Differential cellular localization of antioxidant enzymes in the trigeminal ganglion.

Because of its high oxygen demands, neural tissue is predisposed to oxidative stress. Here, our aim was to clarify the cellular localization of antioxidant enzymes in the trigeminal ganglion. We found that the transcriptional factor Sox10 is localized exclusively in satellite glial cells (SGCs) in the adult trigeminal ganglion. The use of transgenic mice that express the fluorescent protein Venus under the Sox10 promoter enabled us to distinguish between neurons and SGCs. Although both superoxide dismutases 1 and 2 were present in the neurons, only superoxide dismutase 1 was identified in SGCs. The enzymes relevant to hydrogen peroxide degradation displayed differential cellular localization, such that neurons were endowed with glutathione peroxidase 1 and thioredoxin 2, and catalase and thioredoxin 2 were present in SGCs. Our immunohistochemical finding showed that only SGCs were labeled by the oxidative damage marker 8-hydroxy-2'-deoxyguanosine, which indicates that the antioxidant systems of SGCs were less potent. The transient receptor potential vanilloid subfamily member 1 (TRPV1), the capsaicin receptor, is implicated in inflammatory hyperalgesia, and we demonstrated that topical capsaicin application causes short-lasting mechanical hyperalgesia in the face. Our cell-based assay revealed that TRPV1 agonist stimulation in the presence of TRPV1 overexpression caused reactive oxygen species-mediated caspase-3 activation. Moreover, capsaicin induced the cellular demise of primary TRPV1-positive trigeminal ganglion neurons in a dose-dependent manner, and this effect was inhibited by a free radical scavenger and a pancaspase inhibitor. This study delineates the localization of antioxidative stress-related enzymes in the trigeminal ganglion and reveals the importance of the pivotal role of reactive oxygen species in the TRPV1-mediated caspase-dependent cell death of trigeminal ganglion neurons. Therapeutic measures for antioxidative stress should be taken to prevent damage to trigeminal primary sensory neurons in inflammatory pain disorders.

Biphasic action of aldosterone on Akt signaling in cardiomyocytes.

Both aldosterone and Akt signaling play pivotal roles in the pathogenesis of heart failure. However, little is known about the correlation between them. We herein investigated whether aldosterone interacts with Akt signaling in a coordinated manner in cardiomyocytes. Neonatal rat cardiomyocytes were stimulated with aldosterone for either a short (10-min) or long (24-h) time. The phosphorylation of Akt and its downstream effector, GSK3ß, were transiently increased after short-term stimulation, which was blocked by either PI3K or Na(+)/H(+) exchanger inhibitors, but not by the mineralocorticoid receptor antagonist, eplerenone. Long-term stimulation also significantly increased Akt-GSK3ß phosphorylation and this effect was reduced by eplerenone. Thus, these results suggest that aldosterone activates Akt signaling via a biphasic reaction that occurs through different cascades. To understand the significance of the rapid action of aldosterone, cardiomyocytes were exposed to hydrogen peroxide for from 10 to 60 min. A short-term aldosterone stimulation (for up to 30 min) significantly protected cardiomyocytes from oxidative stress-induced cellular damage. Eplerenone did not abrogate this beneficial effect, while a PI3K inhibitor did. Therefore, during the early phase, aldosterone has favorable effects on cardiomyocytes, partly by acute activation of a mineralocorticoid receptor-independent cascade through the Na(+)/H(+) exchanger, PI3K, and Akt. In contrast, its persistent activity produces pathological effects partly by chronic Akt activation in a mineralocorticoid receptor-dependent manner.

Differences in responsiveness of mediodorsal thalamic and medial prefrontal cortical neurons to social interaction and systemically administered phencyclidine in rats.

Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy individuals and behavioral abnormalities with corresponding symptoms of schizophrenia in non-human animals. Our previous studies showed that systemically administered PCP produces tonic activation of neurons in the medial prefrontal cortex (mPFC) of rats and that this activation is mainly via excitatory inputs from regions outside the mPFC. Such long-lasting activation of PFC neurons is now considered to be a pivotal factor in PCP-induced behavioral abnormalities. Although our previous study identified the ventral hippocampus as a possible source of the excitatory inputs, it is not the only source innervating the mPFC. Several regions such as the thalamus also have monosynaptic projections to the mPFC. Recently, increased c-fos expression by systemic PCP administration was reported in the mediodorsal nucleus of the thalamus (MD) and the centromedial nucleus of the thalamus (CM), which have strong reciprocal innervations with the mPFC. However, few studies have reported effects of PCP on the firing activity of MD/CM neurons in unanesthetized animals. In the current study in freely moving rats, we examined effects of systemically administered PCP on the spontaneous firing activity of the MD/CM, after identifying the response properties of recorded neurons in social interaction with an unfamiliar partner. About 30% of MD/CM neurons recorded exhibited tonic excitation following systemic PCP administration, whereas only a few neurons (7%) were inhibited by PCP. The proportion of MD neurons activated by systemic PCP administration was about half of that in the mPFC. Although the proportion of neurons responsive to social interaction did not differ between the two regions (40%), neurons activated during social interaction in the mPFC (90%) were more likely to be affected by systemic PCP administration than those in the MD/CM (45%). These results suggest that neurons responsive to social interaction in the mPFC may be differently affected by PCP than those in the MD/CM.

Locus coeruleus neuronal activity during the sleep-waking cycle in mice.

Using extracellular single-unit recordings in nonanesthetized, head-restrained mice, we examined spontaneous and evoked discharges of noradrenaline-containing locus coeruleus (NA-LC) neurons across the sleep-waking cycle. The neurons were all characterized by triphasic broad action potentials. They discharged as either slow (<6 Hz) tonic, single spikes or phasic clusters of spikes specific to wakefulness (W), the discharge rate being highest during active waking and significantly lower during quiet waking. They remained totally silent during both slow-wave sleep (SWS) and paradoxical (or rapid eye movement (REM)) sleep. The phasic unit activity was related to abrupt activation of electromyographic activity occurring either spontaneously or elicited by alerting sensory stimuli. At the transition from waking to sleep, they ceased firing before the onset of cortical synchronization (deactivation), the first sign of electroencephalographic sleep, a significant decrease in firing rate preceding the onset of unit activity of sleep-specific neurons in the basal forebrain (BFB)/preoptic (POA) hypothalamus, as described previously [Takahashi K, Lin JS, Sakai K (2009) Neuroscience 161:269-292]. At the transition from SWS to waking, they fired before the onset of both cortical activation and a significant decrease in activity of sleep-specific neurons. These findings support the previous view that the NA-LC system is involved in both tonic and phasic processes of arousal, and further support our previous proposals that initiation of sleep is caused by decreased activity of waking-promoting neurons (disfacilitation) and that NA-LC neurons play an important role in the sleep/waking switch, that is from waking to sleep and from sleep to waking [Takahashi K, Lin JS, Sakai K (2009) Neuroscience 161:269-292].

Phencyclidine affects firing activity of basolateral amygdala neurons related to social behavior in rats.

Negative symptoms of schizophrenia, such as social withdrawal and blunted affect, usually persist for a long period, making rehabilitation difficult. Many studies have demonstrated a close relationship between function of the amygdala and social behavior. Normal social behavior is disturbed in animals administered phencyclidine (PCP), which is now considered a reliable pharmacological model of schizophrenia. Recent studies have reported that disruption of social behavior in PCP-treated rats involved dysfunction of the amygdala. Disturbance of function of the amygdala has also been reported in schizophrenic patients. However, no study has yet examined the effects of PCP on the firing activity of amygdala neurons. In the present study, we recorded the unit activity of basolateral amygdala neurons while rats engaged in socially interactive behavior. After identifying the response properties of recorded neurons, we then recorded the same neurons with systemic PCP administration. Approximately half of the neurons recorded from exhibited an increase in spontaneous discharge rate during social interaction. Only a few neurons exhibited suppression of discharge rate during social interaction. Systemic administration of PCP induced long-lasting activation in half of the neurons that exhibited an increase in firing rate during social interaction. PCP activated half of basolateral amygdala neurons related to socially interactive behavior, and might in this fashion produce dysfunction of social behavior.

The septal area, site for the central regulation of penile erection during waking and rapid eye movement sleep in rats: a stimulation study.

The effects of electrical stimulation to the septum on penile erections in rats were examined to clarify the mechanisms for regulation of erectile responses during different states of vigilance. Penile responses were assessed by changes in pressure in the corpus spongiosum of penis (CSP) and electromyography (EMG) of the bulbospongiosus (BS) muscle. In anesthetized and un-anesthetized rats, stimulation in and around the septum induced three erectile patterns; 1) a Normal type response, which was indistinguishable from a spontaneous erection, characterized by a slow increase in CSP pressure with sharp CSP pressure peaks associated with BS muscle bursts, 2) Mixed type response, in which high frequency CSP pressure peaks were followed by a Normal type response, and 3) a Prolonged type response, evoked only in the anesthetized rat, consisting of a single sharp CSP peak followed by a slow increase in CSP pressure and a return to baseline with multiple subsequent events repeated for up to 960 s. In addition, a Micturition type response was also observed involving high frequency CSP pressure oscillations similar to the pressure pattern seen during spontaneous micturition. We found that erections were induced after stimulation to the lateral septum (LS), but not from the medial septum (MS). In anesthetized rats, a few responses were also obtained following stimulation of the horizontal limb of diagonal band (HDB). In un-anesthetized rats, responses were also induced from the HDB and the ventral limb of diagonal band (VDB) and the adjoining areas. The effective sites for eliciting erection during rapid eye movement (REM) sleep were located in the dorsal and intermediate parts of the LS, whereas the ventral part of the LS was the most effective site for eliciting erections during wakefulness. These results suggest a functional role for penile erection in the septum, and further suggest that subdivisions of the LS may have different roles in the regulation of penile erection during wakefulness and REM sleep.

Activation of medial prefrontal cortex neurons by phencyclidine is mediated via AMPA/kainate glutamate receptors in anesthetized rats.

Phencyclidine (PCP) is a psychotomimetic drug that elicits schizophrenia-like symptoms in healthy individuals, and animals administered PCP are now considered a reliable pharmacological model of schizophrenia. Recent studies have shown that systemically administered PCP produces long-lasting activation of medial prefrontal cortex (mPFC) neurons, and that hyperactivation of mPFC neurons plays a critically important role in the development of PCP-induced behavioral abnormalities. However, the receptors mediating this mPFC activation have not been clearly determined. Here, we examined the effects of local application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA/kainate glutamate receptor antagonist, scopolamine, a muscarinic acetylcholine receptor antagonist, and mecamylamine, a nicotinic acetylcholine receptor antagonist, on the increase in firing rate of mPFC neurons induced by systemic PCP in anesthetized rats. After tonic activation of mPFC neurons by PCP had been established, CNQX, scopolamine, or mecamylamine was iontophoretically applied or pressure-ejected on the recorded neuron. CNQX suppressed PCP-induced elevation of firing rate to baseline level, though scopolamine and mecamylamine each induced little change in firing rate. These findings suggest that PCP-induced activation of mPFC neurons is mediated primarily via AMPA/kainate glutamate receptors.

Control of sleep and wakefulness by brainstem monoaminergic and cholinergic neurons.

Noradrenergic projection originating in the locus coeruleus, serotonergic projection from the dorsal raphe nucleus, and cholinergic projection from neurons gathering in the laterodorsal tegmental nucleus and scattering in the pedunculopontine tegmental nucleus constitute three diffuse projection systems arising from the brainstem and innervating wide areas of the brain. They may function as controllers of sleep and wakefulness. We have investigated functional roles of the projections by recording neuronal activity in these brainstem nuclei, and by observing effects of stimulation of the brainstem nuclei. The projection from the locus coeruleus is an arousal system, since the noradrenergic neurons are active specifically during waking, and activation of the noradrenergic projection excites upper brain structures. Functions of the serotonergic projection are still mysterious, since its action on upper brain is inhibitory in spite of waking-specific activity of the neurons. A group of cholinergic neurons constitute a system to induce and maintain paradoxical sleep. The cholinergic projection may have another role, i.e. to induce a rapid, transient elevation of vigilance level by their phasic response to novel, unfamiliar stimuli.

State-dependent activity of neurons in the perifornical hypothalamic area during sleep and waking.

Neurons containing orexins are located in the perifornical hypothalamic area and are considered to have a role in sleep-wake regulation. To examine how this area is involved in the regulation of sleep and wakefulness, we recorded neuronal activity in undrugged, head-restrained rats across sleep-waking cycles. Recordings were made in the perifornical hypothalamic area where orexin-immunoreactive neurons are distributed (PFH), and in the area dorsal to the PFH, including the zona incerta and subincertal nucleus (collectively referred to as ZI). The 40 neurons recorded from in the PFH were divided into five groups: (1) neurons most active during paradoxical sleep (PS, n=14, 35%), (2) neurons active during both waking (W) and PS (n=12, 30%), (3) neurons most active during W (n=7, 18%), (4) neurons most active during slow-wave sleep (SWS, n=3, 7.5%), and (5) neurons whose activity had no correlation with sleep-waking states (n=4, 10%). Of 30 neurons recorded from in the ZI, the corresponding numbers were 13 (43%), seven (23%), six (20%), three (10%), and one (3.3%). In both areas, neuronal activity fluctuated more during PS than during W. Waking-specific neurons (group 3) in the PFH generated action potentials with longer durations than those produced by other types of neurons. About half of the neurons in the PFH that were classified in groups 1, 2, and 3 increased their firing rate after the transition from one state to another, while higher percentages of neurons of groups 1 and 2 in the ZI than those in the PFH increased their firing rate prior to the state shift from SWS to PS. In these ZI neurons, however, the firing rate varied considerably at the state shift. These results suggest that the PFH and ZI are involved in the regulation of PS or W, especially the regulation of phasic events during PS or the maintenance of W. The ZI appears to be more closely involved than the PFH in the induction of PS or some phasic phenomena associated with PS.

Acute administration of phencyclidine induces tonic activation of medial prefrontal cortex neurons in freely moving rats.

Recent studies have reported that acute administration of the psychotomimetic drug phencyclidine results in considerable increases in the amounts of both extracellular glutamate and dopamine in the medial prefrontal cortex (mPFC). However, the effect of phencyclidine on the firing activity of mPFC neurons remains unknown. Here, we report the first data on phencyclidine-induced activation of mPFC neurons in freely moving rats. Unanesthetized rats received an intraperitoneal injection of either phencyclidine (5 mg/kg) or physiological saline (0.5 ml/kg) in order to investigate the impulse activity of mPFC neurons and behavioral activity. The phencyclidine injection induced a remarkable increase (two-fold or more) in the spontaneous discharge rate of the majority of mPFC neurons (20/23), and this increase lasted for more than 70 min. In addition, a considerable augmentation of behavioral activity was observed that nearly paralleled that of the mPFC neuronal activation. In contrast, microiontophoretically applied phencyclidine exerted little influence on the spontaneous firing activity of most mPFC neurons (25/29) in anesthetized rats, although systemically applied phencyclidine produced activation of mPFC neurons even under general anesthesia. These results suggest that the behavioral abnormalities induced by acute administration of phencyclidine may be caused by hyperactivation of mPFC neurons, and that this hyperactivation is elicited through excitatory inputs from brain regions outside the mPFC.

Postnatal development of choline acetyltransferase activity in the rat laterodorsal tegmental nucleus.

Cholinergic neurons in the laterodorsal tegmental nucleus (LDT) have important roles in the regulation of sleep or waking in adult animals. In neonatal animals, sleep is largely occupied by paradoxical sleep. To investigate the relation between the cholinergic neurons in the LDT and the development of neonatal sleep, we dissected the LDT of rat by micropunch method at postnatal day 1--45 and measured the activity of choline acetyltransferase (ChAT). Either specific or total activity of ChAT was weak in the first week, increased strikingly in the second week and then moderately thereafter. The time course of the increase in ChAT activity correlates well to that of the decrease in the amount of paradoxical sleep or body twitches after birth.

State dependent response of the locus caeruleus neurons to bladder distention.

PURPOSE: The precise mechanism by which normal persons wake upon urinary sensation is unclear. The locus caeruleus in the pons is suggested to be involved in the activating systems for arousal. We evaluated the effects of bladder distention on the neural activity in the l. caeruleus under different states of anesthesia. MATERIALS AND METHODS: Experiments were performed on 20 male Sprague-Dawley rats. The spontaneous discharge rate of single neurons in and around the l. caeruleus was recorded with the rat under urethane anesthesia administered intraperitoneally, while the electroencephalogram was monitored simultaneously. The changes of the discharge rate of the neurons were observed during saline infusion into the bladder or during tail pinch stimulation. After recording the location of the neurons was confirmed histologically. RESULTS: Of 42 l. coeruleus neurons whose response was examined during deep anesthesia 31 showed an excitatory response to bladder distention, followed by a change in electroencephalogram pattern to a faster and smaller rate, while the remaining 11 showed no response. Of 28 l. coeruleus neurons examined during light anesthesia only 1 neuron was excited and the remaining 27 showed no response. Virtually all of the l. coeruleus neurons unresponsive to bladder distention were responsive to tail pinch stimulation. Of the nonnoradrenergic neurons ventromedial to the l. coeruleus 4 of 7 during deep anesthesia and 5 of 8 during light anesthesia showed an excitatory response to distention. CONCLUSIONS: The excitatory response of the l. coeruleus neurons to bladder distention was strongly affected by the state of anesthesia. The response was observed only during deep anesthesia and was accompanied by lightening of the anesthesia. L. coeruleus may be involved in arousal which is mediated by bladder distention.

[Relapse of small cell carcinoma of the lung with metastasis to iris].

We reported a case of small cell carcinoma of the lung with metastasis to the iris during a stage of complete remission obtained with chemotherapy and radiation therapy. The patient was a 55-year-old man hospitalized for hoarseness and abnormal chest radiographs in August 1996. Small cell carcinoma of the lung had been diagnosed, and the stage was limited disease. Treatment consisted of 3 cycles of chemotherapy with cisplatin and etoposide, together with radiation therapy. The patient achieved complete remission and was discharged. In mid-December, he visited an eye clinic with the complaints of blurred vision and congestion in the right eye. Metastatic tumor of the iris was diagnosed. At that time, neither local recurrence of the lung cancer nor metastasis to other organs were observed. The patient was treated with cisplatin and etoposide again, resulting in a reduction of the iris tumor's size. After chemotherapy, the right eye was treated with electron irradiation, and the iris tumor and other clinical signs almost entirely disappeared. The patient retained normal vision during the clinical course.

[Sarcoidosis differentially diagnosed from mediastinal tumor by thoracoscopic biopsy].

A 46-year-old man presented with swallowing difficulty and dyspnea when in the supine position. Chest X-ray and computed tomographic (CT) films disclosed left pleural effusion and a tumor shadow extending invasively from superior to anterior mediastinum around the heart and large arteries. These observations called for a differential diagnosis from malignant lymphoma, invasive thymoma, and small cell carcinoma. Bronchofiberscopy and percutaneous tumor biopsy were performed, but the findings were inconclusive. Thoracoscopic biopsy yielded a diagnosis of sarcoidosis. No extrathoracic lesions were detected. Corticosteroid therapy (30 mg/day of prednisolone) was started. After 6 months of treatment (7.5 mg/day of prednisolone), the tumor shadow was reduced in size and the patient's swallowing difficulty and dyspnea subsided. This was a rare case of sarcoidosis extending invasively around the heart and large arteries, and that needed to be differentiated from mediastinal tumor. Thoracoscopic biopsy should be actively enlisted as a diagnostic procedure in difficult cases of this kind.

Selective responsiveness of medial prefrontal cortex neurons to the meaningful stimulus with a low probability of occurrence in rats.

Multi-unit neuronal activity was recorded in the medial prefrontal cortex (mPFC) of 13 chronically prepared male rats while they performed a two-tone discrimination task. Tones at 1000 and 2000 Hz were sequentially presented at intervals of 3-6 s. The duration of each tone was 0.8 s. Rats were trained to press a bar within 1.2 s after the cessation of the 1000 Hz tone (target), and not to press the bar when the other tone (non-target) was presented. Intracranial electrical stimulation (ICS) of the medial forebrain bundle was given as a reward immediately after the rats had correctly responded to the target tone. Probability of the target occurrence was either 30% or 70% in different sessions. When the target tone was presented on only 30% of the trials, the mPFC neurons in the majority of rats tested (10/13) exhibited phasic excitation about 100 ms after the onset of the target tone. However, when the target tone occurred on 70% of the trials, mPFC neurons in most of rats (11/13) did not show excitatory responses, and in some of them (5/13) were inhibited. No mPFC neurons exhibited significant responses to the non-target tone, regardless of its probability. These results suggest that the mPFC neurons selectively respond to meaningful events with a low probability of occurrence.

ERP development in the rat in the course of learning two-tone discrimination task.

To clarify some neurophysiological aspects of learning, we investigated the relationship between the course of learning and development of ERP and investigated developmental processes of ERPs. Nine male Sprague-Dawley rats were trained for a two-tone discrimination task and rat P3 and N1 component were longitudinally recorded. Both rat P3 and N1 gradually increased with learning only for target tones. An improvement in the proportion of correct responses preceded the increase in ERPs, and the increase in P3 and N1 proceeded almost simultaneously. These findings suggest that multiple kinds of information processing were acquired with learning the two-tone discrimination task. ERP development could be utilized as an index of establishment of learning.

The effects of prolactin on the mesopontine tegmental neurons.

In urethane-anaesthetized rats, single neuronal activity was recorded extracellularily in and around the laterodorsal tegmental nucleus, and the response to prolactin applied by pressure injection was examined. Three of six cholinergic neurons tested were excited by prolactin for more than 1 min. In two of three non-cholinergic neurons tested, prolactin application caused excitation which lasted a shorter time than that in the cholinergic neurons. The results suggest that prolactin may have physiological influences on these mesopontine neurons to increase paradoxical sleep.

Are micturition systems influenced by sleep-arousal system?

To clarify a relation between contractile condition of the urinary bladder and vigilance condition, bladder pressure was monitored simultaneously with cortical electroencephalogram (EEG) in urethane-anesthetized rats. Slow waves of large amplitude and those of lower amplitude appeared in EEG alternately. The bladder showed no contractile activity in the former EEG condition, while it contracted intermittently or continuously to urinate in the latter EEG condition. The relative power of EEG delta waves was significantly different in these two conditions. These results suggest that activity of the micturition system changes according to vigilance conditions, which may serve to prevent enuresis during sleep.

Firing of putative cholinergic neurons and micturition center neurons in the rat laterodorsal tegmentum during distention and contraction of urinary bladder.

The relation between unit activity in the laterodorsal tegmental (LDT) area and the state of the urinary bladder was examined in urethane-anesthetized rats. Neurons in the LDT area can be classified into two populations: broad-spike (possibly cholinergic) and brief-spike (non-cholinergic). When the rats showed cortical electroencephalographic activity with large amplitude lower frequency, indicative of deep anesthesia, more than 40% of the broad-spike neurons was excited and about 10% was inhibited by infusion of saline into the bladder. The response was followed by decrease in amplitude and slight increase in frequency of the cortical activity, i.e., lightening of anesthesia. During light anesthesia, excitation was observed only in less than 10% of the units, while 17% was inhibited. In the brief-spike neurons, a similar proportion (about 20%) was excited and less than 10% was inhibited by the distention during either state of anesthesia. About 10% of the broad-spike neurons in the LDT area and 30% of the brief-spike neurons examined were discharged prior to the bladder contraction. Such neurons of the brief-spike category were encountered frequently outside of the central gray; lateral, caudal and ventral to the main mass of cholinergic neurons in the LDT area. These results suggest the possible involvement of the broad-spike (cholinergic) neurons in the elevation of vigilance level caused by bladder distention. The brief-spike (non-cholinergic) neurons firing with relation to bladder contraction may be part of the micturition reflex center.

Effects of repeated administration of methamphetamine on P3-like potentials in rats.

Effects of repeated administration of methamphetamine (MAP) on a component of the cortical event-related potential (ERP), P3-like potential which corresponds to the human P3b, were examined in rats performing an active discrimination task. Rats were trained to press a bar within 1200 ms after cessation of a target tone (1000 Hz) lasting for 800 ms, and to withhold an overt response to the standard tone (2000 Hz). The rats were given intracranial electrical stimulation to the medial forebrain bundle as a reward, only when they correctly responded to the target tone. ERPs before drug administration were recorded after the correct response ratio exceeded 85%. Thereafter, a daily dose of 4 mg/kg of MAP, or the same volume of saline in another group, was administered intraperitoneally 15 times. ERPs were recorded again 7-10 days after the last injection. In the rats which received MAP the amplitude of the P3-like potential decreased with no change in its latency, while the response latency of bar-pressing and the correct response ratio were not altered significantly. These results suggest some changes in catecholaminergic transmission induced by repeated MAP-administration affect a P3 generation mechanism. MAP-treated rats may be useful as an animal model to investigate neural mechanisms of MAP-psychosis and schizophrenia.