Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex

The regulation of the dopamine (DA) receptors is of considerable interest, in part because treatment with antipsychotic drugs is known to upregulate striatal D2-like receptors. While previous studies have focused on the regulation of striatal DA receptors, less is known about the pharmacological regulation of cortical DA receptors. The purpose of this study was to examine the regulation of DA mRNA receptor expression in the cortex compared to the striatum following treatment with antipsychotic agents. Adult male Sprague-Dawley rats were injected daily with haloperidol (2 mg/kg/day), clozapine (20 mg/kg/day) or a control vehicle for a period of 14 days. Following treatment, brains were subjected to in situ hybridization for the mRNAs encoding the five dopamine receptors; only D1, D2, and D3 receptor mRNAs were detected in these regions. Haloperidol tended to either modestly upregulate or have no effect on dopamine receptor mRNAs detected in striatal structures, while clozapine generally downregulated these mRNAs. On the other hand, in the cortex, both drugs had striking effects on D1 and D2 mRNA levels. Cortical D1 mRNA was upregulated by haloperidol, but this effect was primarily restricted to cingulate cortex; clozapine also upregulated D1 mRNA, but primarily in parietal regions. Haloperidol downregulated D2 mRNA in the majority of cortical regions, but most dramatically in frontal and cingulate regions; clozapine typically upregulated this mRNA, but primarily in regions other than frontal and cingulate cortex. These results indicate that clozapine and haloperidol each have regionally-specific effects, and differentially regulate dopamine receptor mRNA expression in striatal and cortical regions of the rat brain.     

Comparative dopamine-acetylcholine interactions in the ventral and dorsal striatum of rabbit and rat brain

A methotrexate-bisphosphonate conjugate containing a peptide bond has been found to possess over five times greater antineoplastic activity against osteosarcoma in experimental animal models compared with methotrexate alone. METHODS: The conjugate was labeled with 99mTc in the presence of stannous ions to determine biologic distribution, with special reference to osseous tissue. Biodistribution studies were carried out in mice after intravenous administration of the labeled conjugate. Radionuclide imaging of rabbits was also performed. RESULTS: The labeled conjugate behaved like a bone-seeking agent. CONCLUSION: The present study indicates that the concept of treating osteosarcoma or metastatic tumors of bone with this class of agents has a firm basis.     

Blunting of the neurotensin mRNA response to haloperidol in the striatum of aging rats: possible relationship to decline in dopamine D2 receptor expression

Neuroleptic drugs such as haloperidol (H) induce a rapid increase in neurotensin/neuromedin N (NT/N) gene expression in the dorsolateral striatum (DLSt) and nucleus accumbens (NA) in young adult rats. This effect may be mediated by post-receptor effectors that are activated by dopamine D2 receptor antagonism. The regional pattern of induction of neurotensin gene expression correlates with the side effect profile of particular neuroleptics. As motor side effects of H differ in aged animals, we hypothesized that the regional expression of the neurotensin gene may differ between young and old animals. We administered H or saline acutely to 3, 14, and 25 month-old Fischer 344 rats, followed by in situ hybridization and quantitative autoradiography for NT/N mRNA. There was a significant age effect on the H-induced NT/N mRNA response in the DLSt, but not the NA, of older animals. In addition to the blunted NT/N mRNA response, significant decreases in D2 receptor mRNA were observed in the lateral striatum of another group of young, middle-aged, and aged rats. Age-related blunting of the NT/N mRNA response to H in the DLSt may be due in part to a decrease in D2 receptors in this structure.     

GM1 ganglioside administration partially counteracts the morphological changes associated with haloperidol treatment within the dorsal striatum of the rat

OBJECTIVE: To study the effectiveness of combining DNA ploidy and the blood-group related membrane antigen Tn as bladder tumour markers which have been individually associated with high tumour grade and poor prognosis. In particular to (i) determine whether use of these two markers would improve tumour detection compared with either alone, particularly of high grade disease and (ii) determine whether intermediate rates of marker expression would occur in bladder cancer patients with no current tumour compared with those with a tumour and a control group with benign prostatic hypertrophy. PATIENTS AND METHODS: A total of 102 patients undergoing cystoscopic monitoring for either benign prostatic hyperplasia (BPH) or for transitional cell carcinoma (TCC) at the Repatriation Hospital and Flinders Medical Centre were included in the study. The patients comprised three study groups, those with BPH (n = 37), with TCC but no tumour present (n = 38) and those with TCC and a tumour present at cystoscopy (n = 27). Exfoliated cells obtained from bladder washings at cystoscopy were double-labelled using a monoclonal antibody to the Tn antigen and a DNA stain, propidium iodide and examined by flow cytometry. RESULTS: Rates of marker expression in 27 patients with tumours were 30% for Tn antigen, 30% for aneuploidy and 48% for either marker. Marker expression was strongly associated with tumour grade, with no expression at grade 1, 38% (3/8) tumours at grade 2 and 90% (9/10) at grade 3. In patients with a history of bladder tumours but no current tumour, rates were intermediate (30%) compared with patients with current transitional cell carcinoma (42%) and control patients (19%). CONCLUSION: The use of Tn antigen combined with DNA flow cytometry can increase tumour detection, particularly of high grade, aggressive disease. Gradation of expression of these markers across patient groups at increasing risk of a tumour, with intermediate expression in patients with no current tumour, suggests that marker expression may be detecting a preneoplastic stage of the disease, which is not possible with cytology. Given two parallel disease processes for superficial papillary and for high grade disease with invasive potential, the expression of high grade tumour markers in cells from cystoscopically normal bladders may represent a pre-clinical stage of aggressive disease. The identification of patients at risk of invasive disease using combinations of tumour markers may offer advantages in clinical management, particularly when no tumour is present and therefore no histopathological assessment is made.     

LSD and d-amphetamine effects on fixed interval responding in the rat

A sixty-eight-year-old male was found to have renal carcinoma after seven months of constitutional symptoms. Initial study of the patient showed a puzzling array of laboratory abnormalities. These led initially to a search for gastrointestinal malignancy and then later to consideration of multiple myeloma. This case serves as a reminder of the propensity of early renal carcinoma to produce striking constitutional symptoms and marked hematologic and serum protein abnormalities. These may occur in the absence of metastases and are frequently reversible as shown in this case with resection of the primary lesion.     

Modulation of synaptic transmission by dopamine and norepinephrine in ventral but not dorsal striatum

Although the ventral striatum (nucleus accumbens; NAc) and dorsal striatum are associated with different behaviors, these structures are anatomically and physiologically similar. In particular, dopaminergic afferents from the midbrain appear to be essential for the normal functioning of both nuclei. Although a number of studies have examined the effects of dopamine on the physiology of NAc or striatal cells, results have varied, and few studies have compared directly the actions of dopamine on both of these nuclei. Here we use slice preparations of the NAc and dorsal striatum to compare how synaptic transmission in these nuclei is modulated by catecholamines. As previously reported, dopamine depressed excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) in the NAc. Surprisingly, however, neither EPSPs nor IPSPs in the dorsal striatum were affected by dopamine. Similarly, norepinephrine depressed excitatory synaptic transmission in the NAc by an alpha-adrenergic receptor-dependent mechanism but was without effect on excitatory transmission in the dorsal striatum. Inhibitory synaptic transmission was not affected by norepinephrine in either structure. These results suggest that the functional roles of dopamine and norepinephrine are not the same in the dorsal striatum and the NAc.     

Effects of haloperidol and d-amphetamine on in vivo 3H-spiroperiodol binding in the rat forebrain(1)

Specific (3)H-spiroperidol ((3)H-Sp) binding was demonstrated to occur, in vivo, throughout the rat forebrain. The highest concentrations of (3)H-Sp were found in regions known to contain dopamine neuron terminals. Acute and repeated administration of low does of haloperidol decreased in vivo (3)H-Sp in subcortical but not cortical regions. Repeated administration of high does of haloperidol followed by washout periods up to 8 days did not lead to an increase in in vivo (3)H-Sp binding; however, a single dose of d-amphetamine caused substantial increases. Analysis of the alterations induced by haloperidol and d-amphetamine suggest that the dopamine receptor changes configuration upon excessive exposure to agonists or antagonists in such a way as to favor the counterpart ligand.     

The effects of thiamin and its phosphate esters on dopamine release in the rat striatum

The effect of thiamin and its phosphate esters on dopamine (DA) release was examined in the rat striatum using an in vivo microdialysis. Intrastriatal administration of thiamin triphosphate (TTP) or thiamin diphosphate (TDP) induced DA release, but thiamin monophosphate (TMP) or thiamin did not show any change. In the absence of Ca2+ in the perfusate, TTP did not increase the DA release. omega-Conotoxin did not decrease the TTP-dependent DA release. These findings suggest that, in contrast to TMP and thiamin, TTP and TDP may play a specific role in DA release from nerve terminals.     

Acute treatment with the N-methyl-D-aspartate receptor antagonist MK-801: effect of concurrent administration of haloperidol or scopolamine on preproenkephalin mRNA levels of the striatum and nucleus accumbens of the rat brain

17 patients underwent an orthognathic operation. The condyle positioning plate was used in each sagittal split ramus osteotomy of mandible in order to maintain the condyle position. The results of postoperative X-ray examination showed that no obvious displacement of condyle in posterioranterior, and vertical dimension was detected in all joints and obvious horizontal condyle displacement were only found in two joints. Based on this work the author believe that condyle positioning plate is useful to position condyle during operation.     

Electrical stimulation of dorsal and ventral striatum differentially alters the copulatory behavior of male rats.

Sexual behavior is a natural reward that activates striatal dopaminergic (DA) circuits, and dopamine exerts a facilitative influence on copulation. Electrical stimulation of the striatum has been shown to be rewarding, but its effect on male sexual behavior display has not been established. The objective of the present work was to assess the effects of low- and high-frequency electrical stimulation of the dorsal and ventral striatum on male rat sexual behavior expression. To this aim, copulatory activity of sexually experienced male rats was recorded during electrical stimulation of the nucleus accumbens (NAcc) or caudate-putamen (CP), at each stimulation frequency, before and after sexual exhaustion. Results showed that electrical stimulation of the NAcc at both frequencies increased the number of ejaculations that male rats were able to show in a 30-min period. By contrast, stimulation delivered to the CP inhibited sexual behavior by slowing its display. Each effect was more pronounced at low than at high stimulation frequencies. In the same rats, once sexually exhausted, electrical stimulation of these brain areas did not reverse the sexual behavior inhibition that characterizes the sexual exhaustion state. It is concluded that dorsal and ventral striatal DA brain regions exert opposite influences on copulatory behavior expression of sexually experienced male rats. Also, that the facilitative effect of NAcc electrical stimulation on sexual activity, with the stimulation parameters used, cannot surmount the sexual behavior inhibition resulting from copulation to satiation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microcarrier enhanced survival of human and rat fetal ventral mesencephalon cells implanted in the rat striatum

The transplantation of tissue containing dopamine-producing cells into the mammalian central nervous system is an emerging treatment for Parkinson's disease, despite relatively poor survival of implanted tissue. Recent evidence has suggested that Cytodex microcarriers enhance the survival of dopaminergic rat chromaffin cells transplanted into the rat striatum in the absence of immunosuppression. The current study was undertaken to evaluate the survival of rat and human fetal ventral mesencephalic neurons (VM) implanted alone or after attachment to microcarriers in the striatum of rats without immunosuppression. Rat fetal VM neurons demonstrated enhanced survival in the rat striatum when transplanted on microcarriers, compared to their transplantation alone during the 3-mo period examined in the present study. Transplants of human fetal VM neurons on microcarriers also survived remarkably well in the rat striatum without systemic immunosuppression. In contrast, human fetal VM cells transplanted alone into the rat striatum did not survive without systemic immunosuppression. There was no evidence of TH fiber sprouting in the vicinity of any transplant site. These data indicated that Cytodex microcarriers provide enhanced survival of both rat allograft and human xenograft fetal mesencephalic cells in the rat striatum without the necessity of systemic immunosuppression, perhaps by inducing a unique neuron-glia environment.     

Some behavioral effects of transecting ventral or dorsal fiber connections of the septum of the rat.

Compared the behavioral effects of large electrolytic lesions in the septal area with those of knife cuts that severed the ventral or dorsal connections of this structure, using 37 adult male albino Sprague-Dawley rats in each of 6 experiments. Ss with septal lesions lost weight and were transiently hyperdipsic. Ventral cuts produced similar effects, but dorsal cuts did not. All 3 operations decreased the latency to eat in a novel environment, increased the intake of sweetened milk, enhanced acquisition of a food-rewarded running response, and facilitated acquisition of a shuttle-box avoidance response. The lesion, but neither of the knife cuts, reduced the effects of punishment and impaired the acquisition of a 1-way avoidance response. (57 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of vinconate on the extracellular levels of dopamine and its metabolites in the rat striatum: microdialysis studies

Multiple endocrine neoplasia type 2B/3 is characterized by multiple mucosal neuromas, a marfanoid appearance, medullary thyroid carcinoma, pheochromocytoma, gastrointestinal ganglioneuromatosis, and thickened corneal nerves. This rare syndrome is inherited in an autosomal dominant pattern. Early recognition followed by appropriate screening and treatment can be life-saving.     

Acute administration of cocaine, but not amphetamine, increases the level of synaptotagmin IV mRNA in the dorsal striatum of rat

We reviewed the real and potential ocular problems in all head and neck injuries at a tertiary care and regional trauma center from April of 1994 to March of 1995. Through a retrospective study, 127 charts were reviewed, specifically looking at the mechanism of injury, types of injury, whether there was any ocular trauma noted in the chart, and whether there was a consultation to the ophthalmology department. Forty-one of these patients were seen by an ophthalmologist as the initial consultant for ocular and orbital injuries recognized by the emergency staff. In the 86 remaining patients, signs of potential ocular injury were recorded in the chart in 62 (72%) of these patients, yet an ophthalmology consultation was requested for only 23 of them (37%). This survey reveals the lack of awareness in a regional trauma center of certain ocular and periocular signs that may be indicative of more serious ocular injuries. It is the purpose of this article to highlight these concerns to the various health professionals involved with head and neck trauma patients in the hope that the patients will, in the end, benefit from a more thorough and complete assessment of the potential ocular and periocular injuries.     

Effects of systemic resiniferatoxin treatment on substance P mRNA in rat dorsal root ganglia and substance P receptor mRNA in the spinal dorsal horn

We have investigated the expression, using immunohistochemical and Western blot methods, of some cytoskeletal proteins including desmin, vimentin, actin, alpha-actinin, and ubiquitin in hereditary myopathy of the diaphragmatic muscles in Holstein-Friesian cattle (the histochemical and electron microscopical aspects have been previously reported). Immunohistochemically, the expression of desmin was observed strongly in the subsarcolemmal regions, but was lacking or faint in the area corresponding to the core-like structures. Vimentin showed almost the same localization as desmin, but no activity could be observed in the core-like structures. In addition, the core-like structures showed strong immunoreactivity for actin and ubiquitin, but no immunoreactivity for alpha-actinin. F-actin stained with phalloidin-tetramethyl-rhodamine was strongly positive in irregular spots that corresponded to the core-like structures, but was negative for desmin-positive regions. Western blot analysis of the diseased muscles revealed a significant increase in the amount of desmin and vimentin immunoreactivities and similar amounts of actin and alpha-actinin compared with the control muscles. Two-dimensional electrophoresis revealed no isoforms of desmin, suggesting the absence of abnormal phosphorylated forms of desmin. Since the co-localization of desmin and vimentin and the absence of phosphorylated desmin suggest that the overexpression of desmin may be reflected in the reactive change or regenerating process, the present myopathy should be regarded as an entity separate from desmin-storage myopathy or desmin-related myopathies. We also discuss the possibility that the present myopathy could be considered as myofibrillar myopathy, a recently proposed nosological entity.     

Widespread expression in adult rat forebrain of mRNA encoding high-affinity neurotensin receptor

The peptides neurotensin (NT) and neuromedin N exert effects on neurons by means of a high-affinity NT receptor (NTRH) belonging to the superfamily of G-protein-coupled receptors. In the present study, we used in situ hybridization histochemistry with sensitive riboprobe methodology to investigate the distribution of NTRH mRNA in the forebrain of adult rats. Labeled cells were abundant in the hypothalamus, epithalamus, ventral thalamus, septum, amygdala, and pallidum, including many regions where NTRH mRNA had not been detected previously. In the hypothalamus, novel sites of NTRH mRNA expression included the arcuate, periventricular, paraventricular, supraoptic, medial preoptic, anterior, ventromedial, and posterior nuclei, as well as the lateral hypothalamic area. In the thalamus, novel sites of expression included the anterodorsal nucleus, lateral habenula, and zona incerta, where labeling was much more extensive than previously reported. Novel telencephalic sites of expression included most bed nuclei of the stria terminalis, most divisions of the amygdala, the main olfactory bulb, the endopiriform nucleus, the claustrum, many parts of retrohippocampal allocortex, and limited parts of most isocortical areas. Novel sites of expression were also observed in the midbrain and pons. Taking into account expected differences in the subcellular locations of receptor mRNA and protein, the regional distribution of NTRH mRNA agrees well with that of NTRH determined previously. Our results identify many novel sites of NTRH mRNA expression in adult brain and provide a basis for investigating involvement of NT and related peptides in regulating the activity of these diverse cells, whose phenotypes remain largely undetermined.     

A kinetic analysis of the effects of beta-phenylethylamine on the concentrations of dopamine and its metabolites in the rat striatum

The purpose of this investigation was to determine whether the increase in the dopamine (DA) concentration in the rat striatum after a rapid iv injection of beta-phenylethylamine (PEA) can be quantitatively explained by the alteration of the striatum PEA concentration using a constructed DA metabolism model and to examine whether the time courses of the striatum DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentration can be described by this DA metabolism model. The time courses of PEA concentration in plasma and the striatum were determined by gas chromatography-mass spectrometry. The plasma PEA concentration was described by a two-compartment model with nonlinear elimination kinetics. The striatum PEA concentration was about 10 times higher than the plasma PEA concentration. The time course of the striatum PEA concentration was described by a diffusion-limited model including a Michaelis-Menten type transport system from plasma to the striatum and nonlinear elimination from the striatum. The DA concentration in the striatum increased immediately after PEA injection. In contrast, the DOPAC concentration in the striatum decreased immediately. HVA concentration in the striatum increased gradually. Assuming that the enhancement of DA concentration in the striatum after PEA injection is caused by the competitive inhibition of PEA on the reuptake of DA into DA neuronal terminals (and the metabolism from DA to DOPAC is then competitively inhibited by PEA in the DA neuronal terminals), the relationship between the enhancement of DA concentration and PEA concentration in the striatum was analyzed using a constructed DA metabolism model. The enhancement of the DA concentration in the striatum was described quantitatively by this model. Thus, it was clarified that a quantitative relationship between PEA concentration and the enhancement of DA concentration in the striatum is present after PEA injection. However, the time courses of the striatum DOPAC (lower dose) and HVA (time delay) concentrations could not be described by this model. These results indicated that other factors might be necessary to explain the time courses of the DOPAC and HVA concentrations in the striatum after PEA injection, such as the separate evaluation of the effect of PEA on the reuptake of DA into DA neuronal terminals and on the monoamine oxidase-B (MAO-B) activity in the DA neuronal terminals, and the metabolic pathway from DOPAC to HVA.     

Relationship between anxiety and serotonin in the ventral striatum

Rats were tested in an elevated plus-maze on two consecutive days. Based on the percentage of time spent in the open arms on the 1st day, they were divided into two subgroups with either low or high anxiety levels. A post-mortem neurochemical analysis showed that animals with high anxiety had lower ventral striatal tissue levels of 5-HT. No such differences were found for 5-HT in other brain areas or in dopamine and norepinephrine levels. The ventral striatal 5-HT levels correlated with plus-maze behavior on the 2nd but not 1st day. These data suggest that individual differences in ventral striatal 5-HT interact with plus-maze behavior, which may help to explain why serotonergic drugs can have inconsistent effects in this paradigm.     

Transsynaptic induction of c-fos in basal forebrain, diencephalic and midbrain neurons following AMPA-induced activation of the dorsal and ventral striatum

In these experiments, induction of the immediate early gene c-fos following excitation of striatal neurons has been used to investigate the organization of the ventral and dorsal striatopallidal systems and the relationship between striatal neurons and cholinergic neurons of the nucleus basalis magnocellularis (of Meynert, nbM). The results demonstrate that FOS immunoreactivity (ir) can be detected in ventral and dorsal striatal neurons following infusions of the non-N-methyl-D-aspartic acid (NMDA) glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). This activation and increased expression of FOS in striatal neurons was itself associated with the sustained appearance of FOS-ir in neurons of the ipsilateral ventral and dorsal pallidum, subthalamic nucleus and some thalamic nuclei. Infusions of AMPA into the ventral striatum (VS), but not the dorsal striatum (DS), also resulted in the appearance of FOS-ir in a proportion (17%) of the cholinergic neurons of the nbM. By combining the retrograde transport of Fluoro-Gold with FOS immunocytochemistry, it was also possible to demonstrate that approximately 46% and 58% of the pallidal neurons containing FOS-ir after infusions of AMPA into the VS or DS, respectively, directly project to the subthalamic nucleus. Taken together, these observations suggest that visualizing the protein product of transsynaptic c-fos induction provides an effective way to study the topographic and transsynaptic, within-system consequences of striatal activation.