Comparison of chronic intermittent haloperidol and raclopride effects on striatal dopamine release and synaptic ultrastructure in rats

See, Ronald E.; Chapman, Mary Ann; Meshul, Charles K.

doi:10.1002/syn.890120208

Cited by 31 publications

(27 citation statements)

References 57 publications

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“…The finding that D2L receptor inactivation favors striatal LTP well correlates with the evidence that, in the striatum, haloperidol increases the size of axon terminals (Benes et al, 1985;Uranova et al, 1991;Kerns et al, 1992), the number of glutamatergic synapses (Meshul and Casey, 1989;Uranova et al, 1991;Kerns et al, 1992;See et al, 1992), and the absolute number of vescicles per synapse (Benes et al, 1985). All these morphological changes indicate hyperactivity of glutamatergic transmission and represent structural correlates of LTP (Eastwood et al, 1997;Toni et al, 1999;Konradi and Heckers, 2001;Steward and Worley, 2002).…”

Section: D2l Receptor Inactivation Facilitates Excitatory Transmissiosupporting

confidence: 60%

“…Based on this observation, it has recently been proposed that the promotion of plastic, slowly developing rearrangements of neuronal connectivity is essential for the mode of action of antipsychotics (Konradi and Heckers, 2001). In line with this idea, chronic but not acute haloperidol treatment causes complex ultrastructural changes of glutamatergic synapses in the striatum (Meshul and Casey, 1989;Uranova et al, 1991;Kerns et al, 1992;See et al, 1992), indicative of its ability to promote long-lasting potentiation of excitatory transmission (Eastwood et al, 1997;Toni et al, 1999;Konradi and Heckers, 2001;Steward and Worley, 2002). Such an effect might play a crucial role in the therapeutic effects of this drug because a reduced glutamate-mediated transmission has been recognized to mediate, at least in part, the symptoms of schizophrenia (Carlsson et al, 2001;Goff and Coyle, 2001), and the striatum serves not only motor, but also critical, cognitive and motivational functions altered in schizophrenia.…”

Section: Introductionmentioning

confidence: 75%

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Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors

Centonze¹,

Usiello²,

Costa³

et al. 2004

J. Neurosci.

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Reduced glutamate-mediated synaptic transmission has been implicated in the pathophysiology of schizophrenia. Because antipsychotic agents might exert their beneficial effects against schizophrenic symptoms by strengthening excitatory transmission in critical dopaminoceptive brain areas, in the present study we have studied the effects of acute and chronic haloperidol treatment on striatal synaptic plasticity. Repetitive stimulation of corticostriatal terminals in slices induced either long-term depression or long-term potentiation (LTP) of excitatory transmission in control rats, whereas it invariably induced NMDA receptor-dependent LTP in animals treated chronically with haloperidol. Haloperidol effects were mimicked and occluded in mice lacking both D2L and D2S isoforms of dopamine D2 receptors (D2RϪ/Ϫ), in mice lacking D2L receptors and expressing normal levels of D2S receptors (D2RϪ/Ϫ;D2LϪ/Ϫ), and in mice lacking D2L receptors and overexpressing D2S receptors (D2LϪ/Ϫ). These data indicate that the blockade of D2L receptors was responsible for the LTP-favoring action of haloperidol in the striatum. In contrast, overexpression of D2S receptors uncovered a facilitatory role of this receptor isoform in LTP formation because LTP recorded from D2LϪ/Ϫ mice, but not those recorded from wild-type, D2RϪ/Ϫ, and D2RϪ/Ϫ;D2LϪ/Ϫ mice, was insensitive to the pharmacological blockade of D1 receptors.The identification of the cellular, molecular, and receptor mechanisms involved in the action of haloperidol in the brain is essential to understand how antipsychotic agents exert their beneficial and side effects.

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Section: D2l Receptor Inactivation Facilitates Excitatory Transmissiosupporting

confidence: 60%

Section: Introductionmentioning

confidence: 75%

Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors

Centonze¹,

Usiello²,

Costa³

et al. 2004

J. Neurosci.

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“…87 Other studies of APD treatment have reported an increased percentage of perforated synapses in the caudate with no change in total number, and no differences present in the NAcc. [88][89][90] These studies do not indicate our results are due to APD treatment. Past studies also indicate that APDs increase striatal volume; [91][92][93][94][95] thus, our finding of increased AS synaptic density is likely not an effect of medication, since a larger volume would reduce synaptic density rather than increase it.…”

Section: Limitationscontrasting

confidence: 58%

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

McCollum

Walker

Roche

et al. 2015

SCHBUL

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The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.Key words: electron microscopy/anatomy/striatum/ synapseThe exact pathophysiology for the origin of schizophrenia (SZ) is unknown, however evidence from decades of research implies that interactions between multiple brain regions and multiple neurotransmitter systems are likely at play. One region that is implicated in SZ pathology is the nucleus accumbens (NAcc). The NAcc integrates signaling from multiple regions of the brain, receiving input from areas including the prefrontal cortex, hippocampus, amygdala, thalamus, and midbrain.1 Importantly, all of these areas have been associated with SZ, making the NAcc a prime region for integrating multiple disrupted areas to provide a comprehensive understanding of SZ pathology.2 Reciprocal connections between the NAcc and substantia nigra/ventral tegmental area (SN/VTA) indicate further importance of this region. Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder.4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.The purpose of this study was to provide the first ultrastructural analysis in postmortem human NAcc, and examine the neurocircuitry in the NAcc in SZ to establish the role this region may play in the disorder. We used stereological analysis of electron micrographs in postmortem SZ to analyze the organization an...

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“…Ultrastructural alterations of synaptic structures (Benes et al, 1985;Kerns et al, 1992;Uranova et al, 1991) and increases in striatal volumes in human brain (Chakos et al, 1994;Heckers et al, 1991;Jernigan et al, 1991;Shihabuddin et al, 1998) have also been described. Interestingly, the number of glutamate-containing synapses is increased in the rat striatum after chronic haloperidol treatment (Kerns et al, 1992;Meshul & Casey, 1989;See et al, 1992;Uranova et al, 1991), and an increase in the number of perforated synapses and double synapses has been reported (Kerns et al, 1992). Thus, haloperidol seems to promote synapse splitting, a process by which synapses multiply in the mature brain (Jones & Harris, 1995;Kirov et al, 1999;Toni et al, 1999) (Fig.…”

Section: Role Of Glutamate In Neuroplasticity By Antipsychotic Drugsmentioning

confidence: 91%

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

Konradi

Heckers

2003

Pharmacology & Therapeutics

296

165

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The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.

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Comparison of chronic intermittent haloperidol and raclopride effects on striatal dopamine release and synaptic ultrastructure in rats

Cited by 31 publications

References 57 publications

Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors

Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

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