RESUMO
RATIONALE: Problematic drug use is associated with difficulty in exerting self-control over behaviors, and this difficulty may be a consequence of atypical morphometric characteristics that are exhibited by drug-experienced individuals. The extent to which these structural abnormalities result from drug use or reflect neurobiological risk factors that predate drug use, however, is unknown. OBJECTIVES: The purpose of this study is to determine how methamphetamine affects corticostriatal structure and how drug-induced changes relate to alterations in inhibitory control. METHODS: Structural magnetic resonance images and positron emission tomography (PET) scans, assessing dopamine D2-like receptor and transporter availability, were acquired in monkeys trained to acquire, retain, and reverse three-choice visual discrimination problems before and after exposure to an escalating dose regimen of methamphetamine (or saline, as a control). Voxel-based morphometry was used to compare changes in corticostriatal gray matter between methamphetamine- and saline-exposed monkeys. The change in gray matter before and after the dosing regimen was compared to the change in the behavioral performance and in dopaminergic markers measured with PET. RESULTS: Methamphetamine exposure, compared to saline, increased gray matter within the right putamen. These changes were positively correlated with changes in performance of methamphetamine-exposed monkeys in the reversal phase, and were negatively correlated with alterations in D2-like receptor and DAT availability. CONCLUSIONS: The results provide the first evidence that exposure to a methamphetamine dosing regimen that resembles human use alters the structural integrity of the striatum and that gray-matter abnormalities detected in human methamphetamine users are due, at least in part, to the pharmacological effects of drug experience.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/patologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Inibição Psicológica , Metanfetamina/farmacologia , Putamen/efeitos dos fármacos , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Chlorocebus aethiops , Cognição/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Imageamento por Ressonância Magnética , Masculino , Metanfetamina/administração & dosagem , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Putamen/metabolismo , Putamen/patologia , Receptores de Dopamina D2/metabolismo , Retenção Psicológica/efeitos dos fármacos , Reversão de Aprendizagem/efeitos dos fármacos , Fatores de TempoRESUMO
Impulsive behavior is thought to reflect a traitlike characteristic that can have broad consequences for an individual's success and well-being, but its neurobiological basis remains elusive. Although striatal dopamine D2-like receptors have been linked with impulsive behavior and behavioral inhibition in rodents, a role for D2-like receptor function in frontostriatal circuits mediating inhibitory control in humans has not been shown. We investigated this role in a study of healthy research participants who underwent positron emission tomography with the D2/D3 dopamine receptor ligand [¹8F]fallypride and BOLD fMRI while they performed the Stop-signal Task, a test of response inhibition. Striatal dopamine D2/D3 receptor availability was negatively correlated with speed of response inhibition (stop-signal reaction time) and positively correlated with inhibition-related fMRI activation in frontostriatal neural circuitry. Correlations involving D2/D3 receptor availability were strongest in the dorsal regions (caudate and putamen) of the striatum, consistent with findings of animal studies relating dopamine receptors and response inhibition. The results suggest that striatal D2-like receptor function in humans plays a major role in the neural circuitry that mediates behavioral control, an ability that is essential for adaptive responding and is compromised in a variety of common neuropsychiatric disorders.
Assuntos
Benzamidas , Corpo Estriado/fisiologia , Lobo Frontal/fisiologia , Neuroimagem Funcional/psicologia , Inibição Neural/fisiologia , Receptores de Dopamina D2/fisiologia , Receptores de Dopamina D3/fisiologia , Adulto , Corpo Estriado/diagnóstico por imagem , Feminino , Radioisótopos de Flúor , Lobo Frontal/diagnóstico por imagem , Neuroimagem Funcional/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/psicologia , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/psicologia , Desempenho Psicomotor/fisiologia , Pirrolidinas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismoRESUMO
Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.
Assuntos
Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metanfetamina/administração & dosagem , Receptores de Dopamina D2/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Chlorocebus aethiops , Comportamento de Escolha/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Retroalimentação Sensorial/efeitos dos fármacos , Retroalimentação Sensorial/fisiologia , Ácido Homovanílico/metabolismo , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Retenção Psicológica/efeitos dos fármacos , Reversão de Aprendizagem/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Fatores de TempoRESUMO
BACKGROUND: Group differences in brain structure between methamphetamine-dependent and healthy research participants have been reported, but findings in the literature present discrepancies. Although most methamphetamine-abusing individuals also smoke cigarettes, the effects of smoking on brain structure have not been distinguished from those of methamphetamine. Changes with abstinence from methamphetamine have also been relatively unexplored. This study, therefore, attempted to account for effects of smoking and brief abstinence from methamphetamine on gray-matter measures in methamphetamine-dependent research participants. METHODS: Gray matter was measured using voxel-based morphometry in three groups: 18 control nonsmokers, 25 control smokers, and 39 methamphetamine-dependent smokers (methamphetamine-abstinent 4-7 days). Subgroups of methamphetamine-dependent and control participants (n=12/group) were scanned twice to determine change in gray matter over the first month of methamphetamine abstinence. RESULTS: Compared with Control Nonsmokers, Control Smokers and Methamphetamine-dependent Smokers had smaller gray-matter volume in the orbitofrontal cortex and caudate nucleus. Methamphetamine-dependent Smokers also had smaller gray-matter volumes in frontal, parietal and temporal cortices than Control Nonsmokers or Smokers, and smaller gray-matter volume in insula than control nonsmokers. Longitudinal assessment revealed gray matter increases in cortical regions (inferior frontal, angular, and superior temporal gyri, precuneus, insula, occipital pole) in methamphetamine-dependent but not control participants; the cerebellum showed a decrease. CONCLUSIONS: Gray-matter volume deficits in the orbitofrontal cortex and caudate of methamphetamine-dependent individuals may be in part attributable to cigarette smoking or pre-morbid conditions. Increase in gray matter with methamphetamine abstinence suggests that some gray-matter deficits are partially attributable to methamphetamine abuse.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/patologia , Encéfalo/patologia , Estimulantes do Sistema Nervoso Central , Metanfetamina , Fumar/patologia , Adolescente , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Núcleo Caudado/patologia , Córtex Cerebral/patologia , Estudos Transversais , Feminino , Globo Pálido/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neostriado/fisiologia , Córtex Pré-Frontal/fisiologia , Fumar/psicologia , Síndrome de Abstinência a Substâncias/psicologia , Adulto JovemRESUMO
Deviations in reward sensitivity and behavioral flexibility, particularly in the ability to change or stop behaviors in response to changing environmental contingencies, are important phenotypic dimensions of several neuropsychiatric disorders. Neuroimaging evidence suggests that variation in dopamine signaling through dopamine D(2)-like receptors may influence these phenotypes, as well as associated psychiatric conditions, but the specific neurocognitive mechanisms through which this influence is exerted are unknown. To address this question, we examined the relationship between behavioral sensitivity to reinforcement during discrimination learning and D(2)-like receptor availability in vervet monkeys. Monkeys were assessed for their ability to acquire, retain, and reverse three-choice, visual-discrimination problems, and once behavioral performance had stabilized, they received positron emission tomography (PET) scans. D(2)-like receptor availability in dorsal aspects of the striatum was not related to individual differences in the ability to acquire or retain visual discriminations but did relate to the number of trials required to reach criterion in the reversal phase of the task. D(2)-like receptor availability was also strongly correlated with behavioral sensitivity to positive, but not negative, feedback during learning. These results go beyond electrophysiological findings by demonstrating the involvement of a striatal dopaminergic marker in individual differences in feedback sensitivity and behavioral flexibility, providing insight into the neural mechanisms that are affected in neuropsychiatric disorders that feature these deficits.
Assuntos
Corpo Estriado/metabolismo , Aprendizagem por Discriminação/fisiologia , Receptores de Dopamina D2/metabolismo , Reforço Psicológico , Animais , Cebus , Chlorocebus aethiops , Corpo Estriado/diagnóstico por imagem , Masculino , Estimulação Luminosa/métodos , Tomografia por Emissão de PósitronsRESUMO
Psychological and neurocognitive studies have suggested that different kinds of self-control may share a common psychobiological component. If this is true, performance in affective and nonaffective inhibitory control tasks in the same individuals should be correlated and should rely upon integrity of this region. To test this hypothesis, we acquired high-resolution magnetic resonance images from 44 healthy and 43 methamphetamine-dependent subjects. Individuals with methamphetamine dependence were tested because of prior findings that they suffer inhibitory control deficits. Gray matter structure of the inferior frontal gyrus was assessed using voxel-based morphometry. Subjects participated in tests of motor and affective inhibitory control (stop-signal task and emotion reappraisal task, respectively); and methamphetamine-dependent subjects provided self-reports of their craving for methamphetamine. Performance levels on the two inhibitory control tasks were correlated with one another and with gray matter intensity in the right pars opercularis region of the inferior frontal gyrus in healthy subjects. Gray matter intensity of this region was also correlated with methamphetamine craving. Compared with healthy subjects, methamphetamine-dependent subjects exhibited lower gray matter intensity in this region, worse motor inhibitory control, and less success in affect regulation. These findings suggest that self-control in different psychological domains involves a common substrate in the right pars opercularis, and that successful self-control depends on integrity of this substrate.
Assuntos
Comportamento Aditivo/psicologia , Encéfalo/fisiologia , Cognição/fisiologia , Inibição Psicológica , Desempenho Psicomotor/fisiologia , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Comportamento Aditivo/fisiopatologia , Feminino , Humanos , Comportamento Impulsivo/fisiopatologia , Comportamento Impulsivo/psicologia , Masculino , Metanfetamina , Testes Neuropsicológicos , Estimulação Luminosa/métodos , Adulto JovemRESUMO
BACKGROUND: Methamphetamine (MA) use disorders are pervasive global social problems that produce large medical and public health burdens. Abnormalities in pituitary hormonal regulation have been observed in preclinical models of substance abuse and in human substance abusers. They have, however, not been studied before in MA-dependent human subjects. OBJECTIVES: To determine if MA-dependent research volunteers differ from healthy control subjects in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, or prolactin, or in pituitary dopamine D(2) receptor availability during early abstinence from MA. METHODS: MA-dependent subjects (N = 31), who were not seeking treatment, resided on an inpatient ward for up to 5 weeks. Abstinence was confirmed by daily urine drug screening. Venous blood was sampled for plasma hormone levels, and positron emission tomography with [(18)F]fallypride was performed to determine dopamine D(2) receptor availability during the first week of abstinence. Venous blood was sampled again for hormone levels during the fourth week of abstinence. Matched healthy volunteers (N = 23) participated as a comparison group. RESULTS: MA-dependent and healthy comparison subjects did not differ in plasma ACTH or cortisol levels, but had an elevated plasma prolactin at both the first week and fourth week of abstinence. There was no group difference in pituitary dopamine D(2) receptor availability. CONCLUSION: MA-dependent individuals have abnormalities in prolactin regulation, which is not likely due to alterations in pituitary dopamine D(2) receptor availability. SCIENTIFIC SIGNIFICANCE: MA dependence is associated with elevated prolactin levels, which may contribute to medical comorbidity in afflicted individuals.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Prolactina/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Análise de Variância , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Metanfetamina , Pessoa de Meia-Idade , Hipófise/diagnóstico por imagem , Hipófise/metabolismo , Cintilografia , Receptores de Dopamina D2/metabolismoRESUMO
While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D(2)/D(3) receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [(18)F]fallypride to measure striatal dopamine D(2)/D(3) receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D(2)/D(3) receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D(2)/D(3) receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D(2)/D(3) receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D(2)/D(3) receptor availability may mediate impulsive temperament and thereby influence addiction.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Comportamento Impulsivo/metabolismo , Metanfetamina/efeitos adversos , Receptores de Dopamina D2/deficiência , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Biomarcadores/análise , Biomarcadores/metabolismo , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/metabolismo , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Inibidores da Captação de Dopamina/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Feminino , Lateralidade Funcional/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Comportamento Impulsivo/induzido quimicamente , Comportamento Impulsivo/fisiopatologia , Masculino , Testes Neuropsicológicos , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Putamen/efeitos dos fármacos , Putamen/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/deficiência , Receptores de Dopamina D3/efeitos dos fármacos , Adulto JovemRESUMO
Converging evidence supports a role for mesocorticolimbic dopaminergic systems in a subject's ability to shift behavior in response to changing stimulus-reward contingencies. To characterize the dopaminergic mechanisms involved in this function, we quantified the effects of subtype-specific dopamine (DA) receptor antagonists on acquisition, retention, and reversal of a visual discrimination task in non-human primates (Chlorocebus aethiops sabaeus). We used a modified Wisconsin General Test Apparatus that was equipped with three food boxes, each fitted with a lid bearing a unique visual cue; one of the cues concealed a food reward, whereas the other two concealed an empty box. The monkeys were trained first to acquire a novel discrimination (eg A(+), B(-), C(-)) in a single session, before experiencing either a reversal of the discrimination (eg A(-), B(+), C(-)) or the acquisition of a completely new discrimination (eg D(+), E(-), F(-)), on the following day. Systemic administration of the D(2)/D(3) receptor antagonist raclopride (0.001-0.03 mg/kg) failed to significantly affect the performance of reversal learning when reversal sessions were run without a retention session. But, raclopride (0.03 mg/kg) significantly impaired performance under the reversal condition when reversal sessions were run right after a retention session; however, it did not affect acquisition of a novel visual discrimination. Specifically, raclopride significantly increased the number of reversal errors made before reaching the performance criterion in the reversal, but not in new learning sessions. In contrast, the D(1)/D(5) receptor antagonist SCH 23390 did not significantly modulate acquisition of a novel discrimination or reversal learning at doses (0.001-0.03 mg/kg, i.m.) that did not suppress behavior generally. In addition, none of the drug treatments affected retention of a previously learned discrimination. The results strongly suggest that D(2)/D(3) receptors, but not D(1)/D(5) receptors, selectively mediate reversal learning, without affecting the capacity to learn a new stimulus-reward association. These data support the hypothesis that phasic DA release, acting through D(2)-like receptors, mediates behavioral flexibility.
Assuntos
Encéfalo/metabolismo , Aprendizagem por Discriminação/fisiologia , Dopamina/metabolismo , Reconhecimento Visual de Modelos/fisiologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzazepinas/farmacologia , Encéfalo/efeitos dos fármacos , Chlorocebus aethiops , Aprendizagem por Discriminação/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Masculino , Testes Neuropsicológicos , Reconhecimento Visual de Modelos/efeitos dos fármacos , Estimulação Luminosa , Racloprida/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/antagonistas & inibidoresRESUMO
Growing evidence suggests a role for metabotropic glutamate receptors (mGluRs) in the behavioral effects of cocaine related to its abuse. The mGluR5 subtype, in particular, has come under scrutiny due to its distribution in brain regions associated with drug addiction. This study investigated interactions between the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and cocaine in squirrel monkeys whose lever-pressing behavior was 1) maintained under a second-order schedule of cocaine self-administration, 2) extinguished and then reinstated by cocaine priming, and 3) controlled by the discriminative stimulus (DS) effects of cocaine. Additional studies determined the effects of MPEP on unconditioned behaviors, coordination, and muscle resistance. In each experiment, the effects of MPEP were compared with those of the N-methyl-d-aspartate antagonist dizocilpine. MPEP attenuated cocaine self-administration, cocaine-induced reinstatement of drug seeking, and the DS effects of cocaine at doses that did not markedly impair motor function or operant behavior in the context of drug discrimination. Dizocilpine also attenuated cocaine self-administration, but it did not significantly alter cocaine-induced reinstatement of drug seeking, and it enhanced rather than attenuated the DS effects of cocaine. The findings point to a significant contribution of mGluR5 mechanisms in the behavioral effects of cocaine related to its abuse and suggest that MPEP has properties of a functional cocaine antagonist, which are not secondary to antagonism at NMDA receptors. The contrasting interactions of MPEP and dizocilpine with cocaine imply that glutamate acting through different metabotropic and ionotropic receptors may modulate the behavioral effects of cocaine in qualitatively different ways.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Aprendizagem por Discriminação/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Feminino , Masculino , Receptor de Glutamato Metabotrópico 5 , Saimiri , AutoadministraçãoRESUMO
Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an alpha(2)-adrenoceptor antagonist, is known to be anxiogenic and induce stress-related responses in humans and animals. Here, we tested the ability of yohimbine to reinstate cocaine-seeking behavior and induce behavioral and physiological signs characteristic of stress in squirrel monkeys. Monkeys were trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Drug seeking subsequently was extinguished by substituting saline for cocaine injections and omitting the cocaine-paired stimulus. The ability of yohimbine and the structurally distinct alpha(2)-adrenoceptor antagonist RS-79948 to reinstate cocaine-seeking behavior was assessed by administering priming injections immediately before test sessions in which the cocaine-paired stimulus was either present or absent. Priming injections of yohimbine (0.1-0.56 mg/kg, i.m.) or RS-79948 (0.01-0.1 mg/kg, i.m.) induced dose-related reinstatement of cocaine-seeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocaine-paired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and self-grooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the alpha(2)-adrenoceptor agonist clonidine (0.1-0.3 mg/kg, i.m.) dose-dependently inhibited yohimbine-induced reinstatement of cocaine seeking. In contrast, pretreatment with the dopamine receptor antagonist flupenthixol failed to inhibit yohimbine-induced reinstatement of cocaine seeking. The results show that pharmacological blockade of alpha(2)-adrenoceptors can induce reinstatement of cocaine-seeking behavior and characteristic stress responses in squirrel monkeys, providing a potentially useful model of stress-induced relapse to drug seeking.
Assuntos
Antagonistas Adrenérgicos alfa/toxicidade , Comportamento Aditivo/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/etiologia , Agonistas alfa-Adrenérgicos/farmacologia , Análise de Variância , Animais , Comportamento Aditivo/etiologia , Clonidina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Flupentixol/farmacologia , Hidrocortisona/metabolismo , Atividade Motora/efeitos dos fármacos , Saimiri , Autoadministração/métodos , Serina Endopeptidases/efeitos dos fármacos , Fatores de Tempo , Vocalização Animal/efeitos dos fármacos , Ioimbina/toxicidadeRESUMO
RATIONALE: Stress has been suggested to play a role in relapse to cocaine-seeking behavior. An important physiological system activated by stress is the hypothalamic-pituitary-adrenal (HPA) axis; however, evidence for a role of HPA axis activation in cocaine relapse has been contradictory. OBJECTIVES: This study examined the effects of pharmacological stimulation of the HPA axis on reinstatement of drug-seeking behavior and salivary cortisol levels in a non-human primate model of cocaine relapse. In addition, the effect of corticotropin releasing hormone type 1 receptor (CRH-R1) blockade on cocaine priming-induced reinstatement was investigated. METHODS: Squirrel monkeys were trained to self-administer cocaine under a second-order schedule in which behavior was maintained by IV drug injections and a drug-paired visual stimulus. A period of extinction was then imposed during which saline was substituted for cocaine and the stimulus was omitted. Subsequently, monkeys were tested for reinstatement of cocaine seeking following priming injections of drugs. During reinstatement tests, the drug-paired stimulus was restored. Salivary cortisol levels were determined to measure the effects of drug treatments on the HPA axis activity. RESULTS: Priming with corticotropin releasing hormone (10 and 50 microg/kg), adrenocorticotropic hormone (1 microg/kg), or cortisol (1-10 mg/kg) did not induce significant reinstatement of cocaine seeking. All of these treatments, however, resulted in a significant increase in salivary cortisol. In contrast, priming injections of cocaine (0.1-1.0 mg/kg) dose-dependently induced reinstatement of drug seeking, but did not increase salivary cortisol. The CRH-R1 antagonist CP-154,526 (10 mg/kg, IV) did not modulate cocaine priming-induced reinstatement of drug seeking, but attenuated CRH-induced increases in salivary cortisol. CONCLUSIONS: The results suggest that activation of the HPA axis is neither necessary nor sufficient for reinstatement of cocaine-seeking behavior in this non-human primate model of cocaine relapse.
Assuntos
Comportamento Aditivo , Cocaína/administração & dosagem , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Hormônio Adrenocorticotrópico/farmacologia , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Hormônio Liberador da Corticotropina/farmacologia , Relação Dose-Resposta a Droga , Hidrocortisona/metabolismo , Hidrocortisona/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Saimiri , AutoadministraçãoRESUMO
Human immunodeficiency virus type 1 (HIV-1) infection is often accompanied by cognitive, motor, and behavioral dysfunction. Cognitive function diminishes in indices of attention, psychomotor speed, and learning and memory. These are collectively termed acquired immunodeficiency syndrome dementia complex (ADC or neuroAIDS). Inoculation with the LP-BM5 murine leukemia virus (MuLV) causes profound immunosuppression (murine acquired immunodeficiency syndrome, or MAIDS) in C57BL/6 mice. Previous studies show that the LP-BM5 MuLV impairs learning and memory without gross motor impairment. Since learning and memory performance deficits can be related to attention deficits, we assessed the effect of LP-BM5 MuLV infection on sustained attention performance using a two-choice serial reaction time task. This task required the animals to detect a visual stimulus presented randomly on the right or the left unit and respond by a nose-poke in the illuminated hole within a 5 s period for water reward. The LP-BM5 MuLV infected group, like the control group, improved sustained attention performance until 7 weeks of virus infection in all measures including choice accuracy, response omission, and correct response time. However, during the late stage of infection, LP-BM5 MuLV infected mice showed selective sustained attention performance deficits. From 8 weeks after LP-BM5 MuLV infection, the virus infected mice started to lose their improved sustained attention performance in response omission and began to make correct responses more slowly than the control mice when the duration of stimulus light was 5 s. Moreover, at 13 and 14 weeks after LP-BM5 MuLV infection, the virus infected group made correct choices significantly less accurately than the control group when duration of stimulus light was shortest (1 s). These data show that LP-BM5 MuLV infection causes not only the previously reported learning and memory deficits but also produces sustained attention performance deficits in mice.