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Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.

Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants’ accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.

Objective: Functional decline in daily life is a common difficulty among patients with dementia. Nevertheless, little is known about the neural correlates of functional decline. We hypothesized that functional impairment is associated with metabolic abnormalities in distinct regions in cases of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Methods: After 49 patients with AD, 13 patients with FTD, and 21 normal participants underwent a [18F] fluorodeoxyglucose (FDG)-positron emission tomography scan, we evaluated the relations between functional decline measured using Functional Assessment Staging (FAST) and regional cerebral glucose metabolism from voxel-based analyses. Results: In patients with AD, we found significant negative correlation between FAST scores and [18F] FDG uptake in the parietal cortex, temporal cortex, cingulate cortex and precuneus. By contrast, for patients with FTD, we found significant negative correlation in the frontal cortex, anterior cingulate cortex, and claustrum. Conclusions: This study identified relations between the functional decline and regional brain hypometabolism, respectively, in patients with AD and FTD.

Oxytocin (OT) and the serotonergic system putatively play important roles in autism spectrum disorder (ASD) etiology and symptoms, but no direct neurobiological evidence exists for long-term OT administration effects on the brain's serotonergic system. This pilot study examined 10 male participants with ASD who were administered OT intranasally for 8–10 weeks in an open-label, single-arm, nonrandomized, and uncontrolled manner. Positron emission tomography (PET) with a radiotracer (11C)−3-amino-4-(2-[(dimethylamino)methyl]phenylthio)benzonitrile (11C-DASB) was used before and after OT treatment. The binding potential of serotonin transporter (11C-DASB BPND) was then estimated. The main outcome measures were changes in 11C-DASB BPND and their correlation with changes in symptoms. ASD participants showed significantly elevated 11C-DASB BPND in the left inferior frontal gyrus extending to the left middle frontal gyrus. No significant correlation was found between the change in any clinical symptom and the change in 11C-DASB BPND. This report of a pilot study is the first describing long-term effects of OT on the brain's serotonin system in ASD. Additional randomized controlled studies must be conducted to confirm whether activation of the serotonergic system contributes to the prosocial effect of OT in people with ASD. Autism Res 2017, 10: 821–828. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Psychostimulant drugs have been reported to increase the expression of some immediate-early genes in the brain. In the present study, immunohistochemical techniques were used to assess the pattern of Fos protein produced by 3,4-methylenedioxymethamphetamine (MDMA) in several brain regions. Furthermore, we also studied the role of the dopamine D and D receptors and the N-methyl- D-aspartate (NMDA) receptor in the induction of Fos protein by MDMA. A single administration of MDMA (5, 10 or 20 mg/kg) caused marked induction of Fos-immunoreactivity in several regions including frontal cortex, striatum and olfactory tubercle of rat brain, in a dose-dependent manner. However, in the hippocampus and cerebellum, there were few or no Fos immunoreactive cells induced by MDMA. Furthermore, the induction of Fos protein in the striatum and olfactory tubercle after administration of MDMA (10 mg/kg) was blocked by pre-treatment with the dopamine D receptor antagonist SCH 23390 (1 mg/kg) or the NMDA receptor antagonist dizocilpine (1 mg/kg), but not by the dopamine D receptor antagonist (-)-sulpiride (100 mg/kg). However, the induction of Fos protein in the frontal cortex and hippocampus by MDMA was unaltered by pretreatment with SCH 23390 (1 mg/kg) or (-)-sulpiride (100 mg/kg). These results suggest that MDMA induces the expression of Fos protein in several regions of rat brain, and that the expression of Fos protein by MDMA in the striatum and olfactory tubercle appears to be mediated at least in part by the dopamine D and NMDA receptors.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist such as an abused drug phencyclidine (PCP) causes the induction of heat shock protein HSP-70, a sensitive marker of neuronal injury, in the retrosplenial cortex of rat brain. The present study was undertaken to examine the role of a -amino-3- hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in the expression of heat shock protein HSP-70 and hsp-70 mRNA in the retrosplenial cortex by PCP. Administration of PCP (50 mg/kg, i.p.) caused the induction of heat shock protein HSP-70 in the retrosplenial cortex of rat brain, whereas no HSP-70 immunoreactivity was detected in the vehicle-treated group. Pretreatment with a potent and selective AMPA receptor antagonist YM90K (1, 3 or 10 mg/kg, i.p; 15 min) inhibited in a dose dependent manner, the induction of heat shock protein HSP-70 by PCP (50 mg/kg). Furthermore, administration of PCP (50 mg/kg, i.p) caused marked expression of hsp-70 mRNA in the retrosplenial cortex of rat brain, whereas the expression of hsp-70 mRNA was NOT found in the vehicle-treated group. Pretreatment with YM90K (1, 3 or 10 mg/kg, i p; 15 min) also inhibited the expression of hsp-70 mRNA by PCP (50 mg/kg), in a dose-dependent manner. These results suggest that AMPA receptor may play a role in the expression of heat shock protein HSP-70 and heat shock gene hsp-70 mRNA in the retrosplenial cortex of rat brain by non-competitive NMDA receptor antagonists such as PCP.

Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD38, a leukaemia cell marker, plays an important role in the hypothalamus in the process of OXT release in adult mice. Disruption of Cd38 (Cd38-/-) produced impairment of maternal behavior and male social recognition in mice, similar to the behavior observed in Oxt and OXT receptor (Oxtr) gene knockout (Oxt-/- and Oxtr-/-, respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalization (USV) calls was lower in Cd38-/- than Cd38+/+ pups. These phenotypes seemed to be caused by the high plasma OXT levels during development from neonates to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of differentiating plasma OXT. Contribution by breastfeeding was an important exogenous source for regulating plasma OXT before weaning by the presence of OXT in milk and the dam's mammary glands. The dissimilarity of Cd38-/- infant behaviour to Oxt-/- or Oxtr-/- mice can be explained partly by this exogenous source of OXT. These results suggest that secretion of OXT into the brain in a CD38-dependent manner may play an important role in the development of social behavior, and mice with OXT signalling deficiency, including Cd38-/-, Oxt -/- and Oxtr-/- mice are good animal models for developmental disorders, such as autism. © 2011 Pharmaceutical Society of Japan.

金沢大学医薬保健研究域医学系, Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 (Cd38 (-/-)) elicited impairment of maternal behaviour and male social recognition in adult mice, similar to the behaviour observed in Oxt and oxytocin receptor (Oxtr) gene knockout (Oxt (-/-) and Oxtr (-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalisation calls was lower in Cd38 (-/-) than Cd38( +/+) pups. However, these behavioural changes were much milder than those observed in Oxt (-/-) and Oxtr (-/-) mice, indicating less impairment of social behaviour in Cd38 (-/-) pups. These phenotypes appeared to be caused by the high plasma oxytocin levels during development from the neonatal period to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of plasma oxytocin differentiation. Breastfeeding was an important exogenous source of plasma oxytocin regulation before weaning as a result of the presence of oxytocin in milk and the dam's mammary glands. The dissimilarity between Cd38 (-/-) infant behaviour and those of Oxt (-/-) or Oxtr (-/-) mice can be explained partly by this exogenous source of oxytocin. These results suggest that secretion of oxytocin into the brain in a CD38-dependent manner may play an important role in the development of social behaviour.

Power spectral analysis of electrocardiogram (ECG) R-R intervals is useful for the detection of autonomic dysfunction in various clinical disorders. Although both panic disorder (PD) and major depressive disorder (MDD) are known to have effects on the cardiac autonomic nervous system, no previous study has tested this among drug-naïve (i.e. no history of treatment) patients with MDD and PD in the same study. The purpose of this study was to compare cardiac autonomic functions among drug-naïve patients with MDD and PD and those of healthy controls. Subjects were 17 drug-naïve PD patients, 15 drug-naïve MDD patients and 15 normal controls. ECGs were recorded under both supine resting and supine deep-breathing conditions (10-12 breaths/min; 0.17-0.20 Hz). We measured the low-frequency power (LF; 0.05-0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15-0.40 Hz), which reflects cardiac parasympathetic activity, as well as the LF/HF ratio. As expected, deep breathing induced an increase in HF power and a decrease in the LF/HF ratio in healthy controls. Compared to these controls, however, the MDD group had a lower response to regular deep breathing in LF power and in LF/HF ratio. PD patients showed intermediate results between normal controls and MDD patients. The results indicate that the reactivity to deep breathing revealed diminished cardiac autonomic reactivity in drug-naïve MDD patients.

We assessed the acute effects of various drugs on amygdaloid kindled seizures induced with low-frequency stimulations. We used the number of stimulating pulses required for the induction of epileptic afterdischarge (pulse-number threshold; PNT) as an indicator of the seizure generating threshold and the duration of induced seizures (AD duration; ADD) as an indicator of the seizures. TRH increased the PNT without affecting the ADD at a high dose (1.2 mg/kg). Flunarizine decreased the PNT and ADD simultaneously at a high dose (50 mg/kg). Lithium increased the PNT without affecting the ADD at two doses (100 mg/kg, 200 mg/kg). Zotepine decreased the PNT without affecting the ADD at two doses (8 mg/kg, 16 mg/kg). We propose that the technique of low-frequency kindling is a useful experimental model in assessing the effects of antipsychotic or antiepileptic drugs on the excitability of the limbic regions.

To clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found that methamphetamine-induced locomotor activity is significantly attenuated in reeler mice. To elucidate the mechanism of this phenomenon, we first investigated presynaptic dopamine release; however, there were no significant differences in wildtype, heterozygous reeler and homozygous reeler mice. Next, we examined the locomotor response to intra-accumbens injection of dopamine D1 and D2 receptor agonists, and found that lack of reelin signaling results in decreases in both D1 and D2 receptor-mediated dopaminergic functions. In addition, we measured dopamine receptor binding in the striatum, and found that both D1 and D2 classes of dopamine receptors are reduced in reeler mice. Furthermore, we found that the phosphorylation levels of DARPP-32 are also changed by lack of reelin signaling. Finally, to distinguish between a developmental role of reelin or an acute role of reelin in adult mouse, we intraventricularly infused CR-50, a monoclonal antibody against reelin. Interestingly, infusion of CR-50 also significantly reduced methamphetamine-induced hyperlocomotion in wildtype mice, showing that reelin has an acute role in the dopaminergic system. These results indicate that reelin signaling plays a pivotal role in the dopaminergic system in adult mice, especially in postsynaptic levels.

Objective A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. Basic methods We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. Main results We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. Conclusions Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.

Milnacipran, one of the serotonin noradrenaline reuptake inhibitors (SNRIs) to which venlafaxine and duloxetine belong, is a new antidepressant that has recently become available in many countries. Despite the advances in pharmacotherapy, almost one third of patients with depressive illness respond inadequately to monotherapy with such an antidepressant. We herein describe five patients with major depression who responded partially, but not fully, to milnacipran alone and remarkably improved with an adjunct of risperidone. In addition, milnacipran plus risperidone was found to be a useful augmentation for treatment-refractory depression in 3 of the 5 patients. The minimum dose of risperidone, 0.5 or 1 mg/d, was efficacious. The time of response after addition of risperidone was within 4 d. Our experience suggests that an augmentation therapy of milnacipran plus risperidone is useful for treating patients with depression who only partially respond to various types of antidepressants and for treatment-refractory depression.

Trimethyltin (TMT) is an organic metal known to induce neuronal degeneration in the hippocampus, and abnormal behavior characterized by seizures, increased aggression and memory deficits. We administered TMT to rats and studied the changes of neuropeptide Y (NPY) and somatostatin (SOM) in the hippocampus. Phenobarbital (PB) was administered as an anticonvulsant to assess the effect of seizures on neuropeptide expressions in both dorsal and ventral hippocampus. Histochemically, NPY-immunoreactivity increased 4 days after TMT treatment in the hilus of the hippocampus, then progressively decreased and dropped to a level below control 16 days after TMT treatment. Detection of NPY mRNA by in situ hybridization preceded the detection of NPY by immunohistochemistry. NPY mRNA signals increased in the hilus 2 days after TMT treatment. SOM-immunoreactivity also increased in the hilus of the hippocampus 2 days after TMT treatment, then decreased rapidly to a normal level. Similar changes in SOM mRNA were demonstrated by in situ hybridization. PB treatment significantly inhibited changes of NPY in terms of both immunoreactivity and mRNA expression; however, the same treatment failed to affect changes in SOM expression. This suggests that NPY and SOM act by different mechanisms in TMT-induced neurodegeneration.

In the present study, we examined the effect of tacrolimus, a specific inhibitor of calcineurin, on the locomotor activity elicited by the selective dopamine D(1) receptor agonist (+/-) 6-chloro-7,8-dyhydroxy-3allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine (SKF82958) and the dopamine D(2)/D(3) receptor agonist quinpirole, in male Wistar rats. Tacrolimus (0.5, 1, 2 or 5 mg/kg, i.p.) alone had no significant effect on basal locomotor activity. The dose-related increase in locomotor activity produced by the administration of SKF82958 (0.1, 1 or 5 mg/kg, i.p.) was not significantly altered by 2 mg/kg of tacrolimus. In addition, the increase in locomotor activity produced by 1 mg/kg of SKF82958 was not significantly altered by tacrolimus (0.5, 1, 2 or 5 mg/kg, i.p.). The administration of quinpirole (0.1, 0.25, 0.5, 1 or 3 mg/kg, i.p.) produced a biphasic response, with the minimum and maximal increase in locomotor activity occurring at 0.1 and 1 mg/kg, respectively. The pretreatment of 2 mg/kg of tacrolimus, compared to vehicle-treated animals, significantly lowered the dose of quinpirole that produce a maximal effect on locomotor activity from 1 to 0.5 mg/kg but did not significantly alter the minimum response. The increase in locomotor activity produced by 0.5 mg/kg of quinpirole was significantly potentiated by 0.5, 1, 2 or 5 mg/kg of tacrolimus compared to vehicle-treated animals. Our results suggest that calcineurin may play a role in the alteration of locomotor activity produced by dopamine D(2)/D(3) receptors, but not dopamine D(1) receptors.

For the past decade evidence has gathered for the implication of lysosomes in the development of programmed cell death. Recent data advocate for dual roles of heat-shock protein 70.1 (Hsp70.1) not only as a molecular chaperone for damaged/aged proteins but also as a guardian of lysosomal integrity. Hsp70.1-mediated lysosomal stabilization is tightly regulated, but its disorder under extreme conditions results in lysosomal rupture to cause cell death. Comparing with the pathological hallmark ‘granulo-vacuolar degenerations’ in Alzheimer’s disease, the postischemic monkey neurons were carefully observed with microscope. Intriguingly, we found very similar change, and identified it as ‘lysosomal vesiculosis’ by electron microscopy. However, the exact molecular and structural impacts of the Hsp70.1 disorder upon the lysosomal membrane are hardly elucidated in the human brain because of the practical and ethical problems. Accordingly, using the monkey brain tissues after in-vivo and in-vitro oxidative stresses, we studied molecular modifications of Hsp70.1 and its counterpart bis(monoacylglycero) phosphate (BMP), because these molecules are closely related to the lysosomal membrane stability by regulating acid sphingomyelinase. It still remains unelucidated whether ischemia/reperfusion can alter composition or amount of BMP in the brain. Regardless of the brain regions studied, the normal monkey brain tissues showed calpain-mediated cleavage of Hsp70.1 after in-vitro oxidative stress. In the CA1 after in-vivo ischemia/reperfusion, we first found that docosahexaenoic and oleic acids in BMP showed a significant decrease on days 1 and 3, compared to non-ischemic controls. Since Hsp70.1- BMP binding is indispensable for activating acid sphingomyelinase and producing ceramide to stabilize lysosomal membrane, dysfunction of Hsp70.1 and BMP presumably causes storage of sphingomyelin and deficiency of ceramide at the lysosomal membrane, leading to its destabilization in the postischemic CA1 neurons. These data, combined together, suggest that lysosomal destabilization induced by calpain-mediated cleavage of carbonylated Hsp70.1 and the concomitant BMP breakdown causes ‘lysosomal vesiculosis’.

Using in situ hybridization, we studied the effects of age and gender on the expression of brain-derived neurotrophic factor (BDNF) mRNA and heat shock protein hsp-70 mRNA in the rat retrosplenial cortex following administration of the noncompetitive NMDA receptor antagonist (+)-MK-801 (dizocilpine). Male and female Sprague-Dawley rats (5 weeks, 12 weeks, or 10 months old) were given a single intraperitoneal injection of saline (1 ml/kg) or dizocilpine (0.3, 1.0, or 3.0 mg/kg). No expression of BDNF mRNA and hsp-70 mRNA was detected in the rat retrosplenial cortex after administration of saline (1 ml/kg, IP). Administration of dizocilpine (0.3, 1.0, or 3.0 mg/kg, IP) caused a marked induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex of male and female rats, in a dose-dependent manner. Female rats were more sensitive to the induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine as compared to male rats. It was also found that adult (12 weeks old) and aged (10 months old) rats were more sensitive to the induction of hsp-70 mRNA and BDNF mRNA in the retrosplenial cortex by dizocilpine as compared to young (5 weeks old) rats. These results suggest that the age and gender differences observed in the expression of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine may be associated with the differences in dizocilpine-induced neurotoxicity observed with gender and age within the same region.

We examined the effect of the acute and repeated administration of M100907 (formerly MDL 100907), a selective 5-HT2A receptor antagonist, on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) of rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of M100907 (0.01–0.64 mg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active SNC and VTA DA neurons. A single injection of either 0.01 or 0.03 mg/kg i.p. of M100907 did not significantly alter the number of spontaneously active DA neurons in either the SNC or VTA areas. However, 0.1 mg/kg i.p. of M100907 significantly increased the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. A single injection of all doses of M100907 significantly decreased the degree of bursting in VTA DA neurons, whereas the 0.1 mg/kg dose increased the degree of bursting in SNC DA neurons. The repeated administration (one injection per day for 21 days) of 0.03 and 0.1 mg/kg i.p. of M100907 produced a significant decrease in the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. The repeated administration of M100907 did not significantly alter the firing pattern of VTA DA neurons but significantly altered the firing pattern of SNC DA neurons. The results of this study indicate that M100907 administration alters the activity of midbrain DA neurons in anesthetized rats. Synapse 40:102–112, 2001. © 2001 Wiley-Liss, Inc.

Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased the Kd, but not Bmax, values of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) binding to adenosine A1 receptors in the prefrontal cortex and hippocampus, but not striatum, of rat brain. However, subchronic treatment with PCP (10 mg/kg, i.p., once daily for 11 days) did not alter the Kd and Bmax values of [3H]DPCPX binding to adenosine A1 receptors in these three regions. Subchronic treatment with MAP or PCP did not alter the Bmax and Kd values of [3H]2-p-(2-carboxyehyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine ([3H]CGS21680) binding to adenosine A2A receptors in the striatum. Furthermore, subchronic treatment with MAP or PCP significantly decreased the specific binding of [3H]CGS21680 to adenosine A2A receptors in the hippocampus, but not in the prefrontal cortex. Thus, these results suggest that MAP and PCP may produce differential effects on the adenosine A2A receptors, but not adenosine A1 receptors in rat brain.

Using in situ hybridization and immunohistochemical techniques, we examined the expression pattern of egr-1 mRNA and Egr-1 protein in several brain regions following administration of 3,4-methylenedioxymethamphetamine (MDMA). Furthermore, we also studied the role of N -methyl- d -aspartate (NMDA) receptor, dopamine D 1 receptor, 5-hydroxytryptamine (5-HT) transporter or 5-HT 2A receptor in the induction of egr-1 mRNA by MDMA. Basal constitutive levels of egr-1 mRNA were detected in control rat brains. A single administration of MDMA (10 mg/kg) caused marked induction of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus. However, no changes in the egr-1 mRNA levels were detected in the CA1 region of hippocampus and occipital cortex after administration of MDMA (10 mg/kg). Furthermore, the expression of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus after administration of MDMA (10 mg/kg) was blocked significantly by pretreatment with NMDA receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5,10-imine ((+)-MK801; 1 mg/kg), dopamine D 1 receptor antagonist SCH 23390 (1 mg/kg) or 5-HT uptake inhibitor paroxetine (5 mg/kg), but not by 5-HT 2A receptor antagonist SR46349B (5 mg/kg). However, high basal levels of Egr-1 immunoreactivity in the rat brain were not altered by administration of MDMA (10 mg/kg). These results suggest that MDMA alters the expression of egr-1 mRNA in several regions of rat brain, and that the expression of egr-1 mRNA by MDMA in the prefrontal cortex, striatum and hippocampal dentate gyrus appears to be mediated, at least in part, by NMDA receptor, dopamine D 1 receptor and 5-HT transporter.

In this study, we assessed the effects of the acute (a single injection) and repeated (once daily injections for 21 days) administration of the atypical antipsychotic drug clozapine (1.5, 5, or 15 mg/kg i.p.) and the typical antipsychotic drug haloperidol (0.15, 0.5, and 1.5 mg/kg, i.p.) on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold (PNT) and the primary afterdischarge duration (ADD), respectively. A single injection of either 5 or 15 mg/kg of clozapine significantly decreased the PNT and significantly increased the primary ADD, indicating a proconvulsant action. The repeated administration of clozapine (1.5, 5, or 15 mg/kg, i.p.) produced dose-dependent, proconvulsant effects by significantly decreasing the PNT and by significantly increasing the primary ADD. In contrast to clozapine, the acute administration of haloperidol did not significantly alter the PNT or the primary ADD. The repeated administration of haloperidol (0.5 and 1.5 mg/kg, i.p.), unlike clozapine, significantly decreased the primary ADD, but did not alter the PNT. Overall, clozapine produces a greater proconvulsant action than haloperidol in an animal model of hippocampal seizures.

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D1 and D2 receptors and the N-methyl-d-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 microgram/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D1 receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5. 0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 microgram/kg). Pretreatment with sulpiride, a dopamine D2 receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D1 receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D2 receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain.

The non-competitive NMDA receptor antagonists such as phencyclidine (PCP) cause neurotoxicity in the retrosplenial cortex of rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is currently unclear. Using an in situ hybridization technique, we studied the effects of PCP on expression of brain-derived neurotrophic factor (BDNF) mRNA in the rat brain. No expression of BDNA mRNA was observed in the retrosplenial cortex of rats treated with vehicle, although a high basal level of BDNF mRNA was detected in the hippocampus of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 hours) caused marked induction of BDNF mRNA in the retrosplenial cortex, in a dosedependent manner. These results suggest that the expression of BDNF mRNA may occur as a trophic response to the neurotoxicity of NMDA receptor antagonists such as PCP.

The effect of NMDA receptor antagonist phencyclidine (PCP) on expression of cyclooxygenase (COX)-2 mRNA in the rat brain was studied. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of COX-2 mRNA and heat shock gene hsp-70 mRNA, a marker of neuronal injury, in the retrosplenial cortex, in a dose-dependent manner. These results suggest that COX-2 may play a role in the neurotoxicity of NMDA receptor antagonists.

High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.

We assessed the effect of an opener of ATP-sensitive K + channel, levcromakalim (BRL 38227, (−)6-cyano-3,4-dihydro-2,2-dimethyl- trans -4-(2-oxo-1-pyrrolidyl)-2 H /it-1-benzopyran-3-ol) on seizure threshold and severity of the hippocampus-generating partial seizures in rats. For comparison, an ATP-sensitive K + channel blocker, glibenclamide; K + channel blocker, tetraethylammonium; Ca 2+ channel antagonist, nimodipine and Ca 2+ channel agonist, (±)-BAY K 8644 (1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridinecarboxylic acid methyl ester) were also examined. Seizure threshold was determined using pulse number threshold and seizure severity was ascertained using afterdischarge duration. Levcromakalim decreased afterdischarge duration at 10 nmol i.c.v. and decreased pulse number threshold at 100 nmol i.c.v. Tetraethylammonium at 10 nmol i.c.v. increased afterdischarge duration selectively and at 100 nmol i.c.v. induced spontaneous seizures. Glibenclamide (1–100 nmol i.c.v.) failed to change pulse number threshold and afterdischarge duration. Nimodipine (40 mg/kg i.p.) decreased afterdischarge duration and pulse number threshold. BAY K 8644 (1 mg/kg i.p.) decreased pulse number threshold and increased afterdischarge duration. In addition, voltage-clamp recording from neuroblastoma × glioma hybrid cells indicates that levcromakalim inhibited the fast component of Ca 2+ -dependent K + currents, in addition to the inhibition of T- and L-types of voltage-dependent Ca 2+ currents reported (Ito et al., FEBS Lett. 262, 313, 1990). These results suggest that levcromakalim shows anti- and proconvulsive actions in the hippocampus-generating partial seizures in rats and these effects might be, at least partly, caused by inhibiting Ca 2+ channel and Ca 2+ -dependent K + channel, respectively.

Extracellular single cell recording was used to examine the effect of intravenous administration of (-), (+), and (+/-)-3,4-methylenedioxymethamphetamine (MDMA) on A10 dopamine (DA) neurons in chloral hydrate anesthetized male rats. Both (+/-)-MDMA and (+)-MDMA inhibited the firing rate of most (79%) A10 DA cells. By contrast, (-)-MDMA induced either no effect or a slight increase in the firing rate of these cells. Analysis of the effects of (+/-)-MDMA on the firing pattern of the DA cells revealed on overall decrease in the percentage of spikes in bursts but both increases and decreases were seen in the coefficient of variation of interspike intervals. To determine the contribution of 5-HT and DA to the (+/-)-MDMA-induced inhibition of A10 DA cells rats were pretreated either with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) or the DA synthesis inhibitor alpha-methyl-p-tyrosine (AMPT). Pretreatment of rats with PCPA did not reduce the ability of (+/-)-MDMA to inhibit the DA cells. However, in rats pretreated with AMPT, the (+/-)-MDMA-induced inhibition was blocked and some cells (44%) showed instead an increase in firing rate following administration of (+/-)-MDMA. The administration of l-3,4-dihydroxyphenylalanine (L-DOPA) to AMPT-treated rats rapidly restored the inhibition of cell firing by (+/-)-MDMA. In conclusion, the results reported here demonstrate that MDMA has an overall inhibitory effect on A10 DA cells. Despite MDMA's greater potency in releasing 5-HT compared to DA, the inhibitory effect of this drug on A10 DA cells appears to be mediated by the latter transmitter.

The role of sigma receptors in the induction of heat shock protein (HSP)-70 by non-competitive N-methyl-Daspartate (NMDA) receptor antagonists (+)-MK-801 (dizocilpine) and phencyclidine (PCP) was studied. HSP-70 is induced in the posterior cingulate and retrosplenial cortex of rat brain 24 hours after a single administration of dizocilpine (1 mg/kg) or PCP (50 mg/kg). The induction of heat shock protein HSP-70 by dizocilpine or PCP was attenuated partially by pre-treatment with the antipsychotic drug haloperidol (3 mg/kg, i.p., 15 minutes previously). However, pre-treatment with high potent and selective sigma receptor ligands, 4-phenyl-4-(1-phenylbutyl)piperidine (4-PPBP, 3 mg/kg, i.p., 15 minutes previously) and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride) (NE-100, 3 mg/kg, i.p., 15 minutes previously) did not alter the induction of HSP-70 by dizocilpine or PCP. These findings suggest that sigma receptors may not play a significant role in the induction of HSP-70 by non-competitive NMDA receptor antagonists dizocilpine and PCP, and that protective effects of haloperidol on induction of HSP-70 protein by dizocilpine or PCP may be due to other effect(s) except sigma receptors.

We studied the mechanism of antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan. The pretreatment with potent and selective σ receptor ligands, 4-phenyl-4-(1-phenylbutyl)piperidine (4-PPBP) and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), did not alter the reduction of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the cerebral cortex by repeated administration of p-chloroamphetamine. These results suggest that σ receptors might not play a significant role in the antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan.

There is a significant difference between the Lewis and Fischer 344 rats regarding their propensity to self-administer drugs of abuse. This study compares the number and the firing pattern of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in these two strains of rats. This was accomplished using the technique of in vivo extracellular recording. The number of spontaneously active DA neurons in the SNC and VTA of the Lewis rat were significantly lower compared to that of the F344 rats. Furthermore, a greater percentage of SNC and VTA DA neurons in the Lewis rats exhibited a burst firing pattern compared to F344 rats. These findings indicate that F344 and Lewis rats possess differences in mesolimbic DA neuronal activity and this may be a factor in explaining the different propensities between the two strains to self-administer drugs.

The authors examined dopamine transporter density in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in methamphetamine users and assessed the relationship of these measures to the subjects' clinical characteristics.Positron emission tomography with [(11)C]WIN 35,428 was used to examine the regions of interest in 11 methamphetamine users and nine healthy comparison subjects. Psychiatric symptoms were evaluated with the Brief Psychiatric Rating Scale.Dopamine transporter density in the three regions studied was significantly lower in the methamphetamine users than in the comparison subjects. The lower dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex was significantly correlated with the duration of methamphetamine use and the severity of psychiatric symptoms.Chronic methamphetamine use may cause dopamine transporter reduction in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in the brain. Psychiatric symptoms in methamphetamine users may be attributable to the decrease in dopamine transporter density in the orbitofrontal cortex and the dorsolateral prefrontal cortex.

© 2012 Munesue et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder?

This study examined the effect of acute and chronic administration of the selective 5-HT3 receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose-response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01-0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)-apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2-fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose-response curve of BRL 46470A. © 1994 Wiley-Liss, Inc.

Schizophrenia has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical circuitry. Alterations in gamma band oscillations have attracted a great deal of interest as they appear to represent a pathophysiological process of cortical dysfunction in schizophrenia. Gamma band oscillations reflect local cortical activities, and the synchronization of these activities among spatially distributed cortical areas has been suggested to play a central role in the formation of networks. To assess global coordination across spatially distributed brain regions, Omega complexity (OC) in multichannel EEG was proposed. Using OC, we investigated global coordination of resting-state EEG activities in both gamma (30–50 Hz) and below-gamma (1.5–30 Hz) bands in drug-naive patients with schizophrenia and investigated the effects of neuroleptic treatment. We found that gamma band OC was significantly higher in drug-naive patients with schizophrenia compared to control subjects and that a right frontal electrode (F3) contributed significantly to the higher OC. After neuroleptic treatment, reductions in the contribution of frontal electrodes to global OC in both bands correlated with the improvement of schizophrenia symptomatology. The present study suggests that frontal brain processes in schizophrenia were less coordinated with activity in the remaining brain. In addition, beneficial effects of neuroleptic treatment were accompanied by improvement of brain coordination predominantly due to changes in frontal regions. Our study provides new evidence of improper intrinsic brain integration in schizophrenia by investigating the resting-state gamma band activity.

Patients with panic disorder (PD) have a bias to respond to normal stimuli in a fearful way. This may be due to the preactivation of fear-associated networks prior to stimulus perception. Based on EEG, we investigated the difference between patients with PD and normal controls in resting state activity using features of transiently stable brain states (microstates). EEGs from 18 drug-naive patients and 18 healthy controls were analyzed. Microstate analysis showed that one class of microstates (with a right-anterior to left-posterior orientation of the mapped field) displayed longer durations and covered more of the total time in the patients than controls. Another microstate class (with a symmetric, anterior-posterior orientation) was observed less frequently in the patients compared to controls. The observation that selected microstate classes differ between patients with PD and controls suggests that specific brain functions are altered already during resting condition. The altered resting state may be the starting point of the observed dysfunctional processing of phobic stimuli.

In this study, the technique of extracellular single unit recording was used to examine the effect of prenatal cocaine exposure on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC or A9) and the ventral tegmental area (VTA or A10) of male Sprague-Dawley rats on postnatal days 56–68. In addition, the effect of the direct DA receptor agonist (±)-apomorphine (APO) on the basal firing rate of A10 DA cells was also determined. A significant decrease in the number of spontaneously active A10 DA cells was observed in offspring whose dams were treated with 40 mg/kg/day of cocaine s.c. from gestational days 8–20 when compared with offspring of pair-fed and non-treated control dams. The number of spontaneously active A9 DA cells was significantly decreased in the offspring of cocaine-exposed dams when compared to pair-fed offspring. In contrast, there were no significant differences among the three prenatal groups regarding the sensitivity of spontaneously active A10 DA cells to APO (2–64 μg/kg, i.v.). Overall, our results suggest that in utero cocaine exposure may alter presynaptic DA activity in offspring long after their exposure has been terminated.

In this study, we have examined the effect of acute and chronic administration of LY 277359, a putative 5-HT3 receptor antagonist, on the number of spontaneously active dopamine cells in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10). This was accomplished using the standard extracellular single unit recording techniques. The acute administration of LY 277359 (0.1 or 1.0 mg/kg i.p.) produced a significant increase in the number of spontaneously active A10, but not A9, dopamine cells compared to saline controls. The acute administration of 10 mg/kg of LY 277359 did not significantly alter the number of spontaneously active dopamine cells in either area. In contrast to its acute effects, the administration of 0.1 mg/kg per day of LY 277359 for 21 days decreased the number of spontaneously active A9 and A10 dopamine cells. However, the i.v. administration of (+/-)-apomorphine (50 micrograms/kg) did not reverse LY 277359's action, suggesting that the chronic LY 277359-induced reduction of dopamine cells was not the result of depolarization block. To test whether chronic administration of LY 277359 at a high dose would induce depolarization block of dopamine cells, rats were treated with 1.0 or 10 mg/kg LY 277359. Interestingly, the chronic administration of 1.0 mg/kg LY 277359 increased the number of A10, but not A9 dopamine cells. In contrast, chronic treatment with 10 mg/kg selectively decreased the number of spontaneously active A10 dopamine cells.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism.Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects.The serum levels (503.5+/-160.5 pg/mL (mean+/-SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0, p0.001) lower than those (817.6+/-232.4 pg/mL (mean+/-SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients.This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism.

SOD2 (superoxide dismutase 2) plays a crucial role in protecting the cells against damage caused by free radicals, by catalyzing their detoxification. On the other hand, cell damage caused by free radical generation following methamphetamine administration has been postulated as one of the possible pathophysiological mechanisms for methamphetamine psychosis. Hence, we investigated the association of SOD2 polymorphisms with the development of methamphetamine psychosis, in two independent populations of Japan and Taiwan. We recruited 116 patients with methamphetamine psychosis and 189 controls in Japan, and 135 patients with methamphetamine psychosis and 204 controls in Taiwan. The methamphetamine group was divided into two clinical subtypes: a transient type of psychosis (i.e., good prognosis) and a prolonged type of psychosis (i.e., poor prognosis), according to the course of the manifestation of psychosis. With reference to the genotypic and allelic frequencies of Ala/Val functional polymorphism in exon 2, we found significant differences between individuals with prolonged methamphetamine psychosis and control samples from Japan and Taiwan in the genotypic (P value 0.014 and 0.016, respectively) and in the allelic (P value 0.004 and 0.047, respectively) frequencies. Our results suggest that Ala/Val polymorphism of the SOD2 gene could be associated with the risk of developing methamphetamine psychosis.

Context In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans. Objective To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers. Design Case-control analysis. Setting A hospital research center. Participants Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community. Interventions The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans -1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([ 11 C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables. Main Outcome Measures The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [ 11 C](+)McN-5652 distribution volume. Results Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers. Conclusions Protracted abuse of methamphetamine may reduce the density of the serotonin transporter in the brain, leading to elevated aggression, even in currently abstinent abusers.

The interactions of selective serotonin reuptake inhibitors and tricyclic antidepressants with subtypes of sigma receptors were investigated. The rank order of affinity (Ki values) from competition experiments of [3H](+)-pentazocine binding to sigma 1 sites was: fluvoxamine > sertraline > S(+)-fluoxetine > (+/-)-fluoxetine > citalopram > imipramine > paroxetine > desipramine > R(-)-fluoxetine > (+/-)-norfluoxetine. The Ki values of all drugs for sigma 2 sites were more than 1000 nM. Furthermore, all drugs were more potent at sigma 1 sites than at sigma 2 sites. These findings suggest that sigma receptors (sigma 1 site) may play, in some way, a role in the actions of selective serotonin reuptake inhibitors.

This study examined the effect of the p.o. administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on the activity of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) in anesthetized male Sprague-Dawley rats. This was accomplished using in vivo electrophysiology. The acute p.o. administration of Y-931 did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals. A single p.o. administration of 3 and 10 mg/kg of Y-931 significantly increased and decreased, respectively, the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The acute administration of 3 mg/kg of Y-931 significantly altered the firing pattern parameters for all spontaneously active SNC DA. The 3 and 10 mg/kg doses of Y-931 significantly increased the degree of bursting and irregular activity of spontaneously active VTA and SNC DA neurons firing in a bursting pattern. The repeated p.o. administration (21 days) of 1, 3, or 10 mg/kg of Y-931 significantly decreased the number of spontaneously active VTA DA neurons but had no significant effect on SNC DA neurons compared to vehicle-treated animals. The repeated administration of Y-931 did not significantly alter the firing pattern of all spontaneously active SNC or VTA DA neurons. Our findings indicate that the acute and chronic administration of Y-931 significantly alters the activity of midbrain DA neurons in rats and the electrophysiological profile of chronic Y-931 resembles that of atypical antipsychotic agents.

(1)The basal ganglia circuitry mediates a wide rage of brain functions such as motor control, behavioral planning, and reward prediction. Dopamine (DA) transmission plays an essential role in the regulation of these brain functions. DA action not only regulates the firing activity of target neurons but also is involved in the pattern formation of their firing. The striatopallidal neurons containing dopamine D(2) receptor plays a dual role in motor coordination dependent on DA transmission. (2)Activation of presynaptic D(2)-like receptors on GABAergic terminals onto striatal cholinergic interneurons selectively blocks N-type Ca(2+) channels, thereby inhibiting GABA release. In addition, contribution of N-type channels and D(2)-like receptor-mediated presynaptic inhibition decreases in parallel with development, implying some relationship between basal ganglia-related function or dysfunction and age. (3)As an approach to determine dopamine neuronal activity, we monitored neuronal activities by measuring cytosolic Ca(2+) concentration in VTA dopamine neurons. The present study indicates that VTA dopamine neurons are the direct targets of orexin-A and psychostimulants, and the [Ca(2+)](i) signaling is thought to play a significant role in the regulation of dopamine neuronal activity. (4)The excitability of neostriatal neurons is regulated by a balance of glutamatergic and dopaminergic inputs. Glutamate has been shown to modulate dopaminergic signaling. Studies on the regulation of DARPP-32 phosphorylation by glutamate provide a molecular basis for both the synergistic and antagonistic effects of glutamate on dopaminergic signaling. (5) Impairment of function of stem/progenitor cells may be implicated in the pathogenesis of schizophrenia. To test this hypothesis, several experiments are currently ongoing in our laboratory, and the preliminary results obtained are described here.

Neuronal dysfunction in the frontal cortex has been reported in the etiology of mental disorders, including schizophrenia. The adenosine A(1) receptor system, as well as the dopaminergic system, are important in the control of cortical neuronal activity. We hypothesize that neuroexcitability in early life is critical to the normal development of the brain, and neurosteroids are factors that modulate neuroexcitability during the development period. In this study, we treated neonatal rats with a neurosteroid, pregnenolone (10 microg/g) from postnatal day (PD) 3 until PD 7. In pregnenolone-treated male and female rats, adenosine A(1) receptor density, the amount of dopamine (DA), serotonin (5-HT) and their metabolites in the fronto-parietal cortex and behavioral responses in the open field were examined pre- and post-puberty. A decrease in K(d) values for the adenosine A(1) receptor binding assay using [(3)H]1,3-dipropyl-8-cyclopentylxanthine (DPCPX), increased formation of DA metabolites and hyper-locomotor activity in the open field were found in pregnenolone-treated rats compared with controls in pre- and post-puberty. An increase in 5-HT metabolites was found in the pregnenolone-treated rats in pre-puberty, but not post-puberty. These effects of pregnenolone were not different between males and females. However, correlations between horizontal and vertical activities in the open field were disrupted only in pregnenolone-treated females. The present results indicate that pregnenolone treatment during the neonatal period influences the cortical dopaminergic and adenosinergic systems as well as behavioral responses in the open field.

In this study, we examined the effect of the acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 (SB) on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, albino, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single cell recording. The acute i.v. administration of SB-243213 (0.025–3.2 mg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to vehicle-treated controls. The acute i.p. administration of either 1 or 10 mg/kg of SB-243213 did not significantly alter the number of spontaneously active DA cells in the SNC or VTA compared to vehicle-treated controls, whereas the 3 mg/kg dose only significantly decreased the number of spontaneously active VTA DA neurons. Overall, the 1 mg/kg dose of SB-243213 did not significantly alter the firing pattern of either SNC or VTA DA neurons compared to vehicle-treated controls. In contrast, the 3 mg/kg dose significantly altered the firing pattern of SNC DA neurons, whereas the 10 mg/kg dose altered the firing pattern of DA neurons in both the SNC and VTA. The repeated i.p. administration (21 days) of 1, 3, and 10 mg/kg of SB-243213 or 20 mg/kg of clozapine produced a significant decrease in the number of spontaneously active DA cells in the VTA compared to vehicle-treated controls. The decrease in the number of spontaneously active VTA DA cells was not reversed by the i.v. administration of (+)-apomorphine (50 μg/kg). The repeated administration of either 1 or 3 mg/kg of SB-243213 had minimal effects on the firing pattern of either SNC or VTA DA neurons. In contrast, the firing pattern of VTA DA neurons was significantly altered by 10 mg/kg dose of SB-243213. Overall, our results indicate that antagonism of the 5-HT2C receptor alters the activity of midbrain DA neurons in anesthetized rats and suggest that SB-243213 has an atypical antipsychotic profile following chronic administration. Synapse 46:129–139, 2002. © 2002 Wiley-Liss, Inc.

Following the chronic use of methamphetamine, some individuals experience psychosis and anxiety. One reason may be the persistence of metabolite abnormalities in the brain of currently abstinent former methamphetamine users. In this study, N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr+PCr), and choline-containing compound (Cho) levels were measured in the left and right basal ganglia using proton magnetic resonance spectroscopy (MRS) in 13 abstinent methamphetamine users and 11 healthy comparison subjects with no history of illicit drug use. The methamphetamine users showed a significantly reduced Cr+PCr/Cho ratio in the bilateral basal ganglia compared with the healthy comparison subjects. Furthermore, the reduction in the Cr+PCr/Cho ratio was significantly correlated with the duration of methamphetamine use and with the severity of residual psychiatric symptoms. NAA/Cho ratios in the bilateral basal ganglia did not significantly differ between methamphetamine users and comparison subjects. These findings suggest that protracted use of methamphetamine may cause metabolite alterations in the basal ganglia. Furthermore, residual psychiatric symptoms may be attributable to the metabolite alterations in the basal ganglia.

Steroid hormones synthesized in the brain, called 'neuro-steroids', modulate neuronal activity. We treated neonatal rats with a main precursor of the neurosteroidogenesis, pregnenolone, and examined adenosine A 2A receptor, 5-hydroxytryptamine (5-HT) 1A and 5-HT 7 receptor densities in the front-parietal cortex in juvenile and adult rats. In receptor binding assay using [ 3 H]CGS21680 and [ 3 H]8-OH-DPAT, it was shown that neonatal pregnenolone-treatment induced a significant decrease in the adenosine A 2A receptor density with no significant effects on the 5-HT 1A and 5-HT 7 receptor densities.