Neurotensin in the nucleus accumbens reverses dopamine supersensitivity evoked by antipsychotic treatment

Servonnet, Alice; Minogianis, Ellie-Anna; Bouchard, Claude; Bédard, Anne-Marie; Lévesque, Daniel; Rompré, Pierre‐Paul; Samaha, Anne‐Noël

doi:10.1016/j.neuropharm.2017.05.015

Cited by 19 publications

(11 citation statements)

References 94 publications

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“…Moreover, antipsychotic-induced dopamine supersensitivity, which decreased serotonin 5-HT2A receptor density in the nucleus accumbens (whereas it increased in other brain regions such as the caudate putamen) and enhanced ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviors, could also be linked to observed changes in 5-HT2A receptor density in the prefrontal cortex and striatum 59 . More interestingly, NT in the nucleus accumbens was found to reverse this dopamine supersensitivity caused by antipsychotic treatment 60 . Therefore, besides confirming that heterogeneous responses in the brain would be expected in response to chronic treatment with antipsychotics, this work also suggests a possible mechanism involving NT and serotonin pathway to explain the differential response of NWR and SHR strains following antipsychotic treatment.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics

Nani

Lee

Yonamine

et al. 2020

Sci Rep

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Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment. We reported previously lower NDEL1 enzyme activity in blood of treated first episode psychosis and chronic schizophrenia (SCZ) compared to healthy control subjects, with even lower activity in treatment resistant chronic SCZ patients, implicating NDEL1 activity in SCZ. Herein, higher NDEL1 activity was observed in the blood and several brain regions of a validated animal model for SCZ at baseline. In addition, long-term treatment with typical or atypical antipsychotics, under conditions in which SCZ-like phenotypes were reported to be reversed in this animal model for SCZ, showed a significant NDEL1 activity reduction in blood and brain regions which is in line with clinical data. Importantly, these results support measuring NDEL1 enzyme activity in the peripheral blood to predict changes in NDEL1 activity in the CNS. Also, acute administration of psychostimulants, at levels reported to induce SCZ-like phenotype in normal rat strains, increased NDEL1 enzyme activity in blood. Therefore, alterations in NDEL1 activity after treatment with antipsychotics or psychostimulants may suggest a possible modulation of NDEL1 activity secondary to neurotransmission homeostasis and provide new insights into the role of NDEL1 in SCZ pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics

Nani

Lee

Yonamine

et al. 2020

Sci Rep

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“…Most importantly, neurotensin injected into the nucleus accumbens attenuates the locomotor response to dopamine agonists [114], and this effect is potentiated in rats with a history of continuous ver-sus extended haloperidol dosing [100]. Because only rats exposed to continuous (versus extended) haloperidol develop a dopamine supersensitive state [39,43,100], the findings suggest that antipsychotic-evoked dopamine supersensitivity is accompanied by an enhanced ability of nucleus accumbens neurotensin to modulate dopamine-dependent behaviour. The implication is that in individuals with established antipsychoticinduced dopamine supersensitivity, the increased responsiveness to neurotensin can be exploited pharmacologically to reverse the expression of this supersensitivity.…”

Section: Neurobiological Effects Of Continuous Versus Extended Antipsmentioning

confidence: 93%

“…After treatment cessation, rats previously treated continuously have a significantly enhanced psychomotor response to dopamine agonists, while animals previously treated using an extended approach show either no change or a modest increase compared to antipsychotic-naïve control rats (Figs. 3C-D) [39,43,44,66,100].…”

Section: Extended Antipsychotic Exposure Is Unlikely To Promote Dopammentioning

confidence: 99%

“…Continuous but not extended antipsychotic treatment enhances neurotensin expression in the caudate-putamen, whereas only extended treatment increases neurotensin type 1 receptor level in the same region [100, see also 113]. Most importantly, neurotensin injected into the nucleus accumbens attenuates the locomotor response to dopamine agonists [114], and this effect is potentiated in rats with a history of continuous ver-sus extended haloperidol dosing [100]. Because only rats exposed to continuous (versus extended) haloperidol develop a dopamine supersensitive state [39,43,100], the findings suggest that antipsychotic-evoked dopamine supersensitivity is accompanied by an enhanced ability of nucleus accumbens neurotensin to modulate dopamine-dependent behaviour.…”

Section: Neurobiological Effects Of Continuous Versus Extended Antipsmentioning

confidence: 99%

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Continuous versus extended antipsychotic dosing in schizophrenia: Less is more

Servonnet

Uchida

Samaha

2021

Behavioural Brain Research

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“…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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Neurotensin in the nucleus accumbens reverses dopamine supersensitivity evoked by antipsychotic treatment

Cited by 19 publications

References 94 publications

Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics

Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics

Continuous versus extended antipsychotic dosing in schizophrenia: Less is more

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

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