Shuzo Abe

Effects of chronic administration of interferon α A/D on serotonergic receptors in rat brain

The effects of chronic administration of interferon (IFN; recombinant human IFN -αA/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.

Effects of cocaine administration on receptor binding and subunits mRNA of GABAA‐benzodiazepine receptor complexes

The effects of intermittent intraperitoneal (i.p.) administration of cocaine (20 mg/kg) on GABAA‐benzodiazepine (BZD) receptors labeled by t‐[35S]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 α1, α6, β2, β3, and γ2 subunits mRNA, with no alteration of [35S]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 β3 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 [35S]TBPS binding and α1 and β3 subunit mRNA in the rats 1 week after a cessation of chronic administration of cocaine. These findings suggest that the disruption of GABAA‐BZD receptor formation is closely involved in the development of cocaine‐related behavioral disturbances. Further studies on the physiological functions on GABAA‐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. Synapse 38:198–215, 2000.

Effects of single and repeated phencyclidine administration on the expression of metabotropic glutamate receptor subtype mRNAs in rat brain

Recent animal studies regarding phencyclidine (PCP), which induces psychotic symptoms in humans, have suggested that group II metabotropic glutamate receptors (mGluRs) represent a novel target for the treatment of PCP psychosis. In the present study, we used in situ hybridization to investigate the gene expressions of the mGluR 1–5 subtypes following single and repeated administration of PCP in rats. A single administration of PCP (7.5mg/kg, i.p.,) resulted in a significant decrease in the mGluR5 mRNA expression of group I mGluR in the subcortical regions (thalamus (−15%), central gray (−23%), inferior colliculus (−23%), and nucleus accumbens (−10%)) and hippocampal formation (CA1 (−14%), CA2 (−15%), CA3 (−18%), and dentate gyrus (−18%)). After repeated PCP administration for 14 days, the mGluR2 mRNA expression of group II mGluR in the anterior cingulate cortex (−23%) and the mGluR4 mRNA expression of group III mGluR in the cortical regions (parietal (−11%), temporal (-13%) and entorhinal cortices (−18%)), the caudate putamen (−12%), thalamus (−17%), and subiculum (−25%) were significantly decreased. These results indicate that PCP affects not only group II mGluR but also group I and III of mGluR, and it is of particular interest that mGluR2 subtype is involved in a development of behavioral abnormality following repeated PCP administration. Single and repeated administrations of PCP independently regulate the expression of mGluR subtypes of mRNA in the brain.

Differential expression of GABAA receptor subunit mRNAs and ligand binding sites in rat brain following phencyclidine administration

Recent biochemical observations have suggested the abnormalities in the γ‐amino‐butyric acid (GABA)ergic system in schizophrenic brains. In the present study, we investigated the subunits gene expressions and ligand binding of the GABAA 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. PCP i.p. administration at a daily dose of 7.5 mg/kg resulted in a significant decrease in expression of α1 subunit mRNA in cerebral cortices (cingulate (‐13%) and temporal cortex (‐6%)) and hippocampal formation (CA1 (‐11%), CA2 (‐10%), CA3 (‐11%) and dentate gyrus (‐12%)) 1 h after a single treatment. In the repeated PCP administrations for 14 days, the expression of β2 mRNA in the cerebellum (‐10%) and of β3 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, [35S]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 GABAA/benzodiazepine (BZD) receptor subunits mRNA and its receptor binding in the brain. Synapse 38:51–60, 2000.

Effects of phencyclidine metabolites on serotonin uptake in rat brain

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.

Quantitative autoradiographic localization of [3H]3-OH-PCP (1-(1(3-Hydroxyphenyl)cyclohexyl)piperidine) binding sites in rat brain

Binding of a novel radioligand, [3H]3-OH-PCP (1(1(3-hydroxyphenyl) cyclohexyl)piperidine), to N-methyl-D-aspartate (NMDA) receptor-coupled and -uncoupled PCP sites was investigated in the rat brain. The highest densities of [3H]3-OH-PCP binding were observed in the hippocampal formation, notably in the stratum radiatum and oriens of CA1 region, and dentate gyrus. There were relatively high levels of binding in the olfactory system, superficial layer of cortices, the amygdala and the thalamus. In contrast, lower levels of binding were found in the globus pallidus, cerebellum, and brain stem, except for the superior colliculus. These findings demonstrate that [3H]3-OH-PCP binds to discrete regions within the rat brain. Its distribution is consistent with autoradiographic localization of [3H]TCP and [3H]MK-801 binding sites in the rat brain, suggesting that [3H]3-OH-PCP binds to NMDA/PCP ion-channel complexes in preference to sigma sites.

Effects of single and repeated phencyclidine administration on [3H]flunitrazepam binding in rat brain

Repeated administration of phencyclidine (PCP) induces behavioral sensitization to dopaminergic neural transmission. This phenomenon has been implicated in the pathophysiology of schizophrenia. Recently, GABAergic agonists have been shown to reduce behavioral activity induced by enhanced dopaminergic neural transmission, which is mediated by the GABA(A)/benzodiazepine (BZD) receptor complex. Thus, to investigate the role of BZD receptors during induction and expression of behavioral sensitization in PCP-sensitized animals, the effects of both single and repeated PCP administration on BZD receptors in rat brain were examined using in vitro quantitative autoradiography. Repeated PCP administration failed to significantly alter levels of [3H]flunitrazepam (FNZ) binding in any of the regions examined. However, significant increases in levels of [3H]FNZ binding were found in the nucleus accumbens and ventral pallidum 1 h after single administration of PCP. These results suggest that BZD binding sites may not play important roles in the development of PCP-induced sensitization at several sites of GABA(A)/BZD receptor complex, while changes in GABA function in the nucleus accumbens differ from other areas following single administration of N-methyl-D-aspartate (NMDA) antagonist.

Effects of repeated phencyclidine treatment on serotonin transporter in rat brain

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.

Hypogammaglobulinemia during antipsychotic therapy

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.

Time-course effects of a single administration of cocaine on receptor binding and subunit mRNAs of GABAA receptors

Abstract 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.