Synergistic effects of MDMA and ethanol on behavior: Possible effects of ethanol on dopamine D2 -receptor-related signaling.

Polydrug abuse is common among drug abusers. In particular, psychostimulants are often taken with ethanol, and the combination of 3,4-methylenedioxymethamphetamine (MDMA) and alcohol is one of the most common forms of polydrug abuse. However, the mechanism by which these drugs influence behavior remains unclear. The present study was designed to delineate the mechanisms that underlie the effects of the interaction between MDMA and ethanol on behavior in rodents. The combination of MDMA with ethanol enhanced their locomotor-increasing, rewarding, and discriminative stimulus effects without enhancing their effects on the release of dopamine from the nucleus accumbens in rodents. In addition, ethanol potently enhanced locomotor activity produced by the dopamine receptor agonist apomorphine in mice. In antagonism tests, the dopamine D1 -receptor antagonist SCH23390, but not the D2 -receptor antagonist haloperidol, completely suppressed hyperlocomotion induced by MDMA. However, hyperlocomotion induced by the co-administration of MDMA and ethanol was potently suppressed by haloperidol. These results suggest that the synergistic effects of MDMA and ethanol are mediated through dopamine transmission, especially through postsynaptical regulation of D2 -receptor-mediated functions.

Increase in neuropeptide Y activity impairs social behaviour in association with glutamatergic dysregulation in diabetic mice.

BACKGROUND AND PURPOSE: Patients with diabetes mellitus are reported to show a raised prevalence of mental disorders, which may be reflected in impaired social interaction. However, the mechanisms underlying such impairment in diabetes are unknown. EXPERIMENTAL APPROACH: The present study investigated whether social interaction is impaired in diabetic mice and whether central neuropeptide Y (NPY) and glutamatergic function are involved in such impairment. KEY RESULTS: In the three-chamber test, social novelty preference, but not sociability, was impaired in streptozotocin (STZ)-induced diabetic mice. The mRNA level of NPY in the hypothalamus was increased in STZ-induced diabetic mice. Injection of the NPY Y2 receptor agonist NPY 13-36 into naïve mice impaired social novelty preference, but not sociability, and this effect was inhibited by the Y2 receptor antagonist BIIE 0246. BIIE 0246 also reversed the impairment of social novelty preference in STZ-induced diabetic mice. Similarly, injection of the AMPA receptor agonist AMPA into naïve mice impaired social novelty preference, but not sociability, and this effect was inhibited by the AMPA receptor antagonist NBQX. Impairment of social novelty preference induced by NPY 13-36 was inhibited by NBQX, whereas impairment of social novelty preference induced by AMPA was not inhibited by BIIE 0246. Finally, impairment of social novelty preference in STZ-induced diabetic mice was reversed by NBQX. CONCLUSION AND IMPLICATIONS: These findings suggest that NPY neurons are activated in diabetic mice and that this may impair social novelty preference by promoting glutamatergic function through Y2 receptors.

Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson's disease-like motor dysfunction.

Ghrelin exerts a wide range of physiological actions throughout the body and appears to be a promising target for disease therapy. Endogenous ghrelin receptors (GHSRs) are present in extrahypothalamic sites including the substantia nigra pars compacta (SNc), which is related to phenotypic dysregulation or frank degeneration in Parkinson's disease (PD). Here we found a dramatic decrease in the expression of GHSR in PD-specific induced pluripotent stem cell (iPSC)-derived dopaminergic (DAnergic) neurons generated from patients carrying parkin gene (PARK2) mutations compared to those from healthy controls. Consistently, a significant decrease in the expression of GHSR was found in DAnergic neurons of isogenic PARK2-iPSC lines that mimicked loss of function of the PARK2 gene through CRISPR Cas9 technology. Furthermore, either intracerebroventricular injection or microinjection into the SNc of the selective GHSR1a antagonist [D-Lys3]-GHRP6 in normal mice produced cataleptic behaviors related to dysfunction of motor coordination. These findings suggest that the down-regulation of GHSRs in SNc-DA neurons induced the initial dysfunction of DA neurons, leading to extrapyramidal disorder under PD.

Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors.

Ghrelin plays roles in a wide range of central functions by activating the growth hormone secretagogue receptor (GHSR). This receptor has recently been found in the substantia nigra (SN) to control dopamine (DA)-related physiological functions. The dysregulation of DA neurons in the SN pars compacta (SNc) and the consequent depletion of striatal DA are known to underlie the motor deficits observed in Parkinson's disease (PD). In the present study, we further investigated the role of the SN-ghrelin system in motor function under the stereotaxic injection of AAV-CMV-FLEX-diphtheria toxin A (DTA) into the SN of dopamine transporter (DAT)-Cre (DATSN::DTA) mice to expunge DA neurons of the SNc. First, we confirmed the dominant expression of GHSR1a, which is a functional GHSR, in tyrosine hydroxylase (TH)-positive DA neurons in the SNc of control mice. In DATSN::DTA mice, we clearly observed motor dysfunction using several behavioral tests. An immunohistochemical study revealed a dramatic loss of TH-positive DA neurons in the SNc and DAT-labeled axon terminals in the striatum, and an absence of mRNAs for TH and DAT in the SN of DATSN::DTA mice. The mRNA level of GHSR1a was drastically decreased in the SN of these mice. In normal mice, we also found the mRNA expression of GHSR1a within GABAergic neurons in the SN pars reticulata (SNr). Under these conditions, a single injection of ghrelin into the SN failed to improve the motor deficits caused by ablation of the nigrostriatal DA network using DATSN::DTA mice, whereas intra-SN injection of ghrelin suppressed the motor dysfunction caused by the administration of haloperidol, which is associated with the transient inhibition of DA transmission. These findings suggest that phasic activation of the SNc-ghrelin system could improve the dysregulation of nigrostriatal DA transmission related to the initial stage of PD, but not the motor deficits under the depletion of nigrostriatal DA. Although GHSRs are found in non-DA cells of the SNr, GHSRs on DA neurons in the SNc may play a crucial role in motor function.

Orthographic Reading Deficits in Dyslexic Japanese Children: Examining the Transposed-Letter Effect in the Color-Word Stroop Paradigm.

In orthographic reading, the transposed-letter effect (TLE) is the perception of a transposed-letter position word such as "cholocate" as the correct word "chocolate." Although previous studies on dyslexic children using alphabetic languages have reported such orthographic reading deficits, the extent of orthographic reading impairment in dyslexic Japanese children has remained unknown. This study examined the TLE in dyslexic Japanese children using the color-word Stroop paradigm comprising congruent and incongruent Japanese hiragana words with correct and transposed-letter positions. We found that typically developed children exhibited Stroop effects in Japanese hiragana words with both correct and transposed-letter positions, thus indicating the presence of TLE. In contrast, dyslexic children indicated Stroop effects in correct letter positions in Japanese words but not in transposed, which indicated an absence of the TLE. These results suggest that dyslexic Japanese children, similar to dyslexic children using alphabetic languages, may also have a problem with orthographic reading.

Changes in the expression of IL-6-Mediated MicroRNAs in the dorsal root ganglion under neuropathic pain in mice.

A multiplex analysis for profiling the expression of candidate microRNAs (miRNAs), which are small noncoding RNAs that function as key post-transcriptional regulators, may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we performed a miRNA array analysis using tissues of the dorsal root ganglion (DRG), a primary site for pain processing, obtained from mice with partial sciatic nerve ligation. Among 1135 total miRNAs, 26 miRNAs showed up-regulation (more than 2-fold change) and only 4 miRNAs showed down-regulation (less than 0.5-fold change) in the DRG of nerve-ligated mice. In a RT-qPCR assay, the levels of miR-21, miR-431, and miR-511-3p were significantly increased on the ipsilateral side of the DRG from 3 to 7 days after sciatic nerve ligation. These elevations were almost absent in IL-6 knockout mice. Furthermore, the expression level of miR-21, but not those of miR-431 or miR511-3p, was significantly increased in exosomes extracted from blood of nerve-ligated mice. These findings suggest that the increased expression of IL-6-regulated miR-21, miR-431, and miR-511-3p in the DRG and increased exosomal miR-21 extracted from blood after sciatic nerve ligation may play at least a partial role in neuropathic pain. Synapse 70:317-324, 2016. © 2016 Wiley Periodicals, Inc.

Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral µ-opioid receptors in mice.

Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral µ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate-dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by µ-opioid antagonist ß-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment.

Delayed disengagement of attention from snakes in children with autism.

In the visual search task, it is well known that detection of a tilted straight line as the target among vertical lines that act as distractors is easier than vice versa, and that detection of a snake image as the target among flower images is easier than vice versa. In this study, the degree of such search asymmetry was compared between 18 children with autism and 14 typically developing (TD) children. The results revealed that compared to TD children, children with autism were disproportionally slow when asked to detect the flower among the snake images, suggesting the possibility that they experienced difficulty of disengaging their attention from the snake images. This delayed disengagement would serve itself as an enhanced attentional bias toward snakes in children with autism that is similar to characteristics of visual search performance in anxiety patients.

Effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice.

Previous studies have shown that sigma-1 receptor chaperone (Sig-1R) ligands can regulate pain-related behaviors, and Sig-1R itself can regulate µ-opioid receptor functions as well as signal transduction. Even though (±)-pentazocine has been used clinically for the treatment of pain through opioid receptors, (+)-pentazocine is known to be a selective Sig-1R agonist. To the best of our knowledge, there is no information available regarding the involvement of Sig-1R agonistic action in the antinociceptive effects of (±)-pentazocine. Therefore, the present study was designed to investigate the effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice. Both and (-)-pentazocine induced biphasic antinociceptive effects as measured by the warm-plate test. The early phase, but not the delayed phase, of the antinociceptive effects induced by (-)-pentazocine, which are mediated by the activation of µ-opioid receptors, were suppressed by pretreatment with (+)-pentazocine. These results suggest that the innate antinociceptive action of (±)-pentazocine could be marginally reduced by the effects of (+)-pentazocine, but (+)-pentazocine can suppress the antinociceptive effects of (-)-pentazocine at certain time points.

Involvement of µ- and δ-opioid receptor function in the rewarding effect of (±)-pentazocine.

Most opioid receptor agonists have abuse potential, and the rewarding effects of opioids can be reduced in the presence of pain. While each of the enantiomers of pentazocine has a differential pharmacologic profile, (±)-pentazocine has been used clinically for the treatment of pain. However, little information is available regarding which components of pentazocine are associated with its rewarding effects, and whether the (±)-pentazocine-induced rewarding effects can be suppressed under pain. Therefore, the present study was performed to investigate the effects of pain on the acquisition of the rewarding effects of (±)-pentazocine, and to examine the mechanism of the rewarding effects of (±)-pentazocine using the conditioned place preference paradigm. (±)-Pentazocine and (-)-pentazocine, but not (+)-pentazocine, produced significant rewarding effects. Even though the rewarding effects induced by (±)-pentazocine were significantly suppressed under pain induced by formalin, accompanied by increase of preprodynorphin mRNA levels in the nucleus accumbens, a high dose of (±)-pentazocine produced significant rewarding effects under pain. In the normal condition, (±)-pentazocine-induced rewarding effects were blocked by a low dose of naloxone, whereas the rewarding effects induced by high doses of pentazocine under pain were suppressed by naltrindole (a δ-opioid receptor antagonist). Interestingly, (±)-pentazocine did not significantly affect dopamine levels in the nucleus accumbens. These findings suggest that the rewarding effects of (-)-pentazocine may contribute to the abuse potential of (±)-pentazocine through µ- as well as δ-opioid receptors, without robust activation of the mesolimbic dopaminergic system. We also found that neural adaptations can reduce the abuse potential of (±)-pentazocine under pain.

Enhanced GABAergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model.

BACKGROUND AND PURPOSE: We demonstrated previously that oxycodone has potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal gray (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain. EXPERIMENTAL APPROACH: We characterized the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model. KEY RESULTS: The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (Kir 3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input-output relationship curve of evoked IPSCs, the increased paired-pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of presynaptic GABA release by oxycodone, but not morphine was enhanced and dependent on Kir 3.1 channels. CONCLUSION AND IMPLICATIONS: Our results demonstrate that Kir 3.1 channels are important for supraspinal antinociception and presynaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via Kir 3.1 channel activation.

The contribution of Gi/o protein to opioid antinociception in an oxaliplatin-induced neuropathy rat model.

Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3-0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017-0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 µg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [(35)S]-GTPγS binding assay, activation of µ-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model.

The color red distorts time perception for men, but not for women.

We investigated the effect of the color red on time perception using a temporal bisection task with human adults. The results showed that the perceived duration of a red screen was longer than was that of a blue screen. However, the results reflected sex differences; men, but not women, overestimated the duration of the red screen. Additionally, the reaction times to a red screen were faster than those to a blue screen, and we found a significant correlation between reaction time and the tendency to overestimate the duration of a red screen. Participants who reacted quickly to a red screen overestimated its duration. These results are discussed within the context of recent studies indicating that the color red exerts certain special psychological effects on human behavior.

Establishment of opioid-induced rewarding effects under oxaliplatin- and Paclitaxel-induced neuropathy in rats.

The rewarding effects of µ-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used µ-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of µ-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug-induced neuropathic pain. Nevertheless, no information is available regarding whether µ-receptor agonists produce psychological dependence under chemotherapeutic drug-induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of µ-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of µ-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of µ-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on µ-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain.

Morphine and oxycodone, but not fentanyl, exhibit antinociceptive effects mediated by G-protein inwardly rectifying potassium (GIRK) channels in an oxaliplatin-induced neuropathy rat model.

It has begun to be understood that µ-opioid receptor (MOR) produces ligand-biased agonism, which contributes to differential physiological functions of MOR agonists. We previously demonstrated that in oxaliplatin-induced neuropathy in rats, morphine and oxycodone exhibited antinociceptive effects while antinociception of fentanyl was partial, and such different efficacies might result from the different level of Gi/o protein activation. Based on our background, to reveal further mechanism, we focused on the role of Gi/o protein-related downstream signaling, the G-protein inwardly rectifying K(+)1 (GIRK1) channel. The GIRK1 channel blocker tertiapin-Q (30pmol) was intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered to rats with oxaliplatin-induced neuropathy. The antinociception of systemic morphine (3mg/kg, subcutaneously (s.c.)) was suppressed only by pretreatment of i.t. tertiapin-Q, while supraspinal tertiapin-Q suppressed only the antinociception of systemic oxycodone (0.56mg/kg, s.c.). Partial antinocicpetion of fentanyl (0.017mg/kg, s.c.) was neither affected by i.c.v nor i.t. tertiapin-Q. These results demonstrated that GIRK1 channels differentially contribute to antinociceptive effects of MOR agonists, and that action site of GIRK1 channels is also different between morphine and oxycodone in oxaliplatin model. This study suggests the possibility that GIRK1 channels have a crucial role for antinociception of MOR agonists in oxaliplatin-induced neuropathy.

Involvement of 5-HT2 receptors in the expression of withdrawal diarrhea in morphine-dependent mice.

The withdrawal syndrome after the cessation of µ-opioid receptor agonists remains an obstacle in the clinical treatment of pain. We recently showed that peripheral opioid receptors play a significant role in the withdrawal signs in morphine-dependent mice. Therefore, the present study was designed to investigate the underlying mechanism of morphine-induced withdrawal symptoms, especially the peripheral oriented body-weight loss that accompanied diarrhea, in mice. Withdrawal signs were precipitated by the injection of naloxone 1 day after the slow-release emulsion administration of morphine. Withdrawal body-weight loss and diarrhea precipitated by naloxone in morphine-dependent mice were significantly suppressed by ritanserin (a 5-HT2 receptor antagonist), olanzapine (5-HT2/D2 receptor antagonist) and fullerene (a free radical scavenger), whereas neither ondansetron (a 5-HT3 receptor antagonist) nor atropine (a muscarine receptor antagonist) significantly suppressed naloxone-precipitated diarrhea. 5-HT3-receptors (but not 5-HT2-receptors) are known to play a significant role in 5-HT-induced diarrhea. Therefore, we also examined the effects of ritanserin and fullerene on 5-HT-induced diarrhea in morphine-dependent mice. Ritaserin significantly suppressed 5-HT-induced diarrhea in morphine-dependent mice, but not saline-treated mice. These results suggest that peripheral 5-HT2-receptor function could be altered in morphine-dependent mice, and the blockade of 5-HT2 receptor or free radical scavengers may be useful for the treatment of opioid-withdrawal diarrhea.

Preliminary evidence that different mechanisms underlie the anger superiority effect in children with and without Autism Spectrum Disorders.

Previous studies have demonstrated that angry faces capture humans' attention more rapidly than emotionally positive faces. This phenomenon is referred to as the anger superiority effect (ASE). Despite atypical emotional processing, adults and children with Autism Spectrum Disorders (ASD) have been reported to show ASE as well as typically developed (TD) individuals. So far, however, few studies have clarified whether or not the mechanisms underlying ASE are the same for both TD and ASD individuals. Here, we tested how TD and ASD children process schematic emotional faces during detection by employing a recognition task in combination with a face-in-the-crowd task. Results of the face-in-the-crowd task revealed the prevalence of ASE both in TD and ASD children. However, the results of the recognition task revealed group differences: In TD children, detection of angry faces required more configural face processing and disrupted the processing of local features. In ASD children, on the other hand, it required more feature-based processing rather than configural processing. Despite the small sample sizes, these findings provide preliminary evidence that children with ASD, in contrast to TD children, show quick detection of angry faces by extracting local features in faces.

Implication of mGlu5 receptor in the enhancement of morphine-induced hyperlocomotion under chronic treatment with zolpidem.

Long-term exposure to zolpidem induces drug dependence, and it is well known that the balance between the GABAergic and glutamatergic systems plays a critical role in maintaining the neuronal network. In the present study, we investigated the interaction between GABAA receptor α1 subunit and mGlu5 receptor in the limbic forebrain including the N.Acc. after treatment with zolpidem for 7 days. mGlu5 receptor protein levels were significantly increased after treatment with zolpidem for 7 days, and this change was accompanied by the up-regulation of phospholipase Cß1 and calcium/calmodulin-dependent protein kinase IIα, which are downstream of mGlu5 receptor in the limbic forebrain. To confirm that mGlu5 receptor is directly involved in dopamine-related behavior in mice following chronic treatment with zolpidem, we measured morphine-induced hyperlocomotion after chronic treatment with zolpidem in the presence or absence of an mGlu5 receptor antagonist. Although chronic treatment with zolpidem significantly enhanced morphine-induced hyperlocomotion, this enhancement of morphine-induced hyperlocomotion was suppressed by treating it with the mGlu5 receptor antagonist MPEP. These results suggest that chronic treatment with zolpidem caused neural plasticity in response to activation of the mesolimbic dopaminergic system accompanied by an increase in mGlu5 receptor.

Differential substitution for the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and methylphenidate in rats.

Previous studies have demonstrated that methylphenidate, MDMA (3,4-methylenedioxymethamphetamine), and other psychostimulants exert stimulant-like subjective effects in humans. Furthermore, MDMA and methylphenidate substitute for the discriminative stimulus effects of psychostimulants, such as amphetamine and cocaine, in animals, which suggests that MDMA and methylphenidate may produce similar discriminative stimulus effects in rats. However, there is no evidence regarding the similarities between the discriminative stimulus effects of MDMA and methylphenidate. To explore this issue, cross-substitution, substitution, and combination tests were conducted in rats that had been trained to discriminate between MDMA (2.5 mg/kg) or methylphenidate (5.0 mg/kg) and saline. In the cross-substitution tests, MDMA and methylphenidate did not cross-substitute for each other. In the substitution test, methamphetamine substituted for the discriminative stimulus effects of methylphenidate, but not for those of MDMA. Furthermore, ephedrine and bupropion, which activate dopaminergic and noradrenergic systems, substituted for the discriminative stimulus effects of methylphenidate. On the other hand, serotonin (5-HT) receptor agonists 5-HT1A and 5-HT2 fully substituted for the discriminative stimulus effects of MDMA. These results suggest that activation of the noradrenergic and dopaminergic systems is important for the discriminative stimulus effects of methylphenidate, whereas activation of the serotonergic system is crucial for the discriminative stimulus effects of MDMA. Even though MDMA, like psychostimulants, exerts stimulant-like effects, our findings clearly indicate that the discriminative stimulus effects of MDMA are distinctly different from those of other psychostimulants in rats.

Japanese monkeys (Macaca fuscata) spontaneously associate alarm calls with snakes appearing in the left visual field.

Many socially living animals are sensitive to a potential predator as part of their antipredator strategy. Alarm calls function to deter predators and to help other group members detect danger. The left visual field is involved in detection of potential threats or predators in many vertebrates, but it is unclear how alarm calls influence visual detection of a potential predator. Here, we experimentally examined how alarm calls spontaneously influence the search for pictures of a potential predator in captive Japanese macaques. We used an audiovisual preferential-looking paradigm by presenting pictures of a snake and a flower simultaneous with either a recording of alarm calls or contact calls. We found no difference in gaze duration between the 2 picture types when playing back contact calls. Monkeys looked significantly longer at pictures of snakes than at those of flowers when alarm calls were played back if the snake pictures were presented on the left side of the monkey's visual field, indicating right hemispheric bias during processing of predator representations. This is the first laboratory demonstration of auditory enhancement of visual detection of predators in the left visual field in animals, which will contribute to a better understanding of alarm call studies conducted in the wild.