RESUMO
BACKGROUND: Beyond their specific experiment, video records of behavior have future value-for example, as inputs for new experiments or for yet unknown types of analysis of behavior-similar to tissue or blood sample banks in life sciences where clinically derived or otherwise well-described experimental samples are stored to be available for some unknown potential future purpose. FINDINGS: Research using an animal model of obsessive-compulsive disorder employed a standardized paradigm where the behavior of rats in a large open field was video recorded for 55 minutes on each test. From 43 experiments, there are 19,976 such trials that amount to over 2 years of continuous recording. In addition to videos, there are 2 video-derived raw data objects: XY locomotion coordinates and plots of animal trajectory. To motivate future use, the 3 raw data objects are annotated with a general schema-one that abstracts the data records from their particular experiment while providing, at the same time, a detailed list of independent variables bearing on behavioral performance. The raw data objects are deposited as 43 datasets but constitute, functionally, a library containing 1 large dataset. CONCLUSIONS: Size and annotation schema give the library high reuse potential: in applications using machine learning techniques, statistical evaluation of subtle factors, simulation of new experiments, or as educational resource. Ultimately, the library can serve both as the seed and as the test bed to create a machine-searchable virtual library of linked open datasets for behavioral performance in defined conditions.
Assuntos
Transtorno Obsessivo-Compulsivo , Roedores , Ratos , Animais , Bibliotecas Digitais , Modelos Animais de Doenças , EncéfaloRESUMO
This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies for OCD are then reviewed, including monotherapy with serotonin reuptake inhibitors and augmentation with antipsychotic medication and with psychologic treatment. Neuromodulatory therapies for OCD are also described, including psychosurgery, deep brain stimulation, and noninvasive brain stimulation. Psychotherapies for OCD are then reviewed, focusing on behavior therapy, including exposure and response prevention and cognitive therapy, and the efficacy of these interventions is discussed, touching on issues such as the timing of sessions, the adjunctive role of pharmacotherapy, and the underlying mechanisms. Next, current research on the neurobiology of OCD is examined, including work probing the role of various neurotransmitters and other endogenous processes and etiology as clues to the neurobiological fault that may underlie OCD. A new perspective on preclinical research is advanced, using the Research Domain Criteria to propose an adaptationist viewpoint that regards OCD as the dysfunction of a normal motivational system. A systems-design approach introduces the security motivation system (SMS) theory of OCD as a framework for research. Finally, a new perspective on psychopharmacological research for OCD is advanced, exploring three approaches: boosting infrastructure facilities of the brain, facilitating psychotherapeutic relearning, and targeting specific pathways of the SMS network to fix deficient SMS shut-down processes. SIGNIFICANCE STATEMENT: A significant proportion of patients with obsessive-compulsive disorder (OCD) do not achieve remission with current treatments, indicating the need for innovations in psychopharmacology for the disorder. OCD may be conceptualized as the dysfunction of a normal, special motivation system that evolved to manage the prospect of potential danger. This perspective, together with a wide-ranging review of the literature, suggests novel directions for psychopharmacological research, including boosting support systems of the brain, facilitating relearning that occurs in psychotherapy, and targeting specific pathways in the brain that provide deficient stopping processes in OCD.
Assuntos
Antipsicóticos/uso terapêutico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/psicologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Animais , Antipsicóticos/farmacologia , Estimulação Encefálica Profunda , Humanos , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/terapia , Psicofarmacologia , Psicoterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
We briefly review current approaches to the diagnosis and treatment of OCD, noting their lack of a strong theoretical foundation. In keeping with the Research Domain Criteria project (RDoC) calls for reconceptualizing psychopathology in ways that better link up with normal brain systems, we advance an adaptationist, brain-network perspective on OCD and propose that OCD represents a dysfunction in the stopping dynamics of a normal brain network that evolved to handle potential danger. We then illustrate how this theoretical perspective can be used to organize possibilities for research on neurotherapeutics for OCD and suggest novel directions for future work.
Assuntos
Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Encéfalo/patologia , Encéfalo/fisiopatologia , Humanos , Modelos Teóricos , Motivação , Plasticidade NeuronalRESUMO
Here we present an empirical study that provides a basis for understanding the impact of the social environment on individuals with mental disorders. Rats treated chronically with the dopamine-agonist quinpirole offer a solid animal model for compulsive behavior that has been comprehensively evaluated and validated in numerous studies. Moreover, the method of behavioral analysis used in the quinpirole rat model has been similarly applied to the analysis of compulsive rituals in OCD patients, revealing similarities to the structure of compulsions in the quinpirole-sensitized rats. Here, we examined how compulsive checking by quinpirole-sensitized rats was modulated by the presence of a partner that was also treated with quinpirole or a partner that was treated with saline, compared to the typical expression of compulsive checking shown by rats tested alone. Our results demonstrate that the presence of a partner does indeed modulate the performance of checking behavior. Specifically, the vigor of compulsive checking was attenuated in the presence of a saline-treated partner, and augmented in the presence of a quinpirole-treated partner. This finding provides compelling evidence that social interactions modulate the expression of compulsive checking in the quinpirole rat model of OCD. This uncovering of the effectiveness of social modulation, indicates the quinpirole preparation as a paradigm for investigating the mechanisms by which the social environment modulates the development and expression of OCD. More generally, it presents a paradigm for the study of the influence of drug effects as a function of social interaction.
Assuntos
Comportamento Compulsivo/psicologia , Transtorno Obsessivo-Compulsivo/psicologia , Comportamento Social , Animais , Modelos Animais de Doenças , Masculino , Atividade Motora , Quimpirol , Ratos Sprague-Dawley , Índice de Gravidade de DoençaRESUMO
Long-term treatment of rats with the D2/D3 dopamine agonist quinpirole induces compulsive checking (proposed as animal model of obsessive-compulsive disorder) and locomotor sensitization. The mechanisms by which long-term use of quinpirole produces those behavioral transformations are not known. Here we examined whether changes in gut microbiota play a role in these behavioral phenomena, by monitoring the development of compulsive checking and locomotor sensitization at the same time as measuring the response of gut microbiota to chronic quinpirole injections. Two groups of rats received nine injections of saline (n=16) or quinpirole (n=15; 0.25 mg/kg), at weekly intervals for the first 5 weeks and then two injections per week until the end of treatment. After each injection, rats were placed on a large open field for 55 min, and their behavior was video recorded for subsequent analysis. Fecal matter was collected after each trial and frozen for bacterial community profiling of the 16S rRNA gene, using paired-end reads of the V3 region. The results indicated that the induction of locomotor sensitization and compulsive checking was accompanied by changes in several communities of bacteria belonging to the order Clostridiales (class Clostridia, phylum Firmicutes), and predominantly in Lachnospiraceae and Ruminococcaceae families of bacteria. It is suggested that changes in these microbes may serve to support the energy use requirements of compulsive checking and obsessive-compulsive disorder.
Assuntos
Comportamento Compulsivo/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Locomoção/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Compulsivo/induzido quimicamente , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Microbioma Gastrointestinal/genética , Locomoção/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Quimpirol/farmacologia , RNA Ribossômico 16S , Ratos , Ratos Long-Evans , Receptores Dopaminérgicos/fisiologia , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.
Assuntos
Transtorno Obsessivo-Compulsivo , Animais , Gânglios da Base , Comportamento Compulsivo , Estimulação Encefálica Profunda , Modelos Animais de Doenças , HumanosRESUMO
Chronic treatment with the dopamine D2/D3 agonist, quinpirole, or the serotonin 1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), induces behavioral sensitization. It is not known whether both drugs produce sensitization through a shared mechanism. Here, we examine whether quinpirole and 8-OH-DPAT show cross-sensitization and impact sensitization, as would be expected from shared mechanisms. Male rats (N=208) were assigned randomly to 16 groups formed by crossing four doses of quinpirole (0, 0.03125, 0.0625, or 0.125 mg/kg) with four doses of 8-OH-DPAT (0, 0.03125, 0.625, or 0.125 mg/kg). After a course of 10 drug treatments administered twice per week in locomotor activity chambers, all groups were challenged on separate tests with quinpirole (0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), or saline, and locomotor activity was evaluated. Challenge tests with quinpirole and 8-OHDPAT showed no cross-sensitization between the drugs. Chronic quinpirole (0.125 mg/kg) administration induced a sensitized quinpirole response that was attenuated dose-dependently by chronic 8-OH-DPAT cotreatment. Cotreatment with quinpirole (0.0625 mg/kg) and 8-OH-DPAT (all doses) induced quinpirole sensitization. Chronic 8-OH-DPAT (0.125 mg/kg) induced a sensitized 8-OHDPAT response that was prevented by chronic cotreatment with the lowest but not the highest dose of quinpirole. Cotreatment with 8-OHDPAT (0.0625) and quinpirole (0.125 mg/kg) induced sensitization to 8-OH-DPAT. The saline challenge test showed elevated locomotor activity in chronic quinpirole (0.125 mg/kg) and 8-OHDPAT (0.0625, 0.125 mg/kg) alone groups, and in seven of nine cotreated groups. The absence of cross-sensitization suggests separate mechanisms of sensitization to quinpirole and 8-OH-DPAT. Cotreatment effects suggest that induction of sensitization can be modulated by serotonin 1A and D2/D3 activity.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Agonistas de Dopamina/farmacologia , Quimpirol/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Quimpirol/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Long-Evans , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Agonistas do Receptor de Serotonina/administração & dosagemRESUMO
Previous studies have shown that the resting electroencephalogram (EEG) alpha patterns of non-clinical participants who score high on measures of negative affect, such as depression and shyness, are different from those who score low. However, we know relatively little about patterns of resting EEG alpha patterns in a non-clinical sample of individuals with high levels of obsessive-compulsive behaviors indicative of obsessive-compulsive disorder (OCD). Here we measured resting EEG alpha activity in frontal and parietal regions of non-clinical participants who scored high and low on the Padua-R, a measure of the severity of OCD-related behaviors. We found that participants who scored high on the Padua-R exhibited decreased overall activity in frontal regions relative to individuals who scored low on the measure. We speculate that frontal hypoactivity may be a possible marker and/or index of risk for OCD.
RESUMO
BACKGROUND AND OBJECTIVES: In previous experiments, OCD washers did not differ significantly from controls in their initial level of activation in response to the potential threat of contamination; however, they were less able to reduce their activation by engaging in hand-washing, suggesting that the key problem in OCD is a faulty stopping mechanism. The main objectives of the present experiments were to develop a similar experimental paradigm for investigating checking behavior, and to use it to test the hypothesis that a faulty stopping mechanism also underlies OCD checking. METHODS: Participants sorted pills under the guise of beta testing a new medication system and then were given suggestions of the possibility of having made mistakes with potentially serious consequences. Later, participants engaged in a 90-s checking period and an unlimited period of checking. At baseline and three other times during the experiment, security motivation was measured with respiratory sinus arrhythmia (RSA) and subjective ratings of confidence. Experiment 1 established the parameters of the paradigm in non-patient participants, and Experiment 2 contrasted OCD checkers with OCD washers and non-patients. RESULTS: Results for both subjective and physiological measures of security motivation closely replicated previous findings for washing behavior. Groups did not differ significantly in initial activation, but the OCD checkers were unable to reduce their activation by engaging in period of checking that was ample for returning controls to baseline. LIMITATIONS: The sample size for the patient groups was modest. CONCLUSIONS: These results lend further support to the security-motivation theory of OCD.
Assuntos
Comportamento Compulsivo/psicologia , Motivação , Transtorno Obsessivo-Compulsivo , Arritmia Sinusal Respiratória/fisiologia , Adolescente , Adulto , Idoso , Análise de Variância , Comportamento Compulsivo/diagnóstico , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/psicologia , Fatores de Tempo , Adulto JovemRESUMO
To investigate the role of the nucleus accumbens core (NAc) in the development of quinpirole-induced compulsive checking, rats received an excitotoxic lesion of NAc or sham lesion and were injected with quinpirole (0.5 mg/kg) or saline; development of checking behavior was monitored for 10 biweekly tests. The results showed that even after the NAc lesion, quinpirole still induced compulsive checking, suggesting that the pathogenic effects produced by quinpirole lie outside the NAc. Although the NAc lesion did not prevent the induction of compulsive checking, it altered how quickly it develops, suggesting that the NAc normally contributes toward the induction of compulsive checking. Saline-treated rats with an NAc lesion were hyperactive, but did not develop compulsive checking, indicating that hyperactivity by itself is not sufficient for the pathogenesis of compulsive checking. It is proposed that compulsive checking is the exaggerated output of a security motivation system and that the NAc serves as a neural hub for coordinating the orderly activity of neural modules of this motivational system. Evidence is considered suggesting that the neurobiological condition for the pathogenesis of compulsive checking is two-fold: activation of dopamine D2/D3 receptors without concurrent stimulation of D1-like receptors and long-term plastic changes related to quinpirole-induced sensitization.
Assuntos
Comportamento Compulsivo/fisiopatologia , Hipercinese/fisiopatologia , Núcleo Accumbens/metabolismo , Quimpirol/farmacologia , Animais , Comportamento Compulsivo/induzido quimicamente , Modelos Animais de Doenças , Hipercinese/induzido quimicamente , Masculino , Ratos , Ratos Long-Evans , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismoRESUMO
There is emerging evidence for a dopamine (DA)-serotonin (5-HT) interaction underlying obsessive-compulsive disorder (OCD). In the quinpirole sensitization rat model of OCD, compulsive checking is induced by chronic treatment with the DA agonist quinpirole, and is attenuated by the 5-HT agonist drug mCPP. However, mCPP has affinity for a number of 5-HT receptor subtypes, and it is unknown by which receptors mCPP exerts its effects on quinpirole-treated animals. The present study tested in rats whether mCPP activity at 5-HT2A/C receptors mediates the attenuation of compulsive checking in quinpirole-treated animals. Rats were chronically treated with quinpirole on the open field for the induction of compulsive checking. Following the induction phase, animals were treated with mCPP (1.25 mg/kg) and the selective 5-HT2A/C receptor antagonist ritanserin (1 mg/kg or 5 mg/kg) to test whether blockade of 5-HT2A/C receptors inhibits attenuation of checking by mCPP. Results showed that as expected, quinpirole induced compulsive checking, and mCPP reduced its performance. However, 5-HT2A/C receptor blockade by ritanserin did not inhibit the attenuation of compulsive checking by mCPP. These results suggest that the reduction in compulsive checking by mCPP is not mediated by activity at 5-HT2A/C receptors, but by another receptor subtype.
Assuntos
Comportamento Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Animais , Modelos Animais de Doenças , Masculino , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Piperazinas/farmacologia , Quimpirol , Ratos , Ratos Long-Evans , Ritanserina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
A previous analysis of the quinpirole sensitisation rat model of obsessive-compulsive disorder revealed that the behavioral phenotype of compulsive checking consists of three constitutive components - vigor of checking performance, focus on the task of checking, and satiety following a bout of checking. As confirmation of this analysis, the aim of the present study was to reconstitute, without quinpirole treatment, each of the putative components, with the expectation that these would self-assemble into compulsive checking. To reconstitute vigor and satiety, the employed treatment was a bilateral lesion of the nucleus accumbens core (NAc), as this treatment was shown previously to exaggerate these components. To reconstitute focus, the employed treatment was a low dose of the serotonin-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (DPAT) (0.0625 mg/kg), as high doses of this drug induce compulsive behavior and exacerbate focus. Results showed that injection of DPAT to NAc lesion rats did yield compulsive checking. Neither the drug alone nor the NAc lesion by itself produced compulsive checking. The demonstrated synthesis of compulsive checking by the combined treatment of low-dose DPAT and NAc lesion strengthened the previous fractionation of the model obsessive-compulsive disorder phenotype into three constitutive components, and suggested a role for serotonin-1A receptors outside the NAc in enhanced focus on the task of checking.
Assuntos
Comportamento Compulsivo/fisiopatologia , Núcleo Accumbens/fisiopatologia , Receptor 5-HT1A de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/lesões , Transtorno Obsessivo-Compulsivo , Fenótipo , Ratos Long-Evans , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
RATIONALE: Acute administration of serotonergic agonist, meta-chlorophenylpiperazine (mCPP), attenuates performance of compulsive checking in an animal model of obsessive-compulsive disorder (OCD). It is not known whether mCPP has a similar effect on development of compulsive checking. OBJECTIVES: The objective of the study was to examine whether similar mechanisms mediate the development versus the performance of compulsive checking in the rat model. METHODS: Four groups of male rats (N = 14/group) were tested: two experimental groups co-injected with D2/D3 dopamine agonist quinpirole (0.25 mg/kg) and mCPP (0.625 mg/kg or 1.25 mg/kg), and two control groups, one co-injected with quinpirole and saline, the other receiving injections of saline. The time course of development of compulsive checking across injections 1 to 10 in quinpirole-treated rats was compared to rats co-injected with quinpirole and mCPP. RESULTS: Results showed that during the course of chronic treatment, mCPP (1.25 mg/kg) significantly attenuated performance of checking behavior. However, when these rats were retested for expression of compulsive checking (that is, with an injection of quinpirole only), their profile of compulsive checking was no different from the control rats treated throughout with quinpirole only. CONCLUSIONS: Findings show that mCPP inhibits performance of compulsive checking but does not block quinpirole from inducing the neural substrate underlying this compulsive behavior. Hence, a separate mechanism underlies the induction of compulsive checking and the performance of it. It is suggested that development of the OCD endophenotype reflects neuroplastic changes produced by repeated dopamine D2/D3 receptor stimulation, while stimulation of serotonergic receptors mediates a negative feedback signal that shuts down the motor performance of checking.
Assuntos
Comportamento Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Piperazinas/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Comportamento Compulsivo/induzido quimicamente , Modelos Animais de Doenças , Masculino , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Quimpirol , Ratos , Ratos Long-Evans , Receptores de Dopamina D3/agonistasRESUMO
Research indicates that there is a specially adapted, hard-wired brain circuit, the security motivation system, which evolved to manage potential threats, such as the possibility of contamination or predation. The existence of this system may have important implications for policy-making related to security. The system is sensitive to partial, uncertain cues of potential danger, detection of which activates a persistent, potent motivational state of wariness or anxiety. This state motivates behaviors to probe the potential danger, such as checking, and to correct for it, such as washing. Engagement in these behaviors serves as the terminating feedback for the activation of the system. Because security motivation theory makes predictions about what kinds of stimuli activate security motivation and what conditions terminate it, the theory may have applications both in understanding how policy-makers can best influence others, such as the public, and also in understanding the behavior of policy-makers themselves.
RESUMO
RATIONALE: The serotonergic agonist, meta-chlorophenylpiperazine (mCPP), produces inconsistent effects on obsessive-compulsive disorder (OCD) symptoms, perhaps because clinical studies have not utilized a homogenous OCD subgroup of patients. OBJECTIVES: This study aimed to evaluate mCPP effects on functional components of compulsive checking, using the quinpirole sensitization rat model of OCD. METHODS: In study 1, the effects of mCPP were evaluated in quinpirole rats with compulsive checking. Two experimental groups were co-injected with quinpirole (0.125 mg/kg) and mCPP (0.625 or 1.25 mg/kg), while one control group was co-injected with quinpirole (0.125 mg/kg) and saline and the other control group received co-injections of saline. In study 2, mCPP (0, 0.3125, 0.625, and 1.25 mg/kg) was administered repeatedly to naïve rats and induction of compulsive checking evaluated. RESULTS: mCPP significantly attenuated quinpirole-induced compulsive checking behavior by reducing vigor of checking (indexed by frequency of checking and length of check) and increasing rest after a bout of checking (indexed by time to the next checking bout), but it did not affect focus on the task of checking (indexed by recurrence time of checking and number of stops before returning to check). In naïve rats, mCPP did not induce compulsive behavior, but the highest dose reduced vigor of checking performance compared to saline controls. CONCLUSIONS: mCPP did not exacerbate or induce compulsive checking behavior. Instead, it ameliorated compulsive checking by reducing vigor of checking and increasing post-checking satiety, without affecting focus on checking. Ameliorative effects of mCPP may involve 5HT2A/2C receptors in substantia nigra pars reticulata that inhibit expression of motor vigor.
Assuntos
Transtorno Obsessivo-Compulsivo/fisiopatologia , Piperazinas/farmacologia , Quimpirol/toxicidade , Agonistas do Receptor de Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Compulsivo/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Piperazinas/administração & dosagem , Ratos , Ratos Long-Evans , Agonistas do Receptor de Serotonina/administração & dosagem , Fatores de TempoRESUMO
We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (<1 year old) learned the task well. However, older untreated mice (>1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when â¼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Cognição/fisiologia , Suplementos Nutricionais , Aprendizagem/fisiologia , Mitocôndrias/metabolismo , Animais , Transtornos Cognitivos/patologia , Sinais (Psicologia) , Transporte de Elétrons , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/metabolismo , Tamanho do ÓrgãoRESUMO
This study investigated whether the serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) can induce compulsive checking in a large open field, as does the dopamine D2/D3 receptor agonist quinpirole. To induce compulsive checking, male rats were exposed to eight injections of either 8-OH-DPAT (1 mg/kg), quinpirole (0.2 mg/kg), or saline. Subsequently, to assess cross-sensitization, rats received an acute challenge of 8-OH-DPAT or quinpirole. The results showed that treatment with 8-OH-DPAT induces compulsive checking and may have a stronger effect on this behavior compared with quinpirole. However, there was no cross-sensitization between 8-OH-DPAT and quinpirole on measures of compulsive checking and locomotion. Moreover, the spatial distribution of locomotor paths in 8-OH-DPAT animals was more confined and invariant than in quinpirole rats; their rate of locomotor sensitization was also faster than that in quinpirole animals. Thus, although 8-OH-DPAT and quinpirole can induce compulsive checking in a large open field, the results suggest that they do so differently. It is suggested that 8-OH-DPAT and quinpirole probably produce compulsive behavior by acting on different parts of a security motivation circuit underlying obsessive-compulsive disorder. Quinpirole may induce compulsive checking behavior by directly driving dopaminergic activity mediating the motivational drive to check. Conversely, 8-OH-DPAT may perpetuate the activated motivational state by inhibiting the serotonergic-negative feedback signals that normally deactivate the obsessive-compulsive disorder circuit.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/toxicidade , Encéfalo/efeitos dos fármacos , Proteínas do Tecido Nervoso/agonistas , Neurônios/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Quimpirol/toxicidade , Agonistas do Receptor de Serotonina/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Compulsivo/induzido quimicamente , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Interações Medicamentosas , Masculino , Neurônios/metabolismo , Distribuição Aleatória , Ratos , Ratos Long-Evans , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/toxicidade , Agonistas do Receptor 5-HT2 de Serotonina/toxicidade , Agonistas do Receptor 5-HT3 de Serotonina/toxicidade , Comportamento Espacial/efeitos dos fármacosRESUMO
BACKGROUND: In obsessive-compulsive disorder (OCD), individuals feel compelled to repeatedly perform security-related behaviors, even though these behaviours seem excessive and unwarranted to them. The present research investigated two alternative ways of explaining such behavior: (1) a dysfunction of activation--a starting problem--in which the level of excitation in response to stimuli suggesting potential danger is abnormally strong; versus (2) a dysfunction of termination--a stopping problem--in which the satiety-like process for shutting down security-related thoughts and actions is abnormally weak. METHOD: In two experiments, 70 patients with OCD (57 with washing compulsions, 13 with checking compulsions) and 72 controls were exposed to contamination cues--immersing a hand in wet diapers--and later allowed to wash their hands, first limited to 30 s and then for as long as desired. The intensity of activation of security motivation was measured objectively by change in respiratory sinus arrythmia. Subjective ratings (e.g., contamination) and behavioral measures (e.g., duration of hand washing) were also collected. RESULTS: Compared to controls, OCD patients with washing compulsions did not differ significantly in their levels of initial activation to the threat of contamination; however, they were significantly less able to reduce this activation by engaging in the corrective behavior of hand-washing. Further, the deactivating effect of hand-washing in OCD patients with checking compulsions was similar to that for controls, indicating that the dysfunction of termination in OCD is specific to the patient's symptom profile. CONCLUSIONS: These results are the first to show that OCD is characterized by a reduced ability of security-related behavior to terminate motivation evoked by potential danger, rather than a heightened initial sensitivity to potential threat. They lend support to the security-motivation theory of OCD (Szechtman & Woody, 2004) and have important implications both for research into the biological mechanisms underlying OCD and for the development of new treatment approaches.
Assuntos
Comportamento Compulsivo/psicologia , Motivação/fisiologia , Transtorno Obsessivo-Compulsivo/etiologia , Transtorno Obsessivo-Compulsivo/psicologia , Adulto , Comportamento Compulsivo/fisiopatologia , Fraldas Infantis , Feminino , Desinfecção das Mãos , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/fisiopatologia , Autoestimulação/fisiologia , Tato/fisiologia , Água/fisiologia , Adulto JovemRESUMO
BACKGROUND: This study focused on hypotheses regarding the source of incompleteness in obsessive-compulsive disorder (OCD). For this, we had to document the behavioral manifestation of incompleteness in compulsive rituals, predicting that an exaggerated focus on acts that are appropriate for the task will support the hypothesis on heightened responsibility/perfectionism. In contrast, activity past the expected terminal act for the motor task would support the "stop signal deficiency" hypothesis. METHODOLOGY AND PRINCIPAL FINDINGS: We employed video-telemetry to analyze 39 motor OCD rituals and compared each with a similar task performed by a non-OCD individual, in order to objectively and explicitly determine the functional end of the activity. We found that 75% of OCD rituals comprised a "tail," which is a section that follows the functional end of the task that the patients ascribed to their activity. The other 25% tailless rituals comprised a relatively high number and higher rate of repetition of non-functional acts. Thus, in rituals with tail, incompleteness was manifested by the mere presence of the tail whereas in tailless rituals, incompleteness was manifested by the reduced functionality of the task due to an inflated execution and repetition of non-functional acts. CONCLUSIONS: The prevalence of activity after the functional end ("tail") and the elevated non-functionality in OCD motor rituals support the "lack of stop signal" theories as the underlying mechanism in OCD. Furthermore, the presence and content of the tail might have a therapeutic potential in cognitive-behavior therapy.