Improvement of schizophrenic symptoms and changes in plasma HVA concentrations, plasma anti-D2 and anti-5-HT2 receptor activities with clozapine

Abstract In order to investigate the biological mechanisms underlying the clinical efficacy of clozapine, 200 mg/day of clozapine was added to the drug regimens of 19 patients with chronic, anti-psychotic-resistant schixophrenia, and the plasma homovanillic acid (HVA), clozapine concentrations, anti-dopamine D₂ and anti-serotonin 5-HT₂ receptor activities were measured. After 28 days, six patients showed an improvement of more than 20% over baseline Brief Psychiatric Rating Scale (BPRS) scores. Mean plasma HVA concentrations and anti-D₂ receptor activities did not change significantly in the entire group or in the six patients showing improvement. However, anti-5-HT₂ receptor activities increased significantly in all 19 patients. Changes in BPRS scores did not correlate significantly with changes in plasma HVA or with changes in clozapine concentrations, or with anti-D₂ and anti-5-HT₂ receptor activities.     

Effect of Chronic Administration of Haloperidol (Intermittently) and Haloperidol-Decanoate (Continuously) on D2 Dopamine and Muscarinic Cholinergic Receptors and on Carbachol-Stimulated Phosphoinositide Hydrolysis in the Rat Striatum

Abstract: It has been reported that apomorphine-induced stereotypy is sensitized after a chronic intermittent administration of haloperidol (HPD), but not after a chronic continuous exposure to haloperidol-decanoate (HPD-D). The present study was undertaken to investigate changes in the D₂ dopamine and muscarinic receptors in the ratstriatum after the administration of HPD intermittently and HPD-D continuously. The number of striatal [³H] spiperone binding sites increased significantly after HPD-D, but did not change after HPD. Neither the number of [³H](–)QNB binding sites nor carbachol-stimulated phosphoinositide hydrolysis changed after either HPD or HPD-D. These results indicate that the increase in striatal D₂ receptors in rats administered HPD-D represents behavioral and biochemical tolerance, and that neither the D₂ dopamine receptor supersensitivity nor muscarinic receptor hyposensitivity underlies sensitization of apomorphine-induced stereotypy.     

Translating 5-HT4 receptor pharmacology

Abstract  Since metoclopramide was first described (in 1964) there have been several attempts to develop compounds which retained gastrointestinal prokinetic activity (via 5-HT₄ receptor activation) but without the limiting side effects associated with dopamine D₂ receptor antagonism. Early compounds (mosapride, cisapride, renzapride, tegaserod) were identified before several of the 5-HT receptors were even described (including 5-HT₄ and 5-HT_2B), whereas prucalopride came later. Several compounds were hampered by non-selectivity, introducing cardiac liability (cisapride: activity at human Ether-a-go-go Related Gene) or potentially, a reduced intestinal prokinetic activity caused by activity at a second 5-HT receptor (renzapride: antagonism at the 5-HT₃ receptor; tegaserod: antagonism at the 5-HT_2B receptor). Poor intrinsic activity at gastrointestinal 5-HT₄ receptors has also been an issue (mosapride, tegaserod). Perhaps prucalopride has now achieved the profile of good selectivity of action and high intrinsic activity at intestinal 5-HT₄ receptors, without clinically-meaningful actions on 5-HT₄ receptors in the heart. The progress of this compound for treatment of chronic constipation, as well as competitor molecules such as ATI-7505 and TD-5108, will now be followed with interest as each attempts to differentiate themselves from each other. Perhaps at last, 5-HT₄ receptor agonists are being given the chance to show what they can do.     

Dopamine D1 and D2 Receptor Antagonists Suppress Acute Stimulant Action of Cocaine, but Enhance Cocaine Sensitization

Abstract: The ambulation increase caused by the repeated dosing of cocaine (10 mg/kg s. c.) was dose-dependently reduced by the simultaneous administration of the selective dopamine D₁ and D₂ receptor antagonists, SCH 23390 (0.01, 0.03 and 0.1 mg/kg s. c.) and YM-09151-2 (nemonapride) (0.01, 0.03 and 0.1 mg/kg s. c.), respectively. However, the mice given cocaine with SCH 23390 (0.03 mg/kg) and cocaine with YM-09151-2 (0.03 and 0.1 mg/kg) 5 times at 3 to 4-day intervals showed significantly higher sensitivity than the mice given cocaine alone to the challenge cocaine. The present results suggest that, although the blockade of either dopamine D₁ or D₂ receptor is effective for a reduction in the stimulant action of cocaine, such treatment enhances the induction of cocaine sensitization.     

DA Uptake Sites, D1, and D2 Receptors, D2 and Preproenkephalin mRNAs and Fos Immunoreactivity in Rat Striatal Subregions after Partial Dopaminergic Degeneration

Stereotaxic injection of a limited amount of 6- hydroxydopamine in the lateral part of the rat substantia nigra induces a partial degeneration of the nigrostriatal dopaminergic system. This animal model in which the destruction of the dopaminergic nigral cell population reaches -50% could be considered as a preclinical Parkinson's model. Autoradiography of dopaminergic uptake sites performed with a specific marker ([³H]GBR 12935) allowed the precise determination of dopaminergic denervated and non-denervated areas in the striatum 1 month after partial lesion of the substantia nigra pars compacta. In both striatal areas, dopaminergic D₁ and D₂receptor densities and dopaminergic D₂ and preproenkephalin mRNAs levels were measured by autoradiography and in situ hybridization coupled to an image analysis system. Our results show that in the denervated striatal subregion, none of the dopaminergic targets were modified, contrary to the observations made after complete lesion of the nigrostriatal DA system at the same post-lesion delay. However, striatal Fos activation induced by amphetamine (5 mg/kg i.p., 2 h before killing) revealed that the number of Fos-positive cells detected in the denervated striatal subregion was lower than that observed in the non-denervated one. These data argue in favour of the existence of compensatory mechanisms different from the up-regulation of DA receptor densities, thereby allowing the maintenance of striatal dopaminergic transmission. Such mechanisms could contribute to the delay of the appearance of neurological symptoms (which are reported to be clinically apparent only when depletion of striatal dopamine levels reaches near 80%) in Parkinsonian patients.     

Opposing Roles for Dopamine D2 and D3 Receptors on Neurotensin mRNA Expression in Nucleus Accumbens

Using in situ hybridization histochemistry in rat nucleus accumbens, we show that the dopamine D₃ receptor mRNA is expressed in the ventromedial part of the shell subdivision, where its gross distribution matches that of neurotensin mRNA. In addition, hybridization studies at the cellullar level show that a large fraction of the neurotensin neurons co-express the D₃ receptor mRNA in this restricted area. In contrast, the dopamine D₂ receptor mRNA is expressed mainly in the core and marginally in the shell, at the level of the cone. In rats treated by haloperidol and sulpiride, two D₂-like receptor antagonists, but not by SCH 23390, a D₁-like receptor antagonist, proneurotensin mRNA was increased in the D₂ receptor mRNA-rich areas but decreased in the D₃ receptor mRNA-rich areas. This suggests that the D₂ and D₃ receptors control neurotensin mRNA expression negatively and positively, respectively.     

PET study of striatal fluorodopa uptake and dopamine D2 receptor binding in a patient with juvenile parkinsonism

We studied pre-synaptic and post-synaptic function in the striatum of a patient with juvenile parkinsonism (JP) using positron emission tomography (PET). [¹⁸F]6-fluorodopa (¹⁸FDOPA), ¹¹C-YM-09151-2 and [¹⁸F]fluoro-2-deoxy- D -glucose (¹⁸FDG) were used to measure fluorodopa uptake, dopamine D₂ receptor binding and glucose metabolism, respectively. In this patient, ¹⁸FDOPA accumulation was decreased markedly in the caudate nucleus and the putamen bilaterally. In the images of ¹¹C-YM-09151-2 and ¹⁸FDG in contrast, no conspicuous changes were observed in the striatum. Thus our PET studies using ¹⁸FDOPA, ¹¹C-YM-09151-2 and ¹⁸FDG provide a useful approach for assisting the diagnosis of JP, because the present findings are different from the results in patients with dopa-responsive dystonia and hereditary progressive dystonia with marked diurnal fluctuation. Furthermore, our findings are of particular interest in relation to the pathogenesis of JP.     

Evidence For Two Neurochemical Divisions in the Human Nucleus Accumbens

The neurochemical anatomy of the human nucleus accumbens was studied by comparing the distributional patterns of [³H]DAMGE (μ opioid receptor), [³H]bremazocine (κ opioid receptor), [³H]SCH-23390 (D₁-like dopamine receptor), [³H]7-OH-DPAT (D₃ dopamine receptor) binding, preproenkephalin mRNA and acetylcholinesterase activity in sections of post mortem human striatum. Our results demonstrate the presence of at least two neurochemically distinct divisions within the human nucleus accumbens, which may be homologous to the 'shell'and'core'divisions of the nucleus as found in the rat.     

Ontogenetic Development of 5-HT1D Receptors in Human Brain: An Autoradiographic Study

The pattern of pre- and postnatal appearance of 5-HT_1D receptors throughout the different areas of the human brain was studied by quantitative in vitro autoradiography, using [¹²⁵I]GTI (serotonin O -carboxymethyl-glycyl-[¹²⁵I]tyrosinamide) as a ligand. The anatomical distribution of 5-HT_1D receptors in neonatal, infant and children's brain was in good agreement with that observed in the adult, the basal ganglia and substantia nigra being the most intensely labelled areas. The development of these receptors throughout the human brain was mainly postnatal: low densities of [¹²⁵I]GTI binding sites were observed at the fetal/neonatal stage in most regions analyzed, in contrast with the high levels of labelling found in infant and children's brains. Indeed, in a number of regions, including the globus pallidus, substantia nigra and visual cortex, a peak of overexpression of 5-HT_1D receptors was observed in the first decade of life. Such overexpression could support a regulatory role for 5-HT_1D receptors in advanced periods of the CNS developmental process. Our results also indicate that the administration of drugs acting on 5-HT_1D receptors during the early postnatal period of life could result in modifications of their properties, as these receptors are already functional in this period.     

Voluntary Intake of Alcohol Is Attenuated by Ipsapirone in Mice and Role of 5–HT1A Receptor

Abstract: Emerging evidences have suggested that the brain serotonin (5-hydroxy-tryptamine, 5-HT) neurotransmitter system is involved in the compulsive alcohol-seeking behaviors in humans and animal models. The aim of this study is to examine the effect of ipsapirone, which is a specific 5-HT_1A, agonist with a pyrimidinylpiperazine structure, on alcohol consumption in mice (C57BL/6J) by a voluntary alcohol intake paradigm. When the consumed 8, kohol was expressed as g/kg B.W., the total 12-day amount was significmtly lower in the ipsapirone-treated mice than in the saline-treated mice. However, 5-HT_1A receptor binding sites labeled with [³H]8-OH-DPAT in hippocampal membranes did not differ significantly in either the total number of binding sites (Bmax) or dissociation constant (Kd) between the two groups. The possible mechanism regarding the role of ipsapirone that attenuated the alcohol consumption, and its relationship to the subtyping 5-HT receptors are further discussed.     

Postischemic changes of [3H]nimodipine and [3H]ryanodine binding in the gerbil striatum and hippocampus

Sequential alterations of [³H]nimodipine and [³H]ryanodine binding in gerbils were investigated in selectively vulnerable regions, such as the striatum and hippocampus, 1 h to 7 days after 10 min of transient cerebral ischemia. [³H]Nimodipine binding showed no significant changes in the striatum and hippocampus up to 48 h after ischemia. Seven days after ischemia, however, a severe reduction in [³H]nimodipine binding was observed in the dorsolateral striatum, hippocampal CA1 (stratum oriens, stratum pyramidale and stratum radiatum) and hippocampal CA3 sector. On the other hand, [³H]ryanodine binding showed a significant increase in the hippocampus 1 h after ischemia. Five hours after ischemia, a significant reduction in [³H]ryanodine binding was observed only in the hippocampal CA1 sector. Thereafter, the striatum and hippocampus showed no significant alterations in [³H]ryanodine binding up to 48 h after ischemia. After 7 days, a marked reduction in [³H]ryanodine binding was observed in the striatum and hippocampus which were particularly vulnerable to ischemia. These results demonstrate that postischemic alteration in [³H]nimodipine and [³H]ryanodine binding is produced with different processes in the hippocampus. They also suggest that the mechanism for striatal cell damage caused by transient cerebral ischemia may, at least in part, differ from that for hippocampal neuronal damage. Furthermore, our findings suggest that abnormal calcium release from intracellular stores may play a pivotal role in the development of hippocampal neuronal damage.     

Localization of Dopamine D2 Receptor in Rat Spinal Cord Identified with Immunocytochemistry and In Situ Hybridization

In the present study the distribution of dopamine D₂ receptors in rat spinal cord was determined by means of immunocytochemistry using an anti-peptide antibody, directed against the putative third intracellular loop of the D₂ receptor and in situ hybridization (ISH) using a [³⁵S]UTP labelled anti-sense riboprobe. With the immunocytochemical technique, labelling was confined to neuronal cell bodies and their proximal dendrites. Strongest labelling was present in the parasympathetic area of the sacral cord and in two sexually dimorphic motor nuclei of the lumbosacral cord, the spinal nucleus of the bulbocavernosus and the dorsolateral nucleus. Moderately labelled cells were present in the intermediolateral cell column, the area around the central canal and lamina I of the dorsal horn. Weak labelling was present in the lateral spinal nucleus and laminae VII and VIII of the ventral horn. Except for the two sexually dimorphic motornuclei of the lumbosacral cord labelled motoneurons were not encountered. With the ISH technique radioactive labelling was present in many neurons, indicating that they contained D₂ receptor mRNA. The distribution of these neurons was very similar to the distribution obtained with immunocytochemistry, but with ISH additional labelled cells were detected in laminae III and IV of the dorsal horn, which were never labelled with immunocytochemistry. The present study shows that the D₂ receptor is expressed in specific areas of the rat spinal cord. This distribution provides anatomical support for the involvement of D₂ receptors in modulating nociceptive transmission and autonomic control. Our data further indicate that D₂ receptors are not directly involved in modulating motor functions with the exception, possibly, of some sexual motor functions.     

The Role of Serotonin Receptor Subtypes in the Behavioural Effects of Neuroleptic Drugs. A Paw Test Study in Rats

The present study was designed to evaluate the roles of serotonin 5-HT_1A and 5-HT₂ receptors in the effects of neuroleptic drugs in the paw test. This behavioural test has been shown to model both the antipsychotic efficacy as well as the extrapyramidal side-effect liability of neuroleptic drugs. Whereas the 5-HT_1A receptor agonist 8-hydroxy-2-(di- n -propylamino)tetralin (8-OHDPAT) reduced the effects of the classical neuroleptic haloperidol, it increased the effects of the atypical neuroleptic clozapine. The 5-HT₂ receptor antagonist ketanserin as well as the 5-HT_1C/5-HT₂ receptor antagonist ritanserin, on the other hand reduced the effects of haloperidol, whereas the 5-HT_1C/5-HT₂ receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOl) reduced the effects of clozapine. The most important finding, however, was that the behavioural effects of different (putative) neuroleptics (fluphenazine, SCH-39166, remoxipride, prothipendyl, thioridazine and risperidone) were differentially influenced by both 8-OHDPAT and DOl, suggesting that there are important differences between the neuronal mechanisms underlying the behavioural effects of these neuroleptic drugs, even within the subclasses of classical and atypical neuroleptics.     

Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats

Abstract  The serotonin neurotransmitter system, including the 5-HT₃ receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT₃ receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT₃ receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT₃ receptor antagonist tropisetron (0.1 mg kg⁻¹) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT₃ receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT₃ receptor antagonism, thereby implicating the 5-HT₃ receptor system in cholestasis associated fatigue.     

[3H]Nitrendipine Binding to Rabbit Colonic Smooth Muscle

We used [³H] nitrendipine binding to isolated smooth muscle cells and isometric tension studies of muscle strips to characterize the calcium channels from rabbit proximal and distal colon. At 25°C [³H] nitrendipine binding was rapid, saturable, reversible, specific, and linearly proportional to cell number. The affinity of the ligand for its receptor was similar in proximal and distal colon (K_D 129 ± 21 pM and 124 ± 17 pM, respectively). In the proximal colon there were 68,000 receptors per cell, compared to 58,000 receptors per cell in the distal colon (p > .1). The Hill coefficient for nitrendipine was close to unity, suggesting binding to a single receptor. Although nitrendipine and nifedipine competitively inhibited [³H]nitrendipine binding, verapamil did not alter [³H] nitrendipine binding, suggesting the presence of at least two discrete, noninteracting sites for the binding of drugs that block calcium channels. In studies with muscle strips nitrendipine competitively inhibited isometric tension stimulated by both bethanechol and high extracellular potassium concentration. There were no significant differences in response from proximal and distal colon. These results suggest that calcium antagonist binding characteristics to calcium channels are similar in proximal and distal colon, and do not explain previously observed differences in the function of muscle in these tissues.     

Lack of Effect of Haloperidol or Methamphetamine Treatment on the mRNA Levels of Two Dopamine D, Receptor Isoforms in Rat Brain

Abstract: In order to investigate whether changes of the two mRNAs encoding the D₂ receptor isoforms were induced by chronic haloperidol or methamphetamine treatment in rats, we measured the brain mRNA levels using in situ hybridization histochemistry (ISHH). We used two oligonucleotide probes, an "insert" probe to hybridize with the longer D, receptor, D₂₍₄₄₄₎, mRNA, and a "spanning" probe to hybridize with the shorter D₂ receptor, D2₍₄₁₅₎, mRNA. Both D₂ mRNAs were detected by ISHH in the caudate putamen, nucleus accumbens, substantia nigra, pars compacta and ventral tegmental men. The distributions and the amounts of the mRNAs for the two D₂ isoforms did not change after chronic administration of haloperidol (1 mg/kg/day for 14 days, ip) or methamphetamine (4 mg/kg/day for 14 days, ip). These results suggest that the changes of D₂ receptor density induced by chronic neuroleptic and psychostimulant treatment are not due primarily to receptor expression.     

5-HT receptor types in the rat ileum longitudinal muscle: focus on 5-HT2 receptors mediating contraction

The 5-hydroxytryptamine (5-HT) receptor(s) that mediate(s) contraction of the rat ileum longitudinal muscle was studied.
5-HT and α-methyl-5-HT equipotently induced contractions, whereas 5-methoxytryptamine and 2-methyl-5-HT (partial agonist) were less potent; this rank order of potency suggests involvement of a 5-HT₂ receptor. Neither tetrodotoxin nor atropine affected the contraction to 5-HT, suggesting a smooth muscle localization of these 5-HT₂ receptors. The presence of either a selective 5-HT_2B (SB 204741), 5-HT₃ (granisetron) or 5-HT₄ (SB 204070) antagonist, slightly affected the contractions to 5-HT. Thus, they were also included in the organ bath solution in all subsequent experiments in order to pharmacologically isolate the main contractile component. Using (if possible) 5-HT_2A receptor-selective concentrations, ketanserin, ritanserin, metergoline, spiperone, mianserin, methiothepin, mesulergine, methysergide and cisapride all inhibited the contractions to 5-HT, causing a depression of the curve to 5-HT (i.e. surmountable antagonism was not observed with any of the above agents). Comparison of the affinities of these compounds for the various 5-HT₂ receptor subtypes revealed that the receptor involved in the contractions to 5-HT most closely resembles the 5-HT_2A receptor. However, cinanserin at a concentration expected to inhibit 5-HT_2A receptor-mediated effects, failed to affect the contractions to 5-HT.
It is thus concluded that on the longitudinal smooth muscle of the rat ileum, at least a part of the contraction to 5-HT is mediated by 5-HT receptors resembling the 5-HT_2A receptor subtype.     

A Comparative Study of α2- and β-Adrenoceptor Distribution in Pigeon and Chick Brain

The pharmacological properties and anatomical distribution of α₂, β₁ and β₂-adrenoceptors in pigeon and chick brains were studied by both homogenate binding and tissue section autoradiography. [³H]Bromoxidine (α₂-adrenoceptor-), [³H]CGP 12177 (β-adrenoceptor) and [¹²⁵1]cyanopindolol (β-adrenoceptor) were used as radioligands. In both species, [³H]bromoxidine binding to avian brain tissue showed a pharmacological profile similar to that previously reported for α₂-adrenoceptors in mammals. Regarding the anatomical distribution, the areas with the highest densities of α₂-adrenoceptors in the pigeon brain included the hyperstriatum, nuclei septalis, tectum opticum and some brainstem nuclei. Most β-adrenoceptors found in tissue membranes and sections from chick and pigeon brain were of the β₂ subtype, in contrast to what has been reported in the mammalian brain, where the β₁ subtype is predominant. A striking difference was found between the two species regarding the densities of these receptors: while pigeon brain was extremely rich in [¹²⁵1]cyanopindolol binding throughout the brain (mainly cerebellum) in the pigeon, the levels of labelling in the chick brain were much lower; the exception was the cerebellum, which displayed a higher density than other parts of the brain in both species. Overall, our results support the proposed anatomical equivalences between a number of structures in the avian and mammalian encephalon.     

Blockade of A2a Adenosine Receptors Positively Modulates Turning Behaviour and c-Fos Expression Induced by D1 Agonists in Dopamine-denervated Rats

In rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway, administration of the A_2a adenosine antagonist SCH 58261 alone did not induce any motor asymmetry but strongly potentiated the contralateral turning behaviour induced by the dopamine D₁ agonist SKF 38393. SCH 58261 also increased the number of Fos-like positive nuclei induced by SKF 38393 in the 6-hydroxydopamine-lesioned striatum. Intense potentiation of D₁-dependent turning behaviour and c-Fos expression was also observed after administration of the A_2a/A₁ antagonist CGS 15943. Administration of the A₁ adenosine receptor antagonist DPCPX induced a small potentiation of D₁-mediated contralateral turning while c-Fos expression induced by SKF 38393 was not modified. The results suggest that endogenous adenosine acting on A_2a receptors can exert an inhibitory influence on the functional expression of D₁-mediated responses in dopamine-denervated rats, and propose new possible therapeutic approaches in the treatment of Parkinson's disease.     

Hypothyroidism Alters the Expression of Prostaglandin D2 Synthase/β- Trace in Specific Areas of the Developing Rat Brain

Lipocalin-type prostaglandin D₂ synthase is the enzyme responsible for the synthesis of prostaglandin D₂, a major prostaglandin in the central nervous system. We analysed the effects of thyroid hormone deprivation on prostaglandin D₂ synthase gene expression in the developing rat brain. By in situ hybridization, the strongest prostaglandin D₂ synthase mRNA signal was detected in the leptomeninges and choroid plexus. The signal was greatly reduced in the cerebellar interlaminar meninges of hypothyroid rats aged 15 and 25 days. lmmunohistochemical studies defined changes in the location of the prostaglandin D₂ synthase protein. In control but not in hypothyroid animals, Cajal-Retzius neurons of cortical layer 1, and pyramidal cortical plate neurons were intensely stained on postnatal day 5. Conversely, prostaglandin D₂ synthase protein levels were higher in neurons of the CA1 and CA3 regions and the dentate gyrus of the hippocampus of hypothyroid animals on postnatal days 5, 15 and 25, and also in subplate neurons on postnatal days 15 and 25. In agreement with the in situ hybridization and northern blotting data, the major difference was found in the cerebellar interlaminar meninges of hypothyroid animals, where the protein was clearly down-regulated on postnatal days 15 and 25. These results show that hypothyroidism causes both age- and region-specific alterations in the expression and location of the prostaglandin D₂ synthase during postnatal brain development, probably reflecting a cell-specific regulatory effect of thyroid hormone on the prostaglandin D₂ synthase.