A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter

Amato, Davide; Canneva, Fabio; Cumming, Paul; Maschauer, Simone; Groos, Dominik; Dahlmanns, Jana Katharina; Grömer, Teja W.; Chiofalo, L; Dahlmanns, Marc; Zheng, Fang; Kornhuber, Johannes; Prante, Olaf; Alzheimer, Christian; Hörsten, Stephan von; Müller, Christian P.

doi:10.1038/s41380-018-0114-5

Cited by 60 publications

(101 citation statements)

References 73 publications

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“…2C-D). While we recapitulated previous reports on partial receptor occupancy 14,34 and dopamine uptake blockade 14 The decrease in Ca 2+ conductance may derive not only from decreased D2-IPSCs 37 , but also from alterations in pre-and post-synaptic excitatory transmission. NAcc glutamatergic terminals express D2r 38 and HAL functionally competes with endogenous dopamine for binding 39 .…”

Section: Msn Firing Rate Is Not Constant But Alternates Between Perisupporting

confidence: 88%

“…16-95%) [6][7][8][9][10] suggest that this mechanism is poorly predictive of antipsychotic response. Assessment of APD function at a circuit level has proven more predictive of behavioral efficacy in humans [11][12][13] and rodents 14 . In human patients, the effects of APDs on striatal circuitry are assessed from fMRI BOLD signal, which is inhibited by APDs 11,12 .…”

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confidence: 99%

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Neuronal signature of an antipsychotic response

Parrilla-Carrero¹,

Kruyer²,

Chalhoub³

et al. 2020

Preprint

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D2 receptor blockade has been cited as a principal mechanism of action of all antipsychotic medications, but is poorly predictive of symptom improvement or neurophysiological responses recorded using human brain imaging. A potential hurdle in interpreting such human imaging studies arises from the inability to distinguish activity within neuronal subcircuits. We used single cell resolution imaging to record activity in distinct populations of medium spiny neurons in vivo within the mouse ventral striatum, a structure associated with schizophrenia symptoms and antipsychotic therapeutic efficacy. While we expected the antipsychotic haloperidol to excite D2 receptor expressing neurons, we report a strong cellular depression mediated by the hypofunctional NMDA channel, which may be mediated in part by the action of haloperidol on the sigma1 receptor. Altogether, the impact of haloperidol on Ca2+ events in D2 receptor expressing neurons predicted psychomotor inhibition. Our results elucidate mechanisms by which antipsychotics act rapidly in the brain to impact psychomotor outputs.

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Section: Msn Firing Rate Is Not Constant But Alternates Between Perisupporting

confidence: 88%

mentioning

confidence: 99%

Neuronal signature of an antipsychotic response

Parrilla-Carrero¹,

Kruyer²,

Chalhoub³

et al. 2020

Preprint

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“…In a condition like PD where patients suffer from chronic motor impairments, typically slowness of movement, it is paramount to assess the long-term symptom relief in an animal model of Parkinsonism. In line with this, sub-chronic haloperidol treatment significantly reduces locomotor activity, resembling a bradykinesia state in rats (Amato et al 2011(Amato et al , 2018. The present study addressed the question whether 50-kHz USV playback ameliorates psychomotor deficits induced by haloperidol in a sub-chronic dosing regimen implemented by drug administration via osmotic mini-pumps.…”

Section: Introductionmentioning

confidence: 54%

Playback of 50-kHz ultrasonic vocalizations overcomes psychomotor deficits induced by sub-chronic haloperidol treatment in rats

et al. 2020

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Rationale In rodents, acute haloperidol treatment induces psychomotor impairments known as catalepsy, which models akinesia in humans and is characterized as an animal model of acute Parkinsonism, whereas sub-chronic haloperidol reduces exploratory behavior, which resembles bradykinesia. Haloperidol-induced catalepsy in rats can be ameliorated by playback of 50-kHz ultrasonic vocalizations (USV), an emotionally and motivationally relevant appetitive auditory stimulus, representing an animal model of paradoxical kinesia. In a condition like PD where patients suffer from chronic motor impairments, it is paramount to assess the long-term symptom relief in an animal model of Parkinsonism. Objectives We investigated whether 50-kHz USV playback ameliorates psychomotor deficits induced by haloperidol in a subchronic dosing regimen. Methods In phase 1, distance traveled and number of rearing behavior were assessed in an activity chamber in order to investigate whether sub-chronic haloperidol treatment induced psychomotor impairments. In phase 2, we investigated whether 50-kHz USV playback could overcome these impairments by assessing exploratory behaviors and approach behavior towards the sound source in the 50-kHz USV radial maze playback paradigm. Results Sub-chronic haloperidol treatment led to psychomotor deficits since the distance traveled and number of rearing behavior were reduced as compared to saline control group or baseline. These psychomotor impairments were ameliorated during playback of 50-kHz USV, with haloperidol treated rats showing a clear social approach behavior towards the sound source exclusively during playback. Conclusions This study provides evidence that 50-kHz USV playback induces paradoxical kinesia in rats exhibiting motor deficits after sub-chronic haloperidol, as we previously showed after acute haloperidol treatment.

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“…For instance, in the caudate-putamen, d-amphetamine-but not cocaine-depletes dopamine-containing vesicles and enhances tonic dopamine release [75]. The effects of antipsychotic treatment on these processes are not yet known, but antipsychotic-treated rats have potentially enhanced striatal DAT function [11].…”

Section: Dopamine Reuptakementioning

confidence: 99%

“…Antipsychotic-induced dopamine supersensitivity is linked to antipsychotic treatment failure and to an exacerbation of psychosis symptoms [1][2][3][4][5][6][7]. In animals, a widely-used index of antipsychotic-induced dopamine supersensitivity is an exaggerated locomotor response to d-amphetamine [8][9][10][11][12][13][14][15][16][17][18]. In this context, d-amphetamine serves as a pharmacological tool to probe the functional consequences of an acute increase in striatal dopamine release, as seen during psychosis [19].…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats

Servonnet

Allain

Gravel-Chouinard

et al. 2020

Preprint

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Antipsychotic treatment can produce a dopamine supersensitive state. In both schizophrenia patients and rodents, this is linked to antipsychotic treatment failure. In rodents, dopamine supersensitivity is often confirmed by an exaggerated behavioural response to the indirect monoamine agonist, d-amphetamine, after discontinuation of antipsychotic treatment. Here we investigated where and how d-amphetamine acts to trigger behavioural expression of dopamine supersensitivity, as this could uncover pathophysiological mechanisms underlying this supersensitivity. First, we examined the contributions of a central increase in dopamine/monoamine activity. Haloperidol-treated rats showed a potentiated psychomotor response to systemic d-amphetamine, confirming dopamine supersensitivity. However, they showed a normal psychomotor response to an increase in ventral midbrain dopamine impulse flow or to intracerebroventricular injection of d-amphetamine. This suggests that d-amphetamine’s peripheral effects are required for a supersensitive response. Second, we determined the specific contributions of dopamine neurotransmission. The D2 agonist quinpirole, but not the D1 agonist SKF38393 or the dopamine reuptake blocker GBR12783 produced a supersensitive psychomotor response in haloperidol-treated rats. In these rats, the D1 antagonist SCH39166 decreased d-amphetamine-induced psychomotor activity, whereas the D2 antagonist sulpiride enhanced it. Thus, when d-amphetamine triggers a supersensitive response, this involves both D1- and D2-mediated transmission. Finally, we measured d-amphetamine-induced changes in D1- and D2-mediated intracellular signalling pathways in the striatum. In haloperidol-treated rats, a supersensitive response to d-amphetamine was linked to enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens, suggesting increased D2-mediated signalling. These findings provide new insights into the neurobiology of antipsychotic-evoked dopamine supersensitivity.

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A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter

Cited by 60 publications

References 73 publications

Neuronal signature of an antipsychotic response

Neuronal signature of an antipsychotic response

Playback of 50-kHz ultrasonic vocalizations overcomes psychomotor deficits induced by sub-chronic haloperidol treatment in rats

Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats

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