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Effects of quinpirole in the ventral tegmental area on impulsive behaviour during performance on the five-choice serial reaction time task.

ABSTRACT: Impulsive behaviour on the five-choice serial reaction time task (5CSRTT), a task measuring attention and impulsivity in rodents, is known to depend on dopamine (DA) neurotransmission in the mesolimbic DA pathway. Previous research in our lab reported that systemic administration of the D2/3 agonist quinpirole, which decreases DA release in the striatum, reduced premature responses in rats performing the 5CSRTT. It is unclear, however, whether this effect is mediated by the activation of inhibitory somatodendritic receptors in the ventral tegmental area (VTA), which in turn leads to a reduction in DA release in the nucleus accumbens, a major terminal region of the mesolimbic DA pathway. In the present study, we investigated this possibility by infusing quinpirole directly into the VTA of rats during performance on the 5CSRTT. We found that quinpirole, at the highest dose, significantly reduced the frequency of premature responses on the 5CSRTT. Thus, the effects of quinpirole and other D2/3 receptor agonists to reduce this form of impulsive behaviour appear to depend on the activation of somatodendritic D2/3 receptors in the VTA.

SUBMITTER: Toschi C

PROVIDER: S-EPMC9895024 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Effects of quinpirole in the ventral tegmental area on impulsive behaviour during performance on the five-choice serial reaction time task.

Toschi Chiara C Robbins Trevor W TW Dalley Jeffrey W JW

Experimental brain research 20230110 2

Impulsive behaviour on the five-choice serial reaction time task (5CSRTT), a task measuring attention and impulsivity in rodents, is known to depend on dopamine (DA) neurotransmission in the mesolimbic DA pathway. Previous research in our lab reported that systemic administration of the D2/3 agonist quinpirole, which decreases DA release in the striatum, reduced premature responses in rats performing the 5CSRTT. It is unclear, however, whether this effect is mediated by the activation of inhibit ...[more]

PMID: 36625968

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Project description:The subthalamic nucleus (STN), a key component of the basal ganglia circuitry, receives inputs from broad cerebral cortical areas and relays cortical activity to subcortical structures. Recent human and animal studies have suggested that executive function, which is assumed to consist of a set of different cognitive processes for controlling behavior, depends on precise information processing between the cerebral cortex and subcortical structures, leading to the idea that the STN contains neurons that transmit the information required for cognitive processing through their activity, and is involved in such cognitive control directly and dynamically. On the other hand, the STN activity also affects intracellular signal transduction and gene expression profiles influencing plasticity in other basal ganglia components. The STN may also indirectly contribute to information processing for cognitive control in other brain areas by regulating slower signaling mechanisms. However, the precise correspondence and causal relationship between the STN activity and cognitive processes are not fully understood. To address how the STN activity is involved in cognitive processes for controlling behavior, we applied Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic manipulation of neural activity to behavioral analysis using a touchscreen operant platform. We subjected mice selectively expressing DREADD receptors in the STN neurons to a five-choice serial reaction time task, which has been developed to quantitatively measure executive function. Chemogenetic suppression of the STN activity reversibly impaired attention, especially required under highly demanding conditions, and increased impulsivity but not compulsivity. These findings, taken together with the results of previous lesion studies, suggest that the STN activity, directly and indirectly, participates in cognitive processing for controlling behavior, and dynamically regulates specific types of subprocesses in cognitive control probably through fast synaptic transmission.

Project description:Decades of research have revealed the remarkable complexity of the midbrain dopamine (DA) system, which comprises cells principally located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Neither homogenous nor serving a singular function, the midbrain DA system is instead composed of distinct cell populations that (1) receive different sets of inputs, (2) project to separate forebrain sites, and (3) are characterized by unique transcriptional and physiological signatures. To appreciate how these differences relate to circuit function, we first need to understand the anatomical connectivity of unique DA pathways and how this connectivity relates to DA-dependent motivated behavior. We and others have provided detailed maps of the input-output relationships of several subpopulations of midbrain DA cells and explored the roles of these different cell populations in directing behavioral output. In this study, we analyze VTA inputs and outputs as a high dimensional dataset (10 outputs, 22 inputs), deploying computational techniques well-suited to finding interpretable patterns in such data. In addition to reinforcing our previous conclusion that the connectivity in the VTA is dependent on spatial organization, our analysis also uncovered a set of inputs elevated onto each projection-defined VTADA cell type. For example, VTADA→NAcLat cells receive preferential innervation from inputs in the basal ganglia, while VTADA→Amygdala cells preferentially receive inputs from populations sending a distributed input across the VTA, which happen to be regions associated with the brain's stress circuitry. In addition, VTADA→NAcMed cells receive ventromedially biased inputs including from the preoptic area, ventral pallidum, and laterodorsal tegmentum, while VTADA→mPFC cells are defined by dominant inputs from the habenula and dorsal raphe. We also go on to show that the biased input logic to the VTADA cells can be recapitulated using projection architecture in the ventral midbrain, reinforcing our finding that most input differences identified using rabies-based (RABV) circuit mapping reflect projection archetypes within the VTA.

Dataset Information

Effects of quinpirole in the ventral tegmental area on impulsive behaviour during performance on the five-choice serial reaction time task.

Publications

Effects of quinpirole in the ventral tegmental area on impulsive behaviour during performance on the five-choice serial reaction time task.

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