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1.
Pharmacol Biochem Behav ; 209: 173257, 2021 Oct.
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.
Behav Brain Res ; 414: 113475, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34280460

RESUMO

Oxandrolone (OXA) is an androgen and anabolic steroid (AAS) that is used to reverse weight loss associated with some medical conditions. One of the side effects of OXA is its potential to induce depressive symptoms. Growing evidence suggested that neuroinflammation and cytokines play crucial roles in sickness behavioral and associated mood disturbances. Previous studies showed that metformin attenuated neuroinflammation. This study investigated the potential protective role of metformin against OXA-induced depression-like behavior and neuroinflammation. Twenty- four Wistar male rats were randomly grouped into four groups: the control group (Control) received only vehicle; the oxandrolone group (OXA) received oxandrolone (0.28 mg/kg, i.p); the metformin group (MET) received metformin (100 mg/kg, i.p); and the oxandrolone / metformin group (OXA + MET) received both oxandrolone (0.28 mg/kg, i.p) and metformin (100 mg/kg, i.p). These treatments were administered for fourteen consecutive days. Behavioral tests to measure depression-like behavior were conducted before and after treatments. qRT-PCR was used to measure the relative expression of proinflammatory and anti-inflammatory cytokines in the hippocampus and hypothalamus. The results showed that oxandrolone induced depression-like behavior and dysregulated pro-/anti-inflammatory cytokines, while metformin attenuated these effects. These findings suggest that metformin is a potential treatment to reverse the depressive effects induced by oxandrolone that involve neuroinflammatory effects.

3.
Neuroscience ; 463: 128-142, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33836247

RESUMO

Tobacco exposure has been linked to neuroinflammation and adaptive/maladaptive changes in neurotransmitter systems, including in glutamatergic systems. We examined the effects of waterpipe tobacco smoke (WTS) on inflammatory mediators and astroglial glutamate transporters in mesocorticolimbic brain regions including the prefrontal cortex (PFC), nucleus accumbens (NAc) and ventral tegmental area (VTA). The behavioral consequences of WTS exposure on withdrawal-induced anxiety-like behavior were assessed using elevated plus maze (EPM) and open field (OF) tests. Male Sprague-Dawley rats were randomly assigned to 3 experimental groups: a control group exposed only to standard room air, a WTS exposed group treated with saline vehicle, and a WTS exposed group treated with ceftriaxone. WTS exposure was performed for 2 h/day, 5 days/week, for 4 weeks. Behavioral tests (EPM and OF) were conducted weekly 24 h after WTS exposure, during acute withdrawal. During week 4, rats were given either saline or ceftriaxone (200 mg/kg i.p.) 30 min before WTS exposure. WTS increased withdrawal-induced anxiety, and ceftriaxone attenuated this effect. WTS exposure increased the relative mRNA levels for nuclear factor ĸB (NFĸB), tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor (BDNF) in the PFC, NAc and VTA, and ceftriaxone treatment reversed these effects. In addition, WTS decreased the relative mRNA of nuclear factor erythroid 2 related factor 2 (Nrf2), glutamate transporter 1 (GLT-1) and cystine-glutamate transporter (xCT) in PFC, NAc and VTA, and ceftriaxone treatment normalized their expression. WTS caused neuroinflammation, alteration in relative mRNA glutamate transport expression, and increased anxiety-like behavior, and these effects were attenuated by ceftriaxone treatment.


Assuntos
Ansiedade/tratamento farmacológico , Ceftriaxona , Fumar , Tabaco para Cachimbos de Água , Sistemas de Transporte de Aminoácidos Acídicos , Animais , Transportador 2 de Aminoácido Excitatório/metabolismo , Masculino , Fator 2 Relacionado a NF-E2 , NF-kappa B , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Fumaça , Fator de Necrose Tumoral alfa
5.
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
7.
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
9.
Pharmacol Biochem Behav ; 192: 172912, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32201298

RESUMO

RATIONALE: Methylenedioxymethamphetamine (MDMA) and methcathinone (MCAT) are abused psychostimulant drugs that produce adverse effects in human users that include hepatotoxicity and death. Recent work has suggested a connection between hepatotoxicity, elevations in plasma ammonia, and brain glutamate function for methamphetamine (METH)-induced neurotoxicity. OBJECTIVES: These experiments investigated the effect of ambient temperature on the toxicity and lethality produced by MDMA and MCAT in mice, and whether these effects might involve similar mechanisms to those described for METH neurotoxicity. RESULTS: Under low (room temperature) ambient temperature conditions, MDMA induced hepatotoxicity, elevated plasma ammonia levels, and induced lethality. Under the same conditions, even a very high dose of MCAT produced limited toxic or lethal effects. High ambient temperature conditions potentiated the toxic and lethal effects of both MDMA and MCAT. CONCLUSION: These studies suggest that hepatotoxicity, plasma ammonia, and brain glutamate function are involved in MDMA-induced lethality, as has been shown for METH neurotoxicity. The toxicity and lethality of both MDMA and MCAT were potentiated by high ambient temperatures. Although an initial mouse study reported that several cathinones were much less toxic than METH or MDMA, the present results suggest that it will be essential to assess the potential dangers posed by these drugs under high ambient temperatures.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Temperatura Alta , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/mortalidade , Propiofenonas/toxicidade , Amônia/sangue , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Masculino , Metanfetamina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Síndromes Neurotóxicas/sangue , Transdução de Sinais/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/mortalidade
10.
Pharmacol Biochem Behav ; 191: 172871, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32061662

RESUMO

RATIONALE: Synthetic psychoactive cathinones (SPCs) are drugs with psychostimulant and entactogenic properties like methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA). Despite clinical reports of human overdose, it remains to be determined if SPCs have greater propensity for adverse effects than MA or MDMA. OBJECTIVES: To determine whether the SPCs cathinone (CAT), methcathinone (MCAT), mephedrone (MMC), and methylenedioxypyrovalerone (MDPV) have lower LD50 values than MA or MDMA. METHODS: Male and female C57Bl/6J mice received single injections of one of 6 doses of a test drug (0-160 mg/kg IP). Temperature and behavioral observations were taken every 20 min for 2 h followed by euthanasia of surviving mice. Organs were weighed and evaluated for histopathological changes. RESULTS: LD50 values for MA and MDMA, 84.5 and 100.9 mg/kg respectively, were similar to previous observations. The LD50 for MMC was 118.8 mg/kg, but limited lethality was observed for other SPCs (CAT, MCAT, MDPV), so LD50 values could not be calculated. For all drugs, death was associated with seizure, when it was observed. Rather than hyperthermia, dose-dependent hypothermia was observed for MMC, MDPV, CAT, and MCAT. Contrary to initial expectations, none of the SPCs studied here had LD50 values lower than MA or MDMA. CONCLUSIONS: These data indicate that, under the conditions studied here: (1) SPCs exhibit less lethality than MA and MDMA; (2) SPCs impair thermoregulation; (3) effects of SPCs on temperature appear to be independent of effects on lethality.


Assuntos
Alcaloides/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Hipotermia/induzido quimicamente , Metanfetamina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Psicotrópicos/farmacologia , Convulsões/induzido quimicamente , Convulsões/mortalidade , Medicamentos Sintéticos/farmacologia , Alcaloides/administração & dosagem , Alcaloides/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Feminino , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , Psicotrópicos/administração & dosagem , Psicotrópicos/efeitos adversos , Medicamentos Sintéticos/administração & dosagem , Medicamentos Sintéticos/efeitos adversos
11.
Neurosci Biobehav Rev ; 110: 150-173, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31101438

RESUMO

The synthetic cathinones are derived from the naturally occurring drug cathinone found in the khat plant (Catha edulis) and have chemical structures and neurochemical consequences similar to other psychostimulants. This class of new psychoactive substances (NPS) also has potential for use and abuse coupled with a range of possible adverse effects including neurotoxicity and lethality. This review provides a general background of the synthetic cathinones in terms of the motivation for and patterns and demographics of their use as well as the behavioral and physiological effects that led to their spread as abused substances and consequent regulatory control. This background is followed by a review focusing on their rewarding and aversive effects as assessed in various pre-clinical animal models and the contribution of these effects to their self-administration (implicating their use and abuse potential). The review closes with an overview of the consequences of synthetic cathinone use and abuse in terms of their potential to produce neurotoxicity and lethality. These characterizations are discussed in the context of other classical psychostimulants.


Assuntos
Alcaloides , Estimulantes do Sistema Nervoso Central , Psicotrópicos/farmacologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Alcaloides/efeitos adversos , Alcaloides/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estimulantes do Sistema Nervoso Central/farmacologia , Humanos , Metanfetamina/efeitos adversos , Metanfetamina/farmacologia , Psicotrópicos/efeitos adversos , Autoadministração
13.
Brain Behav Evol ; 95(5): 230-246, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33849024

RESUMO

Drug dependence has long been thought to have a genetic component. Research seeking to identify the genetic basis of addiction has gone through important transitions over its history, in part based upon the emergence of new technologies, but also as the result of changing perspectives. Early research approaches were largely dictated by available technology, with technological advancements having highly transformative effects on genetic research, but the limitations of technology also affected modes of thinking about the genetic causes of disease. This review explores these transitions in thinking about the genetic causes of addiction in terms of the "streetlight effect," which is a type of observational bias whereby people search for something only where it is easiest to search. In this way, the genes that were initially studied in the field of addiction genetics were chosen because they were the most "obvious," and formed current understanding of the biological mechanisms underlying the actions of drugs of abuse and drug dependence. The problem with this emphasis is that prior to the genomic era the vast majority of genes and proteins had yet to be identified, much less studied. This review considers how these initial choices, as well as subsequent choices that were also driven by technological limitations, shaped the study of the genetic basis of drug dependence. While genome-wide approaches overcame the initial biases regarding which genes to choose to study inherent in candidate gene studies and other approaches, genome-wide approaches necessitated other assumptions. These included additive genetic causation and limited allelic heterogeneity, which both appear to be incorrect. Thus, the next stage of advancement in this field must overcome these shortcomings through approaches that allow the examination of complex interactive effects, both gene × gene and gene × environment interactions. Techniques for these sorts of studies have recently been developed and represent the next step in our understanding of the genetic basis of drug dependence.


Assuntos
Estudo de Associação Genômica Ampla , Transtornos Relacionados ao Uso de Substâncias , Animais , Predisposição Genética para Doença/genética , Humanos , Transtornos Relacionados ao Uso de Substâncias/genética
15.
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
16.
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
17.
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
19.
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
20.
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
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