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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360984

RESUMO

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose-response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Caveolina 1/metabolismo , Corpo Estriado/metabolismo , Potenciação de Longa Duração , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Caveolina 1/genética , Corpo Estriado/efeitos dos fármacos , Masculino , Metanfetamina/toxicidade , Ratos , Ratos Long-Evans , Recompensa
2.
Exp Neurol ; 343: 113793, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34166684

RESUMO

INTRODUCTION: Methamphetamine users are typically young adults, placing them at risk for significant drug-related harms. Neurological harms include stroke and Parkinson's disease, both of which may develop prematurely in the context of methamphetamine use. MATERIAL AND METHODS: We conducted a narrative review examining the evidence first, for stroke under 45 years and second, early onset of Parkinson's disease (PD) and parkinsonism related to methamphetamine use. We summarise epidemiological factors and common clinical features, before examining in detail the underlying pathology and causal mechanisms. RESULTS AND DISCUSSION: Methamphetamine use among young people (<45 years) is associated with heightened risk for haemorrhagic stroke. Compared to age-matched all-cause fatal stroke, haemorrhage secondary to aneurysmal rupture is more common among young people with methamphetamine-related stroke and is associated with significantly poorer prognosis. Aetiology is related primarily to both acute and chronic hypertension associated with methamphetamine's sympathomimetic action. Evidence from a variety of sources supports a link between methamphetamine use and increased risk for the development of PD and parkinsonism, and with their early onset in a subset of individuals. Despite this, direct evidence of degeneration of dopaminergic neurons in methamphetamine users has not been demonstrated to date. CONCLUSIONS: Stroke and Parkinson's Disease/parkinsonism are neurological harms observed prematurely in methamphetamine users.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Doença de Parkinson Secundária/induzido quimicamente , Acidente Vascular Cerebral/induzido quimicamente , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Humanos , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Fatores de Risco , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
3.
Eur J Pharmacol ; 897: 173935, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577836

RESUMO

Stimulant-induced neurochemical changes may occur at different times for different brain regions or neurotransmitter systems. This study sought to examine the behavioral and neurochemical effects of extended access to α-pyrrolidinopentiophenone (α-PVP) and 4-methylmethcathinone (4MMC). Male and female Sprague-Dawley rats were trained to self-administer α-PVP (0.1 mg/kg/infusion) or 4MMC (0.5 mg/kg/infusion) through autoshaping, and then self-administered for 21 days during 1 h (short access; ShA) or 6 h (long access; LgA) sessions. Separate rats were assigned to a naïve control group. Amygdala, hippocampus, hypothalamus, prefrontal cortex (PFC), striatum, and thalamus were extracted, and tissue was analyzed with electrochemical detection and liquid chromatography mass spectrometry. Rats acquired self-administration of α-PVP and 4MMC, and LgA rats showed more escalation of self-administration than ShA rats. Synthetic cathinone administration produced several effects on neurotransmitters. LgA self-administration of α-PVP increased 5-HIAA levels in all brain regions, compared to control. In contrast, both LgA and ShA 4MMC self-administration decreased 5-HT and 5-HIAA levels in most brain regions. LgA exposure to both synthetic cathinones increased DOPAC levels in hypothalamus and striatum, and increased HVA levels in striatum compared to control. LgA self-administration of either synthetic cathinone produced region-specific increases in NE levels, whereas ShA self-administration lowered NE levels in select locations compared to control. These alterations in neurotransmitter levels indicate that synthetic cathinone use may produce differential neurochemical changes during the transition from use to abuse, and that 21 days of self-administration only models the beginning stages of dysregulated drug intake.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metanfetamina/análogos & derivados , Neurotransmissores/metabolismo , Pentanonas/administração & dosagem , Pirrolidinas/administração & dosagem , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Feminino , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Metanfetamina/administração & dosagem , Norepinefrina/metabolismo , Ratos Sprague-Dawley , Autoadministração , Serotonina/metabolismo , Fatores Sexuais , Fatores de Tempo
4.
Pharmacol Biochem Behav ; 201: 173089, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33422599

RESUMO

Methamphetamine (meth) dependence is often characterized by persistent and chronic relapse (i.e., return to drug use). Previous work suggests females may be at greater risk to relapse. In this study, we extended this limited evidence and identified sex-dependent neural substrates related to meth-triggered reinstatement. Male and female Sprague-Dawley rats were implanted with indwelling jugular catheters. Half of the rats were then trained to self-administer meth (0.05 mg/kg/inf); the other half self-administered saline during 21 daily sessions (2 h). Rats were then given 12 extinction sessions. Twenty-four hours after the last extinction session, rats received reinstatement testing. Half of the rats received a meth-prime (0.3 mg/kg, IP) injection and the remaining rats received a saline injection. This design resulted in 4 separate groups for each sex, allowing for careful investigation of brain regions related to meth-triggered reinstatement. Brains were harvested following the reinstatement session and c-Fos immunoreactivity was measured in multiple brain regions. Meth triggered reinstatement in both sexes and this effect was more robust in females compared to males. Significant sex differences were detected. Females showed greater c-Fos immunoreactivity in the cingulate cortex area 1, lateral orbitofrontal cortex, prelimbic cortex, caudate-putamen, nucleus accumbens core and shell, and central nucleus of the amygdala following meth-primed reinstatement.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Metanfetamina/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Núcleo Central da Amígdala/metabolismo , Modelos Animais de Doenças , Extinção Psicológica , Feminino , Giro do Cíngulo/metabolismo , Imuno-Histoquímica/métodos , Masculino , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Recidiva , Autoadministração , Fatores Sexuais
5.
Pharmacol Biochem Behav ; 202: 173104, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33444596

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant. The continuous use of METH may lead to its abuse and neurotoxicity that have been associated with METH-induced increases in release of dopamine (DA) and glutamate in the brain. METH action in DA has been shown to be mediated by redistribution of DA from vesicles into cytoplasm via vesicular monoamine transporter 2 (VMAT2) and the subsequent reversal of membrane DA transporter (DAT), while little is known about the mechanisms underlying METH-induced glutamate release. Recent studies indicate that a subpopulation of midbrain DA neurons co-expresses VMAT2 and vesicular glutamate transporter 2 (VGLUT2). Therefore, we hypothesized that METH-induced glutamate release may in part originate from such a dual phenotype of DA neurons. To test this hypothesis, we used Cre-LoxP techniques to selectively delete VGLUT2 from midbrain DA neurons, and then examined nucleus accumbens (NAc) DA and glutamate responses to METH using in vivo brain microdialysis between DA-VGLUT2-KO mice and their VGLUT2-HET littermates. We found that selective deletion of VGLUT2 from DA neurons did not significantly alter basal levels of extracellular DA and glutamate, but attenuated METH-induced increases in extracellular levels of DA and glutamate. In addition, DA-VGLUT2-KO mice also displayed lower locomotor response to METH than VGLUT2-HET control mice. These findings, for the first time, suggest that cell-type specific VGLUT2 expression in DA neurons plays an important role in the behavioral and neurochemical effects of METH. Glutamate corelease from DA neurons may in part contributes to METH-induced increase in NAc glutamate release.


Assuntos
Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Deleção de Genes , Ácido Glutâmico/metabolismo , Mesencéfalo/metabolismo , Metanfetamina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Vesicular 2 de Transporte de Glutamato/genética , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Técnicas de Inativação de Genes , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microdiálise/métodos , Núcleo Accumbens/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
6.
Sci Rep ; 11(1): 1422, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446840

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant that causes long-lasting effects in the brain and increases the risk of developing neurodegenerative diseases. The cellular and molecular effects of METH in the brain are functionally linked to alterations in glutamate levels. Despite the well-documented effects of METH on glutamate neurotransmission, the underlying mechanism by which METH alters glutamate levels is not clearly understood. In this study, we report an essential role of proline biosynthesis in maintaining METH-induced glutamate homeostasis. We observed that acute METH exposure resulted in the induction of proline biosynthetic enzymes in both undifferentiated and differentiated neuronal cells. Proline level was also increased in these cells after METH exposure. Surprisingly, METH treatment did not increase glutamate levels nor caused neuronal excitotoxicity. However, METH exposure resulted in a significant upregulation of pyrroline-5-carboxylate synthase (P5CS), the key enzyme that catalyzes synthesis of proline from glutamate. Interestingly, depletion of P5CS by CRISPR/Cas9 resulted in a significant increase in glutamate levels upon METH exposure. METH exposure also increased glutamate levels in P5CS-deficient proline-auxotropic cells. Conversely, restoration of P5CS expression in P5CS-deficient cells abrogated the effect of METH on glutamate levels. Consistent with these findings, P5CS expression was significantly enhanced in the cortical brain region of mice administered with METH and in the slices of cortical brain tissues treated with METH. Collectively, these results uncover a key role of P5CS for the molecular effects of METH and highlight that excess glutamate can be sequestered for proline biosynthesis as a protective mechanism to maintain glutamate homeostasis during drug exposure.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Córtex Cerebral/metabolismo , Ácido Glutâmico/metabolismo , Homeostase/efeitos dos fármacos , Metanfetamina/toxicidade , Prolina/biossíntese , Doença Aguda , Aldeído Desidrogenase/metabolismo , Animais , Células CHO , Cricetulus , Humanos , Masculino , Camundongos , Neurônios/metabolismo
7.
Addict Biol ; 26(1): e12876, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017280

RESUMO

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (VT ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA VT (P = .81). No significant correlations between [F-18]FEPPA VT and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Anilidas/metabolismo , Microglia/fisiologia , Tomografia por Emissão de Pósitrons , Piridinas/metabolismo , Receptores de GABA/metabolismo , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Metanfetamina/metabolismo , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/metabolismo
8.
Pharmacol Biochem Behav ; 200: 173087, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309825

RESUMO

Methamphetamine (Meth) seeking progressively increases after cessation from drug self-administration (incubation of Meth craving). We have previously shown that both dorsomedial and dorsolateral striatum (DMS and DLS) play critical roles in this incubation in male rats. Moreover, our recent anatomical tracing study examined afferent projections into DMS and demonstrated a novel role of projections from anterior intralaminar nucleus of thalamus (AIT) to DMS in incubation of Meth craving in male rats. Here we investigated projection-specific activation of afferent glutamate projections into DLS associated with incubated Meth seeking in female rats. We trained female rats to self-administer Meth (6-h/d for 10 d). On abstinence day 12, we injected cholera toxin subunit B (CTb, a retrograde tracer) unilaterally into DLS. On abstinence day 26, we tested rats for relapse to Meth seeking and measured Fos (a neuronal activity marker), and double-labeling of CTb and Fos in anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, basolateral amygdala, AIT, and parafascicular nuclei of thalamus. We observed neuronal activation in both cortical and thalamic regions associated with incubated Meth seeking. At the circuit level, AIT➔DLS projections were strongly activated, followed by other corticostriatal projections. Overall our results suggest that AIT to DLS may play a role in Meth seeking after prolonged abstinence in female rats.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Núcleos Intralaminares do Tálamo/metabolismo , Metanfetamina/farmacologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Fissura/efeitos dos fármacos , Feminino , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Autoadministração/métodos , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
9.
Behav Brain Res ; 396: 112925, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971195

RESUMO

Chronic methamphetamine (METH) treatment induces behavioral sensitization in rodents. During this process, hyperactivation of the mesolimbic dopamine system plays a central role, and dopamine D2-like receptor-based antipsychotics are known to alleviate the behavioral hyperactivity. The atypical antipsychotic, clozapine (Clz), acts partially as a dopamine D4 receptor (D4R) antagonist and mitigates hyperdopaminergic drug addiction and/or comorbid psychotic symptoms; however, it remains unclear whether D4R blockade contributes to the therapeutic effects of Clz. Here, we evaluated the potential role of D4R in regulating hyperdopaminergia-induced behavioral hyperactivity in METH behavioral sensitization and dopamine transporter (DAT) knockdown (KD) mice. Clz or a D4R-selective antagonist, L-745,870, were co-administered to mice with daily METH in a METH sensitization model, and Clz or L-745,870 were administered alone in a DAT KD hyperactivity model. Locomotor activity and accumbal D4R expression were analyzed. Clz suppressed both the initiation and expression of METH behavioral sensitization, as well as DAT KD hyperactivity. However, repetitive Clz treatment induced tolerance to the suppression effect on METH sensitization initiation. In contrast, D4R inhibition by L-745,870 had no effect on METH sensitization or DAT KD hyperactivity. Accumbal D4R expression was similar between METH-sensitized mice with and without Clz co-treatment. In sum, our results suggest the mesolimbic D4R does not participate in behavioral sensitization encoded by hyperdopaminergia, a finding which likely extends to the therapeutic effects of Clz. Therefore, molecular targets other than D4R should be prioritized in the development of future therapeutics for treatment of hyperdopaminergia-dependent neuropsychiatric disorders.


Assuntos
Antipsicóticos/farmacologia , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Clozapina/farmacologia , Dopaminérgicos/farmacologia , Locomoção/efeitos dos fármacos , Metanfetamina/farmacologia , Receptores de Dopamina D4/antagonistas & inibidores , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Antipsicóticos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Clozapina/administração & dosagem , Modelos Animais de Doenças , Dopaminérgicos/administração & dosagem , Metanfetamina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Camundongos Transgênicos , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologia , Piridinas/farmacologia , Pirróis/farmacologia
10.
J Physiol Pharmacol ; 71(4)2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33316768

RESUMO

The abundance of research indicates that enriched environment acts as a beneficial factor reducing the risks of relapse in substance use disorder. There is also strong evidence showing the engagement of brain dopaminergic and glutamatergic signaling through the dopamine D2-like and metabotropic glutamate type 5 (mGlu5) receptors, respectively, that has a direct impact on drug reward and drug abstinence. The present study involved 3,4-methylendioxymethamphetamine (MDMA) self-administration with the yoked-triad procedure in rats kept under different housing conditions during abstinence - enriched environment (EE) or isolation cage (IC) conditions - aimed at evaluating changes in brain receptors affecting drug-seeking behavior as well as density and affinity of the D2-like and mGlu5 receptors in several regions of the animal brain. Our results show that exposure to EE conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated marked decreases of D2-like receptor affinity in the dorsal striatum in rats previously self-administering MDMA under EE and increases in density under IC conditions. Moreover, we found the increases in the density and decreases in the affinity of the D2-like receptor in the prefrontal cortex and nucleus accumbens provoked by IC conditions. The mGlu5 receptor density decreased only in the prefrontal cortex after IC and EE abstinence. Moreover, our study has revealed a clear decrease in mGlu5 receptor density in the nucleus accumbens in the group actively administering MDMA only under EE conditions. This study demonstrates that housing conditions have impact on drug-seeking behavior in rats during abstinence from MDMA self-administration. The observed changes in the dopamine D2-like and mGlu5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of MDMA.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Dopamina D2/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Sinais (Psicologia) , Abrigo para Animais , Masculino , Ratos Wistar , Isolamento Social
11.
Eur J Pharmacol ; 889: 173732, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33220277

RESUMO

Methamphetamine use disorder (MUD) is often modeled using rodent self-administration (SA) experiments. Noncontingent injections of a drug given to rodents before self-administration training can increase drug SA. In the present study, we injected methamphetamine before putting rats through methamphetamine SA to investigate SA escalation. We also measured consequent changes in the expression of glutamate receptors in the hippocampus. Experimental groups included rats that received the methamphetamine injection prior to self-administration (MM) and those that received a prior saline injection before they underwent methamphetamine SA (SM). After SA training, rats also underwent tests of relapse potentials at one day and one month after withdrawal from methamphetamine SA. We used qPCR to identify potential changes in mRNA expression of AMPA, NMDA, and mGluR glutamate receptors. MM rats showed greater escalated methamphetamine intake in comparison to SM animals. There were no differences in incubation of methamphetamine craving between the two groups. In the hippocampus, MM rats showed decreased levels of GluA2 and GluA3 mRNAs in comparison to controls and of GluN2c mRNA in comparison to SM rats. In addition, SM rats had increased mGluR3 mRNA levels in comparison to control and MM rats. These data implicate hippocampal glutamate receptors in the longterm effects of methamphetamine. Further studies are necessary to identify the specific role that changes in the expression of these receptors might play in escalated intake of methamphetamine by human users.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Hipocampo/efeitos dos fármacos , Metanfetamina/toxicidade , Receptores de AMPA/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Animais , Fissura , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Ratos Sprague-Dawley , Receptores de AMPA/genética , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores de Tempo
12.
J Neuroimmune Pharmacol ; 15(4): 743-764, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32929575

RESUMO

HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis. We compare the effects of methamphetamine with those of cannabis, to illustrate how substances may potentiate, worsen, or even buffer the effects of HIV on the CNS. Data from human, animal, and ex vivo studies provide insights into how these drugs have differing effects on the persistent inflammatory state that characterizes HIV infection, including effects on viral replication, immune activation, mitochondrial function, gut permeability, blood brain barrier integrity, glia and neuronal signaling. Moving forward, we consider how these mechanistic insights may inform interventions to improve brain outcomes in PWH. This review summarizes literature from clinical and preclinical studies demonstrating the adverse effects of METH, as well as the potentially beneficial effects of cannabis, on the interacting systemic (e.g., gut barrier leakage/microbial translocation, immune activation, inflammation) and CNS-specific (e.g., glial activation/neuroinflammation, neural injury, mitochondrial toxicity/oxidative stress) mechanisms underlying HIV-associated neurocognitive disorders.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Uso da Maconha , Metanfetamina/efeitos adversos , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Cannabis , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Humanos , Uso da Maconha/epidemiologia , Uso da Maconha/metabolismo , Transtornos Neurocognitivos/tratamento farmacológico , Transtornos Neurocognitivos/metabolismo
13.
Psychiatry Res ; 292: 113269, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32739643

RESUMO

The Met-allele of the COMT Val158Met polymorphism slows metabolism and increases bioavailability of dopamine (DA) in the prefrontal cortex compared to the Val-allele. Healthy Met-carriers outperform Val-carriers on executive function (EF) tests, yet this 'advantage' disappears in methamphetamine (METH) dependence. Met-carriers may be disproportionately vulnerable to METH-related perturbations of DA, yet it is unknown whether COMT modulates METH effects on CSF DA biomarkers. Participants were 75 METH+ and 47 METH- men who underwent neurocognitive testing, COMT genotyping, and lumbar puncture. CSF was assayed for DA and its metabolite, homovanillic acid (HVA). Separate linear models regressed DA, HVA, and HVA/DA ratios on COMT, METH and their interaction. Pearson correlations examined associations between DA and EF. Significant interactions indicated that METH+ had lower DA and higher HVA/DA ratios among Met/Met, but not Val/Met-or Val/Val. Met/Met-exhibited the highest DA levels among METH-, whereas DA levels were comparable between Met/Met-and Val-carriers among METH+. Higher DA correlated with better EF in METH- Met/Met, but did not predict EF in the entire sample. DA was expectedly higher in METH- Met/Met, yet a discordant genotype-phenotype profile emerged in METH+ Met/Met, consistent with the notion that slow DA clearance exacerbates METH-associated DA dysregulation.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/genética , Catecol O-Metiltransferase/genética , Dopamina/genética , Função Executiva/fisiologia , Genótipo , Metanfetamina/efeitos adversos , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Dopamina/metabolismo , Humanos , Masculino , Metionina/genética , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Córtex Pré-Frontal/metabolismo , Valina/genética , Adulto Jovem
14.
Peptides ; 131: 170368, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32668268

RESUMO

BACKGROUND: previous studies have suggested that methamphetamine (METH) abuse may affect orexin regulation. However, the data regarding the relationship between the current level of orexin and the vulnerability to METH abuse are minimal. Here, we have investigated the correlation between the gene expression level of the orexin-1 receptor (OX1R) in the rat prefrontal cortex (PFC) and blood lymphocytes and susceptibility to METH dependence and its impact on novelty-seeking behavior. METHODS: male Wistar rats were first examined for novelty-seeking behavior by the novel object recognition test, and the expression level of OX1R in their blood lymphocytes was evaluated by real-time PCR. Then, the susceptibility to METH abuse was investigated by voluntary METH oral consumption test. According to the amounts of METH consumption, the animals were divided into two groups of METH preferring and non-preferring. Half of the rats in each group were sacrificed, and the level of OX1R in their blood lymphocytes and PFC tissue was measured. The other half were sacrificed for the same reason after two weeks of drug abstinence. RESULTS: The indexes of novelty-seeking behavior were significantly higher in the METH- preferring group compared to the non-preferring animals. Furthermore, the expression level of OX1R in the blood lymphocytes and PFC in the preferring group was considerably higher than the non-preferring group. CONCLUSION: Up-regulation of the mRNA expression level of OX1R in the lymphocytes and PFC may predict vulnerability to the METH consumption and novelty-seeking, which may serve as a potential biomarker for METH abuse.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Comportamento Exploratório/fisiologia , Metanfetamina/farmacologia , Receptores de Orexina/genética , Córtex Pré-Frontal/efeitos dos fármacos , Administração Oral , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Estimulantes do Sistema Nervoso Central/metabolismo , Regulação da Expressão Gênica , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Metanfetamina/metabolismo , Receptores de Orexina/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
15.
J Chem Neuroanat ; 107: 101802, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32416129

RESUMO

Methamphetamine (METH) abuse is accompanied by oxidative stress, METH-induced neurotoxicity, and apoptosis. Oxidative stress has devastating effects on the structure of proteins and cells. Autophagy is an evolutionarily conserved intracellular regulated mechanism for orderly degradation of dysfunctional proteins or removing damaged organelles. The precise role of autophagy in oxidative stress-induced apoptosis of dopaminergic neuronal cells caused by METH has not clarified completely. In this study, we sought to evaluate the effects of METH abuse on autophagy in the prefrontal cortex of postmortem users, mainly focusing on the ATG5 and LC3 during neuroinflammation. Postmortem molecular and histological examination was done for two groups containing 12 non-addicted and 14 METH addicted cases. ATG5 and LC3 expression were analyzed by real-time PCR and immunohistochemistry (IHC) methods. Histopathological analysis was performed by stereological cell counting of neuronal cells using Hematoxylin and Eosin (H & E) staining technique. In order to detect DNA damage in the prefrontal lobe, Tunnel staining was performed. Real-time PCR and IHC assay showed overexpression of ATG5 and LC3 protein in the prefrontal cortex of Meth users. The cell death and neuronal degeneration were increased significantly based on Tunel assay and the stereological analysis in the Prefrontal cortex. Chronic METH exposure probably induces ATG5 and LC3 overexpression and neuronal cell death in the Prefrontal cortex of the postmortem cases.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Proteína 5 Relacionada à Autofagia/metabolismo , Autofagia/fisiologia , Morte Celular/fisiologia , Metanfetamina/envenenamento , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Autofagia/efeitos dos fármacos , Autopsia , Morte Celular/efeitos dos fármacos , Humanos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia
16.
Brain Struct Funct ; 225(3): 1073-1088, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32246242

RESUMO

This study sought to determine if reducing dopamine D1 receptor (D1R) expression in the dorsal striatum (DS) via RNA-interference alters methamphetamine self-administration. A lentiviral construct containing a short hairpin RNA (shRNA) was used to knock down D1R expression (D1RshRNA). D1RshRNA in male rats increased responding for methamphetamine (i.v.) under a fixed-ratio schedule in an extended access paradigm, compared to D1R-intact rats. D1RshRNA also produced a vertical shift in a dose-response paradigm and enhanced responding for methamphetamine in a progressive-ratio schedule, generating a drug-vulnerable phenotype. D1RshRNA did not alter responding for sucrose (oral) under a fixed-ratio schedule compared to D1R-intact rats. Western blotting confirmed reduced D1R expression in methamphetamine and sucrose D1RshRNA rats. D1RshRNA reduced the expression of PSD-95 and MAPK-1 and increased the expression of dopamine transporter (DAT) in the DS from methamphetamine, but not sucrose rats. Sucrose density gradient fractionation was performed in behavior-naïve controls, D1RshRNA- and D1R-intact rats to determine the subcellular localization of D1Rs, DAT and D1R signaling proteins. D1Rs, DAT, MAPK-1 and PSD-95 predominantly localized to heavy fractions, and the membrane/lipid raft protein caveolin-1 (Cav-1) and flotillin-1 were distributed equally between buoyant and heavy fractions in controls. Methamphetamine increased localization of PSD-95, Cav-1, and flotillin-1 in D1RshRNA and D1R-intact rats to buoyant fractions. Our studies indicate that reduced D1R expression in the DS increases vulnerability to methamphetamine addiction-like behavior, and this is accompanied by striatal alterations in the expression of DAT and D1R signaling proteins and is independent of the subcellular localization of these proteins.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Corpo Estriado/metabolismo , Comportamento de Procura de Droga/fisiologia , Metanfetamina/administração & dosagem , Receptores de Dopamina D1/metabolismo , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Corpo Estriado/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Masculino , RNA Interferente Pequeno/administração & dosagem , Ratos Long-Evans , Receptores de Dopamina D2/metabolismo
17.
JAMA Psychiatry ; 77(9): 959-966, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267484

RESUMO

Importance: The prevalence of and mortality associated with methamphetamine use has doubled during the past 10 years. There is evidence suggesting that methamphetamine use disorder could be the next substance use crisis in the United States and possibly worldwide. Observation: The neurobiology of methamphetamine use disorder extends beyond the acute effect of the drug as a monoaminergic modulator and includes intracellular pathways focused on oxidative stress, neurotoxic and excitotoxic effects, and neuroinflammation. Similarly, the clinical picture extends beyond the acute psychostimulatory symptoms to include complex cardiovascular and cerebrovascular signs and symptoms that need to be identified by the clinician. Although there are no pharmacologic treatments for methamphetamine use disorder, cognitive behavioral therapy, behavioral activation, and contingency management show modest effectiveness. Conclusions and Relevance: There is a need to better understand the complex neurobiology of methamphetamine use disorder and to develop interventions aimed at novel biological targets. Parsing the disorder into different processes (eg, craving or mood-associated alterations) and targeting the neural systems and biological pathways underlying these processes may lead to greater success in identifying disease-modifying interventions. Finally, mental health professionals need to be trained in recognizing early cardiovascular and cerebrovascular warning signs to mitigate the mortality associated with methamphetamine use disorder.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/terapia , Estimulantes do Sistema Nervoso Central , Metanfetamina , Humanos
18.
J Neuroimmune Pharmacol ; 15(2): 238-248, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31820289

RESUMO

Methamphetamine (MA) triggers neuroinflammation and medications that counteract MA-induced neuroinflammation may reduce MA-induced neurodegeneration and improve neurocognition and treatment outcomes in MA use disorder. We performed a randomized, placebo-controlled trial to determine the safety and efficacy of ibudilast (IBUD), a phosphodiesterase inhibitor that reduces neuroinflammation, for the treatment of MA use disorder. Treatment-seeking volunteers with MA use disorder were randomly assigned to receive 12 weeks of IBUD 50 mg twice daily (N = 64) or placebo (N = 61) with medication management counseling. Participants visited the outpatient research clinic twice weekly to provide urine specimens for drug screens and undergo study assessments. The primary outcome was end of treatment MA-abstinence (EOTA) during weeks 11 and 12 of treatment. Serum IBUID levels were measured for IBUD participants during week 3 of treatment. There was no difference in EOTA for IBUD (14%) versus placebo (16%, p > 0.05). There was no correlation between serum IBUD levels and MA use during treatment and mean IBUD levels for participants with (mean = 51.3, SD = 20.3) and without (mean = 54.7, SD = 33.0, p = 0.70) EOTA. IBUD was well tolerated. IBUD did not facilitate MA abstinence in this outpatient trial. Whether targeting neuroinflammation, either with IBUD in other subgroups of MA users or clinical trial designs, or with other anti-inflammatory medications, is an effective strategy for treating MA use disorder is not clear. Graphical Abstract The proportion of urine drug screens negative for methamphetamine (MA) during the two week lead-in period (weeks -2 and - 1) and the 12 week medication treatment period (weeks 1-12) for ibudilast versus placebo.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Mediadores da Inflamação/antagonistas & inibidores , Metanfetamina/efeitos adversos , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/uso terapêutico , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Método Duplo-Cego , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
19.
J Clin Neurosci ; 71: 15-20, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31859180

RESUMO

Increasing evidence suggested the dorsolateral prefrontal cortex (DLPFC) is implicated in the pathogenesis of methamphetamine use disorder. Metabolites changes of DLPFC may mediate the progression of addiction. We used proton magnetic resonance spectroscopy (1H-MRS) to examine the changes of metabolites in the left DLPFC in individuals with methamphetamine dependence compared to healthy controls. Fifty patients and twenty age-matched healthy controls participated in this study. The 1H MRS data were automatically fit with linear combination model for quantification of metabolite levels of γ-aminobutyric acid (GABA), glutamate + glutamine (Glx) and other metabolites across groups. The GABA and Glx levels were calculated with the unsuppressed water signal as reference. Methamphetamine users showed reduced GABA and GABA/Glx in left DLPFC than healthy controls. Furthermore, the concentration of GSH, GPC, Ins, NAA, GPC + PCh, NAA + NAAG, Cr + PCr were lower in individuals with methamphetamine dependence compared with controls. The patients group's relative GABA and Glx metabolite concentrations were significantly correlated with age and duration of withdrawal. Our preliminary findings provide the first report of abnormal levels of GABA in left DLPFC of patients with methamphetamine use disorder, indicating that dysregulation of the GABAergic neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of methamphetamine dependence.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Córtex Pré-Frontal/metabolismo , Ácido gama-Aminobutírico/metabolismo , Adulto , Feminino , Humanos , Masculino , Metanfetamina , Espectroscopia de Prótons por Ressonância Magnética , Ácido gama-Aminobutírico/análise
20.
Toxicol Lett ; 321: 73-82, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31862507

RESUMO

An enterogenic infection occurs when intestinal mucosal disruption is followed by the invasion of intestinal bacteria into the blood and distant organs, which can result in severe diseases or even death. Our previous study using Rhesus monkeys as an in vivo model revealed that methamphetamine (MA) induced intestinal mucosal barrier damage, which poses a high risk of enterogenic infection. However, how methamphetamine causes intestinal mucosal barrier damage remains largely unknown. In this study, we employed an in vitro model, and found that MA treatment could inhibit the expression of miR-181c, which directly targets and regulates TNF-α, and ultimately induces apoptosis and damages the intestinal barrier. Moreover, we measured TNF-α serum levels as well as the intestinal mucosal barrier damage indicators (diamine oxidase, d-lactic acid, and exotoxin) and found that their levels were significantly higher in MA-dependents than in healthy controls (P < 0.001). To the best of our knowledge, this is the first report evidencing that miR-181c is involved in MA-induced intestinal barrier injury via TNF-α regulation, which introduces novel potential therapeutic targets for MA-dependent intestinal diseases.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Metanfetamina/efeitos adversos , MicroRNAs/metabolismo , Junções Íntimas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Animais , Apoptose/efeitos dos fármacos , Translocação Bacteriana/efeitos dos fármacos , Biomarcadores/sangue , Estudos de Casos e Controles , Linhagem Celular , Impedância Elétrica , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Permeabilidade , Ratos , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Adulto Jovem
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