Ultrastructural correlates of haloperidol‐induced oral dyskinesias in rat striatum

Roberts, Rosalinda C.; Gaither, Lorie A.; Gao, Xuemin; Kashyap, S.M.; Tamminga, Carol A.

doi:10.1002/syn.890200307

Cited by 88 publications

(78 citation statements)

References 49 publications

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“…This disruption is believed to produce a number of compensatory changes, including increased striatal blood flow as well as activation, regeneration, hypertrophy and change in the number of striatal synapses (Muller and Seeman 1977;Benes et al 1983Benes et al , 1985Meshul and Casey 1989;Meshul et al 1994;Roberts et al 1995). An overriding question, however, is how striatal volume changes may affect either the course of schizophrenia or the efficacy of the different antipsychotic agents.…”

Section: Discussionmentioning

confidence: 99%

Striatal Volume Changes in the Rat Following Long-term Administration of Typical and Atypical Antipsychotic Drugs

Andersson

2002

Neuropsychopharmacology

102

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Caudate-putamen; Basal ganglia; Haloperidol; Clozapine; Olanzapine; Risperidone; Stereology In the last three decades, there has been a notable elucidation concerning the structure, organization and function of the basal ganglia, as well as the clinical relevance of this subcortical structure. The basal ganglia are comprised of four major structures: the striatum (made up of the caudate nucleus, the putamen, and the ventral striatum), the globus pallidus, the substantia nigra, and the subthalamic nucleus. The striatum receives inputs from the neocortex and the substantia nigra and, via the globus pallidus and substantia nigra, modulates thalamic function that, in turn, affects the frontal cortex. Although the role of the basal ganglia in movement planning and execution has been recognized for many years, we now understand that the compartmentalization and diverse chemoarchitecture of the basal ganglia, combined with complex anatomical interrelationships with thalamus and cortex, establishes this structure as a prime component in influencing executive function, emotion, and cognitive behaviors including learning and memory (Alexander et al. 1990). These findings also help explain why lesions of the basal ganglia lead to devastating movement disorders such as Parkinson's and Huntington's disease. Furthermore, due to both the complexity and functional parameters of this structure, the basal ganglia may play an important role in a number of neuropsychiatric disorders such as schizophrenia (Albin et al. 1989).Sensitive structural and functional brain imaging techniques have begun to unravel some of the complicated neuropathology present in schizophrenia. Several structural abnormalities appear to be integral to the disease process itself, including the enlargement of the lateral and third ventricles (Shenton et al. 1997;McCarley et al. 1999) as well as volumetric reductions in temporal cortex (Suddath et al. 1989;Rossi et al. 1990;DeLisi et al. 1991), hippocampus (Bogerts et al. 1985(Bogerts et al. , 1990Suddath et al. 1990), superior temporal gyrus (Barta et al. 1990;Shenton et al. 1992) and thalamus (Andreasen et al. 1994). Other anatomic abnormalities in schizophrenia, however, appear to develop secondarily to the disease process. Postmortem studies and early in vivo imaging studies have reported volumetric increases of the caudate-putamen complex in schizophrenic patients (Heckers et al. 1991;Jernigan et al. 1991). Although initially believed to be a result of a pathological neurodevelopmental process affecting the basal ganglia (Swayze et al. 1992), these structural abnormalities now appear to be probable treatment effects. In a study examining first-episode, treatment-naïve schizophrenia patients, Chakos et al. (1994) demonstrated that the volume of the caudate nucleus increased after an 18-month exposure to typical antipsychotic drugs in direct proportion to the extent of treatment, findings later confirmed by Keshavan et al. (1994). In addition, Doraiswamy et al. (1995) reported that volumetric increase...

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Section: Discussionmentioning

confidence: 99%

Striatal Volume Changes in the Rat Following Long-term Administration of Typical and Atypical Antipsychotic Drugs

Andersson

2002

Neuropsychopharmacology

102

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“…Glutamate-like synapses are more numerous in SZ-Off and are decreased in number with successful treatment and with antipsychotic medication in rats (Roberts et al, 1995), suggesting that antipsychotic medication decreases glutamatergic tone, at least in striatum. Our exploratory finding of elevated vGLUT2 (indicative of increased subcortical glutamate release) (Raju et al, 2006) in SZ-Off, and not SZ-On, subjects are consistent with previous findings of medicationinduced normalization of glutamate release in other brain regions.…”

Section: Treatment Statusmentioning

confidence: 99%

Protein Markers of Neurotransmitter Synthesis and Release in Postmortem Schizophrenia Substantia Nigra

Schoonover

McCollum

Roberts

2016

Neuropsychopharmacol

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The substantia nigra (SN) provides the largest dopaminergic input to the brain, projects to the striatum (the primary locus of action for antipsychotic medication), and receives GABAergic and glutamatergic inputs. This study used western blot analysis to compare protein levels of tyrosine hydroxylase (TH), glutamate decarboxylase (GAD67), and vesicular glutamate transporters (vGLUT1 and vGLUT2) in postmortem human SN in schizophrenia subjects (n = 13) and matched controls (n = 12). As a preliminary analysis, the schizophrenia group was subdivided by (1) treatment status: off medication (n = 4) or on medication (n = 9); or (2) treatment response: treatment resistant (n = 5) or treatment responsive (n = 4). The combined schizophrenia group had higher TH and GAD67 protein levels than controls (an increase of 69.6%, P = 0.01 and 19.5%, P = 0.004, respectively). When subdivided by medication status, these increases were found in the on-medication subjects (TH 88.3%, P = 0.008; GAD67 40.6%, P = 0.003). In contrast, unmedicated schizophrenia subjects had higher vGLUT2 levels than controls (an increase of 28.7%, P = 0.041), but vGLUT2 levels were similar between medicated schizophrenia subjects and controls. Treatment-resistant subjects had significantly higher TH and GAD67 levels than controls (an increase of 121.0%, P = 0.0003 and 58.7%, P = 0.004, respectively). These data suggest increases in dopamine and GABA transmission in the SN in schizophrenia, with a potential relation to treatment and response.

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“…However, we cannot determine if other striatal neuron tic density in the striatum of rats treated for 6 months with ෂ1.5 mg kg −1 day −1 haloperidol; indeed there were populations show a similar change, since their smaller size and lower level of synaptophysin expression make minor decreases in some animals. 27 The different durations and dosages of treatment in these studies may cellular quantitation problematic. Hence we have not speculated upon the significance which synaptic plasexplain the divergence of results.…”

Section: -57mentioning

confidence: 99%

“…4 For example, brain regions differmicroscopy data. [19][20][21][22][23][24][25][26][27][28] entially activated by typical and atypical antipsyMost studies of antipsychotic drug effects on gene chotics have been identified using oncogene expression expression have been limited to acute or subchronic as a marker, 5,6 and mRNAs encoding vesicle-associated treatment. Longer-term studies are also necessary since proteins have been used to localise neuronal and synprolonged or late-onset changes in gene expression may contribute to the delayed therapeutic benefits and side-effects of antipsychotics.…”

Section: Introductionmentioning

confidence: 99%

Chronic haloperidol treatment differentially affects the expression of synaptic and neuronal plasticity-associated genes

1997

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Synaptophysin is a protein used as a marker of presynaptic terminals. We previously showed that, in dorsolateral striatum of the rat, 2 weeks' haloperidol treatment up-regulated synaptophysin mRNA. We have now investigated the effects of 16 weeks' treatment with haloperidol on synaptophysin expression in dorsolateral striatum, frontoparietal cortex and hippocampus, in order to see if the implied haloperidol-induced synaptic plasticity persists. For comparison, in both the 2-and 16-week treatment groups we determined the mRNA abundance of the neuronal plasticity-associated gene GAP-43, and the housekeeping gene cyclophilin. Sixteen weeks' haloperidol administration increased synaptophysin mRNA in striatum and frontoparietal cortex but not in hippocampus. The increase was demonstrable both regionally and per neuron. A similar trend was seen for synaptophysin protein using immunoautoradiography. GAP-43 mRNA was elevated in frontoparietal cortex by 2 weeks' haloperidol but was not significantly changed in any area in the 16-week treatment group. Cyclophilin mRNA, a marker of overall gene expression, was unaffected by haloperidol. The persistent increase in synaptophysin expression supports the evidence that chronic antipsychotic drug treatment induces synaptic reorganisation in some striatal and cortical neuron populations, whereas the GAP-43 mRNA data suggest that haloperidol does not produce a sustained alteration of neuronal plasticity. Further study of plasticity-associated gene expression may be valuable in clarifying the long-term neuronal and synaptic changes produced by antipsychotics, and how these are related to the neurochemical effects of the drugs.

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Ultrastructural correlates of haloperidol‐induced oral dyskinesias in rat striatum

Cited by 88 publications

References 49 publications

Striatal Volume Changes in the Rat Following Long-term Administration of Typical and Atypical Antipsychotic Drugs

Striatal Volume Changes in the Rat Following Long-term Administration of Typical and Atypical Antipsychotic Drugs

Protein Markers of Neurotransmitter Synthesis and Release in Postmortem Schizophrenia Substantia Nigra

Chronic haloperidol treatment differentially affects the expression of synaptic and neuronal plasticity-associated genes

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