Highly impulsive rats: modelling an endophenotype to determine the neurobiological, genetic and environmental mechanisms of addiction

Abstract

Impulsivity describes the tendency of an individual to act prematurely without foresight and is associated with a number of neuropsychiatric co-morbidities, including drug addiction. As such, there is increasing interest in the neurobiological mechanisms of impulsivity, as well as the genetic and environmental influences that govern the expression of this behaviour. Tests used on rodent models of impulsivity share strong parallels with tasks used to assess this trait in humans, and studies in both suggest a crucial role of monoaminergic corticostriatal systems in the expression of this behavioural trait. Furthermore, rodent models have enabled investigation of the causal relationship between drug abuse and impulsivity. Here, we review the use of rodent models of impulsivity for investigating the mechanisms involved in this trait, and how these mechanisms could contribute to the pathogenesis of addiction.

Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity

“…68 We propose that vulnerability to motor impulsivity associates with expression patterns of 5-HT 2A R and 5-HT 2C R (present study), 6,7,9 while multiple studies implicate dopamine 5,7,69 , γ-aminobutyric acid (GABA) 8,10 and glutamate system involvement. 37,70–73 Our observation that knockdown of the mPFC 5-HT 2C R does not fully recapitulate the motor impulsivity phenotype characterized in outbred rats suggests an interplay between serotonergic and other neurochemical circuits may be differentially recruited in the expression of distinct components of impulsive behavior.…”

Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System

“…Given that the constitutive knockout of the 5-HT 2A R results in upregulation of 5-HT 2C R control over the excitability of mPFC neurons (Beique et al, 2007), these data suggest that a 5-HT 2A R/5-HT 2C R interaction at the level of the mPFC may rheostatically control impulsive action (Cunningham and Anastasio, 2014). Future studies will be required to intuit the coordinated serotonergic, dopaminergic, and GABAergic control of the corticostriatal circuitry that contributes to phenotypic impulsive action (Besson et al, 2013;Caprioli et al, 2014;Dalley et al, 2007;Jupp et al, 2013;Simon et al, 2013).…”

“…Individual differences in impulsive action have now been associated with expression patterns of the dopamine D 1 receptor (Simon et al, 2013), D 2/3 receptor (Besson et al, 2013;Dalley et al, 2007;Simon et al, 2013), γ-aminobutyric acid (GABA), and dendritic markers (Caprioli et al, 2014) in the nucleus accumbens as well as the 5-HT 2A R (present results) and the 5-HT 2C R in mPFC ). The precise manner in which these systems coordinate at the level of the neuron and/or circuit remains poorly understood, and it is parsimonious to suggest that these neurobiological factors interact to fine-tune behavioral control afforded by the corticostriatal network (Jupp et al, 2013). For example, in a recent study, we reported that genetic loss of the 5-HT 2C R in the mPFC resulted in increased motor impulsivity , concomitant with augmented 5-HT 2A Rmediated control over impulsive action and increased 5-HT 2A R expression in the mPFC (Anastasio et al, unpublished observations).…”

“…Our observations are a significant contribution toward this goal and stand among few studies to reveal the neurobiological underpinnings of individual differences in motor impulsivity. Given the evolutionary value of natural variation in the predisposition toward impulsive behavior (Stevens et al, 2005), examination of such individual differences affords a strategic approach toward identification of the specific factors that underlie the impulsive phenotype (Jupp et al, 2013) and may collectively lead to refined and optimized treatment of neuropsychiatric disorders characterized by extreme, disadvantageous impulsive behavior.…”

“…The medial aspect of the rodent PFC (mPFC) plays a complex and important role in impulsive action, as demonstrated by lesion, reversible inactivation, and genetic manipulation Chudasama et al, 2003;Muir et al, 1996;Narayanan et al, 2006). Catecholamine and serotonin (5-HT) neurotransmission are important neuromodulators of such corticostriatal dynamics and have been implicated as key modulators of motor impulsivity (for review, see Cunningham and Anastasio, 2014;Dalley et al, 2002;Eagle and Baunez, 2010;Fineberg et al, 2010;Jupp et al, 2013).…”