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1.
Pharmacol Biochem Behav ; 185: 172758, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31430484

RESUMO

BACKGROUND: Acetylcholinergic (ACh) neurons interface with the mesolimbic dopamine pathway implicated in addiction, and acetylcholinesterase inhibitors (AChEis) have been shown to reduce the immediate effects of cocaine and amount used. Our study is the first to examine if the safe and low-interaction AChEi rivastigmine (riv) alters the subjective effects produced by cocaine administration. METHODS: Cocaine-dependent subjects were randomized to daily placebo, riv 3 mg, or riv 6 mg, administered inpatient for 10 days. On day 1 (pre-dose) and day 9, subjects received both IV cocaine 40 mg or placebo in a randomized order with subsequent serial assessments of visual analog scale (VAS) subjective effects and pharmacokinetic measurements. On day 10 all participants received one baseline dose of cocaine 20 mg with assessment of subjective effects, and were then able to purchase additional doses at 15 min intervals with study earnings. RESULTS: 40 subjects were randomized to placebo (n = 16), riv 3 mg (n = 13), or riv 6 mg (n = 12). All subjects completed the study and there were no demographic differences between treatment groups. Pre- and post- treatment, there were no significant pharmacokinetic differences (blood levels of cocaine, BE, EME) following cocaine administration. In a two-way ANOVA, IV cocaine significantly increased positive VAS category ratings compared to placebo, but rivastigmine treatment at either dose had no significant effect on any VAS category ratings. Similarly, there was no significant rivastigmine effect on any category in the day 10 cocaine administration, and no effect on number of subsequent doses participants purchased. CONCLUSION: Rivastigmine 3 or 6 mg had no significant effect on the subjective effects of cocaine after 9 days of treatment. This is an important finding as other drugs in the AChEi class (donepezil, Huperzine A) have produced significant results, but differ in their receptor specificity and PK parameters.


Assuntos
Comportamento Aditivo/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cocaína/administração & dosagem , Cocaína/farmacologia , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/farmacologia , Rivastigmina/farmacologia , Adulto , Análise de Variância , Pressão Sanguínea/efeitos dos fármacos , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Rivastigmina/administração & dosagem , Rivastigmina/efeitos adversos , Autoadministração , Escala Visual Analógica
2.
Psychopharmacology (Berl) ; 236(8): 2451-2471, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31289884

RESUMO

BACKGROUND: In this paper, we reviewed translational studies concerned with environmental influences on the rewarding effects of heroin versus cocaine in rats and humans with substance use disorder. These studies show that both experienced utility ('liking') and decision utility ('wanting') of heroin and cocaine shift in opposite directions as a function of the setting in which these drugs were used. Briefly, rats and humans prefer using heroin at home but cocaine outside the home. These findings appear to challenge prevailing theories of drug reward, which focus on the notion of shared substrate of action for drug of abuse, and in particular on their shared ability to facilitate dopaminergic transmission. AIMS: Thus, in the second part of the paper, we verified whether our findings could be accounted for by available computational models of reward. To account for our findings, a model must include a component that could mediate the substance-specific influence of setting on drug reward RESULTS: It appears of the extant models that none is fully compatible with the results of our studies. CONCLUSIONS: We hope that this paper will serve as stimulus to design computational models more attuned to the complex mechanisms responsible for the rewarding effects of drugs in real-world contexts.


Assuntos
Comportamento Aditivo/psicologia , Cocaína/administração & dosagem , Simulação por Computador , Tomada de Decisões/fisiologia , Heroína/administração & dosagem , Modelos Psicológicos , Analgésicos Opioides/administração & dosagem , Animais , Comportamento Aditivo/diagnóstico , Tomada de Decisões/efeitos dos fármacos , Inibidores da Captação de Dopamina/administração & dosagem , Emoções/efeitos dos fármacos , Emoções/fisiologia , Feminino , Humanos , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Neurociências , Ratos , Ratos Sprague-Dawley , Recompensa
3.
Psychopharmacology (Berl) ; 236(11): 3271-3279, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31183518

RESUMO

RATIONALE: Compounds lacking efficacy at the α1 subunit-containing GABAA (α1GABAA) receptor appear to have reduced abuse potential compared with those having measurable efficacy at this receptor, though their self-administration in nonhuman primates is dependent upon past drug experience. OBJECTIVES: We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at αGABAA receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of ⍺1GABAA receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure. METHODS: One female and three male rhesus monkeys chose between cocaine alone (0.1 mg/kg/injection) vs. the same dose of cocaine combined with midazolam (0.003-0.1 mg/kg/injection), zolpidem (0.003-0.3 mg/kg/injection), or L-838-417 (0.01-0.1 mg/kg/injection). In addition, we evaluated choice between saline and L-838,417 at select doses to determine whether L-838,417 would function as a reinforcer on its own. RESULTS: Consistent with our hypotheses, midazolam- and zolpidem-cocaine mixtures were chosen over cocaine alone at sufficiently high doses. However, L-838,417-cocaine mixtures also were chosen over cocaine alone in three of four subjects with at least one dose. When available alone vs. saline, L-838,417 did not function as a reinforcer in any subject. CONCLUSION: Compounds that lack efficacy at α1GABAA receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context-dependent.


Assuntos
Benzodiazepinas/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Receptores de GABA-A/fisiologia , Animais , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Fluorbenzenos/administração & dosagem , Macaca mulatta , Masculino , Autoadministração , Triazóis/administração & dosagem
4.
Psychopharmacology (Berl) ; 236(7): 2155-2171, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161451

RESUMO

RATIONALE: Exercise shows promise as a treatment option for addiction; but in order to prevent relapse, it may need to be introduced early in the course of treatment. OBJECTIVE: We propose that exercise, by upregulating dorsal medial prefrontal cortex (dmPFC)-nucleus accumbens (NAc) transmission, offsets deficits in pathways targeting glutamate, BDNF, and dopamine during early abstinence, and in doing so, normalizes neuroadaptations that underlie relapse. METHODS: We compared the effects of exercise (wheel running, 2-h/day) during early (days 1-7), late (days 8-14), and throughout abstinence (days 1-14) to sedentary conditions on cocaine-seeking and gene expression in the dmPFC and NAc core of male rats tested following 24-h/day extended-access cocaine (up to 96 infusions/day) or saline self-administration and protracted abstinence (15 days). Based on these data, we then used site-specific manipulation to determine whether dmPFC metabotropic glutamate receptor5 (mGlu5) underlies the efficacy of exercise. RESULTS: Exercise initiated during early, but not late abstinence, reduced cocaine-seeking; this effect was strongly associated with dmPFC Grm5 expression (gene encoding mGlu5), and modestly associated with dmPFC Grin1 and Bdnf-IV expression. Activation of mGlu5 in the dmPFC during early abstinence mimicked the efficacy of early-initiated exercise; however, inhibition of these receptors prior to the exercise sessions did not block its efficacy indicating that there may be redundancy in the mechanisms through which exercise reduces cocaine-seeking. CONCLUSION: These findings indicate that addiction treatments, including exercise, should be tailored for early versus late phases of abstinence since their effectiveness will vary over abstinence due to the dynamic nature of the underlying neuroadaptations.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/terapia , Cocaína/administração & dosagem , Condicionamento Físico Animal/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/prevenção & controle , Comportamento Aditivo/psicologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/psicologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recidiva , Corrida/fisiologia , Corrida/psicologia , Autoadministração
5.
Psychopharmacology (Berl) ; 236(9): 2785-2796, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115612

RESUMO

RATIONALE: Early life stress (ELS), including childhood maltreatment, is a predictive factor for the emergence of cocaine use disorders (CUDs) in adolescence. OBJECTIVE: Accordingly, we examined whether post-pubertal male and female rhesus macaques that experienced infant maltreatment (maltreated, n = 7) showed greater vulnerability to cocaine self-administration in comparison with controls (controls, n = 7). METHODS: Infant emotional reactivity was measured to assess differences in behavioral distress between maltreated and control animals as a result of early life caregiving. Animals were then surgically implanted with indwelling intravenous catheters and trained to self-administer cocaine (0.001-0.3 mg/kg/infusion) under fixed-ratio schedules of reinforcement. Days to acquisition, and sensitivity to (measured by the EDMax dose of cocaine) and magnitude (measured by response rates) of the reinforcing effects of cocaine were examined in both groups. RESULTS: Maltreated animals demonstrated significantly higher rates of distress (e.g., screams) in comparison with control animals. When given access to cocaine, control males required significantly more days to progress through terminal performance criteria compared with females and acquired cocaine self-administration slower than the other three experimental groups. The dose that resulted in peak response rates did not differ between groups or sex. Under 5-week, limited-access conditions, males from both groups had significantly higher rates of responding compared with females. CONCLUSIONS: In control monkeys, these data support sex differences in cocaine self-administration, with females being more sensitive than males. These findings also suggest that ELS may confer enhanced sensitivity to the reinforcing effects of cocaine, especially in males.


Assuntos
Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Esquema de Reforço , Caracteres Sexuais , Maturidade Sexual/efeitos dos fármacos , Estresse Psicológico/psicologia , Animais , Transtornos Relacionados ao Uso de Cocaína/psicologia , Relação Dose-Resposta a Droga , Feminino , Macaca mulatta , Masculino , Distribuição Aleatória , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Autoadministração , Maturidade Sexual/fisiologia
6.
Drugs ; 79(7): 785-790, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31062265

RESUMO

Solriamfetol (Sunosi™) is an orally active, selective dopamine and norepinephrine reuptake inhibitor that was recently approved in the USA as a treatment for excessive daytime sleepiness (hypersomnia) associated with narcolepsy and obstructive sleep apnoea (OSA). Norepinephrine and dopamine influence various physiologic functions, including sleep-wake regulation, and excessive sleepiness has been linked with dysregulation of dopaminergic and norepinephrine systems. This article summarizes the milestones in the development of solriamfetol leading to this first approval as a treatment for excessive daytime sleepiness associated with narcolepsy and OSA.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Inibidores da Captação de Dopamina/farmacocinética , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/efeitos adversos , Inibidores da Captação de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Aprovação de Drogas , Humanos , Narcolepsia/tratamento farmacológico , Inibidores da Captação de Neurotransmissores/administração & dosagem , Inibidores da Captação de Neurotransmissores/efeitos adversos , Inibidores da Captação de Neurotransmissores/farmacocinética , Inibidores da Captação de Neurotransmissores/uso terapêutico , Norepinefrina/metabolismo , Transtornos do Sono-Vigília/tratamento farmacológico , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
7.
Psychopharmacology (Berl) ; 236(9): 2797-2810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31049607

RESUMO

RATIONALE: Previous studies have demonstrated that repeated social defeat (RSD) stress only induces cognitive deficits when experienced during adulthood. However, RSD increases cocaine-rewarding effects in adult and adolescent mice, inducing different expressions of proBDNF in the ventral tegmental area. OBJECTIVE: The aim of the present study was to evaluate the effect of cocaine administration in socially defeated adult or adolescent mice on learning, memory, and anxiety. Additionally, the role of BDNF was also studied. METHODS: Adolescent and young adult mice were exposed to four episodes of social defeat or exploration (control), being treated with a daily injection of four doses of saline or 1 mg/kg of cocaine 3 weeks after the last social defeat. Other groups were treated with the TrkB receptor antagonist ANA-12 during this 21-day period. After this treatment, their cognitive and anxiogenic profiles were evaluated, along with the expression of BDNF, pCREB, and pERK1/2 in the dentate gyrus (DG) and basolateral amygdala (BLA). RESULTS: Cocaine induced an increased expression of pCREB and BDNF in the DG and BLA only in defeated animals. Although RSD did not affect memory, the administration of cocaine induced memory impairments only in defeated animals. Defeated adult mice needed more time to complete the mazes, and this effect was counteracted by cocaine administration. RSD induced anxiogenic effects only when experienced during adulthood and cocaine induced a general anxiolytic effect. Blockade of Trkb decreased memory retention without affecting spatial learning and modified anxiety on non-stressed mice depending on their age. CONCLUSION: Our results demonstrate that the long-lasting effects of social defeat on anxiety and cognition are modulated by cocaine administration. Our results highlight that the BDNF signaling pathway could be a target to counteract the effects of cocaine on socially stressed subjects.


Assuntos
Azepinas/administração & dosagem , Benzamidas/administração & dosagem , Cocaína/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Comportamento Social , Estresse Psicológico/psicologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos , Receptor trkB/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico
8.
Psychopharmacology (Berl) ; 236(9): 2593-2611, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30955107

RESUMO

RATIONALE: Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice. OBJECTIVES: Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD. METHODS: Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another's emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg). RESULTS: Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits. CONCLUSIONS: Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.


Assuntos
Agressão/efeitos dos fármacos , Agressão/psicologia , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/administração & dosagem , Metilfenidato/administração & dosagem , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Transtorno da Conduta/tratamento farmacológico , Transtorno da Conduta/psicologia , Emoções/efeitos dos fármacos , Emoções/fisiologia , Empatia/efeitos dos fármacos , Empatia/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
9.
Psychopharmacology (Berl) ; 236(7): 2143-2153, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30877326

RESUMO

RATIONALE: Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. OBJECTIVES: The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. METHODS: First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. RESULTS: Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. CONCLUSIONS: The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.


Assuntos
Acetilcisteína/administração & dosagem , Cocaína/administração & dosagem , Cognição/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Animais , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cognição/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Aprendizagem por Discriminação/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Depuradores de Radicais Livres/administração & dosagem , Masculino , Estimulação Luminosa/métodos , Primatas , Saimiri , Autoadministração
10.
Psychopharmacology (Berl) ; 236(9): 2569-2577, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30900008

RESUMO

RATIONALE: No pharmacotherapies are approved for cocaine use disorder. Phendimetrazine, a prodrug of the monoamine-releaser phenmetrazine, attenuates the reinforcing effects of cocaine in preclinical models, has minimal abuse potential, and is safe when combined with cocaine. OBJECTIVES: This study determined the influence of phendimetrazine maintenance on the reinforcing effects of cocaine (i.e., choice to self-administer cocaine), along with the subjective, performance, and physiological effects of cocaine. We hypothesized that phendimetrazine would attenuate the reinforcing effects of cocaine. METHODS: Twenty-nine subjects with cocaine use disorder completed this within-subject, inpatient study. The subjects were maintained on placebo and 210 mg phendimetrazine in a counterbalanced order. After at least 7 days of maintenance on the target dose, the subjects completed experimental sessions in which the effects of single doses of 0, 20, 40, and 80 mg of intranasal cocaine were determined. RESULTS: Cocaine functioned as a reinforcer, producing significant dose-related increases in self-administration. Cocaine increased prototypic effects (e.g., ratings of stimulated and blood pressure). Phendimetrazine attenuated ratings on a select set of subjective outcomes (e.g., ratings of talkative/friendly), but failed to reduce the reinforcing effects of cocaine or a majority of positive subjective cocaine effects. Phendimetrazine increased heart rate, indicating a physiologically active dose was tested, but heart rate increases were not clinically significant. CONCLUSIONS: These results indicate that although phendimetrazine can safely be combined with cocaine, it does not attenuate the abuse-related effects of cocaine. It is unlikely, then, that phendimetrazine will be an effective standalone treatment for cocaine use disorder.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Morfolinas/administração & dosagem , Desempenho Psicomotor/efeitos dos fármacos , Administração Intranasal , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Autoadministração
11.
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
12.
Basic Clin Pharmacol Toxicol ; 125(1): 54-61, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30801959

RESUMO

The present clinical trial investigated the impact of selected SNPs in CES1 on the metabolic activity of the enzyme. For this purpose, we used methylphenidate (MPH) as a pharmacological probe and the d-RA/d-MPH (metabolite/parent drug) ratios as a measure of enzymatic activity. This metabolic ratio (MR) was validated against the AUC ratios (AUCd -RA /AUCd -MPH ). CES1 SNPs from 120 volunteers were identified, and 12 SNPs fulfilling predefined inclusion criteria were analysed separately, comparing the effect of each genotype on the metabolic ratios. The SNP criteria were as follows: presence of Hardy-Weinberg equilibrium, a minor allele frequency ≥ 0.01 and a clearly interpretable sequencing result in at least 30% of the individuals. Each participant ingested 10 mg of racemic methylphenidate, and blood samples were drawn prior to and 3 hours after drug administration. The SNP analysis confirmed the considerable impact of rs71647871 (G143E) in exon 4 on drug metabolism. In addition, three volunteers with markedly lower median MR, indicating decreased CES1 activity, harboured the same combination of three SNPs in intron 5. The median MR for these SNPs was 8.2 for the minor allele compared to 16.4 for the major alleles (P = 0.04). Hence, one of these or the combination of these SNPs could be of clinical significance considering that the median MR of the G143E group was 5.4. The precise genetic relationship of this finding is currently unknown, as is the clinical significance.


Assuntos
Hidrolases de Éster Carboxílico/genética , Inibidores da Captação de Dopamina/farmacocinética , Metilfenidato/análogos & derivados , Administração Oral , Adulto , Área Sob a Curva , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Hidrolases de Éster Carboxílico/metabolismo , Estudos Cross-Over , Inibidores da Captação de Dopamina/administração & dosagem , Feminino , Frequência do Gene , Voluntários Saudáveis , Humanos , Masculino , Metilfenidato/administração & dosagem , Metilfenidato/farmacocinética , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Psychopharmacology (Berl) ; 236(7): 2027-2037, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30798402

RESUMO

RATIONALE: Stressful life experiences can persistently increase the motivation for, and consumption of, intensely rewarding stimuli, like cocaine, over time. In rodents, intermittent versus continuous exposure to social stress engenders opposing changes to reward-related behavior, as measured by consumption of sucrose and cocaine. OBJECTIVE: The present study examines if the effects of intermittent versus continuous social stress on cocaine self-administration in mice parallel those seen in rats. METHODS: Both forms of social stress involve a brief daily physical confrontation with an aggressive resident for 10 consecutive days. Continuous social stress involves constant visual and olfactory exposure to an aggressive resident via habitation in a protected portion of the resident's home cage, while exposure to an aggressive resident during intermittent social stress is limited to a single, physical encounter per day. Implementing a femoral vein catheterization method for the first time in mice, we determined divergent changes to intravenous cocaine self-administration. RESULTS: Modestly increased cocaine self-administration after intermittent social stress was confirmed. In a subset of animals, continuous social stress in mice substantially increased cocaine self-administration and sucrose intake. By stark contrast, another subpopulation had substantial attenuation of cocaine self-administration and sucrose intake after continuous social stress. CONCLUSIONS: Bimodal divergence in responding for rewarding stimuli including cocaine after social stress experience likely reflects two opposing forms of coping to continuous social stress that promote either a sensitization or attenuation of reward-seeking.


Assuntos
Agressão/psicologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Relações Interpessoais , Estresse Psicológico/psicologia , Agressão/efeitos dos fármacos , Agressão/fisiologia , Animais , Transtornos Relacionados ao Uso de Cocaína/psicologia , Feminino , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Autoadministração , Sacarose/administração & dosagem
14.
Neuropharmacology ; 150: 217-228, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30768946

RESUMO

Kappa opioid receptor (KOPr) agonists have preclinical anti-cocaine and antinociceptive effects. However, adverse effects including dysphoria, aversion, sedation, anxiety and depression limit their clinical development. MP1104, an analogue of 3-iodobenzoyl naltrexamine, is a potent dual agonist at KOPr and delta opioid receptor (DOPr), with full agonist efficacy at both these receptors. In this study, we evaluate the ability of MP1104 to modulate cocaine-induced behaviors and side-effects preclinically. In male Sprague-Dawley rats trained to self-administer cocaine, MP1104 (0.3 and 1 mg/kg) reduced cocaine-primed reinstatement of drug-seeking behavior and caused significant downward shift of the dose-response curve in cocaine self-administration tests (0.3 and 0.6 mg/kg). The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine (DA) uptake by the dopamine transporter (DAT) in the dorsal striatum (dStr) and nucleus accumbens (NAc). MP1104 (0.3 and 0.6 mg/kg) showed no significant anxiogenic effects in the elevated plus maze, pro-depressive effects in the forced swim test, or conditioned place aversion. Furthermore, pre-treatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. The overall results from this study show that MP1104, modulates DA uptake in the dStr and NAc, and exerts potent anti-cocaine properties in self-administration tests with reduced side-effects compared to pure KOPr agonists. This data supports the therapeutic development of dual KOPr/DOPr agonists to reduce the side-effects of selective KOPr agonists. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.


Assuntos
Analgésicos Opioides/farmacologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Morfinanos/farmacologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Autoadministração
15.
Neuron ; 101(2): 294-306.e3, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30653935

RESUMO

Addiction is a disorder of behavioral control and learning. While this may reflect pre-existing propensities, drug use also clearly contributes by causing changes in outcome processing in prefrontal and striatal regions. This altered processing is associated with behavioral deficits, including changes in learning. These areas provide critical input to midbrain dopamine neurons regarding expected outcomes, suggesting that effects on learning may result from changes in dopaminergic error signaling. Here, we show that dopamine neurons recorded in rats that had self-administered cocaine failed to suppress firing on omission of an expected reward and exhibited lower amplitude and imprecisely timed increases in firing to an unexpected reward. Learning also appeared to have less of an effect on reward-evoked and cue-evoked firing in the cocaine-experienced rats. Overall, the changes are consistent with reduced fidelity of input regarding the expected outcomes, such as their size, timing, and overall value, because of cocaine use.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Autoadministração , Análise de Variância , Animais , Comportamento de Escolha , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Ratos , Recompensa , Área Tegmentar Ventral/citologia
16.
Behav Brain Res ; 357-358: 1-8, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-29660439

RESUMO

Recent work has implicated the Lateral Habenula (LHb) in the production of anxiogenic and aversive states. It is innervated by all the major monoamine neurotransmitter systems and has projections that have been shown to modulate the activity of both dopaminergic and serotonergic brain regions. Cocaine is a stimulant drug of abuse that potentiates neurotransmission in these monoamine systems and recent research suggests that the drug's behavioral effects may be related in part to its actions within the LHb. The present research was therefore devised to test the hypothesis that alterations in serotonin (5-HT) function within the LHb can affect the behavioral response to cocaine. Male rats were fitted with intracranial guide cannula and trained to traverse a straight alleyway once a day for a 1 mg/kg i.v. injection of cocaine. Intra-LHb pretreatment with the 5-HT1B agonist CP 94,253 (0, 0.1, or 0.25 µg/side) attenuated the development of approach/avoidance "retreat" behaviors known to be a consequence of cocaine's dual rewarding (approach) and anxiogenic (avoidance) properties. This effect was reversed by co-administration of a selective 5-HT1B antagonist, NAS-181 (0.1 µg/side), demonstrating drug specificity at the 5-HT1B receptor. These data suggest that 5-HT1B signaling within the LHb contributes to the anxiogenic effects of cocaine.


Assuntos
Ansiedade/tratamento farmacológico , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Habenula/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Análise de Variância , Animais , Ansiedade/induzido quimicamente , Benzopiranos/farmacologia , Cocaína/efeitos adversos , Condicionamento Operante/efeitos dos fármacos , Correlação de Dados , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/efeitos adversos , Relação Dose-Resposta a Droga , Habenula/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Morfolinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Autoadministração , Serotoninérgicos/farmacologia
17.
Behav Brain Res ; 359: 799-806, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30077578

RESUMO

Exposure to prolonged, uncontrollable stress reduces reward-seeking behavior, resulting in anhedonia in neuropsychiatric disorders, such as posttraumatic stress disorder. However, it is unclear to what degree stressed subjects lose interest in rewards themselves or in reward-related cues that instigate reward-seeking behavior. In the present study, we investigated the effects of single prolonged stress (SPS) on cue-directed behavior in two different procedures: Pavlovian conditioned approach (PCA) and cue-induced reinstatement of cocaine-seeking. In Experiment 1, rats were exposed to SPS and tested for the acquisition of sign-tracking (cue-directed) and goal-tracking (reward-directed) behaviors during a PCA procedure. In Experiment 2, rats were exposed to SPS and tested for the expression of sign- and goal-tracking as well as cue-induced reinstatement of cocaine-seeking. Because dopaminergic activity in the nucleus accumbens is known to play a central role in many cue-directed behaviors, including both sign-tracking and cue-induced reinstatement, Experiment 3 used in vivo microdialysis to measure the effect of SPS on baseline and evoked dopamine levels in the nucleus accumbens. SPS decreased sign-tracking and increased goal-tracking during the acquisition of PCA behavior without affecting reward consumption. In addition, SPS decreased cue-induced reinstatement without affecting cocaine self-administration. Finally, SPS decreased evoked but not baseline levels of dopamine in the nucleus accumbens. These results suggest that SPS decreases the motivational, but not consummatory, aspects of reward-seeking behavior, which may result from long-term, SPS-induced reductions in dopamine release in the nucleus accumbens.


Assuntos
Cocaína/administração & dosagem , Condicionamento Clássico/fisiologia , Sinais (Psicologia) , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração , Fatores de Tempo
18.
Behav Brain Res ; 359: 589-596, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296530

RESUMO

Childhood and adolescent adversity are associated with a wide range of psychiatric disorders, including an increased risk for substance abuse. Despite this, the mechanisms underlying the ability of chronic stress during adolescence to alter reward signaling remains largely unexplored. Understanding how adolescent stress increases addiction-like phenotypes could inform the development of targeted interventions both before and after drug use. The current study examined how prolonged isolation stress, beginning during adolescence, affected behavioral and neuronal underpinnings to the response to cocaine in male and female mice. Adolescent-onset social isolation did not alter the ability of mice to learn an operant response for food, nor influence food self-administration or motivation for food on a progressive ratio schedule. However, male and female social isolation mice exhibited an increase in motivation for cocaine and cocaine seeking during a cue-induced reinstatement session. Additionally, we demonstrated that adolescent-onset social isolation increased cocaine-induced neuronal activation, as assessed by c-Fos expression, within the nucleus accumbens core and shell, ventral pallidum, dorsal bed nucleus of the stria terminalis, lateral septum and basolateral amygdala. Taken together, the present studies demonstrate that social isolation stress during adolescence augments the behavioral responses to cocaine during adulthood and alters the responsiveness of reward-related brain circuitry.


Assuntos
Encéfalo/crescimento & desenvolvimento , Transtornos Relacionados ao Uso de Cocaína/psicologia , Comportamento de Procura de Droga , Isolamento Social , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Motivação/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Autoadministração , Maturidade Sexual
19.
Psychopharmacology (Berl) ; 236(2): 787-798, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30443795

RESUMO

RATIONALE: Previous studies have shown that rats trained to self-administer heroin and cocaine exhibit opposite preferences, as a function of setting, when tested in a choice paradigm. Rats tested at home prefer heroin to cocaine, whereas rats tested outside the home prefer cocaine to heroin. Here, we investigated whether drug history would influence subsequent drug preference in distinct settings. Based on a theoretical model of drug-setting interaction, we predicted that regardless of drug history rats would prefer heroin at home and cocaine outside the home. METHODS: Rats with double-lumen catheters were first trained to self-administer either heroin (25 µg/kg) or cocaine (400 µg/kg) for 12 consecutive sessions. Twenty-six rats were housed in the self-administration chambers (thus, they were tested at home), whereas 30 rats lived in distinct home cages and were transferred to self-administration chambers only for the self-administration session (thus, they were tested outside the home). The rats were then allowed to choose repeatedly between heroin and cocaine within the same session for seven sessions. RESULTS: Regardless of the training drug, the rats tested outside the home preferred cocaine to heroin, whereas the rats tested at home preferred heroin to cocaine. There was no correlation between drug preference and drug intake during the training phase. CONCLUSION: Drug preferences were powerfully influenced by the setting but, quite surprisingly, not by drug history. This suggests that, under certain conditions, associative learning processes and drug-induced neuroplastic adaptations play a minor role in shaping individual preferences for one drug or the other.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Cocaína/administração & dosagem , Meio Ambiente , Heroína/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração
20.
J Pharmacol Exp Ther ; 368(1): 41-49, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30373886

RESUMO

Impulsivity and the attentional orienting response to cocaine-associated cues (cue reactivity) promote relapse in cocaine-use disorder (CUD). A time-dependent escalation of cue reactivity (incubation) occurs during extended, forced abstinence from cocaine self-administration in rats. The investigational serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist/inverse agonist M100907 suppresses impulsive action, or the inability to withhold premature responses, and cocaine-seeking behaviors. The present preclinical study was designed to establish the potential for repurposing the Food and Drug Administration-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin as a therapeutic agent to forestall relapse vulnerability in CUD. In male Sprague-Dawley rats, pimavanserin suppressed impulsive action (premature responses) measured in the 1-choice serial reaction time (1-CSRT) task, similarly to M100907. We also used the 1-CSRT task to establish baseline levels of impulsive action before cocaine self-administration and evaluation of cue reactivity (lever presses reinforced by the discrete cue complex previously paired with cocaine delivery). We observed an incubation of cocaine cue reactivity between day 1 and day 30 of forced abstinence from cocaine self-administration. Baseline levels of impulsive action predicted incubated levels of cocaine cue reactivity in late abstinence. We also found that baseline impulsive action predicted the effectiveness of pimavanserin to suppress incubated cue reactivity in late abstinence from cocaine self-administration at doses that were ineffective in early abstinence. These data suggest that integration of clinical measures of impulsive action may inform refined, personalized pharmacotherapeutic intervention for the treatment of relapse vulnerability in CUD.


Assuntos
Cocaína/administração & dosagem , Sinais (Psicologia) , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Animais , Relação Dose-Resposta a Droga , Fluorbenzenos/farmacologia , Masculino , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Autoadministração , Antagonistas da Serotonina/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia
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