RESUMO
AIMS: Like drug addiction, cues associated with palatable foods can trigger food-seeking, even when sated. However, whether susceptibility to the motivating influence of food-related cues is a predisposing factor in overeating or a consequence of poor diet is difficult to determine in humans. Using a rodent model, we explored whether a highly palatable 'junk food' diet impacts responses to reward-paired cues in a Pavlovian-to-instrumental transfer test, using sweetened condensed milk (SCM) as the reward. The hedonic impact of SCM consumption was also assessed by analyzing licking microstructure. METHODS: To probe the effects of pattern and duration of junk food exposure, we provided rats with either regular chow ad libitum (controls) or chow plus access to junk food for either 2 or 24â¯h per day for 1, 3, or 6 weeks. We also examined how individual susceptibility to weight gain related to these measures. RESULTS: Rats provided 24â¯h access to the junk food diet were insensitive to the motivational effects of a SCM-paired cue when tested sated even though their hedonic experience upon reward consumption was similar to controls. In contrast, rats provided restricted, 2â¯h access to junk food exhibited a cue generalization phenotype under sated conditions, lever-pressing with increased vigor in response to both a SCM-paired cue, and a cue not previously paired with reward. Hedonic response was also significantly higher in these animals relative to controls. CONCLUSIONS: These data demonstrate that the pattern of junk food exposure differentially alters the hedonic impact of palatable foods and susceptibility to the motivating influence of cues in the environment to promote food-seeking actions when sated, which may be consequential for understanding overeating and obesity.
Assuntos
Sinais (Psicologia) , Dieta/psicologia , Ingestão de Alimentos/psicologia , Paladar , Adiposidade , Animais , Comportamento Animal , Fast Foods , Masculino , Motivação , Ratos , Ratos Sprague-Dawley , Recompensa , Aumento de PesoRESUMO
Chronic pain attenuates midbrain dopamine (DA) transmission, as evidenced by a decrease in opioid-evoked DA release in the ventral striatum, suggesting that the occurrence of chronic pain impairs reward-related behaviors. However, mechanisms by which pain modifies DA transmission remain elusive. Using in vivo microdialysis and microinjection of drugs into the mesolimbic DA system, we demonstrate in mice and rats that microglial activation in the VTA compromises not only opioid-evoked release of DA, but also other DA-stimulating drugs, such as cocaine. Our data show that loss of stimulated extracellular DA is due to impaired chloride homeostasis in midbrain GABAergic interneurons. Treatment with minocycline or interfering with BDNF signaling restored chloride transport within these neurons and recovered DA-dependent reward behavior. Our findings demonstrate that a peripheral nerve injury causes activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry. Because chronic pain causes glial activation in areas of the CNS important for mood and affect, our findings may translate to other disorders, including anxiety and depression, that demonstrate high comorbidity with chronic pain.
Assuntos
Dor Crônica/patologia , Sistema Límbico/patologia , Microglia/patologia , Rede Nervosa/patologia , Recompensa , Animais , Área Sob a Curva , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Cocaína/uso terapêutico , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Minociclina/uso terapêutico , Morfina/uso terapêutico , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/complicações , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
Opioid peptides are implicated in processes related to reward and aversion; however, how specific opioid peptides are involved remains unclear. We investigated the role of nociceptin (NOC) in voluntary licking for palatable and aversive tastants by studying the effect of intracerebroventricularly administered NOC on licking microstructure in wild-type and NOC receptor knockout (NOP KO) mice. Compared with the wild-type mice, NOP KO mice emitted fewer bouts of licking when training to lick for a 20% sucrose solution. Correspondingly, intracerebroventricular administration of NOC increased the number of licking bouts for sucrose and sucralose in wild-type, but not in NOP KO mice. The ability of NOC to initiate new bouts of licking for sweet solutions suggests that NOC may drive motivational aspects of feeding behavior. Conversely, adulterating a sucrose solution with the aversive tastant quinine reduced licking bout lengths in wild-type and NOP KOs, suggesting that NOC signaling is not involved in driving voluntary consumption of semiaversive tastants. Interestingly, when consuming sucrose following 20 h of food deprivation, NOP KO mice emitted longer bouts of licking than wild types, suggesting that under hungry conditions, NOC may also contribute toward hedonic aspects of feeding. Together, these results suggest differential roles for NOC in the motivational and hedonic aspects of feeding.
Assuntos
Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Animais , Ingestão de Alimentos/psicologia , Comportamento Alimentar/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Motivação , Quinina/administração & dosagem , Receptores Opioides/genética , Transdução de Sinais/fisiologia , Sacarose/administração & dosagem , Receptor de Nociceptina , NociceptinaRESUMO
Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.
Assuntos
Aldeído Desidrogenase/antagonistas & inibidores , Benomilo/toxicidade , Fungicidas Industriais/toxicidade , Doença de Parkinson/epidemiologia , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Citometria de Fluxo , Humanos , Modelos Logísticos , Mesencéfalo/citologia , Mitocôndrias/metabolismo , Degeneração Neural/induzido quimicamente , Razão de Chances , Doença de Parkinson/enzimologia , Ratos , Peixe-ZebraRESUMO
Monoamine neurotransmitters are stored in both synaptic vesicles (SVs), which are required for release at the synapse, and large dense-core vesicles (LDCVs), which mediate extrasynaptic release. The contributions of each type of vesicular release to specific behaviors are not known. To address this issue, we generated mutations in the C-terminal trafficking domain of the Drosophila vesicular monoamine transporter (DVMAT), which is required for the vesicular storage of monoamines in both SVs and LDCVs. Deletion of the terminal 23 aa (DVMAT-Δ3) reduced the rate of endocytosis and localization of DVMAT to SVs, but supported localization to LDCVs. An alanine substitution mutation in a tyrosine-based motif (DVMAT-Y600A) also reduced sorting to SVs and showed an endocytic deficit specific to aminergic nerve terminals. Redistribution of DVMAT-Y600A from SV to LDCV fractions was also enhanced in aminergic neurons. To determine how these changes might affect behavior, we expressed DVMAT-Δ3 and DVMAT-Y600A in a dVMAT null genetic background that lacks endogenous dVMAT activity. When expressed ubiquitously, DVMAT-Δ3 showed a specific deficit in female fertility, whereas DVMAT-Y600A rescued behavior similarly to DVMAT-wt. In contrast, when expressed more specifically in octopaminergic neurons, both DVMAT-Δ3 and DVMAT-Y600A failed to rescue female fertility, and DVMAT-Y600A showed deficits in larval locomotion. DVMAT-Y600A also showed more severe dominant effects than either DVMAT-wt or DVMAT-Δ3. We propose that these behavioral deficits result from the redistribution of DVMAT from SVs to LDCVs. By extension, our data suggest that the balance of amine release from SVs versus that from LDCVs is critical for the function of some aminergic circuits.
Assuntos
Comportamento Animal/fisiologia , Proteínas de Drosophila/metabolismo , Vesículas Secretórias/metabolismo , Vesículas Sinápticas/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Proteínas Vesiculares de Transporte de Monoamina/genéticaRESUMO
Monoamine oxidase A (MAO-A), the catabolic enzyme of norepinephrine and serotonin, plays a critical role in emotional and social behavior. However, the control and impact of endogenous MAO-A levels in the brain remains unknown. Here we show that the RING finger-type E3 ubiquitin ligase Rines/RNF180 regulates brain MAO-A subset, monoamine levels, and emotional behavior. Rines interacted with MAO-A and promoted its ubiquitination and degradation. Rines knock-out mice displayed impaired stress responses, enhanced anxiety, and affiliative behavior. Norepinephrine and serotonin levels were altered in the locus ceruleus, prefrontal cortex, and amygdala in either stressed or resting conditions, and MAO-A enzymatic activity was enhanced in the locus ceruleus in Rines knock-out mice. Treatment of Rines knock-out mice with MAO inhibitors showed genotype-specific effects on some of the abnormal affective behaviors. These results indicated that the control of emotional behavior by Rines is partly due to the regulation of MAO-A levels. These findings verify that Rines is a critical regulator of the monoaminergic system and emotional behavior and identify a promising candidate drug target for treating diseases associated with emotion.
Assuntos
Encéfalo/enzimologia , Emoções/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Monoaminoxidase/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Estimulação Acústica , Animais , Aprendizagem da Esquiva/fisiologia , Encéfalo/ultraestrutura , Adaptação à Escuridão/genética , Emoções/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Células HEK293 , Humanos , Relações Interpessoais , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores da Monoaminoxidase/farmacologia , Mutação/genética , Tempo de Reação/genética , Reflexo de Sobressalto/genética , Natação/fisiologia , Tranilcipromina/farmacologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genéticaRESUMO
Baseline and nicotine-modulated behaviors were assessed in mice harboring a null mutant allele of the nicotinic acetylcholine receptor (nAChR) subunit gene α2 (Chrna2). Homozygous Chrna2(-/-) mice are viable, show expected sex and Mendelian genotype ratios, and exhibit no gross neuroanatomical abnormalities. A broad range of behavioral tests designed to assess genotype-dependent effects on anxiety (elevated plus maze and light/dark box), motor coordination (narrow bean traverse and gait), and locomotor activity revealed no significant differences between mutant mice and age-matched wild-type littermates. Furthermore, a panel of tests measuring traits, such as body position, spontaneous activity, respiration, tremors, body tone, and startle response, revealed normal responses for Chrna2-null mutant mice. However, Chrna2(-/-) mice do exhibit a mild motor or coordination phenotype (a decreased latency to fall during the accelerating rotarod test) and possess an increased sensitivity to nicotine-induced analgesia in the hotplate assay. Relative to wild-type, Chrna2(-/-) mice show potentiated nicotine self-administration and withdrawal behaviors and exhibit a sex-dependent enhancement of nicotine-facilitated cued, but not trace or contextual, fear conditioning. Overall, our results suggest that loss of the mouse nAChR α2 subunit has very limited effects on baseline behavior but does lead to the potentiation of several nicotine-modulated behaviors.
Assuntos
Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Nicotínicos/deficiência , Síndrome de Abstinência a Substâncias/fisiopatologia , Análise de Variância , Animais , Ansiedade/fisiopatologia , Condicionamento Clássico/efeitos dos fármacos , Esquema de Medicação , Reação de Fuga/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfina/efeitos adversos , Neurotransmissores/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação , Reflexo/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/etiologiaRESUMO
Major depressive and bipolar disorders are serious illnesses that affect millions of people. Growing evidence implicates glutamate signalling in depression, though the molecular mechanism by which glutamate signalling regulates depression-related behaviour remains unknown. In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to depression-related behaviour. The NR2A subunit of the NMDA receptor is tyrosine-phosphorylated, with Tyr 1325 as its one of the major phosphorylation site. We have generated mice expressing mutant NR2A with a Tyr-1325-Phe mutation to prevent the phosphorylation of this site in vivo. The homozygous knock-in mice show antidepressant-like behaviour in the tail suspension test and in the forced swim test. In the striatum of the knock-in mice, DARPP-32 phosphorylation at Thr 34, which is important for the regulation of depression-related behaviour, is increased. We also show that the Tyr 1325 phosphorylation site is required for Src-induced potentiation of the NMDA receptor channel in the striatum. These data argue that Tyr 1325 phosphorylation regulates NMDA receptor channel properties and the NMDA receptor-mediated downstream signalling to modulate depression-related behaviour.
Assuntos
Depressão/metabolismo , Depressão/fisiopatologia , Receptores de N-Metil-D-Aspartato/fisiologia , Tirosina/fisiologia , Animais , Linhagem Celular , Depressão/genética , Depressão/psicologia , Modelos Animais de Doenças , Regulação para Baixo/genética , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenilalanina/genética , Fosforilação/genética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/genética , Tirosina/genéticaRESUMO
Opioid-alcohol polysubstance use is prevalent and worsens treatment outcomes. Here we assessed whether co-consumption of oxycodone and alcohol would influence intake of one another, demand for oxycodone, and the neurocircuitry underlying cue-primed reinstatement of oxycodone-seeking. Male and female rats underwent oxycodone intravenous self-administration (IVSA) with access to either alcohol (20% v/v) and water or only water immediately after the IVSA session. Next, economic demand for intravenous oxycodone was assessed while access to alcohol and/or water continued. Control rats self-administered sucrose followed by access to alcohol and/or water. Rats underwent extinction training and brains were processed for c-fos mRNA expression immediately following a cue-primed reinstatement test. While both sexes decreased oxycodone intake if they had access to alcohol, and decreased alcohol intake if they had access to oxycodone, female oxycodone+alcohol rats exhibited decreased demand elasticity for intravenous oxycodone and increased cue-primed reinstatement while male rats did not. Spontaneous withdrawal signs were correlated with oxycodone intake while alcohol intake was correlated with anxiety-like behavior. Alcohol consumption increased the number of basolateral and central amygdala neurons activated during sucrose and oxycodone reinstatement and the number of ventral and dorsal striatum neurons engaged by sucrose reinstatement. Nucleus accumbens shell dopamine 1 receptor containing neurons displayed activation patterns consistent with oxycodone reinstatement. Thus, alcohol alters the motivation to seek oxycodone in a sex-dependent manner and alters the neural circuitry engaged by cue-primed reinstatement of sucrose and oxycodone-seeking.
RESUMO
Opioid-alcohol polysubstance use is prevalent and worsens treatment outcomes. Here we assessed whether co-consumption of oxycodone and alcohol influence the intake of one another, demand for oxycodone, and the neurocircuitry underlying cue-primed reinstatement of oxycodone-seeking. Male and female rats underwent oxycodone intravenous self-administration (IVSA) with homecage access to alcohol (20% v/v) and/or water immediately after the IVSA session. Next, economic demand for intravenous oxycodone was assessed while access to alcohol and/or water continued. Control rats self-administered sucrose followed by access to alcohol and/or water. Rats underwent a cue-primed reinstatement test and brains were processed for c-fos mRNA expression. While both sexes decreased oxycodone intake if they had access to alcohol, and decreased alcohol intake if they had access to oxycodone, only female oxycodone + alcohol rats exhibited decreased demand elasticity and increased cue-primed reinstatement. Alcohol consumption increased the number of basolateral and central amygdala neurons activated during sucrose and oxycodone reinstatement and the number of ventral and dorsal striatum neurons engaged by sucrose reinstatement. Nucleus accumbens shell dopamine 1 receptor expressing neurons displayed activation patterns consistent with oxycodone reinstatement. Thus, alcohol alters the motivation to seek oxycodone in a sex-dependent manner and the neural circuitry engaged by cue-primed reinstatement of sucrose and oxycodone-seeking.
Assuntos
Motivação , Oxicodona , Feminino , Ratos , Masculino , Animais , Sacarose/metabolismo , Consumo de Bebidas Alcoólicas , Etanol/metabolismo , Receptores Dopaminérgicos/metabolismo , Neurônios/metabolismo , Água/metabolismo , Autoadministração , Extinção PsicológicaRESUMO
Inter-relationships between pain sensitivity, drug reward, and drug misuse are of considerable interest given that many analgesics exhibit misuse potential. Here we studied rats as they underwent a series of pain- and reward-related tests: cutaneous thermal reflex pain, induction and extinction of conditioned place preference to oxycodone (0.56 mg/kg), and finally the impact of neuropathic pain on reflex pain and reinstatement of conditioned place preference. Oxycodone induced a significant conditioned place preference that extinguished throughout repeated testing. Correlations identified of particular interest included an association between reflex pain and oxycodone-induced behavioral sensitization, and between rates of behavioral sensitization and extinction of conditioned place preference. Multidimensional scaling analysis followed by k-clustering identified three clusters: (1) reflex pain, rate of behavioral sensitization and rate of extinction of conditioned place preference (2) basal locomotion, locomotor habituation, acute oxycodone-stimulated locomotion and rate of change in reflex pain during repeated testing, and (3) magnitude of conditioned place preference. Nerve constriction injury markedly enhanced reflex pain but did not reinstate conditioned place preference. These results suggest that high rates of behavioral sensitization predicts faster rates of extinction of oxycodone seeking/reward, and suggest that cutaneous thermal reflex pain may be predictive of both.
Assuntos
Neuralgia , Oxicodona , Animais , Ratos , Oxicodona/farmacologia , Limiar da Dor , Reflexo , RecompensaRESUMO
Inter-relationships between pain sensitivity, drug reward, and drug misuse are of considerable interest given that many analgesics exhibit misuse potential. Here we studied rats as they underwent a series of pain- and reward-related tests: cutaneous thermal reflex pain, induction and extinction of conditioned place preference to oxycodone (0.56 mg/kg), and finally the impact of neuropathic pain on reflex pain and reinstatement of conditioned place preference. Oxycodone induced a significant conditioned place preference that was extinguished throughout repeated testing. Correlations identified of particular interest included an association between reflex pain and oxycodone-induced behavioral sensitization, and between rates of behavioral sensitization and extinction of conditioned place preference. Multidimensional scaling analysis followed by k-clustering identified three clusters: (1) reflex pain and the rate of change in reflex pain response throughout repeated testing, (2) basal locomotion, locomotor habituation, and acute oxycodone-stimulated locomotion, and (3) behavioral sensitization, strength of conditioned place preference, and rate of extinction. Nerve constriction injury markedly enhanced reflex pain but did not reinstate conditioned place preference. These results support the notion that behavioral sensitization relates to the acquisition and extinction of oxycodone seeking/reward, but suggest that generally cutaneous thermal reflex pain poorly predicts oxycodone reward-related behaviors except for behavioral sensitization.
RESUMO
Tonic dopamine (DA) signaling is widely regarded as playing a central role in effort-based decision making and in the motivational control of instrumental performance. The current study used microdialysis to monitor changes in extracellular DA levels across subregions of the nucleus accumbens and dorsal striatum of rats as they lever pressed for food reward on a probabilistic schedule of reinforcement, a procedure that ensured they would experience variation in the amount of effort needed to earn rewards across tests. Each rat was given three tests. Rats were hungry for the first and last test, but were sated on food before the middle test, allowing us to assess the effects of a downshift in motivational state on task performance and conditioning-induced DA efflux. During hungry tests, DA levels rose in both the shell and core of the accumbens and, to a lesser degree, in both the medial and lateral divisions of the dorsal striatum. Interestingly, changes in DA efflux across hungry tests in the accumbens core were negatively correlated with changes in the effort required to obtain rewards. We also found that--across regions--the DA response to instrumental conditioning was attenuated when rats were sated before testing. Furthermore, the effect of satiety on DA efflux in the accumbens shell was positively correlated with its effect on task performance. Together, the results indicate that tonic DA contributes to the control of instrumental performance by conveying information about the costs and benefits of responding to different striatal subregions.
Assuntos
Condicionamento Operante/fisiologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Líquido Extracelular/metabolismo , Motivação/fisiologia , Análise de Variância , Animais , Corpo Estriado/citologia , Eletroquímica/métodos , Jejum/fisiologia , Modelos Lineares , Masculino , Microdiálise/métodos , Núcleo Accumbens/metabolismo , Ratos , Ratos Long-Evans , Saciação/fisiologiaRESUMO
SLITRK2 encodes a transmembrane protein that modulates neurite outgrowth and synaptic activities and is implicated in bipolar disorder. Here, we addressed its physiological roles in mice. In the brain, the Slitrk2 protein was strongly detected in the hippocampus, vestibulocerebellum, and precerebellar nuclei-the vestibular-cerebellar-brainstem neural network including pontine gray and tegmental reticular nucleus. Slitrk2 knockout (KO) mice exhibited increased locomotor activity in novel environments, antidepressant-like behaviors, enhanced vestibular function, and increased plasticity at mossy fiber-CA3 synapses with reduced sensitivity to serotonin. A serotonin metabolite was increased in the hippocampus and amygdala, and serotonergic neurons in the raphe nuclei were decreased in Slitrk2 KO mice. When KO mice were treated with methylphenidate, lithium, or fluoxetine, the mood stabilizer lithium showed a genotype-dependent effect. Taken together, Slitrk2 deficiency causes aberrant neural network activity, synaptic integrity, vestibular function, and serotonergic function, providing molecular-neurophysiological insight into the brain dysregulation in bipolar disorders.
RESUMO
Understanding how emotion is generated, how conflicting emotions are regulated, and how emotional states relate to sophisticated behaviors is a crucial challenge in brain research. Model animals showing selective emotion-related phenotypes are highly useful for examining these issues. Here, we describe a novel mouse model that withdraws in approach-avoidance conflicts. X11-like (X11L)/Mint2 is a neuronal adapter protein with multiple protein-protein interaction domains that interacts with several proteins involved in modulating neuronal activity. X11L-knock-out (KO) mice were subordinate under competitive feeding conditions. X11L-KO mice lost significantly more weight than cohoused wild-type mice without signs of decreased motivation to eat or physical weakness. In a resident-intruder test, X11L-KO mice showed decreased intruder exploration behavior. Moreover, X11L-KO mice displayed decreased marble-burying, digging and burrowing behaviors, indicating aberrant ethological responses to attractive stimuli. In contrast, X11L-KO mice were indistinguishable from wild-type mice in the open field, elevated plus maze, and light/dark transition tests, which are often used to assess anxiety-like behavior. Neurochemical analysis revealed a monoamine imbalance in several forebrain regions. The defective ethological responses and social behaviors in X11L-KO mice were rescued by the expression of X11L under a Camk2a promoter using the Tet-OFF system during development. These findings suggest that X11L is involved in the development of neuronal circuits that contribute to conflict resolution.
Assuntos
Aprendizagem da Esquiva/fisiologia , Caderinas/deficiência , Comportamento Competitivo/fisiologia , Conflito Psicológico , Proteínas do Tecido Nervoso/deficiência , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Adaptação Psicológica/fisiologia , Análise de Variância , Animais , Ansiedade/genética , Comportamento Animal/fisiologia , Monoaminas Biogênicas/metabolismo , Peso Corporal/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteínas de Transporte , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento de Ingestão de Líquido/fisiologia , Ingestão de Alimentos/genética , Comportamento Exploratório/fisiologia , Comportamento Alimentar/fisiologia , Galactosídeos/metabolismo , Força da Mão/fisiologia , Hipotermia Induzida , Relações Interpessoais , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Sinais de Localização Nuclear/genética , Prosencéfalo/metabolismo , Domínios e Motivos de Interação entre Proteínas , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The ability of addictive drugs to induce adaptations in mesolimbic dopamine (DA) activity offers an attractive neurobiological explanation for enhanced incentive motivation toward drug-associated stimuli in addiction. However, direct evidence supporting this is sparse. By tracking neurochemical activity within the mouse nucleus accumbens via microdialysis during repeated pairing of morphine with environmental stimuli, we reveal a predictive relationship between enhanced DA responses to morphine and subsequent preference towards a morphine-paired stimulus. A similar relationship for serotonin (5-HT) was observed, suggesting that these neuromodulatory systems work in concert. During expression of preference towards a morphine-paired stimulus, extracellular DA was not enhanced but was negatively associated with this behavior on a subject-by-subject basis. In contrast, avoidance of an aversively-paired stimulus (the opiate antagonist naloxone) was associated with enhanced extracellular DA levels, and also the balance between DA and 5-HT responses. These findings reveal a tangible predictive relationship between drug-induced neural adaptations and conditioned behavior, and emphasize that DA activity is not generalized to all subcomponents of behavior conditioned by addictive drugs. They further provide evidence for an active role of DA-5-HT interactions in the expression of learned behavior.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/fisiologia , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Serotonina/metabolismo , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Condicionamento Operante/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise/métodos , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Estatística como AssuntoRESUMO
C57BL/6J (B6) and DBA2/J (D2) mice differ markedly in voluntary consumption of tastants and responses to abused drugs. In particular, compared to D2 mice, B6 mice avidly drink ethanol and sucrose solutions, but avoid quinine solutions. In the first study, we compared taste reactivity in B6 and D2 mice to determine the extent to which differences in drinking patterns depend on orosensory processing. Both strains showed concentration-dependent increases in positive reactions to sucrose (0.01 to 1 M). Quinine (0.03 to 3 mM) elicited concentration-dependent aversive reactions in B6 mice, whereas all reactions to quinine were virtually indistinguishable from reactions to water in D2 mice. In contrast, D2 mice reacted with relatively strong aversive responses to ethanol (5 to 30%). In the second study, we evaluated the effect of subcutaneous morphine (1 to 4 mg/kg) and methamphetamine (0.5 to 2 mg/kg) on taste reactivity to sucrose. Morphine generally decreased reactions to sucrose in both strains, suggesting a general motor depressant effect. Methamphetamine shifted sucrose responses towards aversion in both strains; particularly in D2 mice. These results suggest that strain-dependent differences in voluntary ethanol and quinine drinking depend at least partially on differences in orosensory responses. However, differences in voluntary sucrose intake may relate solely to genetic differences in post-ingestive factors. Finally, as has been suggested by previous place conditioning studies, methamphetamine appears to induce a dysphoric state in D2 mice, which may be reflected in fewer positive and more negative taste reactions to sucrose in the current study.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Metanfetamina/farmacologia , Morfina/farmacologia , Entorpecentes/farmacologia , Paladar/efeitos dos fármacos , Análise de Variância , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Especificidade da Espécie , Paladar/fisiologiaRESUMO
Previous studies show that the opioid peptide nociceptin stimulates food intake. Here, we studied nociceptin receptor knockout (NOP KO) mice in various behavioral paradigms designed to differentiate psychological and physiological loci at which endogenous nociceptin might control feeding. When presented a choice under food restriction, NOP KO mice displayed reduced preference for high sucrose diet, but lower intake of high fat diet under no-choice conditions. These responses were absent under ad libitum feeding conditions. Conditioned place preference to high fat diet under food-deprived conditions was unaltered in NOP KO mice, suggesting no difference in reward responses. Furthermore, operant food self-administration under a variety of conditions showed no genotype-dependent differences, suggesting no differences in the motivational properties of food. Taste reactivity to sucrose was unchanged in NOP KO mice, though NOP KO mice had altered aversive reactions to quinine solutions under ad libitum feeding, suggesting minor differences in the affective impact of palatable and unpalatable tastants. Although NOP KO mice re-fed following food-deprivation showed normal increases in plasma glucose and insulin, multidimensional scaling analysis showed that the relationship between these measures, body weight and plasma leptin was substantially disrupted in NOP KO, particularly in fasted mice. Additionally, the typical positive relationship between body weight and plasma leptin was considerably weaker in NOP KO mice. Together, these findings suggest that endogenous nociceptin differentially modulates diet preference depending on macronutrient content and homeostatic state, independently of the motivating, rewarding or orosensory properties of food, but may involve metabolic or postingestive processes.
Assuntos
Preferências Alimentares/fisiologia , Preferências Alimentares/psicologia , Motivação , Peptídeos Opioides/fisiologia , Recompensa , Animais , Glicemia , Peso Corporal , Condicionamento Operante , Gorduras na Dieta , Sacarose Alimentar , Comportamento de Ingestão de Líquido/fisiologia , Feminino , Privação de Alimentos , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos Opioides/genética , Receptores Opioides/genética , Percepção Gustatória/fisiologia , Receptor de Nociceptina , NociceptinaRESUMO
The opioid peptide nociceptin (orphanin FQ) suppresses drug reward, drug self-administration, and impedes some of the processes believed to underlie the transition to addiction. As virtually all previous studies have used administration of nociceptin receptor agonists to evaluate the role of nociceptin on addiction-like behavior, the current study used a pharmacological (nociceptin receptor antagonist) and genetic (nociceptin receptor knockout mice) approach to elucidate the role of endogenous nociceptin. The nociceptin receptor antagonist UFP-101 induced a modest place preference, and enhanced the conditioned place preference induced by methamphetamine. In agreement with this, nociceptin receptor knockout mice had slightly enhanced methamphetamine and ethanol conditioned place preferences compared to wild-type mice. This effect did not appear to depend on differences in learning ability, as nociceptin receptor knockout mice had slightly weaker-conditioned place aversions to lithium chloride, the kappa-opioid receptor agonist, U50488H, and the general opiate antagonist, naloxone. The development of behavioral sensitization to methamphetamine was lower in nociceptin receptor knockout mice, and attenuated by UFP-101 administration to wild-type mice. Additionally, ethanol consumption and preference in a two-bottle choice test was lower in nociceptin receptor knockout mice, though ethanol-stimulated locomotion was stronger. Whereas the rewarding effect of methamphetamine and ethanol following chronic treatment, as measured by place conditioning, strengthened in wild-type mice, this effect was absent in nociceptin receptor knockout mice. These results suggest that endogenous N/OFQ suppresses basal and drug-stimulated increases in hedonic state, and plays either a permissive or facilitatory role in the development of addiction.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Operante/efeitos dos fármacos , Etanol/farmacologia , Metanfetamina/farmacologia , Peptídeos Opioides/metabolismo , Recompensa , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos Opioides/farmacologia , Receptores Opioides/deficiência , Fatores de Tempo , Receptor de Nociceptina , NociceptinaRESUMO
RATIONALE: Marble burying and forced swimming behavior are widely used and sensitive tests for identifying clinically effective antidepressant drugs, although the underlying neurobiology of these behaviors is not fully elucidated. OBJECTIVES: The objective of this study was to determine the relationship between the behavioral effects of antidepressant drugs and their ability to modulate extracellular neurotransmitter levels in the prefrontal cortex. MATERIALS AND METHODS: The effects of fluoxetine, fluvoxamine, citalopram, imipramine, and desipramine (0 to 60 mg/kg by oral gavage, except fluoxetine at 0 to 40 mg/kg) were studied independently in CD-1 mice in the marble-burying task, forced swim task and on extracellular concentrations of serotonin, norepinephrine, and dopamine in the prefrontal cortex by freely moving microdialysis. RESULTS: Fluvoxamine, fluoxetine, and citalopram all suppressed marble-burying behavior, but produced no change in immobility time in the forced swim test. In contrast, imipramine and desipramine suppressed both marble-burying behavior and increased swimming time in the forced swim test, although desipramine mildly suppressed locomotor activity at the maximal dose. Fluvoxamine, fluoxetine, and citalopram all increased extracellular levels of cortical serotonin. Desipramine and imipramine increased extracellular dopamine levels. Fluoxetine, desipramine, and imipramine increased extracellular norepinephrine levels. Correlational analysis revealed a positive correlation between efficacy of drugs in the forced swim test and cortical extracellular dopamine levels, whereas a positive correlation was found between efficacy in the marble-burying test and extracellular serotonin levels. CONCLUSIONS: Although marble burying and forced swimming behavior have strong predictive validity in tests of antidepressant action, each assay appears to be underpinned by entirely different neurochemical systems.