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Higher impulsivity is a risk factor for criminal involvement, substance abuse, and suicide. However, only a few drugs are clinically available for the treatment of deficient impulse control. We recently proposed a strategy for identifying potential drugs to treat such disorders by investigating clinically available drugs that increase extracellular dopamine levels in the medial prefrontal cortex and stimulate dopamine D1-like receptors without increasing extracellular dopamine levels in the ventral striatum. To determine whether this strategy is promising, we examined the effects of duloxetine, a serotonin-noradrenaline reuptake inhibitor that might meet these criteria, on impulsive action in adult male Wistar/ST rats using a 3-choice serial reaction time task. The effects of duloxetine on extracellular dopamine levels in the medial prefrontal cortex and nucleus accumbens, a part of the ventral striatum were evaluated using in vivo microdialysis, as the noradrenaline transporter transports dopamine in some brain regions. Our results showed that the administration of duloxetine reduced impulsive actions and increased extracellular dopamine levels in the mPFC but not in the nucleus accumbens. Microinjection of a selective D1-like receptor antagonist into the infralimbic cortex blocked the suppression of impulsive action by duloxetine. In addition, we demonstrated that the microinjection also blocked the suppression of impulsive action by atomoxetine, a noradrenaline reuptake inhibitor and an established anti-impulsive drug. These results support our proposed strategy for identifying and developing anti-impulsivity drugs.

Higher impulsivity is a risk factor for criminal involvement and drug addiction. Because nicotine administration enhances impulsivity, the effects of stop-smoking aids stimulating nicotinic acetylcholine receptors (nAChRs) on impulsivity must be determined in different conditions. Our goals were 1) to confirm the relationship between varenicline, a stop-smoking aid and α4β2 nAChR partial agonist, and impulsivity, 2) to elucidate the mechanisms underlying the effects of varenicline, 3) to examine whether a low dose of varenicline that does not evoke impulsive action could block the stimulating effects of nicotine on impulsive action, 4) to determine whether the route of administration could modulate the effects of varenicline on impulsive action, and 5) to determine whether the effects of varenicline on impulsivity could be altered by smoking status. We used a 3-choice serial reaction time task to assess impulsivity and other cognitive functions in rats. Our findings are as follows: 1) acute subcutaneous (s.c.) injection of varenicline evoked impulsive action in a dose-dependent manner; 2) the effects of varenicline on impulsivity were blocked by the microinjection of dihydro-β-erythroidine, a α4β2 nAChR antagonist, into the infralimbic cortex; 3) the low dose of varenicline did not attenuate the effects of nicotine on impulsive action at all; 4) oral administration of varenicline evoked impulsive action in a similar manner to s.c. injection; and 5) the stimulating effects of varenicline on impulsive action were not observed in rats that received nicotine infusion for 8 days or nicotine-abstinent rats after discontinuing infusion. Additionally, we found that oral varenicline administration enhanced attentional function whether nicotine was infused or not. Thus, although varenicline administration could be harmless to heavy smokers or ex-smokers, it could be difficult for non-smokers with respect to impulsivity, whereas it may be beneficial with respect to attentional function.

High impulsivity will increase the risk of criminal behavior, drug abuse, and suicide. We chose two drugs by following a strategy recently we proposed for identifying potential anti-impulsivity drugs, and examined the effects on impulsive action in rats by using a 3-choice serial reaction time task. We showed that the administration of blonanserin, an atypical antipsychotic, reduced impulsive actions in a U-shaped manner. 1-(2-Pyriidinyl)-piperazine, an active metabolite of buspirone or tandospirone, also slightly reduced impulsive actions, though it impaired motor functions. These results affirm the validity of our strategy, but require its refinement for developing anti-impulsivity drugs. (C) 2019 The Authors. Production and hosting by Elsevier B.V.

The data shows attentional function, impulsivity, motivation, motor function, and motor activity in rats treated with varenicline, a stop-smoking aid. The data also shows these parameters in rats treated with varenicline after acute/chronic nicotine administration. Our interpretation and discussion of these data were described in the article "Varenicline Provokes Impulsive Action by Stimulating α4β2 Nicotinic Acetylcholine Receptors in the Infralimbic Cortex in a Nicotine Exposure Status-Dependent Manner" (Ohmura et al., 2017) [1].

Immaturity in impulse control among adolescents could result in substance abuse, criminal involvement, and suicide. The brains of adolescents and adults are anatomically, neurophysiologically, and pharmacologically different. Therefore, preclinical models of adolescent impulsivity are required to screen drugs for adolescents and elucidate the neural mechanisms underlying age-related differences in impulsivity. The conventional 3- or 5-choice serial reaction time task, which is a widely used task to assess impulsivity in adult rodents, cannot be used for young mice because of two technical problems: impaired growth caused by food restriction and the very long training duration. To overcome these problems, we altered the conventional training process, optimizing the degree of food restriction for young animals and shortening the training duration. We found that almost all basal performance levels were similar between the novel and conventional procedures. We also confirmed the pharmacological validity of our results: the 5-hydroxytryptamine 2C (5-HT2C) receptor agonist Ro60-0175 (0.6 mg/kg, subcutaneous) reduced the occurrence of premature responses, whereas the 5-HT2C receptor antagonist SB242084 (0.5 mg/kg intraperitoneal) increased their occurrence, consistent with results of previous studies using conventional procedures. Furthermore, we detected age-related differences in impulsivity using the novel procedure: adolescent mice were found to be more impulsive than adult mice, congruent with the results of human studies. Thus, the new procedure enables the assessment of impulsivity in adolescent mice and facilitates a better understanding of the neurophysiological/pharmacological properties of adolescents.