Navarra, R. L. | bioRxiv Science

bioRxiv2024

SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting

RationalePsychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without psychostimulant-like side effect liability. ObjectivesWe compared AMPH, MPH, and SK609 within dose ranges that display their cognitive enhancing properties in a probabilistic discounting task (PDT) of risk/reward decision making behavior to assess their potential to increase risky choice preference. MethodsRats chose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with descending probabilities across a session (100-6.25%) following administration of AMPH (0.25-1 mg/kg), MPH (2-8 mg/kg), and SK609 (4 mg/kg). ResultsAMPH and MPH increased risky choice behavior at doses previously reported to enhance cognition, whereas SK609 did not. AMPH and MPH also reduced sensitivity to non-rewarded risky choices. ConclusionsThese data highlight the combination of NE transporter blockade and selective D3 activation in pro-cognitive action without psychostimulant-like side effect liability. The absence of DA transporter blockade and non-selective dopaminergic activation are beneficial properties of SK609 that differentiates it from the traditional pro-cognitive psychostimulants.

animal behavior and cognition↗

bioRxiv2024

Perturbations in Risk/Reward Decision Making and Frontal Cortical Catecholamine Regulation Induced by Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) can disrupt cognitive processes that influence risk taking behavior. Athletes, military personnel, and domestic violence victims often experience multiple mTBIs; however, little is known regarding the effects of repetitive injury (rmTBI) on risk/reward decision making or whether these outcomes are sex specific. Risk/reward decision making is mediated by the prefrontal cortex (PFC), which is composed of several sub-regions including the medial PFC (mPFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). These regions are densely innervated by catecholaminergic fibers, which modulate PFC-mediated cognitive processes. Aberrant catecholamine activity within the PFC has been documented following TBI, which may underlie TBI-induced risky behavior. Tyrosine hydroxylase (TH) and norepinephrine transporter (NET) regulate catecholamine homeostasis within the PFC; however, it has not been determined how rmTBI affects these proteins. The present study aimed to characterize the effects of rmTBI on risk/reward decision making behavior and catecholamine transmitter regulatory proteins within the PFC. Risk/reward decision making was evaluated using a probabilistic discounting task (PDT) which required rats to choose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with decreasing probabilities over a session. Rats were first trained on the PDT and then exposed to sham, single (smTBI), or a series of three closed-head control cortical impact (CH-CCI) injuries over the course of one week, followed by four weeks of PDT testing. In week 1 post-final surgery, mTBI generally enhanced preference for the larger/riskier option with these effects seemingly more prominent in females. These effects resolved by week 2 post-final surgery indicating that the effects of mTBI on choice behavior are transient. By week 4, males, but not females, exhibited increased latencies to make riskier choices following rmTBI, demonstrating a delayed effect of injury on information processing speed. A separate group of rats was used to measure changes in levels of TH and NET within the mPFC, ACC, and OFC forty-eight hours after mTBI. No injury-induced differences were observed within the mPFC or ACC. In the OFC, females exhibited dramatic increases in TH levels following smTBI, but only small increases following rmTBI. Both males and females; however, experienced reduced levels of NET following rmTBI, which may function as a compensatory response to increased extracellular levels of catecholamines. Together, these results suggest that OFC is more susceptible to catecholamine instability after rmTBI, a finding indicating that not all areas of the PFC contribute equally to the observed TBI-induced catecholamine imbalances. Overall, combining the CH-CCI model of rmTBI with the PDT proved effective in revealing time-dependent and sex-specific changes in risk/reward decision making and catecholamine regulation following repetitive mild head injuries.

animal behavior and cognition↗