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2.
Brain ; 142(7): 1887-1893, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505542

RESUMO

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Dopamina/deficiência , Dopamina/metabolismo , Estado Vegetativo Persistente/metabolismo , Terminações Pré-Sinápticas/metabolismo , Adulto , Lesões Encefálicas Traumáticas/complicações , Corpo Estriado/metabolismo , Dextroanfetamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Feminino , Humanos , Levodopa/farmacologia , Masculino , Estado Vegetativo Persistente/complicações , Tomografia por Emissão de Pósitrons , Terminações Pré-Sinápticas/efeitos dos fármacos , Racloprida/metabolismo , Receptores de Dopamina D2/metabolismo , Substância Negra/metabolismo , Tegmento Mesencefálico/metabolismo , Tálamo/metabolismo , Adulto Jovem
3.
Behav Pharmacol ; 30(7): 605-616, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31503070

RESUMO

Individuals with attention-deficit/hyperactivity disorder tend to make risker choices during probabilistic-discounting procedures. Thus, how common attention-deficit/hyperactivity disorder medications affect probabilistic discounting is of interest. In general, d-amphetamine increases risk-taking while atomoxetine has produced mixed effects in rats. Results from previous studies may result from genetic factors. Lewis and F344 rats have neurochemical differences that may be relevant to probabilistic discounting and how drugs affect such behavior. In this study, we evaluated dose-dependent effects of d-amphetamine and atomoxetine on probabilistic discounting of Lewis and F344. Male Lewis and F344 chose between one food pellet delivered 100% of the time and three food pellets delivered following decreasing probabilities of delivery (i.e. 100%, 66.7%, 33.3%, 16.5%, and 8.25%). Saline, d-amphetamine (0.1-1.8 mg/kg), and atomoxetine (0.1-7.8 mg/kg) were tested acutely. Lewis and F344 did not differ in choice at baseline. d-Amphetamine increased risky choice for both rat strains at low-to-moderate doses, although it did so at a lower dose (0.1 and 0.3 mg/kg) for F344 as compared to Lewis (0.3 mg/kg only). At high doses (1.0 and 1.8 mg/kg), d-amphetamine disrupted choice, increased frequencies of omitted trials, and reduced reinforcer sensitivity. Although atomoxetine increased frequencies of omitted trials at high doses (5.6 and 7.8 mg/kg), it had no effect on probabilistic discounting for either rat strain. Although Lewis and F344 differ in various types of impulsivity (i.e. motor, choice), with Lewis being the more impulsive of the two, the present results suggest that Lewis and F344 do not differ in risk-based decision-making. Effects of d-amphetamine on probabilistic discounting may be biology-dependent and differ from effects of atomoxetine.


Assuntos
Cloridrato de Atomoxetina/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Dextroanfetamina/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Esquema de Reforço , Reforço Psicológico , Assunção de Riscos
4.
J Addict Nurs ; 30(3): 219-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31478970

RESUMO

BACKGROUND: The ongoing drug crisis in the United States continues to be headlined with numbers of deaths related to opioid overdose. Less known to the public and health care providers is the rise in methamphetamine use, often in conjunction with opioids or adulterated with fentanyl. An old practice with a new twist is the use of methamphetamine in conjunction with an opioid such as heroin. PURPOSE: Although there are no Food and Drug Administration-approved medications to treat individuals with stimulant use disorders, a review of available studies suggests a few promising medications that may be helpful for patients in early recovery from methamphetamine. OUTCOME: Some individuals are more likely to respond to medications such as long-acting naltrexone, bupropion, and mirtazapine, who have light-to-moderate use of methamphetamine. Naloxone kits should be considered for all patients who are actively using stimulants because of a high potential of adulterated methamphetamine.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/reabilitação , Estimulantes do Sistema Nervoso Central , Metanfetamina , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Bupropiona/uso terapêutico , Dextroanfetamina/uso terapêutico , Aprovação de Drogas , Humanos , Drogas Ilícitas , Metilfenidato/uso terapêutico , Mirtazapina/uso terapêutico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Epidemia de Opioides/estatística & dados numéricos , Transtornos Relacionados ao Uso de Opioides/reabilitação , Resultado do Tratamento , Estados Unidos/epidemiologia
5.
Pharmacol Biochem Behav ; 183: 56-63, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31158395

RESUMO

The present study evaluated the effects of the coadministration of lithium (Li) and Cel on inflammatory parameters in an animal model of mania induced by dextroamphetamine (D-amph). It was used Wistar rats 60 days old (250-350 g). The animals (n = 10 per group) received D-amph (2 mg/kg) or saline solution of NaCl 0.9% (Sal) intraperitoneally once a day for 14 days. From day eight until 14, the animals from the D-amph and Sal groups received Li (24 mg/kg), Cel (20 mg/kg), Li + Cel or water via gavage. Behavioral analyses were performed using the open-field test. The levels of IL-1ß, IL-4, IL-10, and TNF-α were evaluated. The administration of D-amph induced hyperactivity in the rats, as well increased the IL-4, IL-10, and TNF-α levels in the serum, frontal cortex, and striatum of rats compared to those of the controls, and treatment with Li plus Cel reversed these alterations. In general, the administration of Li or Cel per se did not have effects on the behavioral and biochemical parameters. However, the treatment with Cel per se decreased only the IL-10 levels in the serum of animals. Besides, the treatment with Li or Cel decreased the IL-4 levels in the serum and reversed the effects of D-amph on this parameter in the frontal cortex. The treatment with Li reversed the effects of D-amph on the TNF-α levels in all tissues evaluated, and the administration of Cel reversed this alteration only in the striatum. It can be observed that treatment with Li plus Cel was more effective against damages caused by D-amph when compared to the administration of both treatments per se, suggesting that the coadministration can be more effective to treat BD rather than Li or Cel itself. The treatment with Li plus Cel was effective against the inflammation induced by D-amph.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antimaníacos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Celecoxib/uso terapêutico , Dextroanfetamina/farmacologia , Compostos de Lítio/uso terapêutico , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antimaníacos/administração & dosagem , Celecoxib/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Citocinas/metabolismo , Dextroanfetamina/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Compostos de Lítio/administração & dosagem , Masculino , Ratos , Ratos Wistar
6.
Psychopharmacology (Berl) ; 236(11): 3363-3370, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31209507

RESUMO

RATIONALE: One risk factor for alcohol and substance misuse is hypomanic experiences, or periods of mood elevation. Young people who report hypomanic states are more likely to develop bipolar disorder (BP), and BP and other mood disorders increase the risk of addiction. We recently reported that young adults with a history of mood elevation experience less subjective effects from a low dose of alcohol, which may be predictive of future alcohol use. The finding with alcohol raised the question of whether this dampened response to a drug also applies to other drugs, such as amphetamine. OBJECTIVE: This study assessed responses of d-amphetamine in healthy young adults with varying experiences of mood elevation, as measured by the Mood Disorders Questionnaire (MDQ). METHODS: Healthy 18-19-year-olds (N = 30) with a range of MDQ scores participated in three 4-h laboratory sessions in which they received placebo, 10 mg, or 20 mg d-amphetamine. They completed mood questionnaires and cardiovascular measures. RESULTS: Individuals with higher MDQ scores reported less stimulation and euphoria after 10 mg, but not 20 mg, d-amphetamine, than individuals with lower scores. MDQ scores were not related to cardiovascular responses to the drug. CONCLUSIONS: A history of mood elevation experiences or hypomania states is related to dampened response to a low dose of a psychostimulant drug, extending previous findings with dampened response to alcohol. This phenotype for mood disorders of dampened responses to drugs may contribute to risk for subsequent drug use or misuse.


Assuntos
Comportamento Aditivo/diagnóstico , Comportamento Aditivo/psicologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Dextroanfetamina/administração & dosagem , Euforia/efeitos dos fármacos , Adolescente , Afeto/efeitos dos fármacos , Afeto/fisiologia , Comportamento Aditivo/induzido quimicamente , Estimulantes do Sistema Nervoso Central/efeitos adversos , Dextroanfetamina/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Euforia/fisiologia , Feminino , Humanos , Masculino , Inquéritos e Questionários , Adulto Jovem
7.
Pharmacol Biochem Behav ; 182: 12-21, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31129199

RESUMO

Aminopeptidase A is responsible for the hydrolysis of angiotensin II and cholecystokinin. By measuring its activity we obtain a reflection of the functional status of its endogenous substrates. Dopamine coexists with these neuropeptides in striatum and prefrontal cortex. If the content of any of them is altered, the others and the functions they are involved in would also be affected. Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) are rat models with different motor behavior and mood. We hypothesized that aminopeptidase A activity could be modified in WKY or SHR affecting the brain dopamine. The results may provide new insights for the understanding of dopamine-related disorders such as schizophrenia, depression or Parkinson's disease. To analyze the influence of unilateral depletions of dopamine on the intra- and inter-hemispheric behavior of aminopeptidase A in striatum and prefrontal cortex of WKY and SHR, aminopeptidase A activity was measured fluorometrically, using an arylamide derivative as substrate, in the left and right sides of striatum and prefrontal cortex of WKY and SHR treated with saline (control groups) or following left or right intrastriatal injections of 6-hydroxydopamine (lesioned groups). Differential asymmetrical intra- and inter-hemispheric behaviors of aminopeptidase A were observed, depending on the lesioned hemisphere, the region and the strain analyzed. Results also demonstrated differential intra and inter-hemispheric correlations between striatum and prefrontal cortex and between both regions and motor behavior depending on the side of lesion. The changes mostly involved the left hemisphere. The functions in which the aminopeptidase A activity is involved could be modified depending on whether the dopamine depletion occurs on the left or right hemisphere.


Assuntos
Corpo Estriado/metabolismo , Glutamil Aminopeptidase/metabolismo , Oxidopamina/farmacologia , Córtex Pré-Frontal/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Dextroanfetamina/administração & dosagem , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Ativação Enzimática/efeitos dos fármacos , Seguimentos , Masculino , Modelos Animais , Atividade Motora , Oxidopamina/administração & dosagem , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Solução Salina/administração & dosagem , Solução Salina/farmacologia , Transdução de Sinais/efeitos dos fármacos
8.
Psychopharmacology (Berl) ; 236(3): 1015-1029, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30980094

RESUMO

RATIONALE: The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused. OBJECTIVE: Direct-acting 5-HT2A/2C receptor agonists and antagonists and D1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT2A/2C and D1-3 receptor antagonists were examined in both groups. METHODS: Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline. RESULTS: In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates. CONCLUSIONS: A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.


Assuntos
Alcaloides/farmacologia , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Metanfetamina/análogos & derivados , Antagonistas da Serotonina/farmacologia , Animais , Benzazepinas/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Condicionamento Operante/fisiologia , Dextroanfetamina/farmacologia , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Drogas Ilícitas/farmacologia , Ketanserina/farmacologia , Masculino , Metanfetamina/farmacologia , Psicotrópicos/farmacologia , Ratos , Ratos Sprague-Dawley
9.
Obes Facts ; 12(1): 91-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30844799

RESUMO

BACKGROUND: A limited number of published case reports suggest a positive effect of dextroamphetamine, an adrenergic agonist affecting both the central nervous system (CNS) and peripheral nervous system, on physical activity and weight in patients with hypothalamic obesity (intractable obesity following CNS insult). Here, we present our clinical experience with dextroamphetamine treatment for hypothalamic obesity. METHODS: The clinical course of all patients started on dextroamphetamine treatment for severe hypothalamic obesity at our institution between 2010 and 2013 is reported. Dextroamphetamine administration was initiated at a single dose of 5 mg per day and titrated to effect up to a dose of 20 mg/day. BMI z-score velocity was calculated as change in BMI z-score over standardized intervals of 12 months. Parameters of treatment success and adverse events were assessed in a standardized fashion. RESULTS: Seven patients (2 males; mean age 17.6 years [range 12.9-24.5]) underwent individual treatment attempts with dextroamphetamine between 2010 and 2013. The primary diagnoses were craniopharyngioma (n = 4), ganglioglioma WHO I (n = 1), astrocytoma (n = 1), and neonatal meningitis (n = 1). Time from initial CNS insult to initiation of dextroamphetamine treatment averaged 5.2 years (range 2.4 months to 16.5 years). All patients demonstrated a steady increase in BMI z-score from the time of initial diagnosis until initiation of dextroamphetamine treatment. Mean baseline BMI z-score was +3.17 ± 0.93 (+1.9 to +4.4). Mean BMI z-score velocity decelerated to -0.18 ± 0.12 per year during the first year of treatment and stabilized at +0.05 ± 0.32 per year during the second year of treatment. No significant adverse events were reported. CONCLUSION: Dextroamphetamine treatment led to stabilization or reduction of BMI z-score in a cohort of 7 patients with hypothalamic obesity, with no adverse effects. Considering the projected increase in BMI z-score according to the natural course of the disease, these findings are promising and warrant further study.


Assuntos
Dextroanfetamina/uso terapêutico , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/tratamento farmacológico , Obesidade/tratamento farmacológico , Obesidade/etiologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Estudos de Coortes , Exercício Físico , Feminino , Nível de Saúde , Humanos , Masculino , Obesidade Mórbida/tratamento farmacológico , Obesidade Mórbida/etiologia , Obesidade Pediátrica/tratamento farmacológico , Obesidade Pediátrica/etiologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
10.
Neurotoxicology ; 72: 61-73, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30769003

RESUMO

Gestational exposure to methylmercury (MeHg), an environmental neurotoxicant, and adolescent administration of d-amphetamine (d-AMP) disrupt dopamine neurotransmission and alter voluntary behavior in adult rodents. We determined the impact of adolescent exposure to MeHg and d-AMP on monoamine neurotransmission in mice by assessing sensitivity to acute d-AMP, desipramine, and clomipramine, drugs that target dopamine, norepinephrine, and serotonin reuptake, respectively. Male C57Bl/6n mice were given 0 (control) or 3 ppm MeHg via drinking water from postnatal day 21 to 60 (murine adolescence). Within each group, mice were given once-daily injections of d-AMP or saline (i.p.) from postnatal day 28 to 42. This exposure regimen produced four treatment groups (n = 10-12/group): control, d-AMP, MeHg, and d-AMP + MeHg. As adults, the mice lever pressed under fixed-ratio schedules of reinforcement (FR 1, 5, 15, 30, 60, and 120). Acute i.p. injections of d-AMP (.3-1.7 mg/kg), desipramine (5.6-30 mg/kg), and clomipramine (5.6-30 mg/kg) were administered in adulthood after a stable behavioral baseline was established. Adolescent MeHg exposure increased saturation rate and minimum response time, an effect that was mitigated by chronic administration of d-AMP in adolescence. In unexposed mice, the three monoamine reuptake inhibitors had separable behavioral effects. Adolescent d-AMP increased sensitivity to acute d-AMP, desipramine, and clomipramine. Adolescent MeHg exposure alone did not alter drug sensitivity. Combined adolescent d-AMP + MeHg exposure enhanced sensitivity to acute d-AMP's and desipramine's effects on minimum response time. Adolescence is a vulnerable developmental period during which exposure to chemicals can have lasting effects on monoamine function and behavior.


Assuntos
Inibidores da Captação Adrenérgica/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Dextroanfetamina/toxicidade , Compostos de Metilmercúrio/toxicidade , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Clomipramina/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Desipramina/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Esquema de Reforço
11.
J Affect Disord ; 245: 1106-1113, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30699853

RESUMO

BACKGROUND: Bipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats. METHODS: Wistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (d-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with d-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with d-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without d-AMPH challenge, depressive- and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. RESULTS: D-AMPH for 14 days augmented locomotor sensitization to a lower dose of d-AMPH (0.5 mg/kg) after the withdrawal. d-AMPH withdrawal induced depressive- and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after d-AMPH sensitization. LIMITATIONS: Although d-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse. CONCLUSIONS: Together, vulnerability to mania-like behavior following d-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology.


Assuntos
Ansiedade/metabolismo , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Depressão/metabolismo , Dextroanfetamina/farmacologia , Fatores de Crescimento Neural/metabolismo , Animais , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Depressão/induzido quimicamente , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Fator de Crescimento Neural/efeitos dos fármacos , Fator de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/efeitos dos fármacos , Neurotrofina 3/efeitos dos fármacos , Neurotrofina 3/metabolismo , Ratos , Ratos Wistar
12.
Psych J ; 8(1): 90-109, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30793518

RESUMO

Drug studies are powerful models to investigate the neuropharmacological mechanisms underlying temporal processing in humans. This study administered dexamphetamine to 24 healthy volunteers to investigate time perception at different time scales, along with contributions from working memory. Healthy volunteers were administered 0.45 mg/kg dexamphetamine or placebo in a double-blind, crossover, placebo-controlled design. Time perception was assessed using three experimental tasks: a time-discrimination task, which asked participants to determine whether a comparison interval (1200 ± 0, 50, 100, 150, 200 ms) was shorter or longer than a standard interval (1200 ms); a retrospective time estimation task, which required participants to verbally estimate time intervals (10, 30, 60, 90 and 120 s) retrospectively; and a prospective time-production task, where participants were required to prospectively monitor the passing of time (10, 30, 60, 90 and 120 s). Working memory was assessed with the backwards digit span. On the discrimination task, there was a change in the proportion of long-to-short responses and reaction times in the dexamphetamine condition (but no association with working memory), consistent with an increase in the speed of an internal pacemaker, and an overestimation of durations in the timing of shorter intervals. There was an interaction between dexamphetamine, working memory, and performance on the estimation and production tasks, whereby increasing digit span scores were associated with decreasing interval estimates and increased produced intervals in the placebo condition, but were associated with increased interval estimates and decreased produced intervals after dexamphetamine administration. These findings indicate that the dexamphetamine-induced increase in the speed of the internal pacemaker was modulated by the basal working memory capacity of each participant. These findings in healthy humans have important implications for the role of dopamine, and its contributions to timing deficits, in models of psychiatric disorders.


Assuntos
Dextroanfetamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Memória de Curto Prazo/fisiologia , Percepção do Tempo/efeitos dos fármacos , Adulto , Estudos Cross-Over , Dextroanfetamina/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Adulto Jovem
13.
J Pharmacol Exp Ther ; 369(1): 107-120, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30733244

RESUMO

Acute central nervous system exposure to dextroamphetamine (d-amphetamine) elicits a multitude of effects, including dual action on the dopamine transporter (DAT) to increase extracellular dopamine, and induction of a negative feedback response to limit the dopamine increase. A semimechanistic pharmacokinetic and pharmacodynamic (PK/PD) model with consideration of these multiple effects as a basis was developed. Integrated pharmacokinetics of d-amphetamine in plasma, brain extracellular fluid (ECF) via microdialysis, and cerebrospinal fluid were characterized using a population approach. This PK model was then linked to an indirect-response pharmacodynamic model using as a basis the measurement of extracellular striatal dopamine, also via microdialysis. In both rats and nonhuman primates (NHPs), d-amphetamine stimulation of dopamine outflow (reverse transport) through DAT was primarily responsible for the dose-linear increase in dopamine. As well, in both species a moderator function was needed to account for loss of the dopamine response in the presence of a relatively sustained d-amphetamine ECF exposure, presumptive of an acute tolerance response. PK/PD model structure was consistent between species; however, there was a 10-fold faster return to baseline dopamine in NHPs in response to an acute d-amphetamine challenge. These results suggest preservation from rodents to NHPs regarding the mechanism by which amphetamine increases extracellular dopamine, but a faster system response in NHPs to tolerate this increase. This microdialysis-based PK/PD model suggests greater value in directing preclinical discovery of novel approaches that modify reverse transport stimulation to treat amphetamine abuse. General value regarding insertion of an NHP model in paradigm rodent-to-human translational research is also suggested.


Assuntos
Dextroanfetamina/farmacologia , Dextroanfetamina/farmacocinética , Dopamina/metabolismo , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Animais , Dextroanfetamina/efeitos adversos , Cinética , Macaca fascicularis , Masculino , Ratos , Segurança
14.
Psychopharmacology (Berl) ; 236(3): 963-971, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30554256

RESUMO

RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) is a popular synthetic cathinone reported to have a high abuse potential. Recent preclinical research indicates the psychopharmacology of MDPV is comparable to cocaine. Despite a recent influx of research on the psychopharmacology of MDPV, few studies have employed preclinical drug discrimination methods to discern the neurochemical mechanisms involved in its interoceptive stimulus effects. OBJECTIVE: The aim of this study was to evaluate a variety of monoaminergic agents for substitution, potentiation, or antagonism in rats trained to discriminate MDPV. METHODS: Male Sprague-Dawley rats were trained to discriminate 0.5 (experiment 1) or 1 mg/kg MDPV (experiment 2) from saline under an FR 20 schedule of food reinforcement. In experiment 1, MDMA, MDA, and their respective optical isomers (0.75-3 mg/kg), cocaine (2.5-20 mg/kg), GBR 12909 (5-40 mg/kg), and desipramine (3.2-10 mg/kg) were assessed for substitution. GBR 12909 (40 mg/kg) and desipramine (3.2 mg/kg) were subsequently assessed for potentiation of the MDPV cue. In experiment 2, stimulus antagonism tests were conducted with dopamine antagonists (Sch 23390, haloperidol) and serotonin antagonists (pirenperone, MDL100907, WAY 100635). RESULTS: The MDMA and MDA enantiomers produced divergent results, with virtually no substitution by (-)-MDMA or (-)-MDA, partial substitution with (+)-MDA, and full substitution with (+)-MDMA, as well as full substitution by the racemates, (±)-MDMA and (±)-MDA. Consistent with previous findings, cocaine fully substituted for MDPV. Although no dose of GBR 12909 or desipramine substituted for MDPV, these reuptake inhibitors enhanced the discriminative stimulus effects of lower MDPV doses. Both D1 (Sch 23390) and D2 (haloperidol) DA antagonists attenuated 1 mg/kg MDPV discrimination, whereas none of the 5-HT antagonists assessed altered MDPV discrimination. CONCLUSIONS: These findings indicate MDPV's interoceptive stimulus effects are mediated predominantly by dopaminergic actions, although serotonergic and/or noradrenergic modulation of these effects cannot be ruled out. Further investigations into the neurochemical actions involved in the discriminative stimulus effects of MDPV may serve to inform medication discovery and development for the treatment of MDPV abuse.


Assuntos
Benzodioxóis/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Pirrolidinas/farmacologia , Reforço Psicológico , Alcaloides/farmacologia , Animais , Cocaína/farmacologia , Dextroanfetamina/farmacologia , Aprendizagem por Discriminação/fisiologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley
15.
Psychopharmacology (Berl) ; 236(2): 581-590, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30350220

RESUMO

RATIONALE: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed. OBJECTIVES: Here, we sought to investigate sex differences in dopamine release after oral D-amphetamine administration. METHODS: We used [18F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBPND, an index of dopamine release) between placebo and D-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males. RESULTS: Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in D-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control. CONCLUSIONS: While our finding in young adults from one dataset of greater %ΔBPND in males is partially consistent with a previously published study on sex differences in D-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Estriado Ventral/efeitos dos fármacos , Adulto , Idoso , Benzamidas , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Caracteres Sexuais , Fatores Sexuais , Estriado Ventral/diagnóstico por imagem , Estriado Ventral/metabolismo , Adulto Jovem
16.
Pharmacol Biochem Behav ; 176: 23-32, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30444984

RESUMO

Systemic pharmacological manipulation of dopamine (DA) signaling has been central to many investigations of 50 kHz ultrasonic vocalizations (USVs) in the rat. In particular, the indirect DA releaser d-amphetamine (AMPH) has been used extensively in many such investigations. The possible unique character of the native transmitter relative to DA-stimulating drugs such as AMPH in inducing and modulating emission of 50 kHz USVs has not been investigated. Adult male Long Evans rats were tested with intracerebral application of DA into the nucleus accumbens shell at several doses (3.75 µg-120 µg) to determine its capacity to induce 50 kHz USV emission. Additionally, the call profile characteristics of intracerebral DA injections were compared with those of intracerebral application of AMPH. Results indicated that local increases in DA signaling within the nucleus accumbens shell are sufficient to increase 50 kHz call rate, reduce latency to call, and increase the degree of frequency modulation of emitted USVs. However, our results found that microinjections of DA were not as efficacious in either inducing 50 kHz USVs or increasing frequency modulation without antagonism of the dopamine reuptake transporter when compared with AMPH. In summary, these results support the notion that the native transmitter DA is driving the increase in frequency modulation seen after administration of DA stimulating drugs. These results also suggest that drugs affecting dopamine may be altering the 50 kHz call profile in a distinct manner from the native transmitter and thus caution should be used in interpreting their effects.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Dopaminérgicos/farmacologia , Dopamina/farmacologia , Microinjeções/métodos , Núcleo Accumbens/efeitos dos fármacos , Ondas Ultrassônicas , Análise de Variância , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Dextroanfetamina/administração & dosagem , Dopamina/administração & dosagem , Dopaminérgicos/administração & dosagem , Inibidores da Captação de Dopamina/farmacologia , Masculino , Piperazinas/farmacologia , Ratos , Ratos Long-Evans , Vocalização Animal/efeitos dos fármacos
17.
J Steroid Biochem Mol Biol ; 186: 212-225, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30381248

RESUMO

The novel d-amphetamine prodrug lisdexamfetamine is applied to treat attention-deficit/hyperactivity disorder (ADHD). d-Amphetamine releases dopamine and norepinephrine and stimulates the hypothalamic-pituitary-adrenal (HPA) axis, which may contribute to its reinforcing effects and risk of abuse. However, no data is currently available on the effects of lisdexamfetamine on circulating steroids. This randomized, double-blind, placebo-controlled, cross-over study evaluated the effects of equimolar doses of d-amphetamine (40 mg) and lisdexamfetamine (100 mg) and placebo on circulating steroids in 24 healthy subjects. Plasma steroid and d-amphetamine levels were determined up to 24 h. Delayed increase and peak levels of plasma d-amphetamine concentrations were observed following lisdexamfetamine treatment compared with d-amphetamine administration, however the maximal concentrations and total exposure (area under the curve [AUC]) were similar. Lisdexamfetamine and d-amphetamine significantly enhanced plasma levels of adrenocorticotropic hormone, glucocorticoids (cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, and 11-deoxycortisol), androgens (dehydroepiandrosterone, dehydroepiandrosterone sulfate, and Δ4-androstene-3,17-dione [androstenedione]), and progesterone (only in men) compared with placebo. Steroid concentration-time curves were shifted to later time points due to a non-significantly later onset following lisdexamfetamine administration than after d-amphetamine, however maximal plasma steroid concentrations and AUCs did not differ between the active treatments. None of the active treatments altered plasma levels of the mineralocorticoids aldosterone and 11-deoxycorticosterone or the androgen testosterone compared with placebo. The effects of the amphetamines on glucocorticoid production were similar to those that were previously reported for methylphenidate (60 mg) but weaker than those for the serotonin releaser 3,4-methylenedioxymethamphetamine (MDMA; 125 mg) or direct serotonin receptor agonist lysergic acid diethylamide (LSD; 0.2 mg). Lisdexamfetamine produced comparable HPA axis activation and had similar pharmacokinetics than d-amphetamine, except for a delayed time of onset. Thus, serotonin (MDMA, LSD) may more effectively stimulate the HPA axis than dopamine and norepinephrine (D-amphetamine).


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Esteroides/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Efeito Placebo , Adulto Jovem
19.
Behav Brain Res ; 361: 131-138, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30550950

RESUMO

Although scientific research using mammalian models has made great strides in uncovering the enigmatic neural and molecular mechanisms orchestrating the state of drug addiction, a complete understanding has thus far eluded researchers. The complexity of the task has led to the use of invertebrate model systems to complement the research of drug-induced reward in mammalian systems. Invertebrates, such as crayfish, offer excellent model systems to help reveal the underlying mechanisms of drug addiction as they retain the ancestral neural reward circuit that is evolutionarily conserved across taxa, and they possess relatively few, large neurons, laid out in an accessible, modularly organized nervous system. Crayfish offer the benefits of delineated developmental life stages, a large body size suitable for a variety of experimental methods, and stereotyped behaviors. Unique among crayfish is the parthenogenetic marbled crayfish (Procambarus fallax forma virginalis), a species of asexually reproducing, genetically identical clones. With the benefits of reduced individual variation, high fecundity, and easy lab husbandry, the marbled crayfish would make a particularly powerful addition to the animal model repertoire. Here we characterize the locomotor response of juvenile P. f. f. virginalis exposed to the psychostimulant, d-amphetamine sulfate. Custom video-tracking software was used to record the movement patterns of juveniles exposed to water infused with varying concentrations of d-amphetamine sulfate. ANOVA demonstrated that crayfish locomotion was significantly impacted by drug concentration. These psychostimulant effects provide the foundation of P. f. f. virginalis as a model for parsing the neural and molecular mechanisms of drug addiction.


Assuntos
Astacoidea/efeitos dos fármacos , Dextroanfetamina/farmacologia , Locomoção/efeitos dos fármacos , Animais , Astacoidea/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Sistema Nervoso/efeitos dos fármacos , Partenogênese , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
20.
Addict Biol ; 24(2): 303-314, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29314376

RESUMO

Behavioral economic purchase tasks quantify drug demand (i.e. reinforcing value of a drug) and have been used extensively to assess the value of various drugs among current users. However, purchase tasks have been rarely used with unfamiliar drugs to address a compound's abuse liability, and the current study sought to validate the paradigm in this capacity. Using a double-blind placebo-controlled within-subjects drug challenge design, the study evaluated differential drug demand on an experimental drug purchase task for a 20 mg dose of oral D-amphetamine (versus placebo), a prototypic psychostimulant, in 98 stimulant-naïve participants. Compared with placebo, amphetamine significantly increased intensity, breakpoint and Omax , and significantly decreased elasticity. Mechanistic analyses revealed that Omax and breakpoint mediated the relationship between subjective drug effects and 'willingness to take again', a putative indicator of liability via motivation for future drug-seeking behavior. These findings validate the purchase task paradigm for quantifying the reinforcing value and, in turn, abuse liability of unfamiliar compounds, providing a foundation for a variety of future applications.


Assuntos
Estimulantes do Sistema Nervoso Central/economia , Dextroanfetamina/economia , Economia Comportamental , Transtornos Relacionados ao Uso de Substâncias/economia , Administração Oral , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Motivação , Adulto Jovem
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