The ability of win-paired cues to amplify ropinirole-induced increases in motor impulsivity may explain why compulsive use of EGMs is particularly common in iGD. These data offer valuable insight into the cognitive-behavioral mechanisms through which chronic dopamine agonist treatments may induce iGD and related impulse control disorders.
Assuntos
Sinais (Psicologia) , Agonistas de Dopamina/administração & dosagem , Jogo de Azar/induzido quimicamente , Jogo de Azar/psicologia , Comportamento Impulsivo/efeitos dos fármacos , Indóis/administração & dosagem , Estimulação Acústica/métodos , Animais , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Agonistas de Dopamina/toxicidade , Comportamento Impulsivo/fisiologia , Indóis/toxicidade , Masculino , Estimulação Luminosa/métodos , Ratos , Ratos Long-Evans , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/fisiologia , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/fisiologiaRESUMO
Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Ritmo Circadiano , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Imunidade Inata , Naltrexona/administração & dosagem , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Fotoperíodo , Recompensa , Receptor 4 Toll-Like/metabolismoRESUMO
RATIONALE: Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues. OBJECTIVES: Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats. METHODS: The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 µl bilateral; 3 µM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively. RESULTS: We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field. CONCLUSIONS: These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control.
Assuntos
Comportamento de Escolha/fisiologia , Corpo Estriado/fisiologia , Tempo de Reação/fisiologia , Tálamo/fisiologia , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Comportamento de Escolha/efeitos dos fármacos , Clozapina/análogos & derivados , Clozapina/farmacologia , Corpo Estriado/efeitos dos fármacos , Sinais (Psicologia) , Inibição Psicológica , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Long-Evans , Tempo de Reação/efeitos dos fármacos , Recompensa , Transmissão Sináptica , Tálamo/efeitos dos fármacosAssuntos
Compostos Azabicíclicos/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Motivação/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Inibidores da Captação Adrenérgica/farmacologia , Animais , Compostos Azabicíclicos/química , Comportamento de Escolha/fisiologia , Inibidores da Captação de Dopamina/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Motivação/fisiologia , Ratos , Ratos Sprague-Dawley , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/fisiologiaRESUMO
The leaves of Jodina rhombifolia (Hook. & Arn.) Reissek (Santalaceae) are utilized as anti-alcoholic in Argentine folk medicine. This study was designed to investigate the anti-alcohol properties in adolescent male Wistar rats (postnatal day 29; 83-105 g of weight). We utilized the "self-administration model", which ethanol was offered in the standard home-cage through two-bottle free-choice regimen between an ethanolic solution (20% in tap water, v/v) and tap water with unlimited access for 24h per day for 10 consecutive days. The results obtained show that repeated administration of J. rhombifolia lyophilized extract, markedly reduced ethanol voluntary intake on dose dependent bases. The magnitude in reduction of daily ethanol intake was approximately 29%, 44% and 68%, for the rat groups treated with 62.5, 125 and 250 mg/kg of extract, respectively. Ethanol preference (proportion of ethanol intake versus total fluid intake) was significantly reduced: 21.37% ± 0.79 (0 mg/kg); 15.83% ± 0.93 (62.5 mg/kg); 15.22% ± 1.30 (125 mg/kg) and 9.38% ± 0.57 (250 mg/kg). Daily food intake was significantly higher (p<0.05) in the group treated with 250 mg/kg of JRLE in comparison with vehicle-dose group; the reduction in ethanol intake was associated with a compensatory increase in food intake, probably because in the control group animals a part of the total caloric intake was supplied by ethanol. Treatment was very well tolerated by all animals and without apparent side-effects. These results contribute to the scientific validation of the antialcoholic indication of this botanic species in Argentine folk medicine.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Etanol/administração & dosagem , Extratos Vegetais/uso terapêutico , Folhas de Planta , Santalaceae , Fatores Etários , Consumo de Bebidas Alcoólicas/psicologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Masculino , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective µ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol-drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction.
Assuntos
Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Comportamento de Procura de Droga/efeitos dos fármacos , Indanos/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Triazóis/farmacologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Consumo de Bebidas Alcoólicas/psicologia , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Concentração Alcoólica no Sangue , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Sinais (Psicologia) , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Comportamento de Procura de Droga/fisiologia , Masculino , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Receptores Opioides mu/metabolismo , Reforço Psicológico , Especificidade da EspécieRESUMO
Zebrafish larvae spend more time in brightly illuminated area when placed in a light/dark testing environment. Here we report that the anxiolytic drugs lorazepam and diazepam increased the time larval fish spent in the dark compartment in the light/dark test. Lorazepam did not affect the visual induced optokinetic response of larval fish. Gene expression levels of c-fos and crh were significantly increased in the hypothalamus of fish larvae underwent light/dark choice behavior, whilst lorazepam treatment alleviated the increased c-fos and crh expressions. Furthermore, we found estrogen receptor ß gene expression level was increased in fish larvae underwent light/dark choice. We next examined effects of estrogen receptor modulators (estradiol, BPA, PHTPP, and WAY-200070) in the light/dark test. We identified WAY-200070, a highly selective ERß agonist significantly altered the light/dark choice behavior of zebrafish larvae. Further investigation showed WAY-200070 treatment caused a reduction of crh expression level in the hypothalamus, suggesting activation of ERß signaling attenuate the stress response. Interestingly, WAY-200070 treatment caused marked increase of c-fos expression in the habenula of fish larvae underwent behavior test. These results suggest WAY-200070 activation of ERß mediated signaling may regulate anxiety related behavior in zebrafish through modulation of neuronal activity in habenula.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Lorazepam/farmacologia , Oxazóis/farmacologia , Fenóis/farmacologia , Animais , Ansiedade/metabolismo , Compostos de Boro/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Diazepam/farmacologia , Estradiol/análogos & derivados , Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Habenula/efeitos dos fármacos , Habenula/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Larva , Luz , Modelos Animais , Testes Neuropsicológicos , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
RATIONALE: While it is known that tobacco use varies across the 24-h day, the time-of-day effects are poorly understood. Findings from several previous studies indicate a potential role for melatonin in these time-of-day effects; however, the specific underlying mechanisms have not been well characterized. Understanding of these mechanisms may lead to potential novel smoking cessation treatments. OBJECTIVE: The objective of this study is examine the role of melatonin and melatonin receptors in nicotine free-choice consumption METHODS: A two-bottle oral nicotine choice paradigm was utilized with melatonin supplementation in melatonin-deficient mice (C57BL/6J) or without melatonin supplementation in mice proficient at melatonin synthesis (C3H/Ibg) compared to melatonin-proficient mice lacking both or one of the high-affinity melatonin receptors (MT1 and MT2; double-null mutant DM, or MT1 or MT2). Preference for bitter and sweet tastants also was assessed in wild-type and MT1 and MT2 DM mice. Finally, home cage locomotor monitoring was performed to determine the effect of melatonin administration on activity patterns. RESULTS: Supplemental melatonin in drinking water significantly reduced free-choice nicotine consumption in C57BL/6J mice, which do not produce endogenous melatonin, while not altering activity patterns. Independently, genetic deletion of both MT1 and MT2 receptors in a melatonin-proficient mouse strain (C3H) resulted in significantly more nicotine consumption than controls. However, single genetic deletion of either the MT1 or MT2 receptor alone did not result in increased nicotine consumption. Deletion of MT1 and MT2 did not impact taste preference. CONCLUSIONS: This study demonstrates that nicotine consumption can be affected by exogenous or endogenous melatonin and requires at least one of the high-affinity melatonin receptors. The fact that expression of either the MT1 or MT2 melatonin receptor is sufficient to maintain lower nicotine consumption suggests functional overlap and potential mechanistic explanations.
Assuntos
Melatonina/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores de Melatonina/efeitos dos fármacos , Animais , Comportamento de Escolha/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ingestão de Líquidos , Masculino , Melatonina/deficiência , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Receptor MT1 de Melatonina/genética , Receptores de Melatonina/genética , Paladar/efeitos dos fármacosRESUMO
BACKGROUND: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment's efficacy in decreasing cocaine consumption is unknown. METHODS: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. RESULTS: In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. CONCLUSIONS: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Inibidores da Captação de Dopamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Cocaína/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Dextroanfetamina/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Preferências Alimentares/efeitos dos fármacos , Macaca mulatta , Masculino , Autoadministração , Fatores de TempoRESUMO
Commercial pigs display an innate attraction for sweet taste compounds. However, the impact of long-term availability to supplementary carbohydrate solutions on their general feeding behavior has not been examined. In this work we assess the effect of 12-days exposure to 16% sucrose and 16% maltodextrin solutions on the feed intake and growth performance of piglets, and on their preference and appetence for sweet or protein solutions. The innate preference of piglets was assessed by an initial choice test between 2% sucrose and 2% animal plasma solutions for a period of three minutes. Piglets showed higher intake and preference for 2% sucrose than for 2% animal plasma. In Experiment 1, piglets were then free-offered a 16% sucrose solution as a supplement to the diet, showing a higher intake of it than water and a reduction in feed intake and weight gain. A similar situation occurred during the last days of free-exposure to a 16% maltodextrin solution in Experiment 2. The choice test between 2% sucrose and 2% animal plasma solution was repeated after the exposure to the concentrated solutions. In both experiments, a reduction in the initial preference for 2% sucrose was observed. Similarly, piglets that had previous access to the 16% sucrose and 16% maltodextrin solutions showed a decrease in the appetence for 2% sucrose in comparison with that for 2% animal plasma, as measured by a one-pan test at the end of the experiments. It is concluded that long-term exposure to concentrated sucrose and maltodextrin solutions reduces feed intake and growth in weanling piglets, and also reverses their innate preference and appetence for dilute sweet over protein solutions.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Sacarose/administração & dosagem , Aumento de Peso/efeitos dos fármacos , Animais , Comportamento de Escolha/efeitos dos fármacos , Dieta , Feminino , Masculino , Suínos , Paladar/efeitos dos fármacosRESUMO
Rodents show a stronger preference for fat than sucrose, even if their diet is isocaloric. This implies that the preference mechanisms for fat and sucrose differ. To compare the contribution of the opioid system to the preference of fat and sucrose, we examined the effects of mu-, delta-, kappa-, and non-selective opioid receptor antagonists on the preference of sucrose and fat, assessed by a two-bottle choice test and a licking test, in mice naïve to sucrose and fat ingestion. Administration of non-selective and mu-selective opioid receptor antagonists more strongly inhibited the preference of fat than sucrose. While the preference of fat was reduced to the same level as water by the antagonist administration that of sucrose was still greater than water. Our results suggest that the preference of fat relies strongly on the opioid system, while that of sucrose is regulated by other mechanisms in addition to the opioid system.
Assuntos
Preferências Alimentares/fisiologia , Fosfolipídeos/administração & dosagem , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Óleo de Soja/administração & dosagem , Sacarose/administração & dosagem , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Gorduras na Dieta/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Emulsões/administração & dosagem , Preferências Alimentares/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naloxona/análogos & derivados , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidoresRESUMO
One of the main treatment challenges in alcohol use disorder (AUD) is the high rate of craving in combination with decreased cognitive functioning including impaired decision making and impulse control that often lead to relapse. Recent studies show that guanfacine, an α-2-adrenoceptor agonist and FDA-approved ADHD medication, attenuates stress-induced relapse of several drugs of abuse including alcohol. Here we evaluated guanfacine's effects on voluntary alcohol intake, the alcohol deprivation effect (ADE), alcohol seeking behavior, and cue/priming-induced reinstatement in Wistar rats that had voluntarily consumed alcohol for at least 2 months before treatment. In addition, guanfacine's ability to regulate glutamatergic neurotransmission was evaluated through electrophysiological recordings in medial prefrontal cortex (mPFC) slices prepared from long-term drinking rats (and alcohol-naive controls) that had received three daily guanfacine (0.6 mg/kg/day) or vehicle injections in vivo. Guanfacine decreased alcohol intake in high, but not low, alcohol-consuming rats and the effects were generally more long lasting than that of the AUD medication naltrexone. Repeated guanfacine treatment induced a long-lasting decrease in alcohol intake, persistent up to five drinking sessions after the last injection. In addition, guanfacine attenuated the ADE as well as alcohol seeking and cue/priming-induced reinstatement of alcohol seeking. Finally, subchronic guanfacine treatment normalized an alcohol-induced dysregulated glutamatergic neurotransmission in the mPFC. These results support previous studies showing that guanfacine has the ability to improve prefrontal connectivity through modulation of the glutamatergic system. Together with the fact that guanfacine appears to be clinically safe, these results merit evaluation of guanfacine's clinical efficacy in AUD individuals.
Assuntos
Dissuasores de Álcool/farmacologia , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Guanfacina/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/fisiopatologia , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Etanol/administração & dosagem , Ácido Glutâmico/metabolismo , Masculino , Naltrexona/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos Wistar , Técnicas de Cultura de Tecidos , Resultado do TratamentoRESUMO
Recently, PPAR-γ activation has emerged as a potential treatment for alcoholism. However, the adverse effects of synthetic PPAR-γ activators, despite being effective drugs, prompted the need for novel PPAR-γ agonists that retain efficacy and potency with a lower potential of side effects. Hence, naringin, a bioflavonoid isolated from citrus fruits and recently identified as a natural ligand of PPAR-γ, has begun to be evaluated for treatment of alcoholism. It is well known to possess several therapeutic benefits in addition to its anti-anxiety and antidepressant properties. In the present study, we assessed whether naringin treatment possesses anti-ethanol reward properties in C57BL/6 mice. We used the two-bottle choice drinking paradigm and ethanol-induced conditioned place preference (CPP) to examine the effect of naringin treatment on ethanol drinking. Results have shown that, compared with vehicle, naringin (10-100 mg/kg) significantly and dose-dependently decreased voluntary ethanol intake and preference in a two-bottle choice drinking paradigm [3-15% (v/v) escalating over 2 weeks], with no significant effect observed on saccharin [0.02-0.08% (w/v)] or on quinine [15-60 µM (w/v)] intake. In addition, there was no significant difference in blood ethanol concentration (BEC) between groups following naringin administration of 3 g of ethanol/kg body weight. Interestingly, when mice were treated with vehicle or naringin (30 mg/kg) before injection of ethanol (1.5 g/kg) during conditioning days, naringin inhibited the acquisition of ethanol-CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, GW9662. Taken together, the present findings are the first to implicate naringin and PPAR-γ receptors in the behavioral and reward-related effects of ethanol and raise the question of whether specific drugs that target PPAR-γ receptors could potentially reduce excessive ethanol consumption and preference.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Flavanonas/uso terapêutico , Flavonoides/uso terapêutico , Consumo de Bebidas Alcoólicas/psicologia , Anilidas/farmacologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Flavanonas/antagonistas & inibidores , Flavonoides/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/antagonistas & inibidores , Recompensa , Comportamento Espacial/efeitos dos fármacosRESUMO
The stress hormone cortisol has been shown to affect hemodynamic activity of human brain structures, presumably via a nongenomic mechanism. However, behavioral implications of this finding remain unknown. In a placebo-controlled, blinded, cross-over design the rapid effects of IV hydrocortisone (5mg) on cross-modal integration of simultaneous, unilateral visual and acoustic signals in a challenging startle and reaction time (RT) paradigm were studied. On two separate days 1 week apart, 24 male volunteers responded by button push to either up- or down pointing triangles presented in random sequence in the periphery of one of the visual hemi-fields. Visual targets were accompanied by unilateral acoustic startle noise bursts, presented at the same or opposite side. Saccadic latency, manual RT, and startle eye blink responses were recorded. Faster manual reactions and increased startle eye blink responses were observed 11-20 min after hydrocortisone administration when visual targets and unilateral acoustic startle noises were presented in the same sensory hemi-field, but not when presented in opposite sensory hemi-fields. Our results suggest that a nongenomic, cortisol-sensitive mechanism enhances psychomotor and startle reactions when stimuli occur in the same sensory hemi-field. Such basic cognitive effects of cortisol may serve rapid adaptation and protection against danger stimuli in stressful contexts.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Hidrocortisona/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica , Adulto , Estudos Cross-Over , Humanos , Hidrocortisona/metabolismo , Masculino , Movimentos Sacádicos/efeitos dos fármacos , Saliva/metabolismo , Método Simples-Cego , Adulto JovemRESUMO
Centrally acting oxytocin (OT) inhibits feeding. Recent evidence suggests a link between OT and control of carbohydrate and saccharin intake, but it is unclear whether OT affects appetite for only carbohydrates, especially sweet ones, or sweet tastants irrespective of their carbohydrate content. Therefore, a blood-brain barrier penetrant OT receptor antagonist, L-368,899, was administered in mice and intake of liquid diets containing carbohydrates sucrose, glucose, fructose, polycose, or cornstarch (CS) or the noncarbohydrate, noncaloric sweetener saccharin was studied in episodic intake paradigms: one in which only one tastant was available and the other in which a choice between a carbohydrate (sucrose, glucose, or fructose) and saccharin was provided. We also used real-time PCR to examine hypothalamic Ot mRNA levels in mice provided short-term access to sucrose, CS, or saccharin. In the no-choice paradigm, L-368,899 increased the intake of all carbohydrates, whereas its effect on saccharin consumption showed only a trend. A 10 times lower dose (0.3 mg/kg) stimulated intake of sucrose than other carbohydrates. In the choice test, a very low 0.1 mg/kg dose of L-368,899 doubled the proportion of sucrose consumption relative to saccharin, but did not affect fructose or glucose preference. Ot gene expression increased after sucrose and CS, but not saccharin exposure compared with the controls; however, a higher level of significance was detected in the sucrose group. We conclude that OT inhibits appetite for carbohydrates. Sucrose consumption considerably enhances Ot gene expression and is particularly sensitive to OT receptor blockade, suggesting a special functional relationship between OT and sugar intake.
Assuntos
Apetite/fisiologia , Carboidratos da Dieta/administração & dosagem , Preferências Alimentares/fisiologia , Ocitocina/metabolismo , Sacarina/administração & dosagem , Animais , Apetite/efeitos dos fármacos , Canfanos/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Relação Dose-Resposta a Droga , Preferências Alimentares/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Piperazinas/farmacologia , RNA Mensageiro/metabolismo , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismoRESUMO
Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.
Assuntos
Antidepressivos/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Depressão/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Benzazepinas/farmacologia , Benzofenonas/farmacologia , Bupropiona/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Depressão/induzido quimicamente , Antagonistas de Dopamina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Masculino , Nitrofenóis/farmacologia , Pirazóis/farmacologia , Ratos Sprague-Dawley , Salicilamidas/farmacologia , Selegilina/farmacologia , Tolcapona , Xantinas/farmacologiaRESUMO
Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1)H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolômica , Neurotransmissores/metabolismo , Nicotina/farmacologia , Aminoácidos/metabolismo , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Análise dos Mínimos Quadrados , Masculino , Membranas/efeitos dos fármacos , Membranas/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Classical conditioning is widely used to study motivational properties of addictive drugs in animals, but has rarely been used in humans. We established a procedure suitable for studying the neurobiology and individual determinants of classical conditioning in humans. Healthy volunteers were randomly assigned to four groups that received methamphetamine or placebo in the presence of distinctive environmental cues under paired or unpaired conditions. During each session, subjects performed tasks known to activate the ventral striatum. Tasks were performed in the presence of a distinctive context, consisting of a screen background image of a beach or mountains, accompanied by corresponding sounds. Separate groups of subjects carried out the tasks under high ($35-50) or low ($5-20) reward conditions. Within each of the two reward conditions, one group (paired) received methamphetamine (20 mg, oral) or placebo consistently associated with one of the contexts, while the other (unpaired) received drug or placebo unrelated to context. A fifth group (paired) performed the tasks with contextual cues but in the absence of monetary incentives. Before and after conditioning, participants carried out a series of forced choice tasks for the contextual cues, and change of preference over time was analyzed. All paired groups showed a significant increase in preference for the drug-associated context, with a linear trend for increase across the levels of reward. Preference was unrelated to subjective drug effects, and did not change in the unpaired group. These data support the translational utility of our conditioning procedure for studies of reward mechanisms in humans.