The effect of risperidone on polydipsia-hyponatremia was evaluated in six hospitalized schizophrenic patients. The normalized diurnal weight gain (NDWG), urine-specific gravity (USG), urine and plasma osmolarity, and serum sodium were monitored during 9 months of risperidone treatment. The dose of risperidone (mean +/- SD=8.0 +/- 1.0, range=6-9 mg/day) was determined as approximately half of the haloperidol-equivalent dose of previous neuroleptics. Before risperidone treatment, the mean (+/- SD) BPRS score was 23.5 +/- 7.1; no significant improvement was observed after risperidone (22.0 +/- 7.5). The subjects showed relatively high serum prolactin before risperidone treatment (mean +/- SD=16.5 +/- 9.7 ng/mL), that was not significantly decreased by risperidone (14.2 +/- 7.9 ng/mL). The monthly means (+/- SD) of NDWG and USG before risperidone were 5.5 +/- 1.5 (%) and 1.002 +/- 0.001, respectively. These and other indices did not significantly improve throughout the study period. Although the sample size is relatively small, our preliminary data showed that risperidone might not be effective on polydipsia-hyponatremia of schizophrenic patients.

Respective contributions of arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) to the urinary sodium concentration were evaluated in 23 naturalistic incidents of polydipsia-hyponatremia observed in 11 hospitalized schizophrenics (10 males and 1 female). The sodium concentration of the spontaneously excreted urine was examined before and after the forced water restriction. Before the water restriction, mean (±S.D.) plasma ANP was 52.8±33.9 pg/ml (range=6.9–137). Plasma AVP levels were below 0.3 pg/ml in 15 episodes; relatively high levels (≥0.3) were noted in eight episodes. Means of urinary sodium concentration (mEq/l) were significantly higher in episodes with high AVP (≥0.3) alone (25.0±8.2, n=4), with high ANP (>43) alone (21.3±7.4, n=9), and with high AVP and ANP (26.8±6.4, n=4) as compared to that of the low AVP (<0.3) and ANP (≤43) group (13.5±3.7, n=6). The data indicate that the elevated urinary sodium in polydipsic patients is possibly due to the AVP-induced antidiuresis and/or the ANP-induced natriuresis. In addition, we observed a close relationship between elevated plasma AVP and vomiting, suggesting that vomiting is one of the causal factors responsible for AVP elevations in this syndrome.

To investigate the effects of phencyclidine (PCP) on N-methyl-d-aspartate (NMDA) receptors, we examined the effects of both single and repeated administrations of PCP on the NMDA receptor subunits in rat brain using in situ hybridization. Intraperitoneal (i.p.) administration of a daily dose of 7.5mg/kg PCP resulted in significantly decreased in expression of NMDAR2A subunit mRNA in the cingulate cortex Ih after a single administration. Repeated PCP administrations for 14 days resulted in significantly decreased the expression of NMDAR1(-) mRNA in the nucleus accumbens and piriform cortex. These results suggest that region-specific decreases of NMDA receptor subunits may represent a compensatory response to enhanced glutamate availability in the limbic region.

We investigated the time-course effects of a single administration of cocaine (20 mg/kg) on GABAA receptor binding labeled by t-[35S]butylbicyclophophorothionate (TBPS) and on several types of GABAA receptor subunit mRNAs in the rat brain by in vitro quantitative receptor autoradiography and in situ hybridization. The levels of α1, β2, and β3 subunit mRNAs in several brain regions such as the cortex, cerebellum, and striatum were significantly decreased within 1 h, while β3 subunit mRNA was increased in the dentate gyrus. All of these changes were transient, occurring within 1 h after the injection of cocaine. In the cortex and cerebellum, the reduction in α1 subunit mRNA was followed by a significant decrease in [35S]TBPS receptor binding, which occurred 4 h after cocaine injection. These findings suggest that acute cocaine administration discretely regulates GABAA receptor subunit mRNA levels in several brain regions through a change in transcription or turnover rates of subunit mRNAs, which may be closely related to cocaine-induced behavioral abnormalities.

Recent biochemical observations have suggested the abnormalities in the gamma-amino-butyric acid (GABA)ergic system in schizophrenic brains. In the present study, we investigated the subunits gene expressions and ligand binding of the GABA(A) receptor following acute and chronic administration of phencyclidine (PCP), which induces schizophrenia-like symptoms, in rats using in situ hybridization and in vitro quantitative autoradiography. PCF i.p. administration at a daily dose of 7.5 mg/kg resulted in a significant decrease in expression of alpha 1 subunit mRNA in cerebral cortices (cingulate (-13%) and temporal cortex (-6%)) and hippocampal formation (CA1 (-11%), CA2 (-10%), CA3 (-11%) and dentate gyrus (-1.2%)) 1 h after a single treatment. In the repeated PCP administrations for 14 days, the expression of beta 2 mRNA in the cerebellum (-10%) and of beta 3 mRNA in the cerebral cortices (cingulate (-12%), parietal (-16%) and temporal cortex (-16%), caudate putamen (-18%), inferior colliculus (-18%), and cerebellum (-15%) were significantly decreased. In addition, [S-35] t-butylbicyclophosphorothionate (TBPS) binding was also reduced in layer IV of the frontoparietal cortex (-14%), inferior colliculus (-17%), and cerebellum (-12%) following chronic PCP treatment, while no changes were observed following acute PCP treatment. These results indicate that single and repeated administrations of PCP independently regulate the expression of GABA(A)/benzodiazepine (BZD) receptor subunits mRNA and its receptor binding in the brain. Synapse 38:51-60, 2000. (C) 2000 Wiley-Liss, Inc.

Phencyclidine (PCP) is known to be an inhibitor of serotonin (5-HT) uptake and to increase serotonergic activity. The development of tolerance to serotonergic stereotyped behaviors induced by repeated PCP treatment and changes of 5-HT transporters were examined. Backpedalling was significantly reduced in frequency following 14 days PCP treatment (7.5 mg/kg per day). Furthermore, repeated PCP treatment decreased the equilibrium dissociation constant (Kd) of [3H]paroxetine binding to 5-HT transporters in whole brain excluding the cerebellum without any change of maximum number of binding sites (Bmax). Single treatment with PCP failed to change binding parameters. These results indicate that repeated PCP treatment causes tolerance in serotonergic stereotyped behavior and increases affinity of 5-HT transporters for [3H]paroxetine binding. The increased affinity of 5-HT transporters could represent compensatory responses to chronic inhibition of 5-HT uptake by PCP.

The effects of intermittent intraperitoneal (i.p.) administration of cocaine (20 mg/kg) on GABA(A)-benzodiazepine (BZD) receptors labeled by t-[(35)S]butylbicyclophosphorothionate (TBPS), and on several types of mRNA subunits were investigated in rat brain by in vitro quantitative receptor autoradiography and in situ hybridization. Phosphor screen imaging with high sensitivity and a wide linear range of response was utilized for imaging analysis. There was a significant decrease in the level of alpha 1, alpha 6, beta 2, beta 3, and gamma 2 subunits mRNA, with no alteration of [(35)S]TBPS binding in any regions in the brain of rats at 1 h following a single injection of cocaine. In chronically treated animals, the mean scores of stereotyped behavior were increased with the number of injections. The level of beta 3 subunit mRNA was decreased in the cortices and caudate putamen, at 24 h after a final injection of chronic administrations for 14 days. In the withdrawal from cocaine, the frontal cortex and hippocampal complexes showed a significant increase in [(35)S]TBPS binding and alpha1 and beta 3 subunit mRNA in the rats 1 week after a cessation of chronic administration of cocaine. These findings suggest that the disruption of GABA(A)-BZD receptor formation is closely involved in the development of cocaine-related behavioral disturbances. Further studies on the physiological functions on GABA(A)-BZD receptor complex will be necessary for an explanation of the precise mechanisms underlying the acute effects, development of hypersensitization, and withdrawal state of cocaine.

The effects of single and repeated administration of cocaine on mRNA subunits of glutamate receptors were investigated in the rat brain by in situ hybridization. A significantly increased level of NMDAR1 subunits mRNA in the hippocampus was seen 1hr after a single injection of cocaine. Repeatedly treated-rats showed a decreased level of NMDAR1 subunit mRNA in the cortices, striatum, nucleus accumbens and ventral pallidum, and an increased level in the dentate gyrus 24 hrs after a final injection of chronic administration. During cocaine withdraw al, thecortes, striatum, hippocampus and cerebellum showed a significantly decreased level of NMDAR1 and mGluR5 subnuit mRNAs. These findings suggest that a reduction in glutamate receptor subunit mRNA level may reflect a compensatory don:regulation related to enhanced glumate transmission during sensitized and withdrawal state.

An autopsy case of myotonic dystrophy (MD) is reported. The patient was a 58-year-old male. He presented with muscular weakness and muscular atrophy at the age of 33 and was diagnosed as having MD from myotonic symptoms (i.e. percussion and grip myotonia) at 49 years old. Mental disorders including a delusional hallucinatory state, mental slowness, indifference, and lack of spontaneity as well as visual cognitive impairments were noted at the age of 55. He showed Parkinsonism and died of septic shock. T2-weighted magnetic resonance imaging demonstrated diffuse cortical atrophy with a marked frontal atrophy and high-intensity signals in the white matter. Single photon emission computed tomography demonstrated hypoperfusion in the frontal cortex. Neuropathologic observation revealed neuronal loss in the superficial layer of the frontal and parietal cortices and extensive neuronal loss in the occipital cortex, intracytoplasmic inclusion body in the nerve cell of the medial thalamic nuclei, neuronal loss and presence of Lewy bodies in the substantia nigra and locus ceruleus corresponding to the pathologic features of Parkinson's disease, as well as abnormalities of myelin in the white matter. The present case suggests that in MD brain, various neuropathologic changes may occur and they contribute to the mental disorders.

The relationship between urine specific gravity (USG) and the incidence of polydipsia/hyponatremia in hospitalized schizophrenic patients was examined. On the basis of five independent USG values, we identified 49% (35 out of 72) of male and 22% (8 out of 37) of female patients with hyposthenuria (mean USG≤1.008). Review of 2 years of records of routine laboratory examinations identified 12 males with hyponatremia, 11 males with borderline hyponatremia, and 49 males with normal values; among female patients, only one patient with hyponatremia and three patients with borderline values were identified. A significantly lower mean USG (1.003±0.001) for the male patients with hyponatremia compared with the male patients with normal serum sodium data (1.011±0.005) was observed. All of the male patients with hyponatremia, as well as 18 of the 49 male patients with normal serum sodium values, exhibited hyposthenuria. The USG values of all the patients with hyponatremia were consistently quite low (≤1.005), whereas 14 of the 18 normonatremia/hyposthenuria patients had normal USG values (i.e.≥1.009) in at least one of five determinations; the mean USG values for most (16 of 18) of the normonatremia /hyposthenuria patients ranged from 1.006 to 1.008. Thus, many hospitalized schizophrenic patients exhibit hyposthenuria of varying degrees, but consistently low USG values are most suggestive of the risk of polydipsia/hyponatremia.

The effects of chronic administration of interferon (IFN; recombinant human IFN-alphaA/D) on serotonergic binding sites in rat brain were investigated. IFN was injected daily for 2 weeks at a dose of 100000 I.U./kg, (i.p.) in male Wistar rats. IFN did not alter either [3H]ketanserin binding to 5-HT2A receptors or [3H]paroxetine binding to 5-HT transporters. Scatchard analysis of [3H]8-hydroxy-dipropylaminotetraline (8-OH-DPAT) binding to 5-HT1A receptors demonstrated the presence of high- and low-affinity binding sites in both treatment and control groups. IFN significantly increased both Kd and Bmax measures of [3H]8-OH-DPAT binding at low-affinity binding sites, but not at the high-affinity sites. These results suggest that IFN affects the low-affinity 5-HT1A receptors sites and may be involved in the development of IFN-induced psychiatric disturbances.

Suzuki, Toshihito MD, PhD; Hori, Takafumi MD, PhD; Baba, Atsuomi MD, PhD; Abe, Shuzo MD; Shiraishi, Hiroyasu MD, PhD; Moroji, Takashi MD, PhD; Piletz, John E. PhD Author Information

Abstract Hypogammaglobulinemia in a 22‐year‐old woman with brief psychotic disorder developed during antipsychotic therapy. Severe decreases in immunoglobulin IgM, IgG, and IgA concentration in serum were observed 4 months after the treatment with chlorpromazine (CPZ) and the other types of antipsychotics. Neither physical diseases nor family history for immunological disturbances was seen. No clinical symptoms in relation to immunological disturbances (i.e. infectious disease), were noted. Gammaglobulin levels in serum returned to a normal range after a replacement of chlorpromazine to timiperone. The hypogammaglobulinemia in the present case was considered to be due to the inhibition of gammaglobulin synthesis by CPZ.

A single intraperitoneal administration of methamphetamine (MAP) reduces cholecystokininlike immunoreactivity (CCK-LI) in medial prefrontal cortex (mPFC) of the rat brain. This report examines the effects of various dopamine (DA) receptor antagonists [haloperidol (HAL), sulpiride (SUL), YM09151-2 (YM), and SCH23390 (SCH)] on MAP-induced abnormal behaviors and the changes of CCK-LI in the rat mPFC. A single subcutaneous administration of HAL (0.25 mg/kg), YM (0.1 mg/kg), or SUL (250 mg/kg) significantly reduced the basal CCK-LI in mPFC by 20–40%; a selective D1 antagonist, SCH (up to 1.0 mg/kg), had no effect on basal CCK-LI. However, the reduction of CCK-LI induced by MAP (20–40%) was abolished by the pretreatment with HAL (0.025 and 0.25 mg/kg), YM (0.01 and 0.1 mg/kg), or SCH (1.0 mg/kg), without being affected by SUL (up to 250 mg/kg). This effect of DA antagonists on MAP-induced change in CCK-LI was associated with an inhibition of MAP-induced stereotyped behaviors. These data suggest that the CCK-containing neurons in rat mPFC are functionally related to the mesocortical DA system and may participate in a development of abnormal behaviors induced by MAP.

The pharmacological characteristics and the regional distribution of [3H]3-OH-PCP (1-[1(3-hydroxyphenyl)-cyclohexyl]piperidine) binding were investigated in rat brain by quantitative autoradiography. Kinetic analysis of [3H]3-OH-PCP binding revealed fast and slow components, in the association and dissociation studies. The regional distribution of binding closely corresponded to those of binding sites labeled by [3H]N-[1-(2-thienyl)-cyclohexyl]3,4-piperidine (TCP) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK 801). High densities of [3H]3-OH-PCP binding sites were found in the stratum radiatum and oriens of field CA1 in the hippocampus and in the outer layers of cerebral cortices. In contrast, low levels of binding were seen in the brain stem and the granular cell layer of the cerebellum. [3H]3-OH-PCP binding was strongly inhibited by MK 801 and 3-OH-PCP, while the potency of (+)-SKF 10047 in inhibiting [3H]3-OH-PCP binding was less in the cerebral cortex and hippocampus. The antagonists for the glutamate, glycine and polyamine recognition sites at the NMDA/PCP receptor complex displaced [3H]3-OH-PCP binding sites with a potency similar to that of [3H]MK 801. These findings suggest that the [3H]3-OH-PCP binding site is similar or identical to the PCP binding site labeled by [3H]TCP and [3H]MK 801.

The effects of phencyclidine (PCP) and its metabolites on serotonin (5-hydroxytryptamine, 5-HT) receptors were studied. PCP and its metabolites inhibited the uptake of [3H]5-HT and the binding of [3H]paroxetine in rat brain, while they failed to inhibit either [3H]5-HT binding to 5-HT1 receptors or [3H]ketanserin binding to 5-HT2 receptors. The trans-isomer of 4-phenyl-4-(I-piperidinyl)cyclo-hexanol (trans-4-PPC), the major metabolite of PCP, rather than PCP itself, inhibited [3H]5-HT uptake most potently. These results suggest that the serotonergic effects of PCP, in part, may be based on the effects of PCP metabolites on 5-HT uptake.

Psychostimulants such as amphetamine are widely abused by humans.I The repeated administration of amphetamine induces a syndrome similar to paranoid schizophrenia in humans and behavioral sensitization in animals.* Sensitization has been explained by using mechanisms that focus on functional changes in the mesolimbic dopamine (DA) system. That is, augmentation of the ability of amphetamine to increase extracellular DA concentrations in the nucleus accumbens ( N A c ) , ~ ~ subsensitivity of DA autoreceptors located on DA cell bodies in the ventral tegmental area6.7 and supersensitivity of D1 receptors in the NAc.* This DA hypothesis, however, does not sufficiently account for amphetamine sensitization, since dissociation is sometimes found between the intensity of amphetamine-stimulated behavioral responses and amphetamine-stimulated dopamine release in the NAC.~-~O These and the following observations have led to the speculation that a kindling-like mechanism is involved in the development of stimulant-related psychiatric symptomato1ogy.l' Kirby et a1.'2-13 have shown a synergistic relationship between amphetamine treatment and amygdaloid kindling on the basis of these observations. The kindling rate increases by coadministration of amphetamine during the kindling procedure, and kindling acquisition is en-

To investigate the modulatory effects of sigma ligands on the N-methyl- D-aspartate (NMDA) receptor-ion channel complex in vivo, we examined the intact cell binding of 3H-N-[1-(2-thienyl)cyclohexyl]piperidine (3H- TCP) to cultured neuronal cells prepared from fetal rat telencephalon. The 3H-TCP binding was saturable, reversible, and inhibited by a selective NMDA receptor antagonist, D-amino-5-phosphonovaleric acid. MII-limolar Mg2+ inhibited 3H-TCP binding both in the absence and presence of L-glutamate. 5-Methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK801) inhibited 3H-TCP intact cell binding in a competitive manner, while haloperidol inhibited it in a noncompetitive manner. The effect of the test drugs to inhibit 3H-TCP intact cell binding was in the order of dextromethorphan, haloperidol > (+/-)MK 801 > (+)pentazocine > (-)pentazocine > DTG > PCP > (+)-N- allylnormetazocine [(+)SKF 10047] > (+)3-(3-hydroxyphenyl)-N- (1- propyl)piperidine [(+)3-PPP] > (-)SKF 10047 > (-)3-PPP. The IC50 values of the six sigma ligands for 3H-TCP binding were closely correlated with the Ki values of the corresponding drugs for DTG site 1 in the guinea pig brain reported by Rothman et al. (1991). These findings suggest that the sigma ligand indirectly modulates the NMDA receptor ion channel complex, presumably through sigma 1 sites in vivo as well as in vitro.

N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), a potent and highly selective sigma ligand, haloperidol, (+)pentazocine, 1-(cyclopropyl-methyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine HBr (DuP 734) and 4-(2'-(4"-cyanophenyl)-2'-oxoethyl) 1-(cyclopropylmethyl)piperidine (XJ 448) inhibited carbachol-induced inositol 1,4,5-triphosphate (IP3) formation in a dose-dependent manner. The rank order of potency of the tested drugs for inhibition was: haloperidol > or = (+)pentazocine = NE-100 > DuP 734 = XJ 448. In addition, the effects of NE-100, DuP 734 and XJ 448 upon [3H]TCP binding were examined using primary cultured neuronal cells derived from the fetal rat telencephalon. These drugs inhibited [3H]TCP binding to intact cells. The ability of the test drugs to inhibit [3H]TCP binding to primary cultured neuronal cells was in the order: NE-100 > DuP 734 > XJ 448. These observations suggest that NE-100 indirectly modulates the N-methyl-D-aspartate (NMDA)/phencyclidine (PCP) receptor ion channel complex (NMDA receptor-ion channel), presumably through sigma-1 sites.