Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting. impulsivity

NEUROPHARMACOLOGY

卷:123

Article

Isherwood, Sarah N.^1,2,3  Robbins, Trevor W.^2,3  Nicholson, Janet R.¹  Dalley, Jeffrey W.^2,3,4  Pekcec, Anton¹ 

[1] Boehringer Ingelheim Pharma GmbH & Co KG, Div Res Germany, Birkendorfer Str 65, D-88397 Biberach An Der Riss, Germany

[2] Univ Cambridge, Behav & Clin Neurosci Inst, Downing St, Cambridge CB2 3EB, England

[3] Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England

[4] Univ Cambridge, Dept Psychiat, Downing St, Cambridge CB2 2QQ, England

关键词: Glutamate;    Dopamine;    mGluR4;    D-2 receptors;    Striatum;    Indirect pathway;   

DOI  :  10.1016/j.neuropharm.2017.05.006

来源: Elsevier

【 摘 要 】

Background: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D-2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D-2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D-2 receptor antagonist eticlopride, on two distinct forms of impulsivity. Methods: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. Results: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRIT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpdll also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. Conclusions: These findings demonstrate that mGluR4s, in conjunction with D-2 receptors, affect motor and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes. (C) 2017 The Authors. Published by Elsevier Ltd.

【 授权许可】

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