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1.
Pharmacol Biochem Behav ; 209: 173257, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418452

RESUMO

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.

2.
Neuropsychopharmacol Rep ; 41(1): 91-101, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33547882

RESUMO

AIMS: 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine analogue. The present study examined whether the effects of 5-MeO-DIPT involve the serotonin transporter (SERT) and serotonin 5-hydroxytryptamine-1A (5-HT1A ) receptor in the striatum and prefrontal cortex (PFC). METHODS: We investigated the effects of 5-MeO-DIPT on extracellular 5-HT (5-HTex ) and dopamine (DAex ) levels in the striatum and PFC in wildtype and SERT knockout (KO) mice using in vivo microdialysis, and for comparison the effects of the 5-HT1A receptor antagonist WAY100635 and the 5-HT1A receptor agonist 8-OH-DPAT on 5-HTex . RESULTS: 5-MeO-DIPT decreased 5-HTex levels in the striatum, but not PFC. In SERT-KO mice, 5-MeO-DIPT did not affect 5-HTex levels in the striatum or PFC. In the presence of WAY100635, 5-MeO-DIPT substantially increased 5-HTex levels, suggesting that 5-MeO-DIPT acts on SERT and these effects are masked by its 5-HT1A actions in the absence of WAY100635. 8-OH-DPAT decreased 5-HTex levels in the striatum and PFC in wildtype mice. WAY100635 antagonized the 8-OH-DPAT-induced decrease in 5-HTex levels. In SERT-KO mice, 8-OH-DPAT did not decrease 5-HTex levels in the striatum and PFC. 5-MeO-DIPT dose-dependently increased DAex levels in the PFC, but not striatum, in wildtype and SERT-KO mice. The increase in DAex levels that was induced by 5-MeO-DIPT was not antagonized by WAY100635. CONCLUSION: 5-MeO-DIPT influences both 5-HTex and DAex levels in the striatum and PFC. 5-MeO-DIPT dually acts on SERT and 5-HT1A receptors so that elevations in 5-HTex levels produced by reuptake inhibition are limited by actions of the drug on 5-HT1A receptors.


Assuntos
5-Metoxitriptamina/análogos & derivados , Corpo Estriado/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , 5-Metoxitriptamina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Corpo Estriado/metabolismo , Feminino , Masculino , Camundongos , Camundongos Knockout , Microdiálise , Piperazinas/farmacologia , Córtex Pré-Frontal/metabolismo , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
3.
Neurosci Lett ; 738: 135378, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920046

RESUMO

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been linked to multiple aspects of cognition. For example, in rodents, discrimination and reversal learning are altered by experimentally induced changes in brain serotonin levels, and reduced expression of the 5-HT2B receptor subtype in mice and humans is associated with decreased serotonergic tone and increased behavioral impulsivity. Serotonin modulates cognitive flexibility as well as fear and anxiety, but the specific contributions of 5-HT2B receptors to these behaviors is unknown. The current study assessed mice with partial Htr2b deletion for performance on a touchscreen-based pairwise visual discrimination and reversal learning task followed by a test of cued fear learning. Male Htr2b heterozygous mice (+/-) and littermate controls (+/+) were trained to discriminate between two visual stimuli presented on a touch-sensitive screen, one which predicted delivery of a 14-mg food pellet and the other which was not rewarded. Once discrimination performance criterion was attained, the stimulus-reward contingencies were reversed. Htr2b +/- mice were faster to reach discrimination criterion than +/+ controls, and made fewer errors. Htr2b +/- mice were also slower to make responses and collect rewards. Conversely, measures of reversal learning were not different between genotypes. Pavlovian cued fear conditioning was also normal in Htr2b +/-mice. These data demonstrate a selective improvement in touchscreen-based discrimination learning in mice with partial deletion of the 5-HT2B receptor, and provide further insight into the role of the 5-HT2B receptor in cognition.


Assuntos
Aprendizagem por Discriminação/fisiologia , Deleção de Genes , Receptor 5-HT2B de Serotonina/genética , Reversão de Aprendizagem , Percepção Visual/genética , Animais , Cognição/fisiologia , Condicionamento Operante/fisiologia , Discriminação Psicológica/fisiologia , Masculino , Camundongos
4.
Brain Res ; 1740: 146873, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387137

RESUMO

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H3 receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H3 receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H1 receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H1 receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H2 receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H4 receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H3 receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H3 receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H3 receptors, which then bind to the post-synaptic histamine receptor H1 (but not H2 or H4). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Hipercinese/induzido quimicamente , Metanfetamina/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Hipercinese/tratamento farmacológico , Hipercinese/fisiopatologia , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfolinas/administração & dosagem , Piperidinas/administração & dosagem
5.
Dev Psychopathol ; 32(2): 703-718, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31256767

RESUMO

The study examined (a) whether alcohol use subgroups could be identified among African Americans assessed from adolescence through early adulthood, and (b) whether subgroup membership was associated with the interaction between internalizing symptoms and antisocial behavior polygenic risk scores (PRSs) and environmental characteristics (i.e., parental monitoring, community disadvantage). Participants (N = 436) were initially recruited for an elementary school-based prevention trial in a Mid-Atlantic city. Youths reported on the frequency of their past year alcohol use from ages 14-26. DNA was obtained from participants at age 21. Internalizing symptoms and antisocial behavior PRSs were created based on a genome-wide association study (GWAS) conducted by Benke et al. (2014) and Tielbeek et al. (2017), respectively. Parental monitoring and community disadvantage were assessed at age 12. Four classes of past year alcohol use were identified: (a) early-onset, increasing; (b) late-onset, moderate use; (c) low steady; and (d) early-onset, decreasing. In high community disadvantaged settings, participants with a higher internalizing symptoms PRS were more likely to be in the early-onset, decreasing class than the low steady class. When exposed to elevated community disadvantage, participants with a higher antisocial behavior PRS were more likely to be in the early-onset, increasing class than the early-onset, decreasing and late-onset, moderate use classes.


Assuntos
Afro-Americanos , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Afro-Americanos/genética , Consumo de Bebidas Alcoólicas , Transtorno da Personalidade Antissocial/genética , Criança , Humanos , Herança Multifatorial , Adulto Jovem
6.
Ann Clin Transl Neurol ; 6(2): 406-415, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30847375

RESUMO

Progressive depletion of selected dopamine neurons is central to much Parkinson's disease (PD) disability. Although symptomatic treatments can ameliorate the disabilities that this neuronal depletion causes, no current strategy is documented to slow these losses. There is substantial evidence that dopamine in intracytoplasmic/extravesicular neuronal compartments can be toxic. Here, I review evidence that supports roles for dopamine compartmentalization, mediated largely by serial actions of plasma membrane SLC6A3/DAT and vesicular SLC18A2/VMAT2 transporters, in the selective patterns of dopamine neuronal loss found in PD brains. This compartmentalization hypothesis for the dopamine cell type specificity of PD lesions nominates available drugs for amelioration of damage arising from miscompartmentalized dopamine and raises cautions in using other drugs.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
7.
Neuropsychopharmacol Rep ; 39(2): 130-133, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30719871

RESUMO

AIM: Repeated psychostimulant drug treatment, including methamphetamine, in rodents readily produces behavioral sensitization, which reflects altered brain function caused by repeated drug exposure. Dendritic remodeling of medium spiny neurons in the nucleus accumbens is thought to be an essential mechanism underlying behavioral sensitization. We recently showed that chronic methamphetamine treatment did not produce behavioral sensitization in serotonin transporter knockout mice. METHODS: In this study, we report the spine density of medium spiny neurons in the nucleus accumbens after repeated methamphetamine injection to examine morphological alterations in serotonin transporter knockout mice. RESULTS: Golgi-COX staining clearly showed that the spine density of medium spiny neurons in the nucleus accumbens increased following repeated methamphetamine treatment in both wild-type and serotonin transporter knockout mice. CONCLUSIONS: Our results suggested that augmented serotonergic neurotransmission produced by serotonin transporter deletion prevents the development of behavioral sensitization in a manner that is independent of dendritic remodeling in the nucleus accumbens.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Metanfetamina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Animais , Espinhas Dendríticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
8.
Ann N Y Acad Sci ; 1451(1): 5-28, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30644552

RESUMO

Substance and alcohol use disorders impose large health and economic burdens on individuals, families, communities, and society. Neither prevention nor treatment efforts are effective in all individuals. Results are often modest. Advances in neuroscience and addiction research have helped to describe the neurobiological changes that occur when a person transitions from recreational substance use to a substance use disorder or addiction. Understanding both the drivers and consequences of substance use in vulnerable populations, including those whose brains are still maturing, has revealed behavioral and biological characteristics that can increase risks of addiction. These findings are particularly timely, as law- and policymakers are tasked to reverse the ongoing opioid epidemic, as more states legalize marijuana, as new products including electronic cigarettes and newly designed abused substances enter the legal and illegal markets, and as "deaths of despair" from alcohol and drug misuse continue.


Assuntos
Comportamento Aditivo/fisiopatologia , Encéfalo/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Plasticidade Neuronal/fisiologia
9.
Ann N Y Acad Sci ; 1451(1): 112-129, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30648269

RESUMO

Receptor-type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive-compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction-related effects, and the implications of these findings for the PTPRD-associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.


Assuntos
Comportamento Aditivo/genética , Encéfalo/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Animais , Comportamento Aditivo/metabolismo , Modelos Animais de Doenças , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo
10.
Mol Autism ; 9: 60, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498565

RESUMO

Background: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. Methods: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Results: Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. Conclusions: These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.


Assuntos
Transtorno Autístico/genética , Encéfalo/metabolismo , Serotonina/metabolismo , Comportamento Social , Animais , Transtorno Autístico/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Triptofano/deficiência , Triptofano/metabolismo
11.
Front Psychiatry ; 9: 441, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30283366

RESUMO

Background: µ-opioid receptor knockout (MOP-KO) mice display baseline hyperalgesia. We have recently identified changes in tissue volume in the periaqueductal gray matter (PAG) using magnetic resonance imaging voxel-based morphometry. Changes in the structure and connectivity of this region might account for some behavior phenotypes in MOP-KO mice, including hyperalgesia. Methods: Adult male MOP-KO and wild-type (WT) mice were studied. Immunohistochemistry was performed to detect microglia, astrocytes, and neurons in the PAG using specific markers: ionized calcium-binding adaptor molecule 1 (Iba-1) for microglia, glial fibrillary acidic protein (GFAP) for astrocytes, and the neuronal nuclei antigen (NeuN; product of the Rbfox3 gene) for neurons, respectively. Cell counting was performed in the four parallel longitudinal columns of the PAG (dorsomedial, dorsolateral, lateral, and ventrolateral) at three different locations from bregma (-3.5, -4.0, and -4.5 mm). Results: The quantitative analysis showed larger numbers of well-distributed Iba1-IR cells (microglia), NeuN-IR cells (neurons), and GFAP-IR areas (astrocytes) at all the anatomically distinct regions examined, namely, the dorsomedial (DM) PAG, dorsolateral (DL) PAG, lateral (L) PAG, and ventrolateral (VL) PAG, in MOP-KO mice than in control mice. Conclusions: The cellular changes in the PAG identified in this paper may underlie aspects of the behavioral alterations produced by MOP receptor deletion, and suggest that alterations in the cellular structure of the PAG may contribute to hyperalgesic states.

12.
Proc Natl Acad Sci U S A ; 115(45): 11597-11602, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30348770

RESUMO

Receptor-type protein tyrosine phosphatase D (PTPRD) is a neuronal cell-adhesion molecule/synaptic specifier that has been implicated in addiction vulnerability and stimulant reward by human genomewide association and mouse cocaine-conditioned place-preference data. However, there have been no reports of effects of reduced expression on cocaine self-administration. There have been no reports of PTPRD targeting by any small molecule. There are no data about behavioral effects of any PTPRD ligand. We now report (i) robust effects of heterozygous PTPRD KO on cocaine self-administration (These data substantially extend prior conditioned place-preference data and add to the rationale for PTPRD as a target for addiction therapeutics.); (ii) identification of 7-butoxy illudalic acid analog (7-BIA) as a small molecule that targets PTPRD and inhibits its phosphatase with some specificity; (iii) lack of toxicity when 7-BIA is administered to mice acutely or with repeated dosing; (iv) reduced cocaine-conditioned place preference when 7-BIA is administered before conditioning sessions; and (v) reductions in well-established cocaine self-administration when 7-BIA is administered before a session (in WT, not PTPRD heterozygous KOs). These results add to support for PTPRD as a target for medications to combat cocaine use disorders. 7-BIA provides a lead compound for addiction therapeutics.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cumarínicos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Recompensa , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Animais , Cateteres de Demora , Transtornos Relacionados ao Uso de Cocaína/enzimologia , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Condicionamento Psicológico , Cumarínicos/síntese química , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Injeções Intravenosas , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas de Entorpecentes/síntese química , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/patologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/antagonistas & inibidores , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/deficiência , Autoadministração , Transdução de Sinais , Abuso de Substâncias por Via Intravenosa/enzimologia , Abuso de Substâncias por Via Intravenosa/genética , Abuso de Substâncias por Via Intravenosa/fisiopatologia , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica
13.
Drug Alcohol Depend ; 191: 365-373, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30195949

RESUMO

Externalizing disorders have been extensively linked to substance use problems. However, less is known about whether genetic factors underpinning externalizing disorders and environmental features interact to predict substance use disorders (i.e., marijuana abuse and dependence) among urban African Americans. We examined whether polygenic risk scores (PRS) for conduct disorder (CD) and attention-deficit hyperactivity disorder (ADHD) interacted with contextual factors (i.e., parental monitoring, community disadvantage) to influence risk for marijuana use disorders in a sample of African American youth. Participants (N=1,050; 44.2% male) were initially recruited for an elementary school-based universal prevention trial in a Mid-Atlantic city and followed through age 20. Participants reported on their parental monitoring in sixth grade and whether they were diagnosed with marijuana abuse or dependence at age 20. Blood or saliva samples were genotyped using the Affymetrix 6.0 microarrays. The CD and ADHD PRS were created based on genome-wide association studies conducted by Dick et al. (2010) and Demontis et al. (2017), respectively. Community disadvantage was calculated based on census data when participants were in sixth grade. There was an interaction between the CD PRS and community disadvantage such that a higher CD PRS was associated with greater risk for a marijuana use disorder at higher levels of neighborhood disadvantage. This finding should be interpreted with caution owing to the number of significance tests performed. Implications for etiological models and future research directions are presented.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno da Conduta/genética , Estudo de Associação Genômica Ampla , Abuso de Maconha/genética , Herança Multifatorial/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Comorbidade , Transtorno da Conduta/epidemiologia , Transtorno da Conduta/psicologia , Suscetibilidade a Doenças/epidemiologia , Suscetibilidade a Doenças/psicologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Abuso de Maconha/epidemiologia , Abuso de Maconha/psicologia , Uso da Maconha/epidemiologia , Uso da Maconha/genética , Uso da Maconha/psicologia , Adulto Jovem
14.
Neuropsychopharmacol Rep ; 38(3): 149-153, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30175528

RESUMO

AIM: Attention-deficit/hyperactivity disorder is a heterogeneous neurobiological disorder that is characterized by inattention, impulsivity, and an increase in motor activity. Although methylphenidate has been used as a medication for decades, unknown is whether methylphenidate treatment can cause drug dependence in patients with attention-deficit/hyperactivity disorder. This study investigated the reward-enhancing effects of methylphenidate using intracranial self-stimulation in an animal model of attention-deficit/hyperactivity disorder, dopamine transporter knockout mice. METHODS: For the intracranial self-stimulation procedures, the mice were trained to nosepoke to receive direct electrical stimulation via an electrode that was implanted in the lateral hypothalamus. After the acquisition of nosepoke responding for intracranial self-stimulation, the effects of methylphenidate on intracranial self-stimulation were investigated. RESULTS: In the progressive-ratio procedure, dopamine transporter knockout mice exhibited an increase in intracranial self-stimulation compared with wild-type mice. Treatment with 5 and 10 mg/kg methylphenidate increased intracranial self-stimulation responding in wild-type mice. Methylphenidate at the same doses did not affect intracranial self-stimulation responding in dopamine transporter knockout mice. We then investigated the effects of high-dose methylphenidate (60 mg/kg) in a rate-frequency procedure. High-dose methylphenidate significantly decreased intracranial self-stimulation responding in both wild-type and dopamine transporter knockout mice. CONCLUSIONS: These results suggest that low-dose methylphenidate alters the reward system (ie, increases intracranial self-stimulation responding) in wild-type mice via dopamine transporter inhibition, whereas dopamine transporter knockout mice do not exhibit such alterations. High-dose methylphenidate appears to suppress intracranial self-stimulation responding not through dopamine transporter inhibition but rather through other mechanisms. These results support the possibility that methylphenidate treatment for attention-deficit/hyperactivity disorder does not increase the risk of drug dependence, in attention-deficit/hyperactivity disorder patients with dopamine transporter dysfunction.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Metilfenidato/farmacologia , Recompensa , Animais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/deficiência , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Pharmacol Biochem Behav ; 172: 9-16, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30017858

RESUMO

A single administration with morphine (30 mg/kg, i.p.) induced long-lasting hyperlocomotion in male ICR mice. Pretreatment of mice with a benzoquinolizine derivative tetrabenazine (TBZ; a reversible vesicular monoamine transporter-2 inhibitor) (1 mg/kg, i.p.) for 30 min significantly attenuated the hyperlocomotion induced by morphine, as compared with vehicle (saline)-pretreated mice. No significant change in locomotion was observed in mice pretreated with TBZ (1 mg/kg) alone. Mice treated with TBZ (1 mg/kg) showed an increase in immobility time in a tail suspension test, as compared with saline-treated mice. Pretreatment with TBZ (1 mg/kg) had no effect on morphine (1-30 mg/kg)-induced antinociception. TBZ at a dose of 1 mg/kg inhibited dopamine turnover (the ratio of 3,4-dihydroxyphenylacetic acid/dopamine) and 5-hydroxytryptamine turnover (the ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine) in the cerebral cortex of mice challenged with morphine, as compared with saline-pretreated mice challenged with morphine. No stereotypic behavior was observed in mice treated with morphine (30 mg/kg) in combination with TBZ (1 mg/kg), so the reduction in observed locomotion did not result from induction of stereotypical behavior. Moreover, TBZ (1 and 2 mg/kg) pretreatment had no effect on stereotyped behaviors observed in mice challenged with 10 mg/kg methamphetamine. These data support the potential antagonistic actions of TBZ on some opiate actions, and encourage further exploration of potential effects on morphine reinforcement.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Córtex Cerebral/efeitos dos fármacos , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Morfina/farmacologia , Serotonina/metabolismo , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Córtex Cerebral/metabolismo , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos ICR
16.
Neural Plast ; 2018: 9803764, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29675039

RESUMO

A variety of genetic approaches, including twin studies, linkage studies, and candidate gene studies, has established a firm genetic basis for addiction. However, there has been difficulty identifying the precise genes that underlie addiction liability using these approaches. This situation became especially clear in genome-wide association studies (GWAS) of addiction. Moreover, the results of GWAS brought into clarity many of the shortcomings of those early genetic approaches. GWAS studies stripped away those preconceived notions, examining genes that would not previously have been considered in the study of addiction, consequently creating a shift in our understanding. Most importantly, those studies implicated a class of genes that had not previously been considered in the study of addiction genetics: cell adhesion molecules (CAMs). Considering the well-documented evidence supporting a role for various CAMs in synaptic plasticity, axonal growth, and regeneration, it is not surprising that allelic variation in CAM genes might also play a role in addiction liability. This review focuses on the role of various cell adhesion molecules in neuroplasticity that might contribute to addictive processes and emphasizes the importance of ongoing research on CAM genes that have been implicated in addiction by GWAS.


Assuntos
Comportamento Aditivo/genética , Moléculas de Adesão Celular Neuronais/genética , Predisposição Genética para Doença , Plasticidade Neuronal/genética , Animais , Genótipo , Humanos , Neurônios/fisiologia , Fenótipo , Polimorfismo de Nucleotídeo Único
17.
Biomed Pharmacother ; 100: 116-123, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29427922

RESUMO

A single administration of mice with memantine (1-amino-3,5-dimethyladamantane), a glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, induced stereotyped behaviors in dose- and time-dependent manners. The predominant behavioral component of the stereotypy was a continuous, exaggerated sniffing which was accompanied by persistent locomotion. In contrast, a psychostimulant methamphetamine (METH) predominantly induced a stereotyped biting and other forms of intense stationary stereotypical behaviors. Memantine-induced stereotyped sniffing was attenuated by pretreatment with haloperidol, a dopamine D2 receptor antagonist, in a dose-dependent manner. The memantine-induced stereotyped sniffing was also attenuated by pretreatment with betahistine (2-[2-(methylamino)ethyl]pyridine), an agent which increases histamine turnover and releases histamine in the brain. These observations suggest that memantine might induce stereotypies through neuronal mechanisms that are somewhat different from those of METH, but still overlap to a certain extent, since memantine-induced stereotypies can be attenuated by the mechanisms that also suppress METH-induced stereotypy. Importantly, these data suggests that the effects of memantine may be more limited to the ventral striatum including nucleus accumbens than those of METH, which is associated with dorsal striatal stimulation at high doses. In this respect memantine may also have pharmacological properties such as compartmentation (i.e. brain distribution) and neuronal mechanisms different from those of other NMDA receptor antagonists, such as ketamine, which may have important implications for therapeutic uses of these drugs.


Assuntos
Dopaminérgicos/farmacologia , Memantina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Comportamento Estereotipado/efeitos dos fármacos , Estriado Ventral/efeitos dos fármacos , Animais , Dopaminérgicos/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Memantina/farmacocinética , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/agonistas , Fatores de Tempo , Estriado Ventral/metabolismo
18.
Int J Neuropsychopharmacol ; 20(5): 403-409, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28031268

RESUMO

Background: Opioid and dopamine systems play crucial roles in reward. Similarities and differences in the neural mechanisms of reward that are mediated by these 2 systems have remained largely unknown. Thus, in the present study, we investigated the differences in reward function in both µ-opioid receptor knockout mice and dopamine transporter knockout mice, important molecules in the opioid and dopamine systems. Methods: Mice were implanted with electrodes into the right lateral hypothalamus (l hour). Mice were then trained to put their muzzle into the hole in the head-dipping chamber for intracranial electrical stimulation, and the influences of gene knockout were assessed. Results: Significant differences are observed between opioid and dopamine systems in reward function. µ-Opioid receptor knockout mice exhibited enhanced intracranial electrical stimulation, which induced dopamine release. They also exhibited greater motility under conditions of "despair" in both the tail suspension test and water wheel test. In contrast, dopamine transporter knockout mice maintained intracranial electrical stimulation responding even when more active efforts were required to obtain the reward. Conclusions: The absence of µ-opioid receptor or dopamine transporter did not lead to the absence of intracranial electrical stimulation responsiveness but rather differentially altered it. The present results in µ-opioid receptor knockout mice are consistent with the suppressive involvement of µ-opioid receptors in both positive incentive motivation associated with intracranial electrical stimulation and negative incentive motivation associated with depressive states. In contrast, the results in dopamine transporter knockout mice are consistent with the involvement of dopamine transporters in positive incentive motivation, especially its persistence. Differences in intracranial electrical stimulation in µ-opioid receptor and dopamine transporter knockout mice underscore the multidimensional nature of reward.


Assuntos
Analgésicos Opioides/metabolismo , Dopamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Receptores Opioides mu/deficiência , Animais , Biofísica , Proteínas da Membrana Plasmática de Transporte de Dopamina/deficiência , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Estimulação Elétrica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Motivação , Atividade Motora/efeitos dos fármacos , Receptores Opioides mu/genética , Recompensa , Autoadministração , Fatores de Tempo
19.
Sleep Med ; 31: 71-77, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27539027

RESUMO

Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these interactions can extend to the adenosine A1 and A2A receptors, which are also prominently expressed in the striatum. Interactions between adenosine and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets for treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to consider dynamic changes in the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes in the connectome based on alterations in cell adhesion molecules, and receptor interactions that may extend beyond the dopamine system itself.


Assuntos
Encéfalo/fisiopatologia , Dopamina/metabolismo , Síndrome das Pernas Inquietas/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Conectoma , Humanos , Vias Neurais/diagnóstico por imagem , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Síndrome das Pernas Inquietas/diagnóstico por imagem
20.
Mol Med ; 22: 537-547, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27579475

RESUMO

The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5 choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

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