Iku Tsutsui-Kimura

Lithium, but not valproic acid or carbamazepine, suppresses impulsive-like action in rats.

RationaleHigher impulsivity is a pathological symptom in several psychiatric disorders, including bipolar disorder, and is a risk factor for suicide.ObjectivesOur goal was to determine whether major mood-stabilizing drugs used for the treatment of bipolar disorder could suppress impulsive-like action in the three-choice serial reaction time task (3-CSRTT).MethodsFollowing training for the 3-CSRTT, rats were acutely administered lithium chloride (LiCl; 0, 3.2, 10, and 32xa0mg/kg, i.p.), valproic acid (0, 10, 32, and 100xa0mg/kg, i.p.), or carbamazepine (0, 10, 20, and 30xa0mg/kg, i.p.). To assess the anorexic effects of lithium, a simple food consumption test was conducted.ResultsLiCl dose-dependently decreased the number of premature responses, an index of impulsive-like action. A high dose of LiCl (32xa0mg/kg) decreased food consumption, but its anorexic effects were not correlated with the effects of LiCl on premature responses. A moderate dose of LiCl (20xa0mg/kg) significantly reduced the number of premature responses without affecting motivation-related measures in the 3-CSRTT or the amount of food consumption. Although carbamazepine prolonged reward latency, an index of motivation for food, neither valproic acid nor carbamazepine significantly affected premature responses.ConclusionIt is likely that lithium has a suppressive effect on impulsive action independent of the anorexic effect. Lithium may suppress impulsive behavior and thereby decrease the risk of suicide. The present results could provide an explanation for the antisuicidal effects of lithium and suggest that lithium could be a beneficial treatment for impulsivity-related disorders.

Near-infrared deep brain stimulation via upconversion nanoparticle–mediated optogenetics

Stimulating deep inside the brain Noninvasive deep brain stimulation is an important goal in neuroscience and neuroengineering. Optogenetics normally requires the use of a blue laser inserted into the brain. Chen et al. used specialized nanoparticles that can upconvert near-infrared light from outside the brain into the local emission of blue light (see the Perspective by Feliu et al.). They injected these nanoparticles into the ventral tegmental area of the mouse brain and activated channelrhodopsin expressed in dopaminergic neurons with near-infrared light generated outside the skull at a distance of several millimeters. This technique allowed distant near-infrared light to evoke fast increases in dopamine release. The method was also used successfully to evoke fear memories in the dentate gyrus during fear conditioning. Science, this issue p. 679; see also p. 633 Optogenetic experiments can be performed inside the mouse brain by using near-infrared light applied outside the skull. Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

The effects of serotonin and/or noradrenaline reuptake inhibitors on impulsive-like action assessed by the three-choice serial reaction time task: a simple and valid model of impulsive action using rats.

Impulsivity is a pathological symptom in several psychiatric disorders, underscoring the need for animal models of impulsive action to develop a brief screening method for novel therapeutic agents of impulsive action. The aims of this study were (i) to evaluate whether the three-choice serial reaction time task (3-CSRTT), a simple version of the five-choice serial reaction time task (5-CSRTT), is appropriate for brief assessment of impulsive-like action and (ii) to examine the effects of fluvoxamine, a selective serotonin reuptake inhibitor, and milnacipran, a serotonin/noradrenaline reuptake inhibitor, on impulsive-like action using the 3-CSRTT. After training in the 3-CSRTT, rats were administered nicotine (0, 0.1, 0.2, and 0.4u2009mg/kg, salt, subcutaneously), atomoxetine [0, 0.01, 0.1, and, 1.0u2009mg/kg, intraperitoneally (i.p.)], fluvoxamine (0, 2, 4, and 8u2009mg/kg, i.p.), or milnacipran (0, 3, and 10u2009mg/kg, i.p.). The training time for the 3-CSRTT was significantly shorter than that for the 5-CSRTT. Nicotine increased, whereas atomoxetine decreased the number of premature responses, an index of impulsive-like action, which is consistent with earlier studies. Milnacipran, but not fluvoxamine, dose-dependently decreased premature responses. These results indicate that the 3-CSRTT could provide an appropriate and simpler rodent model of impulsive-like action and that milnacipran could have some beneficial effects on impulsivity-related disorders.

The Serotonergic Projection from the Median Raphe Nucleus to the Ventral Hippocampus is Involved in the Retrieval of Fear Memory Through the Corticotropin-Releasing Factor Type 2 Receptor

Several different studies have separately established that serotonin, corticotropin-releasing factor (CRF) receptors, and the hippocampus are involved in fear memory retrieval. The main aim of this study is to connect these separate studies. To assess the levels of anxiety/fear, we used the contextual fear-conditioning test and the elevated plus maze test as memory-dependent and memory-independent tasks, respectively. We injected CRF receptor antagonists or vehicle into the median raphe nucleus (MRN) 10u2009min before behavioral tests. As a result, 1000u2009ng of astressin 2B (CRF2 receptor antagonist), but not 250u2009ng of antalarmin (CRF1 receptor antagonist), significantly suppressed the expression rate of freezing behavior in the contextual fear-conditioning test. However, in the elevated plus maze test, there was no difference between astressin 2B-injected rats and saline-injected rats in the time spent in open arms. Neither the amount of exploratory behavior nor the moving distance in the EPM of astressin 2B-injected rats differed from that of vehicle-injected rats. Moreover, when we assessed the extracellular serotonin release in the ventral hippocampus in freely moving rats through in vivo microdialysis, it was shown that the blockade of the CRF2 receptor in the MRN suppressed serotonin release in the ventral hippocampus during fear memory retrieval. These results indicated that endogenous CRF and/or related ligands that were released in the MRN could activate the CRF2 receptor and stimulate serotonin release in the ventral hippocampus, thereby inducing fear memory retrieval.

Nicotine provokes impulsive-like action by stimulating α4β2 nicotinic acetylcholine receptors in the infralimbic, but not in the prelimbic cortex

RationaleNicotine, a major addictive component of tobacco, has been suggested to provoke impulsivity by activating central α4β2 nicotinic acetylcholine receptors (nAChRs). Although lesion studies have demonstrated the involvement of the medial prefrontal cortex (mPFC) in impulsive action, the precise brain sites responsible for nicotine-induced impulsive action have not been identified.ObjectivesOur goal was to determine whether α4β2 nAChRs in the prelimbic cortex (PL) and/or infralimbic cortex (IL), which are subregions of the mPFC, mediate nicotine-induced impulsive-like action in the three-choice serial reaction time task (3-CSRTT).MethodsThe 3-CSRTT is a simple version of five-choice serial reaction time task and a rodent model of impulsive action in which the animal is required to inhibit the response until a light stimulus is presented randomly in one of three holes. Following the completion of the training, rats were bilaterally injected with dihydro-β-erythroidine (DHβE; 6 and 18xa0μg/side), a selective α4β2 nAChRs antagonist, into the PL or IL before systemic injection of nicotine (0.2xa0mg/kg, salt, s.c.).ResultsIntra-IL DHβE infusions dose-dependently blocked nicotine-induced impulsive-like action, while infusions of DHβE into the PL failed to block the effects of nicotine on impulsive-like action.ConclusionThe present results suggest a critical role for α4β2 nAChRs in the IL in mediating the effects of nicotine on impulsive-like action in the 3-CSRTT.

Endogenous acetylcholine modulates impulsive action via α4β2 nicotinic acetylcholine receptors in rats

Nicotine has been well established as an impulsive action-inducing agent, but it remains unknown whether endogenous acetylcholine affects impulsive action via nicotinic acetylcholine receptors. In the present study, the 3-choice serial reaction time task (3-CSRTT), a simple and valid assessment of impulsive action, was employed. Male Wistar/ST rats were trained to detect and respond to 1-s flashes of light presented in one of three holes until stable performance was achieved. Following training on the 3-CSRTT, rats received intracerebroventricular injections of the preferential alpha4beta2 nicotinic acetylcholine receptor antagonist dihydro-beta-erythroidine (DHbetaE; 0, 3, 10, and 30 microg) or the selective alpha7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA; 0, 3, 10, and 30 microg) 5 min before test sessions. Injection of 10 microg of DHbetaE significantly suppressed premature responses, an index of impulsive-like action, without changing other behavioral parameters. On the other hand, MLA infusions failed to affect impulsive-like action at any dose. These results suggest that the central alpha4beta2 nicotinic acetylcholine receptors that enable a provoking effect of endogenous acetylcholine play a critical role in impulsive action. Substances that modulate nicotinic acetylcholine receptors, especially the alpha4beta2 subtype, may be beneficial for the treatment of psychiatric disorders characterized by lack of inhibitory control.

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex

RationaleElevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action.ObjectivesOur goal was to identify whether D1- and/or D2-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task.MethodsThe rats were bilaterally injected with SCH23390, a selective D1-like receptor antagonist (0.3 or 3xa0ng/side) or eticlopride, a selective D2-like receptor antagonist (0.3 or 1xa0μg/side) into the IL after acute intraperitoneal administration of milnacipran (10xa0mg/kg).ResultsIntra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action.ConclusionsThis is the first report that demonstrates a critical role for D1-like receptors of the IL in milnacipran-enhanced control of impulsive action.

Milnacipran remediates impulsive deficits in rats with lesions of the ventromedial prefrontal cortex.

Background: Deficits in impulse control are often observed in psychiatric disorders in which abnormalities of the prefrontal cortex are observed, including attention-deficit/hyperactivity disorder and bipolar disorder. We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats. However, whether milnacipran could suppress elevated impulsive action in rats with lesions of the ventromedial prefrontal cortex, which is functionally comparable with the human prefrontal cortex, remains unknown. Methods: Selective lesions of the ventromedial prefrontal cortex were made using quinolinic acid in rats previously trained on a 3-choice serial reaction time task. Sham rats received phosphate buffered saline. Following a period of recovery, milnacipran (0 or 10mg/kg/d × 14 days) was orally administered 60 minutes prior to testing on the 3-choice task. After 7 days of drug cessation, Western blotting, immunohistochemistry, electrophysiological analysis, and morphological analysis were conducted. Results: Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug. Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats. Conclusions: The findings of this study suggest that milnacipran treatment could be a novel strategy for the treatment of psychiatric disorders that are associated with a lack of impulse control.

Varenicline provokes impulsive action by stimulating α4β2 nicotinic acetylcholine receptors in the infralimbic cortex in a nicotine exposure status-dependent manner

Abstract 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 &agr;4&bgr;2 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‐&bgr;‐erythroidine, a &agr;4&bgr;2 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. HighlightsAcute varenicline evoked impulsive action regardless of the route of administration.&agr;4&bgr;2 nAChRs in the infralimbic cortex were responsible for the effects of varenicline.Low dose of varenicline did not attenuate the effects of nicotine on impulsive action.The effects of varenicline disappeared in nicotine‐infused or nicotine‐abstinent rats.In addition, oral varenicline administration enhanced attentional function.

Neuronal codes for the inhibitory control of impulsive actions in the rat infralimbic cortex.

Poor impulse control is a debilitating condition observed in various psychiatric disorders and could be a risk factor for drug addiction, criminal involvement, and suicide. The rat infralimbic cortex (IL), located in the ventral portion of the medial prefrontal cortex, has been implicated in impulse control. To elucidate the neurophysiological basis of impulse control, we recorded single unit activity in the IL of a rat performing a 3-choiceserial reaction time task (3-CSRTT) and 2-choice task (2-CT), which are animal models for impulsivity. The inactivation of IL neuronal activity with an injection of muscimol (0.1 μg /side) disrupted impulse control in the 3-CSRTT. More than 60% (38/56) of isolated IL units were linked to impulse control, while approximately 30% of all units were linked to attentional function in the 3-CSRTT. To avoid confounding motor-related units with the impulse control-related units, we further conducted the 2-CT in which the animals motor activities were restricted during recording window. More than 30% (14/44) of recorded IL units were linked to impulse control in the 2-CT. Several types of impulse control-related units were identified. Only 16% of all units were compatible with the results of the muscimol experiment, which showed a transient decline in the firing rate immediately before the release of behavioral inhibition. This is the first study to elucidate the neurophysiological basis of impulse control in the IL and to propose that IL neurons control impulsive actions in a more complex manner than previously considered.