Selective and interactive effects of D 2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity

Abstract

BackgroundMetabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 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 D2 receptor antagonist eticlopride, on two distinct forms of impulsivity.MethodsRats 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.ResultsSystemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT 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. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity.ConclusionsThese findings demonstrate that mGluR4s, in conjunction with D2 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.

Differences in trait impulsivity do not bias the response to pharmacological drug challenge in the rat five-choice serial reaction time task

“…It has not been assessed up to this point if differences in glutamatergic signaling might underlie individual differences in trait-like impulsivity. Previous studies from our group demonstrate that neither modulation of metabotropic glutamate receptor 4 (group III) nor metabotropic glutamate receptor 5 (group I) differentially affects premature responses in HI or LI rats (Isherwood et al 2015 ; Isherwood et al 2017 ). In this study, the effects of the NMDA receptor antagonist MK-801 also did not depend on trait-like baseline impulsivity but resulted in a dose-dependent increase in the number of premature responses, which was concomitant with a dose-dependent decrease in accuracy.…”

“…The 5-CSRTT training protocol has been described previously (Isherwood et al 2015 , 2017 ). Each training session comprised 100 discrete trials and lasted up to 30 min.…”

Ethanol induces maladaptive impulse control and decreased seeking behaviors in mice

“…Furthermore, the anxiety‐like behavior seen in the continuous cohort was also demonstrated in the “abstinent group” 20 days after the last ethanol exposure. Prior to the initiation of ethanol treatments, the mice were tested to evaluate baseline impulsiveness using a 7‐second ITI . In contrast to the “continuous cohort,” baseline premature responses faced an irregular pattern in the “abstinent cohort.” Responses overall were much lower than the “continuous cohort” initially (40% vs 10%).…”

Neural circuitry and mechanisms of waiting impulsivity: relevance to addiction

“…When administered locally in the PFC, atomoxetine improved inhibition on the stop-signal reaction time task [69], indicating that stopping and waiting forms of impulsivity are differentially modulated by cortical and subcortical NA-ergic mechanisms. Other neurotransmitter systems have also been extensively investigated in delay discounting and 5CSRTT impulsivity, including ionotropic and metabotropic glutamate receptors [70][71][72] and endocannabinoids [55,73].…”