Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors.

BACKGROUND: We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA). METHODS: 6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/DeltaFosB expression were examined immunohistochemically. RESULTS: L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and chronic administration. Similar levels were observed in matrix and striosomes, and in enkephalin-positive and dynorphin-positive neurons. The severity of dyskinesia was positively correlated with phospho-ERK1/2 levels. Phosphorylation of ERK1/2 and MSK-1 was dose-dependently blocked by SCH23390, but not by raclopride. SCH23390 also inhibited the development of dyskinesia and the induction of FosB/DeltaFosB. CONCLUSIONS: L-DOPA produces pronounced activation of ERK1/2 signaling in the dopamine-denervated striatum through a D1-receptor-dependent mechanism. This effect is associated with the development of dyskinesia. Phosphorylated ERK1/2 is localized to both dynorphinergic and enkephalinergic striatal neurons, suggesting a general role of ERK1/2 as a plasticity molecule during L-DOPA treatment.

Electroconvulsive shock enhances striatal dopamine D1 and D3 receptor binding and improves motor performance in 6-OHDA-lesioned rats.

OBJECTIVE: Electroconvulsive therapy (ECT) is a widely used and effective treatment for mood disorders and appears to have positive effects on the motor symptoms of Parkinson's disease (PD), improving motor function for several weeks. Because repeated electroconvulsive shock (ECS) in normal animals enhances striatal dopamine (DA) D(1) and D(3) receptor binding, we hypothesized that upregulation of D(1) and D(3) receptors may also be occurring in the parkinsonian brain after repeated ECS treatment. METHODS: Rats were rendered hemi-parkinsonian through unilateral infusion of the DA-specific neurotoxin 6-hydroxydopamine into the medial forebrain bundle and substantia nigra. The animals were tested for hindlimb and forelimb function before and 48 hours after the last of 10 daily treatments with ECS or sham. After sacrifice, DA receptor binding was determined autoradiographically. RESULTS: While there was no increase in forelimb use in the cylinder test, ECS treatment significantly improved hindlimb motor performance on a tapered beam-walking test and enhanced striatal D(1) and D(3) receptor binding, without affecting D(2) receptor binding. CONCLUSION: This study suggests that at least part of the mechanism of action of ECT in PD may be enhanced DA function within the direct pathway of the basal ganglia and may support the further study and use of ECT as a potential adjunct treatment for PD.

Animal models of neurodegenerative disease: insights from in vivo imaging studies.

Animal models have been used extensively to understand the etiology and pathophysiology of human neurodegenerative diseases, and are an essential component in the development of therapeutic interventions for these disorders. In recent years, technical advances in imaging modalities such as positron emission tomography (PET) and magnetic resonance imaging (MRI) have allowed the use of these techniques for the evaluation of functional, neurochemical, and anatomical changes in the brains of animals. Combining animal models of neurodegenerative disorders with neuroimaging provides a powerful tool to follow the disease process, to examine compensatory mechanisms, and to investigate the effects of potential treatments preclinically to derive knowledge that will ultimately inform our clinical decisions. This article reviews the literature on the use of PET and MRI in animal models of Parkinson's disease, Huntington's disease, and Alzheimer's disease, and evaluates the strengths and limitations of brain imaging in animal models of neurodegenerative diseases.

Evaluation of the integrity of the dopamine system in a rodent model of Parkinson's disease: small animal positron emission tomography compared to behavioral assessment and autoradiography.

PURPOSE: In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), it is important to determine lesion severity. This evaluation can be performed in vivo, through evaluation of dopamine (DA)-dependent motor function or with small animal positron emission tomography (microPET), or at postmortem, by examining markers for DA neurons. PROCEDURES: Rats were given mild or severe unilateral 6-OHDA lesions, scanned with the tracer [(11)C](+/-)dihydrotetrabenazine ([(11)C]DTBZ), and tested on a tapered/ledged beam-walking task. At postmortem, autoradiography was performed with [(11)C]DTBZ. RESULTS: Autoradiography was significantly correlated with microPET and behavioral scores, whereas the microPET and behavioral data were not significantly correlated. CONCLUSIONS: This study shows that behavioral analysis, microPET, and autoradiography are all good tools for measuring the integrity of the DA system, and demonstrates the utility of the tapered/ledged beam-walking test to screen for lesion severity, as well as the importance of including postmortem analysis after in vivo imaging studies.

Electroconvulsive shock decreases binding to 5-HT2 receptors in nonhuman primates: an in vivo positron emission tomography study with [18F]setoperone.

BACKGROUND: Dysfunction within the serotonin (5-HT) system plays a major role in the etiology of human depression, and treatment with antidepressant drugs downregulates 5-HT(2) receptors in rodents and humans. The consequences of another effective antidepressant treatment, electroconvulsive therapy (ECT), on 5-HT(2) receptors are less established. METHODS: We studied the effects of a course of electroconvulsive shock (ECS) on 5-HT(2) receptor binding in nonhuman primates in vivo using positron emission tomography (PET) and the radiotracer [(18)F]setoperone. Seven adult male rhesus monkeys received two bilateral ECS treatments per week for 3 weeks; PET scans were performed before treatment, and 24 hours, 1 week, and 4-6 weeks after completion of the course of ECS. Regions of interest were placed throughout the cortex, and the data analyzed as the ratio of specific:nonspecific radioactivity accumulation, with the cerebellum used as a measure of nonspecific binding. RESULTS: Serotonin 5-HT(2) binding was significantly decreased at 24 hours and 1 week post-ECS, but returned to baseline 4-6 weeks posttreatment. CONCLUSIONS: These results show for the first time in a primate species that chronic ECS decreases binding to 5-HT(2) receptors and indicate that 5-HT(2) receptor downregulation may be a common effect of both pharmacologic and nonpharmacologic antidepressant treatments.

Quantitative in vitro phosphor imaging using [3H] and [18F] radioligands: the effects of chronic desipramine treatment on serotonin 5-HT2 receptors.

Traditionally, autoradiography of neuroreceptors is performed in vitro using tritiated ligands and low sensitivity X-ray film, requiring long exposure times. In vivo imaging of neuroreceptors using positron emission tomography (PET) suffers poor spatial resolution, but in vitro PET autoradiography is difficult with film due to the short half-life of the isotopes. Storage phosphor screens provide an extremely sensitive alternative to film. To demonstrate and validate quantitative in vitro phosphor imaging with PET and tritiated ligands, we treated rats chronically with the antidepressant desipramine, which results in decreased binding to serotonin 5-HT(2) receptors. Serotonin 5-HT(2) binding decreased significantly in all cortical regions examined as measured by both [(3)H]ketanserin and [(18)F]setoperone. The data from the two radioligands were not significantly different, and the distribution of the receptors was in agreement with previous reports. We also present data on the reusability of tritium-sensitive phosphor screens, and show that the use of simple corrections allows receptor binding data with PET ligands to be compared across different days. The results indicate that phosphor imaging is a valid, fast, and quantifiable technique for measuring neuroreceptor regulation, and that it provides an excellent tool to corroborate in vivo PET data in vitro at higher resolution.

Intracerebroventricular corticotropin-releasing factor increases limbic glucose metabolism and has social context-dependent behavioral effects in nonhuman primates.

Corticotropin-releasing factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic, and hormonal responses to stress within the central nervous system. Patients suffering from depression have abnormal activity in stress responsive brain regions and elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder include behavioral changes such as depressed mood, anhedonia, and psychomotor agitation/retardation. We studied the effects of 434 microgram of CRF given intracerebroventricularly over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like, and externally oriented. Externally oriented behaviors decreased, and anxiety-like behaviors increased regardless of how the animals were housed. Interestingly, increased depressive-like behaviors were only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys by using positron emission tomography and [(18)F]fluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitary/infundibulum, the amygdala, and hippocampus. These results indicate that increased central CRF tone affects primate behavior in a context-dependent manner, and that it activates limbic and stress-responsive regions. The fact that intracerebroventricular CRF increases depressive-like behavior in socially housed animals and increases activity in limbic brain regions may help explain the behavioral and metabolic alterations in humans with affective disorders, and this model could therefore have significant value in the development of novel antidepressant treatments.