RESUMO
Cannabis-related impairments to cognitive function may represent novel therapeutic targets for cannabis-use disorder, although the nature, persistence, and reversibility of such deficits remain unclear. Adult male rhesus monkeys (N = 6) responded in the morning on tasks designed to assess different cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) touchscreens followed by responding maintained under a fixed-ratio (FR) 10 schedule of food presentation in different operant chambers. First, the acute effects of Δ9-tetrahydrocannabinol (THC; 0.01-0.56 mg/kg, i.v.) on cognitive performance, FR responding, and body temperature were determined. Next, THC (1.0-2.0 mg/kg, s.c.) was administered daily after FR 10 sessions for 12 weeks, during which the residual effects of THC (i.e., 22 hours after administration) on cognition were examined and the acute effects of THC were redetermined. In a subgroup of monkeys, dopamine D2/D3 receptor availability was assessed after 4 weeks of chronic THC exposure and compared with drug-naive controls using positron emission tomography and [11C]-raclopride (N = 4/group). Acute THC pretreatments dose-dependently decreased FR responding and body temperature, and impairment to cognitive performance was task specific. During chronic treatment, THC produced persistent residual impairment only to working memory; tolerance differentially developed to acute cognitive impairments. There was recovery from residual cognitive impairments to working memory within 2 weeks of abstinence. Compared with controls, D2/D3 receptor availability was not altered during chronic THC treatment. In conclusion, THC-induced disruptions in cognition were task-specific, as was tolerance development, and not related to changes in D2/D3 receptor availability. Intervention strategies for cannabis-use disorder that enhance working memory performance may facilitate positive treatment outcomes.
Assuntos
Cognição/efeitos dos fármacos , Dronabinol/farmacologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Macaca mulatta , Masculino , Fatores de TempoRESUMO
Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.
Assuntos
Cocaína , Tomografia por Emissão de Pósitrons , Haplorrinos , Animais , Feminino , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Dopamina , Receptores de Dopamina D3 , Cocaína/administração & dosagem , Cocaína/efeitos adversos , Autoadministração , RaclopridaRESUMO
Dopamine neurotransmission is associated with high susceptibility to cocaine abuse. Positron emission tomography was used in 12 rhesus macaques to determine if dopamine D2 receptor availability was associated with the rate of cocaine reinforcement, and to study changes in brain dopaminergic function during maintenance of and abstinence from cocaine. Baseline D2 receptor availability was negatively correlated with rates of cocaine self-administration. D2 receptor availability decreased by 15-20% within 1 week of initiating self-administration and remained reduced by approximately 20% during 1 year of exposure. Long-term reductions in D2 receptor availability were observed, with decreases persisting for up to 1 year of abstinence in some monkeys. These data provide evidence for a predisposition to self-administer cocaine based on D2 receptor availability, and demonstrate that the brain dopamine system responds rapidly following cocaine exposure. Individual differences in the rate of recovery of D2 receptor function during abstinence were noted.
Assuntos
Comportamento Aditivo , Encéfalo/fisiologia , Cocaína/administração & dosagem , Receptores de Dopamina D2/metabolismo , Reforço Psicológico , Animais , Comportamento Animal/fisiologia , Encéfalo/anatomia & histologia , Alimentos , Moduladores GABAérgicos/metabolismo , Humanos , Lorazepam/metabolismo , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons , Autoadministração , Fatores de TempoRESUMO
BACKGROUND: Islet cell adaptation to insulin resistance in type 2 diabetes mellitus may be due in part to increased stimulation of beta cells by the autonomic nervous system. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor correlates with cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[18F]fluorobenzyltrozamicol ([18F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. In this study, we utilize [18F]FBT PET to demonstrate pancreatic cholinergic activity before and after dextrose infusion in nonhuman primates with normal (NGT) and impaired (IGT) glucose tolerance. METHODS: Seven adult female vervet (Chlorocebus aethiops) monkeys were maintained on an atherogenic Western diet. They were divided into two groups: four with NGT and three with IGT. Each subject underwent [18F]FBT PET twice: first, a baseline PET under fasting conditions; and second, PET under fasting conditions but after intravenous infusion of dextrose solution. Quantitative analysis of pancreatic uptake at 60 min post-injection was performed. RESULTS: There was no difference in pancreatic uptake of [18F]FBT on baseline scans between the two groups. Pancreatic uptake of [18F]FBT increased in every subject after dextrose infusion (P = 0.03). On post-dextrose PET scans, pancreatic uptake of [18F]FBT was significantly higher in IGT subjects compared with NGT subjects (P = 0.03). The post-dextrose to pre-dextrose uptake ratios were higher in IGT subjects (P = 0.08). CONCLUSIONS: Acute increases in pancreatic cholinergic activity in vivo were detected in the pancreata of nonhuman primates with NGT and IGT after intravenous dextrose infusion on [18F]FBT PET. In subjects with IGT, this activity was significantly higher, suggesting increased autonomic nervous system stimulation of the pancreatic islets in insulin-resistant subjects.
Assuntos
Intolerância à Glucose/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Glicemia/metabolismo , Chlorocebus aethiops , Feminino , Radioisótopos de Flúor , Fluorbenzenos , Intolerância à Glucose/sangue , Insulina/sangue , Piperidinas , Primatas , Valores de Referência , Triglicerídeos/sangueRESUMO
BACKGROUND: Pancreatic neuronal changes associated with beta cell loss in type 1 diabetes mellitus are complex, involving, in part, parasympathetic mechanisms to compensate for preclinical hyperglycemia. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor has been shown to be a useful marker of cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[(18)F]fluorobenzyltrozamicol ([(18)F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. The compound 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), available in a tritiated form, binds to M3 muscarinic receptors on beta cells and is a potential target for assessing pancreatic beta cell mass. In this study, we investigate the feasibility of dual radiotracer analysis in identifying neurofunctional changes that may signify type 1 diabetes mellitus in its early preclinical state. METHODS: Ex vivo determinations of pancreatic uptake were performed in prediabetic nonobese diabetic mice and controls after intravenous injection of [(18)F]FBT or 4-[(3)H]DAMP. Beta cell loss in prediabetic mice was confirmed using immunohistochemical methods. RESULTS: [(18)F]FBT uptake was significantly higher in prediabetic pancreata than controls: 3.22 +/- 0.81 and 2.51 +/- 1.04, respectively (P < 0.03). 4-[(3)H]DAMP uptake was significantly lower in prediabetic pancreata than controls: 0.612 +/- 0.161 and 0.968 +/- 0.364, respectively (P = 0.01). CONCLUSIONS: These data suggest that a combination of radiotracer imaging agents that bind to neuronal elements intimately involved in insulin production may be an effective method of evaluating changes associated with early beta cell loss using PET.
Assuntos
Radioisótopos de Flúor , Células Secretoras de Insulina/patologia , Pâncreas/patologia , Estado Pré-Diabético/diagnóstico , Trítio , Animais , Fluorbenzenos/farmacocinética , Células Secretoras de Insulina/diagnóstico por imagem , Camundongos , Pâncreas/diagnóstico por imagem , Parassimpatolíticos/farmacocinética , Piperidinas/farmacocinética , Estado Pré-Diabético/diagnóstico por imagem , Estado Pré-Diabético/patologia , RadiografiaRESUMO
Although serotonin (5-HT) can interact with dopamine (DA) systems to modulate the subjective and reinforcing effects of psychostimulants such as cocaine and 3,4-methyldioxymethamphetamine (MDMA, ecstasy), the long-term effects of exposure to psychostimulants on brain 5-HT systems are not well characterized. The present study assessed 5-HT transporter (SERT) availability using positron emission tomography (PET) in rhesus monkeys with the SERT-specific radioligand [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB). SERT availability was assessed in regions of interest including the caudate nucleus, putamen, anterior cingulate cortex, and cerebellum. [(11)C]DASB distribution volume ratios (DVRs) were calculated using the cerebellum as the reference region. DVRs were calculated in control monkeys and in cocaine or MDMA self-administering monkeys approximately 24 h after the last self-administration (SA) session. SERT availability did not differ between monkeys with a history of MDMA SA and control monkeys in any region examined. In contrast, monkeys with a history of cocaine SA showed significantly higher levels of SERT availability in the caudate nucleus and putamen compared to control subjects. These results suggest that chronic SA of cocaine, but not MDMA, leads to alterations in serotonergic function in brain areas relevant to drug abuse. The higher level of SERT availability in cocaine-experienced monkeys may lead to a reduced inhibitory tone of 5-HT on the DA system, which may explain, in part, differences in the abuse liability between cocaine and MDMA.
Assuntos
Núcleo Caudado/metabolismo , Cocaína/farmacologia , Giro do Cíngulo/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Putamen/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/efeitos dos fármacos , Cocaína/administração & dosagem , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Putamen/efeitos dos fármacos , Radiografia , Autoadministração , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacosRESUMO
Disruption of the dopaminergic system has been implicated in the etiology of many pathological conditions, including drug addiction. Here we used positron emission tomography (PET) imaging to study brain dopaminergic function in individually housed and in socially housed cynomolgus macaques (n = 20). Whereas the monkeys did not differ during individual housing, social housing increased the amount or availability of dopamine D2 receptors in dominant monkeys and produced no change in subordinate monkeys. These neurobiological changes had an important behavioral influence as demonstrated by the finding that cocaine functioned as a reinforcer in subordinate but not dominant monkeys. These data demonstrate that alterations in an organism's environment can produce profound biological changes that have important behavioral associations, including vulnerability to cocaine addiction.
Assuntos
Encéfalo/metabolismo , Cocaína/administração & dosagem , Receptores de Dopamina D2/metabolismo , Predomínio Social , Animais , Comportamento Animal , Encéfalo/diagnóstico por imagem , Abrigo para Animais , Macaca fascicularis , Masculino , Autoadministração , Meio Social , Isolamento Social , Tomografia Computadorizada de EmissãoRESUMO
CONTEXT: Current animal models of depression are inadequate to further our understanding of depression. New models that allow for analysis of cognitive function and sex differences are needed. OBJECTIVE: To characterize serotonin 1A (5-HT(1A)) receptor binding potential (BP) and its relationship with specific characteristics of behavioral depression in cynomolgus monkeys. DESIGN: A 23-month case-control study. SETTING: Small social groups in the laboratory. Subjects Seventeen adult female cynomolgus monkeys. MAIN OUTCOME MEASURES: Serotonin 1A receptor BP was examined by positron emission tomography using the radioligand 4,2"-(methoxyphenyl)-1-[2"-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine in the raphe, amygdala, hippocampus, and anterior cingulate cortex in monkeys characterized by behavioral observation as depressed or not depressed. Aggression, submission, affiliation, pathologic behaviors, and activity levels were determined by behavioral observation. Heart rate and hypothalamic-pituitary-adrenal function were also determined. RESULTS: Throughout the brain areas examined, there was a reduction in 5-HT(1A) BP in depressed monkeys. The 5-HT(1A) BP in the amygdala and hippocampus was associated with aggression and submission. Friendly interaction, grooming, and locomotion were associated with 5-HT(1A) BP in the left cingulate cortex, whereas attention directed toward the environment was associated with 5-HT(1A) BP in the right cingulate cortex. The 5-HT(1A) receptor BP was inversely associated with heart rate in the raphe, left cingulate, and right amygdala. CONCLUSIONS: This is the fourth in a series of studies that suggest that depressive behavior in adult female cynomolgus monkeys is similar to that observed in humans. It has been observed in 2 large groups of monkeys randomly selected from feral populations, suggesting that the capacity for depression is inherent in the species. This animal model holds promise to further our understanding of the basic mechanisms of affective behavior, the neuropathophysiologic characteristics of depression and the cognitive dysfunction that accompanies them, genetic and environmental factors that may affect depression risk, and the role of reproductive function in the excess depression risk in women.
Assuntos
Comportamento Animal/fisiologia , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Macaca fascicularis/metabolismo , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Receptor 5-HT1A de Serotonina/metabolismo , Agressão/fisiologia , Agressão/psicologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Animais , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Transtorno Depressivo/diagnóstico por imagem , Dexametasona , Feminino , Fluordesoxiglucose F18 , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Hidrocortisona/sangue , Piperazinas , Piridinas , Ensaio Radioligante , Compostos RadiofarmacêuticosRESUMO
RATIONALE: Social rank has been shown to influence dopamine (DA) D(2) receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D(1) receptors. OBJECTIVE: Examine the effects of a high-efficacy D(1) agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D(1) agonist on cocaine self-administration, as well as the effects of cocaine exposure on D(2) receptor function across social ranks, as determined by positron emission tomography (PET). METHODS: Effects of the high-efficacy D(1) agonist SKF 81297 and cocaine (0.3-3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D(1) agonist SKF 38393 (0.1-17 mg/kg) to decrease cocaine self-administration (0.003-0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D(2) receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET. RESULTS: SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D(2) receptor levels did not differ across social ranks. CONCLUSIONS: These results suggest that D(1) receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D(2) receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D(2) receptor levels such that D(2) receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Hierarquia Social , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Análise de Variância , Animais , Benzamidas/farmacocinética , Benzazepinas/farmacologia , Piscadela/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Macaca fascicularis , Masculino , Neostriado/diagnóstico por imagem , Piperidinas/farmacocinética , Autoadministração , Distribuição Tecidual/efeitos dos fármacos , Tomografia Computadorizada de Emissão/métodosRESUMO
RATIONALE: Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronic treatment with a partial D2/D3 receptor agonist are not clear. OBJECTIVE: We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on food-reinforced behavior (n = 5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n = 9). METHODS: Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and 4 days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [18F]fluoroclebopride (FCP). Four additional monkeys were studied using [11C]raclopride and treated sequentially with each dose of ARI for 17 days. RESULTS: ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs) in the caudate nucleus and putamen in most monkeys, but decreases were observed in monkeys with the highest baseline DVRs. CONCLUSIONS: The results indicate that repeated treatment with a low-efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity.
RESUMO
BACKGROUND: Current image sharing is carried out by manual transportation of CDs by patients or organization-coordinated sharing networks. The former places a significant burden on patients and providers. The latter faces challenges to patient privacy. OBJECTIVE: To allow healthcare providers efficient access to medical imaging data acquired at other unaffiliated healthcare facilities while ensuring strong protection of patient privacy and minimizing burden on patients, providers, and the information technology infrastructure. METHODS: An image sharing framework is described that involves patients as an integral part of, and with full control of, the image sharing process. Central to this framework is the Patient Controlled Access-key REgistry (PCARE) which manages the access keys issued by image source facilities. When digitally signed by patients, the access keys are used by any requesting facility to retrieve the associated imaging data from the source facility. A centralized patient portal, called a PCARE patient control portal, allows patients to manage all the access keys in PCARE. RESULTS: A prototype of the PCARE framework has been developed by extending open-source technology. The results for feasibility, performance, and user assessments are encouraging and demonstrate the benefits of patient-controlled image sharing. DISCUSSION: The PCARE framework is effective in many important clinical cases of image sharing and can be used to integrate organization-coordinated sharing networks. The same framework can also be used to realize a longitudinal virtual electronic health record. CONCLUSION: The PCARE framework allows prior imaging data to be shared among unaffiliated healthcare facilities while protecting patient privacy with minimal burden on patients, providers, and infrastructure. A prototype has been implemented to demonstrate the feasibility and benefits of this approach.
Assuntos
Confidencialidade , Diagnóstico por Imagem , Disseminação de Informação/métodos , Participação do Paciente , Sistemas de Informação em Radiologia , Redes de Comunicação de Computadores , Segurança Computacional , Estudos de Viabilidade , Registros de Saúde Pessoal , Humanos , Armazenamento e Recuperação da Informação , North Carolina , Estados Unidos , Interface Usuário-ComputadorRESUMO
BACKGROUND: Chronic cocaine use is associated with neurobiological and cognitive deficits that persist into abstinence, hindering success of behavioral treatment strategies and perhaps increasing likelihood of relapse. The effects of current cocaine use and abstinence on neurobiology and cognition are not well characterized. METHODS: Adult male rhesus monkeys with an extensive cocaine self-administration history (â¼ 5 years) and age-matched control animals (n = 4/group) performed cognitive tasks in morning sessions and self-administered cocaine or food in afternoon sessions. Positron emission tomography and [(18)F]-fluorodeoxyglucose were employed to assess cerebral metabolic rates of glucose utilization during cognitive testing. RESULTS: Cocaine-experienced monkeys required significantly more trials and committed more errors on reversal learning and multidimensional discriminations, compared with control animals. Cocaine-naive, but not cocaine-experienced, monkeys showed greater metabolic rates of glucose utilization during a multidimensional discrimination task in the caudate nucleus, hippocampus, anterior and posterior cingulate, and regions associated with attention, error detection, memory, and reward. Using a delayed match-to-sample task, there were no differences in baseline working memory performance between groups. High-dose cocaine self-administration disrupted delayed match-to-sample performance but tolerance developed. Acute abstinence from cocaine did not affect performance, but by day 30 of abstinence, accuracy increased significantly, while performance of cocaine-naive monkeys was unchanged. CONCLUSIONS: These data document direct effects of cocaine self-administration on cognition and neurobiological sequelae underlying cognitive deficits. Improvements in working memory can occur in abstinence, albeit across an extended period critical for treatment seekers, suggesting pharmacotherapies designed to enhance cognition may improve success of current behavioral modification strategies.
Assuntos
Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína , Cocaína , Discriminação Psicológica/efeitos dos fármacos , Glucose/metabolismo , Reversão de Aprendizagem/efeitos dos fármacos , Animais , Cocaína/administração & dosagem , Cocaína/efeitos adversos , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fluordesoxiglucose F18 , Macaca mulatta , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodos , Autoadministração , Análise e Desempenho de TarefasRESUMO
Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [¹8F]fluoroclebopride (DA D2/D3) and [¹8F]-(+)-N-(4-fluorobenzyl)-2ß-propanoyl-3ß-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.
Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/farmacologia , Dopamina/fisiologia , Metilfenidato/administração & dosagem , Metilfenidato/farmacologia , Animais , Química Farmacêutica , Condicionamento Operante/efeitos dos fármacos , Preparações de Ação Retardada , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Crescimento/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons , Receptores Dopaminérgicos/efeitos dos fármacos , Reforço Psicológico , AutoadministraçãoRESUMO
BACKGROUND: Brain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, although most research has used males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement. METHODS: DA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n = 16) with positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed, and again when individually housed. In addition, PET was used to examine changes in dopamine transporter (DAT) availability after social hierarchy formation. After imaging studies were complete, monkeys received implantation with indwelling intravenous catheters and self-administered cocaine (.001-.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered. RESULTS: Neither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed after formation of social hierarchies. DA D2/D3 receptor availability significantly increased in females that became dominant, whereas DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys. CONCLUSIONS: The relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement seems, on the basis of these findings, opposite in females and males. These data indicate that the social environment profoundly affects the DA system but does so in ways that have different functional consequences for females than for males.
Assuntos
Núcleo Caudado/metabolismo , Cocaína/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Putamen/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Predomínio Social , Análise de Variância , Animais , Núcleo Caudado/fisiopatologia , Cocaína/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Macaca fascicularis , Ciclo Menstrual/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Putamen/fisiopatologia , Receptores Dopaminérgicos/metabolismo , Autoadministração , Fatores SexuaisRESUMO
Cocaine self-administration alters brain dopaminergic and serotonergic function primarily in mesolimbic and prefrontal brain regions whereas 3,4-methylenedioxymethamphetamine (MDMA) self-administration predominately alters brain serotonergic function in a more widespread distribution across cortical regions. We previously reported that, compared to drug-naïve rhesus monkeys, self-administration of cocaine but not MDMA was associated with increased serotonin transporter (SERT) availability in two mesolimbic regions, the caudate nucleus and putamen, as measured by positron emission tomography (PET) using the SERT-specific ligand [(11)C]-3-amino-4(2-dimethylamino-methyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB). The goal of the present study was to extend this comparison between cocaine and MDMA self-administration to SERT availability in cortical regions, which have been shown previously to be affected in human drug abusers and are associated with executive function. PET studies using [(11)C]DASB were conducted in adult male rhesus monkeys with a history of cocaine (mean intake = 742.6 mg/kg) or MDMA (mean intake = 121.0 mg/kg) self-administration, and drug-naïve controls (n = 4/group). Regions of interest were drawn for several cortical (prefrontal, temporal, parietal, occipital and midcingulate) and subcortical (thalamus, amygdala and hippocampus) areas. Cortical SERT availability was significantly higher in monkeys with a cocaine self-administration history compared to controls whereas MDMA self-administration resulted in lower levels of SERT availability. These data extend our previous findings indicating that cocaine and MDMA self-administration differentially alter SERT availability in subcortical and cortical regions, which may have implications for development of treatment drugs.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cocaína/administração & dosagem , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Córtex Cerebral/diagnóstico por imagem , Haplorrinos , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons/métodos , AutoadministraçãoRESUMO
RATIONALE: Studies in socially housed monkeys have demonstrated an influence of position in the social dominance hierarchy on brain dopamine D2 receptors and the reinforcing effects of cocaine that dissipates after long-term cocaine self-administration. OBJECTIVE: The aims of the study were to examine the effects of abstinence from cocaine on D2 receptors in socially housed monkeys and to extend behavioral characterizations to measures of reactivity to a novel object. MATERIALS AND METHODS: Twelve socially housed male cynomolgus monkeys with extensive cocaine self-administration experience were used (average lifetime intakes â¼270 and 215 mg/kg for dominant and subordinate monkeys, respectively). Abstinence lasted for approximately 8 months, after which D2 receptor availability was assessed using positron emission tomography and the D2 ligand [18F]fluoroclebopride. Reaction to novelty was also assessed in these subjects as well as nine individually housed monkeys. RESULTS: During abstinence, D2 receptor availability in the caudate nucleus was significantly higher in dominant versus subordinate monkeys. Average latency to touch a novel object was also significantly higher in dominant monkeys compared to subordinates or individually housed monkeys. In socially experienced monkeys, a significant positive correlation was observed between caudate nucleus D2 receptor availability and latencies to touch the novel object. CONCLUSIONS: Although chronic cocaine self-administration blunts the ability of social dominance to alter D2 receptor availability and sensitivity to the reinforcing effects of cocaine, this influence reemerges during abstinence. In addition, the data suggest that prior experience with social dominance can lead to longer latencies in reaction to novelty--a personality trait associated with low vulnerability to cocaine abuse.
Assuntos
Núcleo Caudado/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Animais , Núcleo Caudado/diagnóstico por imagem , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Modelos Animais de Doenças , Radioisótopos de Flúor , Hierarquia Social , Abrigo para Animais , Macaca fascicularis , Masculino , Tomografia por Emissão de Pósitrons/métodos , Putamen/diagnóstico por imagem , Putamen/metabolismo , Ensaio Radioligante/métodos , AutoadministraçãoRESUMO
RATIONALE: Cocaine use during pregnancy is associated with alterations in the dopamine (DA) system in the fetal brain. However, little is known about the effects of prenatal cocaine exposure on the postnatal dopaminergic system. OBJECTIVES: The objective of the study was to examine DA receptor function in adult monkeys that were prenatally exposed to cocaine. MATERIALS AND METHODS: Male and female rhesus monkeys (approximately 13 years old) that had been prenatally exposed to cocaine (n = 10) and controls (n = 10) were used in all studies. First, DA D2-like receptor availability was assessed using positron emission tomography and the D2-like receptor radiotracer [(18)F]fluoroclebopride (FCP). Next, D(3) receptor function was assessed by measuring quinpirole-induced yawning (0.03-0.3 mg/kg). Finally, D1-like receptor function was examined by measuring eye blinking elicited by the high-efficacy D1-like receptor agonist SKF81297 (0.3-3.0 mg/kg). RESULTS: There were no differences between groups or sexes in D2-like receptor availability in the caudate nucleus, putamen or amygdala. However, quinpirole elicited significantly more yawns in prenatally cocaine-exposed monkeys compared with control monkeys. A significant correlation between gestational dose of cocaine and peak effects of quinpirole was observed. In all monkeys, administration of SKF81297 elicited dose-dependent increases in eye blinks that did not differ between groups. CONCLUSIONS: These findings suggest that prenatal cocaine exposure can have long-term effects on DA D(3) receptor function in adults.
Assuntos
Cocaína/toxicidade , Prenhez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/efeitos dos fármacos , Animais , Benzamidas/análise , Benzazepinas/farmacologia , Piscadela/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Feminino , Radioisótopos de Flúor/análise , Macaca mulatta , Masculino , Piperidinas/análise , Gravidez , Quimpirol/farmacologia , Ensaio Radioligante/métodos , Bocejo/efeitos dos fármacosRESUMO
Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [(18)F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants.
Assuntos
Ciclo Menstrual/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Benzamidas , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/metabolismo , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Feminino , Fase Folicular/fisiologia , Fase Luteal/fisiologia , Macaca fascicularis , Imageamento por Ressonância Magnética , Ciclo Menstrual/fisiologia , Piperidinas , Tomografia por Emissão de Pósitrons , Progesterona/sangue , Putamen/diagnóstico por imagem , Putamen/metabolismo , Receptores de Dopamina D2/agonistasRESUMO
Previous studies have demonstrated that cocaine use alters availability of brain dopamine D2 receptors (D2R) and transporters (DAT). The present study examined the effects of low doses of cocaine on this neuroadaptation. Using positron emission tomography (PET), D2R and DAT availability in the caudate nucleus (Cd), putamen (Pt), anterior cingulate cortex (ACC), and amygdala (AMY) were assessed before and after monkeys acquired cocaine self-administration. Twelve rhesus monkeys were trained to self-administer intravenous cocaine (0.03 mg/kg per injection) under conditions that resulted in low drug intakes. PET scans using radiotracers targeting D2R ([F]fluoroclebopride, FCP) or DAT ([F]-(+)-N-(4-fluorobenzyl)-2ß-propanoyl-3ß-(4-chlorophenyl)tropane, FCT) were performed when monkeys were cocaine naive and after 9 weeks of self-administration. Before self-administration, D2R availability was significantly higher only in left vs. right Cd, whereas DAT availability was higher in left vs. right Cd, Pt, and ACC. Nonetheless, after cocaine exposure, left-right differences in D2R were apparent in 3 of 4 regions, but only in the ACC for DAT availability. Self-administration of this dose of cocaine did not significantly affect DAT availability in any region and only decreased D2R availability in the ACC. These results demonstrate lateralization of D2R and DAT availability in brain areas that mediate cocaine self-administration, even under conditions in which cocaine does not affect overall receptor availability.
RESUMO
Previous research using positron emission tomography (PET) in monkeys has shown that attaining social dominance can result in increased DA D2 receptor availability and attenuated sensitivity to the reinforcing effects of cocaine. The present study utilized a within-subjects design to determine whether chronic treatment with the D2 receptor antagonist raclopride could similarly increase D2 receptor availability. Using the D2-selective radioligand [(18)F]fluoroclebopride (FCP), three adult male cynomolgus monkeys were scanned before and after chronic treatment with raclopride (0.01 mg/kg per h for 30 +/- 1 day) administered by a subcutaneous osmotic pump. Food-reinforced operant behavior was assessed during treatment. A transitory decrease in responding was observed during the initial eight days of raclopride treatment. Tolerance developed by the tenth session, and responding remained at baseline levels for the duration of treatment and after treatment was discontinued. Averaged across monkeys, chronic raclopride administration increased FCP distribution volume ratios (DVRs) between 12 and 20% in the caudate nucleus, putamen, and anterior cingulate cortex. When monkeys were re-scanned 9-12 months after termination of raclopride treatment, FCP DVRs remained elevated in two subjects, and decreased below baseline levels in the third monkey. Considering the reported 2% test/retest variability for FCP, these findings indicate that chronic treatment with a D2 receptor antagonist can produce large increases in D2 receptor availability as measured with PET. Individual differences in rates of recovery were observed, such that the increases in DVR persisted in two of three subjects.