Yu Ohmura

Discounting Delayed and Probabilistic Monetary Gains and Losses by Smokers of Cigarettes

RationaleNicotine dependence has been associated with impulsivity and discounting delayed/uncertain outcomes.ObjectivesThis study had two main objectives: (1) to examine the relationship between the number of cigarettes consumed per day and the degree to which delayed and uncertain monetary gains and losses are discounted by smokers, and (2) to determine the relationship between the estimated dose of nicotine intake per day and the degree to which four types of discounting occur.MethodsTwenty seven habitual smokers and 23 never smokers participated in this experiment. They were required to choose between immediate and delayed monetary rewards (or losses), or between guaranteed and probabilistic rewards (or losses).ResultsThe degree to which delayed monetary gains were discounted was significantly and positively correlated with both the number of cigarettes smoked and the estimated dose of nicotine intake per day. Conversely, there was no relationship between smoking and the remaining three types of discounting. Also, mild smokers in our sample did not differ from never smokers in discounting monetary gains or losses.ConclusionsIn general, our results suggest that both the frequency of nicotine self-administration, as well as the dosage, are positively associated with greater delay discounting of gains. One neuropsychopharmacological explanation for this effect is that chronic nicotine intake may induce neuroadaptation of the neural circuitry involved in reward processing.

Three-month stability of delay and probability discounting measures.

Psychopharmacologists are interested in delay and probability discounting because the tendency to discount the value of future and uncertain rewards has been linked with drug dependency. However, relatively little is known about the long-term stability of discounting measures typically studied in clinical psychopharmacology. To evaluate the stability of discounting over a 3-month period, the authors compared points of subjective equality (indifference points) with those collected from the same subjects 3 months earlier. Seven delay periods, ranging from 1 week to 25 years, and 7 probability values, ranging from .95 to .05, were assessed in an undergraduate sample (n=22, delay discounting; n=18, probability discounting). The authors examined both differential stability (stability of individual differences) and absolute stability (stability of the group mean) of delay and probability discounting measures as well as their respective indifference points. The results demonstrate that standard delay and probability discounting parameters (e.g., hyperbolic k and area under the curve) had both differential stability and absolute stability across 3 months. Moreover, most indifference points in the delay and probability discounting tasks demonstrated both differential and absolute stability. All together, these results suggest that delay and probability parameters are stable enough to predict future behavior, such as substance abuse. Additional findings indicated that a hyperbolic function fitted the data better than an exponential function and that delay and probability discounting parameters were not significantly correlated.

Distinct neurochemical and functional properties of GAD67-containing 5-HT neurons in the rat dorsal raphe nucleus.

The serotonergic (5-HTergic) system arising from the dorsal raphe nucleus (DRN) is implicated in various physiological and behavioral processes, including stress responses. The DRN is comprised of several subnuclei, serving specific functions with distinct afferent and efferent connections. Furthermore, subsets of 5-HTergic neurons are known to coexpress other transmitters, including GABA, glutamate, or neuropeptides, thereby generating further heterogeneity. However, despite the growing evidence for functional variations among DRN subnuclei, relatively little is known about how they map onto neurochemical diversity of 5-HTergic neurons. In the present study, we characterized functional properties of GAD67-expressing 5-HTergic neurons (5-HT/GAD67 neurons) in the rat DRN, and compared with those of neurons expressing 5-HTergic molecules (5-HT neurons) or GAD67 alone. While 5-HT/GAD67 neurons were absent in the dorsomedial (DRD) or ventromedial (DRV) parts of the DRN, they were selectively distributed in the lateral wing of the DRN (DRL), constituting 12% of the total DRL neurons. They expressed plasmalemmal GABA transporter 1, but lacked vesicular inhibitory amino acid transporter. By using whole-cell patch-clamp recording, we found that 5-HT/GAD67 neurons had lower input resistance and firing frequency than 5-HT neurons. As revealed by c-Fos immunohistochemistry, neurons in the DRL, particularly 5-HT/GAD67 neurons, showed higher responsiveness to exposure to an open field arena than those in the DRD and DRV. By contrast, exposure to contextual fear conditioning stress showed no such regional differences. These findings indicate that 5-HT/GAD67 neurons constitute a unique neuronal population with distinctive neurochemical and electrophysiological properties and high responsiveness to innocuous stressor.

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 0.4 mg/kg, salt, subcutaneously), atomoxetine [0, 0.01, 0.1, and, 1.0 mg/kg, intraperitoneally (i.p.)], fluvoxamine (0, 2, 4, and 8 mg/kg, i.p.), or milnacipran (0, 3, and 10 mg/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.

Corticotropin releasing factor enhances attentional function as assessed by the five-choice serial reaction time task in rats

Previous studies have shown that psychological stress affects attentional function, and corticotropin releasing factor (CRF) is closely related to stress responses. In the present study, we examined the effect of CRF on attentional function using a five-choice serial reaction time task (5-CSRTT) in rats. Accuracy in the 5-CSRTT was used as the index of attentional function. Human/rat CRF was intracerebroventricularly injected (0, 0.01, 0.1, or 1 microg/5 microl saline) 20 min before the beginning of the test trial in male Lister hooded rats that generally show high performance in the 5-CSRTT. As a result, 0.1 microg of CRF, but not other doses of CRF, increased accuracy in the 5-CSRTT. However, 0.1 microg of CRF did not affect impulsivity, motivation/appetite, perseverative tendency, or motor function. Even when Wistar rats, which generally show poor performance in the 5-CSRTT were used, 0.1 microg of CRF increased accuracy in the 5-CSRTT. However, the effect of CRF was not significantly attenuated by intracerebroventricular injection of the CRF(1) receptor antagonist antalarmin (5 microg). These results showed that CRF selectively enhances attentional function regardless of baseline attentional performance and rat strain, but this effect may be due to the pathways other than CRF(1) receptors. The present results suggest that CRF is involved in stress-related changes of attention and indicate that moderate stress, but not severe stress, may enhance attentional performance. Furthermore, these findings also indicate that the CRF-related substance could be a target for the development of an agent to improve attentional function.

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) 10 min before behavioral tests. As a result, 1000 ng of astressin 2B (CRF2 receptor antagonist), but not 250 ng 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.

Anxiolytic effects of yokukansan, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stress

ETHNOPHARMACOLOGICAL RELEVANCE Yokukansan, a traditional Japanese medicine (Kampo), has been reported in the treatment of behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety and depression in patients with Alzheimers disease and other forms of senile dementia. AIMS OF THE STUDY In the present study, we investigated the anxiolytic effects of yokukansan on anxiety-related behaviors in rats that have experienced aversive stress. MATERIALS AND METHODS We used male Wistar/ST rats which received an electrical footshock as aversive stress. Yokukansan at a dose of 1.0 g/kg was administered orally once a day for 14 or 16 day before behavioral tests. To evaluate the anxiolytic effects, we used the contextual fear conditioning (CFC) test and elevated plus-maze (EPM) test. And we also investigated effects of yokukansan on locomotor activity in the Open-field (OF) test and on the change in plasma corticosterone after CFC stress, in rats that had experienced footshock stress. RESULTS In the CFC test, rats that had experienced footshock showed significant freezing behavior on re-exposure to the box 14 day after footshock stress. Yokukansan significantly suppressed freezing behavior in the CFC test. In the EPM test on the 16th day after the CFC test, yokukansan significantly increased the time spent in open arms after footshock stress compared to control rats. However, repeated administration of yokukansan on the 14th day did not affect the decrease in locomotor activity and the increase in plasma corticosterone by re-exposure to the box 14 day after footshock stress in the OF test and determination of serum corticosterone, respectively. These anxiolytic effects by yokukansan were antagonized by WAY-100635, a selective 5-HT(1A) receptor antagonist, in the CFC test, but not the EPM test. Furthermore, 5-HT(1A) receptor agonist buspirone significantly suppressed freezing behavior in the CFC test; however, buspirone induced no change in the time spent in open arms in the EPM test. CONCLUSION These findings suggested that yokukansan has anxiolytic effects on anxiety-like behaviors induced by both innate fear and memory-dependent fear. In particular, yokukansan produced anxiolytic effects via 5-HT(1A) receptors in memory-dependent fear induced by aversive stress. Furthermore, yokukansan could be useful as one of the therapeutic drugs for the treatment of anxiety disorders and various mental disorders that have comorbid anxiety.

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.

Corticotropin releasing factor in the median raphe nucleus is involved in the retrieval of fear memory in rats

In the present study, we examined the role of corticotropin releasing factor (CRF) in the median raphe nucleus (MRN) on fear-related behaviors in rats. We employed the contextual fear conditioning test and the elevated plus maze test as memory-dependent and -independent tasks, respectively. Human/rat CRF (10 ng) in 0.5 microl saline was injected into the MRN. Administration of CRF significantly increased memory dependent, but not independent, fear expression. These results suggest that CRF release in the MRN is involved in the retrieval of fear memory.

Dopamine D1/5 and D2/3 agonists differentially attenuate somatic signs of nicotine withdrawal in rats.

Abrupt tobacco/nicotine cessation after chronic use causes various withdrawal symptoms/signs. There is evidence that dysfunction of brain dopaminergic system might be responsible for some nicotine withdrawal symptoms. The hypothesis for the present study was that different dopaminergic agonists would relieve different nicotine withdrawal signs. Adult male Sprague-Dawley rats were used. (-)-Nicotine bitartrate (9 mg/kg/day, salt content) or equimolar sodium tartrate was infused into each rat via a subcutaneous (s.c.) osmotic minipump for 7 days. To assess nicotine withdrawal signs, several somatic abstinence signs including teeth-chattering/chews, stretches/gasps, ptosis, shakes, and yawns were counted one day after removal of pumps. These signs were attenuated by the s.c. injection of 0.4 mg/kg nicotine bitartrate. Both a dopamine D(1/5) agonist (SKF81297) and a D(2/3) agonist (pramipexole) relieved abstinence signs dose-dependently but differentially. SKF81297 (0.32 mg/kg, s.c.) reduced teeth-chattering/chews but not shakes. Pramipexole (1mg/kg, s.c.) decreased both teeth-chattering/chews and shakes. A low dose of pramipexole (0.1mg/kg, s.c.) significantly increased yawns, consistent with previous studies that the stimulation of D(3) receptors induces yawning. These results indicate that a D(2)-selective agonist should be considered a candidate to relieve nicotine withdrawal symptoms.