Haloperidol-induced synaptic changes in striatum are associated with glutamate synapses
Research Service, VA Medical Center, Portland, OR 97201. Brain Research
(Impact Factor: 2.84).
07/1994; 648(2):181-95. DOI: 10.1016/0006-8993(94)91117-7
Sub-chronic treatment with the typical neuroleptic, haloperidol (0.5 mg/kg/d, s.c.), but not the atypical neuroleptic, clozapine (35 mg/kg/day, s.c.), causes an increase in synapses containing a perforated postsynaptic density (referred to as 'perforated' synapses) and in dopamine (DA) D2 receptors within the caudate nucleus . To determine if these perforated synapses are glutamatergic, we systemically co-administered MK-801 (0.3 mg/kg/day for 2 weeks), a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor-associated ion channel, and haloperidol. MK-801 blocked the haloperidol-induced increase in striatal perforated synapses, but not the haloperidol-induced increase in DA D2 receptors. Injection of MK-801 into the striatum also attenuated the haloperidol-induced increase in perforated synapses. Post-embedding immuno-gold electron microscopy using antibodies to glutamate indicated that the gold particles were localized within striatal presynaptic nerve terminals that make contact with perforated postsynaptic densities. These findings support the hypothesis that the haloperidol-induced increase in perforated synapses is regulated by the NMDA subtype of excitatory glutamate receptor. The increase in perforated synapses following administration of haloperidol, which is associated with a high incidence of extrapyramidal side effects (EPS), and the lack of a synaptic change following administration of clozapine, known to have a low frequency of EPS, suggests that glutamate synapses play a role in the motoric side effects that are observed with typical neuroleptic drug treatment.
Available from: Aaron Mercer
- "K. Meshul and M. J. Low, unpublished observations). Using transgenic mice expressing enhanced GFP (EGFP) under control of the Pomc promoter (Cowley et al., 2001), axon terminals from POMC neurons were identified by pre-embedding immunohistochemistry and electron microscopy following the methods of Meshul and McGinty (Meshul et al., 1994, 1999; Meshul and McGinty, 2000). POMC neurons were identified using primary antisera to GFP or ACTH and visualized using biotinylated secondary antibodies and an avidin-coupled DAB reaction product, whereas GABA and glutamate were detected at EGFP- and ACTH-positive synaptic terminals with immunogold-coupled antibodies. "
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ABSTRACT: Central proopiomelanocortin (POMC) neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS) remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: how and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance.
Available from: usc.edu
- "The differences between the experimental groups were analyzed using the Student's t-test. The specificity of the immunolabeling for the glutamate antibody was previously established by incubating the antibody overnight with 3 mM glutamate (Meshul et al., 1994). This mixture was then applied to the sections as detailed above, with the final results showing a lack of tissue immunolabeling. "
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ABSTRACT: The goal of this study was to determine whether there was a difference in glutamate within the dorsolateral striatum in mice exhibiting either a high (HR) or low (LR) locomotor response to a novel environment. The number of line crossings over a 30-min-period when the mice were placed in a novel environment was determined, and those mice for which the values were above the mean were in the HR group and those with the values below the mean were in the LR group. In vivo microdialysis was carried out to determine the basal extracellular level of striatal glutamate, and the contralateral striatum was taken to measure the density of glutamate immunolabeling within nerve terminals making an asymmetrical (excitatory) synaptic contact using quantitative immuno-gold electron microscopy. There was a statistically significant difference (35%) in the basal extracellular level of striatal glutamate between the HR and LR groups, with the HR group having a lower level, compared with that of the LR group. There was a 25% difference in the density of nerve terminal glutamate immuno-gold labeling associated with the synaptic vesicle pool in the HR, compared with that in the LR group, but this difference was not statistically significant. There was no change in the basal extracellular level of striatal dopamine between the two groups, but there was a statistically significant difference (73%) in the basal turnover ratio of striatal dopamine and its metabolites in the HR, compared with that in the LR group. The data suggests that the difference in extracellular striatal glutamate between the HR and LR groups is not due to an alteration in basal extracellular dopamine but could be due to an increase in dopamine turnover.
- "The differences between treatment groups were analyzed using a one-way ANOVA and significant main effects were further characterized using the Fisher post-hoc test for comparison of multiple means. The specificity of the immunolabeling for the glutamate antibody was previously established by incubating the antibody overnight with 3 mM glutamate (Meshul et al., 1994). This mixture was then applied to the sections as detailed above. "
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ABSTRACT: A unilateral lesion of the rat nigrostriatal pathway with 6-hydroxydopamine (6-OHDA) results in a decrease in the basal extracellular level of striatal glutamate, a nearly complete loss of tyrosine hydroxylase (TH) immunolabeling, an increase in the density of glutamate immunogold labeling within nerve terminals making an asymmetrical synaptic contact, and an increase in the number of apomorphine-induced contralateral rotations. [Meshul et al. (1999) Neuroscience 88:1-16; Meshul and Allen (2000) Synapse 36:129-142]. In Parkinson's disease, a lesion of either the subthalamic nucleus (STN) or the motor thalamic nucleus relieves the patient of some of the motor difficulties associated with this disorder. In this rodent model, either the STN or motor thalamic nucleus was electrolytically destroyed 2 months following a unilateral 6-OHDA lesions. Following a lesion of either the STN or motor thalamic nucleus in 6-OHDA-treated rats, there was a significant decrease (40-60%) in the number of apomorphine-induced contralateral rotations compared to the 6-OHDA group. There was a significant decrease (<30%) in the basal extracellular level of striatal glutamate in all of the experimental groups compared to the sham group. Following an STN and/or 6-OHDA lesion, the decrease in striatal extracellular levels was inversely associated with an increase in the density of nerve terminal glutamate immunolabeling. There was no change in nerve terminal glutamate immunogold labeling in either the motor thalamic or motor thalamic plus 6-OHDA lesion groups compared to the sham group. The decrease in the number of apomorphine-induced rotations was not due to an increase in TH immunolabeling (i.e., sprouting) within the denervated striatum. This suggests that alterations in striatal glutamate appear not to be directly involved in the STN or motor thalamic lesion-induced reduction in contralateral rotations.
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