Role of serotonin transporter function in rat orbitofrontal cortex in impulsive choice

Abstract

Impulsivity is a multi-faceted personality construct that plays a prominent role in drug abuse vulnerability. Dysregulation of 5-hydroxytryptamine (serotonin, 5-HT) systems in subregions of the prefrontal cortex has been implicated in impulsivity. Extracellular 5-HT concentrations are regulated by 5-HT transporters (SERTs), indicating that these transporters may be important molecular targets underlying individual differences in impulsivity and drug abuse vulnerability. The present study evaluated the role of SERT in mediating individual differences in impulsivity. Rats were tested for both impulsive action using the cued go/no-go task and for impulsive choice using a delay discounting task in a counterbalanced design. Following behavioral evaluation, Km and Vmax were obtained from kinetic analysis of [3H]5-HT uptake by SERT using synaptosomes prepared from both orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) obtained from each individual rat. Vmax for SERT in OFC, but not mPFC, was negatively correlated with mean adjusted delay scores in the delay discounting task. In contrast, Vmax for SERT in OFC and mPFC was not correlated with performance in the cued go/no-go task. To further evaluate the relationship between SERT function and impulsive choice, a selective SERT inhibitor, fluoxetine (0, 15, 50 and 150 pmol/side) was microinjected bilaterally into OFC and effects on the delay discounting task determined. Following stabilization of behavior, fluoxetine increased mean adjusted delay scores (decreased impulsivity) in high impulsive rats compared to saline microinjection, but had no effect in low impulsive rats. These ex vivo and in vivo results suggest that enhanced SERT function in OFC underlies high impulsive choice behavior.

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

“…The k t is in good agreement with estimates of the endogenous tissue concentrations of p -tyramine, indicating that uptake by this transporter is likely to be physiologically relevant. The V max equates to a value of 1.8 pmol/mg protein/min and is similar to values reported for the selective transport of dopamine by DAT71 or serotonin by SERT72 in synaptosome preparations. Although we controlled for diffusion of p -tyramine into the synaptosomes, we cannot prevent diffusion back out, and this may well result in the apparent net V max obtained being an underestimate of the true value.…”

Individual differences in impulsive action and dopamine transporter function in rat orbitofrontal cortex

“…Also, Spearman correlation analyses indicated that the non-significant Pearson correlations were not due to a narrow spread of V max values. Overall, the current results, in conjunction with our previous work (Darna et al, 2015; Yates et al, 2015), indicate that inherent variation of monoamine transporter function in mPFC may not underlie individual differences in distinct facets of impulsivity.…”

“…Kinetic parameters of transporter function (i.e., V max [pmol/min/mg] and K m [μM]) for [ 3 H]DA uptake were determined using a previously published method (Darna et al, 2015). Each rat brain was dissected on an ice-cold plate to obtain OFC and mPFC.…”

A framework for understanding and advancing intertemporal choice research using rodent models

“…Importantly, each is implicated in the etiology and treatment of neuropsychiatric disorders characterized by impulsive choice and is known to subserve a unique array of psychological processes. Yet, few studies have explored the contribution of their global and local neurotransmission (global: (Mobini et al, 2000; Catharine A Winstanley et al, 2005) for serotonin; (van Gaalen et al, 2006) for norepinephrine; and (Mendez, Gilbert, Bizon, & Setlow, 2012; Scattoni, Adriani, Calamandrei, Laviola, & Ricceri, 2006; Tian, Qin, Sun, Li, & Wei, 2016)for acetylcholine; local: only serotonin (Darna et al, 2015)). Such experiments may inform our understanding of those neuropsychiatric disorders and/or lead to pharmacological treatments for improving intertemporal choices.…”