bluuebunny/crossref_metadata_2025 huggingface dataset:
Specificity of the effects of neuroleptics on the release of glutamate from the rat amygdala
Authors: Mott J. , Sherman A. D.
Published: January 2005

The purpose of this study was to determine if the depression of calcium‐dependent glutamate release from synaptosomes derived from the rat amygdala is specific to neuroleptics. To this end the effects of nine nonneuroleptic agents and nine previously untested neuroleptic agents (or isomers) on nondependent and calcium‐dependent glutamate release were determined by gas‐chromatographic and radioisotopic methods. All of the neuroleptics except reserpine depressed calcium‐dependent release at 10−7 M with only a weak, inconsistent reduction of nonspecific release. None of the nonneuroleptic agents at concentrations of 10−6 M 10−5 M produced depression of calcium‐dependent release without also strongly depressing nonspecific release. Reserpine was without effect on release at concentrations as high as 10−7 M. Also shown was that the representive neuroleptics Haloperidol, chlorpromazine, and clozapine depressed the calcium‐dependent release of glutamine‐derived glutamate to a greater extent over glucose derived glutamate. These data suggest that the specific depression of stimulus‐coupled glutamate release is not a characteristic of noneuroleptic compounds, but is highly associated with neuroleptics of the phenothiazine or butyrophenone classes.
Differential up‐regulation of D‐1 and D‐2 dopamine receptor function in mesostriatal areas but not in cortical‐limbic brain regions of rats chronically treated with (—)sulpiride and SCH 23390
Authors: Memo Maurizio , Pizzi Marina , Nisoli Enzo , Missale Cristina , Carruba Michele O. , Spano Pierfranco
Published: January 2005

In the present study, the possible functional modifications of both D‐1 and D‐2 dopamine (DA) receptor subtypes have been studied following chronic treatment with DA antagonists that selectively act on a single class of DA receptors. Particularly, the functional state of D‐1 and D‐2 receptors has been evaluated by measuring SKF 82526‐stimulated and bromocriptine‐inhibited adenylate cyclase activity in different brain regions of rats treated with saline, SCH 23390, or (−)sulpiride for 35 days.

The results indicate that in striatum, nucleus accumbens, and substantia nigra, chronic blockade of D‐1 DA receptors by SCH 23390 induces up‐regulation of D‐1 receptors without changing the functional activity of D‐2 receptors. Likewise, chronic blockade of D‐2 DA receptors by (−)sulpiride causes an up‐regulation of D‐2 but not D‐1 DA receptors in striatum, nucleus accumbens, and substantia nigra. SCH 23390 or (−)sulpiride did not modify the functional activity of either D‐1 or D‐2 DA receptors located in frontal cortex and hippocampus. In conclusion, these results indicate that treatment with selective D‐1 or D‐2 DA receptor blockade for 5 weeks induces a receptor‐specific up‐regulation which involves the DA receptors located in the nigrostriatal system but not those present in the limbic‐cortical areas.
SL 81.0385: A novel selective and potent serotonin uptake inhibitor
Authors: Scatton Bernard , Claustre Yves , Graham David , Dennis Trevor , Serrano André , Arbilla Sonia , Pimoule Carmen , Schoemaker Hans , Bigg Denis , Langer Salomon Z.
Published: January 2005

SL 81.0385 (4‐[(2‐naphthalenyl)methoxy]piperidine) is a potent competitive inhibitor of serotonin uptake into rat hypothalamic synaptosomes and human platelets (IC50 values of 18 and 13 nM, respectively), which exhibits a high selectivity for inhibiting serotonin uptake relative to noradrenaline or dopamine uptake in vitro. SL 81.0385 also exhibits potent serotonin uptake inhibiting properties in vivo as demonstrated by its ability to antagonize the p‐chloroamphetamine‐induced depletion of rat cerebral serotonin levels (ED50 = 2.5 mg/kg i.p.). Similarly, SL 81.0385 is a potent inhibitor of 3H‐imipramine and 3H‐paroxetine binding to the serotonin transporter complex in rat cortical membranes (Ki values of 0.5 and 3.2 nM, respectively), but it exhibits a much lesser affinity for radioligand binding to the noradrenaline, adrenaline, and dopamine transporters. The selectivity of SL 81.0385 for serotonergic systems is also demonstrated by its effects on cerebral monoamine metabolism. Indeed, SL 81.0385 decreases, ex vivo, endogenous 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the rat striatum, and, in vivo, extracellular 5‐HIAA concentrations (as measured by differential pulse voltammetry) in the rat cerebral cortex. In contrast, SL 81.0385 fails to decrease striatal levels of 3,4‐dihydroxyphenylacetic acid and homovanillic acid and hypothalamic levels of total, 3,4‐dihydroxyphenylethyleneglycol. SL 81.0385 is devoid of inhibitory activity toward monoamine oxidase and has no affinity for cerebral muscarinic, H1 histaminergic, α1‐, α2‐, and β‐adrenergic, D2 dopaminergic, and benzodiazepine receptors, and it possesses only weak affinity for 5‐HT2 receptors. The present results indicate that SL 81.0385 is a highly potent and selective inhibitor of serotonin uptake, chemically unrelated to the tricyclics, and it should find application in the treatment of depression, obesity, and alcoholism.
Atrial natriuretic factor: Structural requirements of the peptide for receptor binding, biological activity, and cGMP stimulation
Authors: Holleman William H. , Bush Eugene N. , Devine Edward M. , Firestone Susan L. , Rockway Todd W. , Sarin Virender K. , Budzik Gerald P.
Published: January 2005

The atrial natriuretic factor (ANF) family of peptides possesses diverse functional properties including smooth‐muscle relaxation, inhibition of aldosterone biosynthesis, and hypotensive activities. These separate activities are most likely mediated by the binding of the peptide to specific receptors located in the target organs. The present study was initiated to more closely examine the relationship between biological activity and the requirements of the various receptors for interaction with ANF and with ANF analogs. Binding affinities (Ki) were measured in plasma membranes isolated from rabbit kidney cortex, aorta, and adrenal, and in cultured rabbit aortic vascular smooth muscle cells (VSMC) using 125I‐Tyr‐28‐ANF (1–28) as the ligand. The VSMC were also utilized to quantitate stimulation of cGMP synthesis. Vasorelaxation (pD2) was measured in histamine‐contracted rabbit aortic rings. The activities of 19 ANF (5–28) analogs were compared, and a significant correlation between pD2 and Ki (r = −.83; p < 0.01) was obtained. The (D)Phe‐8 and Asn‐13 analogs were exceptions to this correlation; pD2 = 7.1 and 7.2, and pKi = 6.0 and 8.1, respectively. All analogs examined possessed comparable affinities in the four receptor assays. Conversely, comparison of vasorelaxant and cGMP stimulatory activities resulted in a much larger separation of activities. Tyr‐8 ANF (5–27) did not stimulate cGMP synthesis but relaxed smooth muscle (pD2 = 7.9), while ANF (7–23) was 500‐fold less active than ANF (5–28) in the vasorelaxant assay (pD2 = 6.1 and 8.9, respectively) but equipotent in the cGMP system. These and other experiments suggest the presence of ANF receptor subtypes and question the causative role of cGMP for inducing vasorelaxation of histamine‐constricted aortic rings.
Bupropion and thiothixene versus placebo and thiothixene in the treatment of depression in schizophrenia
Authors: Dufresne Robert L. , Kass David J. , Becker Robert E.
Published: January 2005

The authors performed a double‐blind study in which 38 inpatients diagnosed as schizophrenic with depressive symptoms were treated with either bupropion and thiothixene or placebo and thiothixene. Of the 36 patients who completed 4 weeks of study treatment, the placebo‐thiothixene treated patients did significantly better than the bupropion‐thiothixene treated patients on BPRS total scores as well as anxiety and depression items. The bupropion‐thiothixene treated patients reported significantly more dry mouth and constipation than the placebo‐thiothixene treated group, whereas the placebo‐thiothixene treated group reported more frequent occurrences of increased appetite, menstrual disturbance, and decreased sex drive. Neither group differed on ratings of pseudoparkinson or dyskinetic signs. The antidepressant bupropion as an adjunct to thiothixene was less effective in the treatment of depressed schizophrenic patients than the antipsychotic alone and appeared to inhibit the therapeutic effects of thiothixene primarily in the depressive symptoms of the syndrome.
Calcium channel antagonists modulate calcium by increasing magnesium influx: A hypothesis
Authors: Singh R. B.
Published: January 2005

Mg2+ and Ca2+ ‐channel blockers exert similar effects on the cardiovascular system. These agents have been successfully used for treating hypertension and for protecting against myocardial ischaemia. The exact mechanism of action of Ca2+ ‐blocking drugs, including verapamil, is unknown. It is proposed that Ca2+ ‐blockers stimulate the Mg2+ transport system and Mg2+ diffusion into the cell, thereby enhancing Mg2+ influx. This, in turn, causes suppression of the slow inward Ca2+ current and fast inward Na+ current, resulting in decreased transport of Ca2+ and Na+. Ca2+ ‐blockers might also influence outward K+ and Mg2+ currents, thereby altering the shape and duration of the action potential. Since Mg2+ is involved in maintaining the structural and functional integrity of the cardiovascular system, Mg2+ ‐mediated mechanisms of action for Ca2+ ‐antagonists appear possible.
Effect of luteinizing hormone releasing hormone (LHRH) agonists on body weight in rats
Authors: Ataya Khalid , Weintraub Alan , Dunbar Joseph , Zimniski Stephen , Puett David , Lemaire William
Published: January 2005

As the potential clinical applications of LHRH agonists increase, the issue of side effects on nonreproductive organ systems assumes greater significance. LHRH agonists administered continuously or in twice‐daily injections accelerated body weight gain in female rats. Two different LHRH agonists produced similar effects on body weight in female rats. When Leuprolide (LHRHa) was given to female rats in twice‐daily injections, the adrenal weight increased after 21 days of treatment, whereas administration by osmotic minipumps produced no significant effect on adrenal weight. When another agonist, Zoladex (LHRHz), was given continuously for 52 and 229 days to female rats, the adrenal weight decreased. No change was noted in adrenal weight or body‐weight gain of male rats given LHRHz continuously for 51 and 62 days. Reproductive‐organ weights were significantly reduced in all LHRH‐agonist‐treated animals. Serum progesterone in female rats and testosterone in male rats were significantly decreased following treatment with LHRHz. No significant differences were noted in serum prolactin, growth hormone, or corticosterone. The mechanisms and significance of these findings are discussed.
Antiamnesic effects of magnesium pyrrolidone carboxylate (MAG 2) in three models of amnesia in the mouse
Authors: Porsolt Roger D. , Lenègre Antoine , Avril Isabelle , Parot Philippe , Tran Gilles
Published: January 2005

The effects of magnesium pyrrolidone carboxylate (MAG 2) on the amnesias induced by scopolamine, diazepam, and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse and compared with the effects of a standard dose of piracetam. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg intraperitoneally [i.p.]) 30 min before or ECS administered immediately after the first session (S1) of the passive avoidance task. MAG 2 was studied in a dose range of 128 to 1,024 mg/kg and compared with piracetam (2,048 mg/kg), both drugs being administered orally (p.o.) 60 min before S1. Retention was measured 24 hr later (S2) in the absence of any treatment. Further experiments investigated the effects of repeated administration of MAG 2 (twice daily for 3 days) on diazepam‐induced amnesia. Additional experiments investigated the interactions of the compound with the major behavioral effects of the amnesic treatments, namely scopolamine‐induced hyperactivity, diazepam‐induced release of punished behavior (four plates test), and ECS‐induced convulsions. MAG 2 dose‐dependently attenuated the memory deficits induced by the three amnesic treatments after acute treatment and more effectively antagonized diazepam‐induced amnesia after repeated than after acute treatment. It did not affect either scopolamine‐induced hyperactivity, diazepam‐induced release of punished behavior or ECS‐induced convulsions. These results point to the specificity of MAG 2′s antiamnesic activity and suggest that it might be a useful agent for the treatment of memory deficits of different origins in man.
Acne: Androgens and microbiology
Authors: Pochi Peter E.
Published: January 2005

Acne, the most prevalent disease of the skin, is a multifactorial follicular disorder in which androgens and microbiology are essential for the occurrence of the pathogenic events that characterize it. The role of the androgen is to stimulate the development and secretory activity of the sebaceous gland, which performs several important actions in the etiopathogenesis of acne. The anaerobic diphtheroid Propionibacterium acnes, a resident organism in acne‐susceptible follicles, is directly responsible for much of the inflammation in acne. This review deals with a description of these events and the therapeutic modalities that have been developed in an attempt to counteract them.
Antagonism of diazepam hyperphagia by propranolol in rats
Authors: Kamatchi G. Lenin , Chandra Dinesh , Rajasekaran M. , Rao K. Madhusudana , Venkatadri N. , Bapna J. S.
Published: January 2005

The effects of adrenergic beta‐receptor blockers on the hyperphagia produced by diazepam were studied in free‐feeding rats. The hyperphagia produced by 1.0 mg/kg subcutaneous (s.c.) diazepam, was antagonised by dl‐propranolol (6.0 mg/kg s.c.) and 1‐propranolol (6.0 mg/kg s.c.), but not by d‐propranolol (6.0 mg/kg s.c.). Intracerebroventricular administration of dl‐propranolol (50, 100, and 200 μg) failed to antagonise this hyperphagia. Other specific β1 and β2 blockers, metoprolol (10.0 mg/kg s.c.), and butoxamine (10.0 mg/kg s.c.) also did not antagonise this hyperphagia. It is suggested that some intrinsic property other than β‐blockade, tranquilising, or local anesthetic activity is responsible for this antagonism caused by s.c. administration of dl‐ or l‐propranolol.
Partial and complete blockade of 5‐hydroxytrytophan (5‐HTP)‐induced head twitches in the rat: A study of ritanserin (R 55 667), risperidone (R 64 766), and related compounds
Authors: Meert Theo F. , Niemegeers Carlos J. E. , Awouters Frans , Janssen Paul A. J.
Published: January 2005

A series of test compounds were studied for their ability to inhibit and block the head‐twitch response to either intraperitoneal (i.p.) 5‐hydroxytryptophan (5‐HTP) or intravenous (i.v.) mescaline in rats. Both responses were found to be sensitive to serotonin S2 antagonists, and there was very good agreement between the inhibitory doses in both tests, particularly for the selective serotonin S2 antagonists ritanserin and seganserin. However, these two compounds did not block the 5‐HTP response, although they completely abolished the mescaline response. In contrast, the mixed serotonin‐dopamine‐norepinephrine antagonist risperidone was a potent blocker of both responses. The use of various antagonists and the combination treatments of ritanserin with haloperidol or prazosin indicated that the 5‐HTP response is abolished when potent serotonin S2 antagonism is associated with antagonistic activity on either dopamine D2 or α1 receptors.
Tazadolene: A centrally‐acting, non‐narcotic analgesic
Authors: Piercey Montford F.
Published: January 2005

Intravenous tazadolene elevated the threshold stimulus for rabbits to respond to electrical tooth‐pulp stimulation. Systemic tazadolene also increased the latency for mice to lick their paws in the hot‐plate analgesic test. However, tazadolene did not alter the mouse tail flick, a spinal reflex most sensitive to analgesics acting at spinal sites. Tazadolene analgesia was not antagonized by naloxone. Intracranial (i.c.), but not intraspinal (i.s.), injections of tazadolene were more effective than systemic injections in producing analgesic effects in the hot‐plate test. It is concluded that tazadolene is a centrally‐acting, non‐narcotic analgesic.
Mutagenicity evaluation of tetrahydro‐amino acridine by the Salmonella/microsome mutagenicity ames test
Authors: Townsend Steven E. , Sehgal Suren N.
Published: January 2005

1,2,3,4‐tetrahydro‐5‐amino acridine (THA), a cholinesterase inhibitor currently under investigation for use in the treatment of senile dementia, exhibited mutagenic activity with and without metabolic microsomal S‐9 activation against tester strain TA97a in the Salmonella typhimurium incorporation assay. The mutagenic response was concentration‐dependent within the dose range of 500 to 2,500 μg/plate.
GABA agonists enhance morphine and fentanyl antinociception in rabbit tooth pulp and mouse hot plate assays
Authors: Bergman Stewart A. , Wynn Richard L. , Peterson Michael D. , Rudo Frieda G.
Published: January 2005

Parallel experiments in the rabbit tooth pulp and mouse hot plate paradigms were performed to elucidate the effect of pretreatment with the GABA mimetic compound muscimol (M) and diazepam (DZ) on the antinociceptive effect of both morphine sulfate (MS) and fentanyl citrate (F). The ED50 values for F in both rabbits and mice were lowered significantly (p ≤ 0.05) by pretreatment with either i.v. DZ or M in rabbits or i.p DZ or i.v. M in mice. There was a significant 7‐fold shift of the F dose‐response curve after pretreatment with M in rabbits and a 3‐fold shift in mice compared to controls; a 10‐fold shift after pretreatment with i.v. DZ in rabbits and a 2‐fold shift after i.p DZ in mice. The ED50 values for MS in both rabbits and mice were lowered significantly (p ≤ 0.05) by pretreatment with i.v. muscimol but not DZ (p ≤ 0.18). Similarly, pretreatment with i.v. M, in rabbits and mice, but not i.v DZ in rabbits or i.p DZ in mice, significantly shifted the dose‐response curves of MS to the left compared to controls. DZ and M i.v. significantly prolonged the duration of antinociception (rabbit) of an ED98 dose of MS and ED90 dose of F. Time to 50% maximal possible antinociceptive effect (MPE) increased from 240 min for MS + vehicle to 425 min for MS + DZ, and over 450 min for MS + M. Time to 50% MPE increased from 25 min for F + vehicle to 38 min for F + DZ. Similar results were observed for F + M. DZ pretereatment enhances the antinociceptive potency of 2X ED50 of F. In general, the average % MPE of F + DZ was twice tha tof F + vehicle over the first 20 min postopioid injection. A similar trend was noted following 2 × ED50 pf MS, whereas scopolamine had no significant effect. These results suggest that GABAA agonists, both direct M and indirect DZ enhance the antinociceptive effect of the opioids F and MS. since naloxone completely reversed this effect and scopolamine had no significant effect, this implies that GABAA agonists enhance opioid antinociception by an opioid and not a cholinergic mechanism.
Pyrazoloquinolines and zolpidem: Effects on hypertonic saline consumption in rehydrating rats
Authors: Cooper Steven J. , Desa Asmawati
Published: January 2005

Male rats were adapted to a 22‐hr‐daily water‐deprivation schedule and to consuming an aversive 2.7% NaCl solution in a 30‐min period. Previous reports had shown that benzodiazepines and other anxiolytics stimulate ingestion of hypertonic saline under these conditions; however, two pyrazoloquinolines, CGS 9895 and CGS 9896, failed to do so [Cooper, 1987]. The present experiments were designed to investigate possible antagonist properties of CGS 9895 and CGS 9896 in this model and also to characterize the effects of a newly described pyrazoloquinoline, CGS 17867A, on saline drinking. In addition, a novel sedative‐hypnotic, zoloidem, and a benzodiazepine peripheral‐type receptor compound, Ro5‐4864, were treated. The results indicate that CGS 9895 and CGS 9896 exhibited antagonistic activity in this model, that CGS 17867A increased salt drinking without displaying antagonist activity, and that neither zolpidem nor Ro5‐4864 affected drinking responses.
Efficacy of denbufylline in patients with multi‐infarct dementia
Authors: O'Connolly M. , Dierdorf D. , Greb W. H. , Mayer M.‐E. R. , Wolf D.
Published: January 2005

The efficacy and tolerance of denbufylline (25 and 50 mg tid for three months) were investigated in 20 inpatients with cerebrovascular disease in a placebo‐controlled, doubleblind parallel study. Denbufylline at 50 mg tid significantly improved the mental, emotional, and social capabilities of the patients; tolerance was acceptable.
Correlation between cerebral circulation and intellectual impairment in patients with “aging brain,” and the effect of vinpocetine on cerebral circulation
Authors: Miyazaki Manabu
Published: January 2005

The Doppler ultrasonic technique is useful for the examination of cerebral circulation as well as for the evaluation of cerebral circulation‐improving drugs. This study deals with a correlation of cerebral circulation with intellectual impairment in subjects with aging brain syndrome and with measuring the effect of vinpocetine on cerebral circulation, using the Doppler technique.

The correlatiion between cerebral circulation and intellectual impairment was first studied in 48 patients with aging brain and intellectual impairment. As a parameter for cerebral ciruclation, the Continuous Index (CI), as calculated from the blood flow pattern recorded at the internal carotid artery, was used together with Hasegawa's Dementia Scale (HDS) for intellectual impairment.

Second, blood flow change of the internal carotid and vertebral artery was measured after a single oral dose of 5 mg vinpocetine and after multiple oral doses of 5 mg vinpocetine three times daily for 7 days in six patients with aging brain.

The mean correlation coefficient (r) between CI and HDS was 0.391 (P < 0.01) in 48 patients. It was 0.612 (P < 0.01) in 27 patients with moderate to severe intellectual impairment, 0.735 (P < 0.01) in 14 patients with vascular type impairment, and 0.443 (not significant) in 10 patients with the Alzheimer type. The results suggest some correlation between cerebral circulation and intellectual impairment in the aging brain, especially in patients with the vascular type.

An increase of blood flow was recognizable after a single oral dose of 5 mg vinpocetine and was more conspicuous after multiple oral doses. Thus, the effect of vinpocetine in improving cerebral circulation was evident, suggesting its clinical efficacy in improving intellectual impairment in patients with aging brain.
Multicenter clinical placebo‐controlled study with acetyl‐l‐carnitine (LAC) in the treatment of mildly demented elderly patients
Authors: Cucinotta Domenico , Passeri Mario , Ventura Sandro , Lannuccelli Maurizio , Senin Umberto , Bonati Piero Angelo , Parnetti Lucilla
Published: January 2005

Acetyl‐l‐carnitine (LAC) was administered for 3 months, 2 g/daily, to 30 elderly patients with mild mental deterioration. Results were compared to those of a homogeneous control group of 28 patients treated with placebo. The study was carried out according to a double‐blind, randomized methodology. A complete battery of rating scales and psychometric tests was used for for evaluating the modifications induced by either drug or placebo. The statistical evaluation of results showed a sufficient clear efficacy of the drug studied: results from patients on LAC were frequently different from those receiving placebo. Therefore, LAC must be taken into consideration as a useful drug for the global treatment of demented elderly patients.
Computed tomography study of cerebral infarctions treated with vinpocetine
Authors: Kalvach Pavel , Bauer Jiří , Vymazal Josef
Published: January 2005

A group of 20 persons with cerebral infarctions who had been treated with vinpocetine was compared with a group of 20 similar patients who had been treated with other vasoregulative drugs. Two computed tomography (CT) examinations were evaluated for each patient. The initial scan was done during the first ten days, and the second between the 20th and 50th day after the stroke. Three parameters were studied: extension of the lesion, intensity of hypodensity, and presence of postcontrast enhancement. In the first and second criteria, the vinpocetine‐treated patients exhibited better results, whereas the third did not yield any explicit data.
Strategies and new aspects in the pharmacology of drugs for the treatment of senile dementia
Authors: Schmidt Joachim , Fischer Hans‐Dieter , Wustmann Christian
Published: January 2005

Rational therapeutic strategies can be derived only from an understanding of the etiopathogenetic processes leading to dysfunction in the demented brain. Senile dementias (SD) of different origins are associated with biochemical changes in functionally important transmission systems, in energy metabolism, and in synthesis of macromolecules. Much evidence supports a particularly important role of dysfunction in central cholinergic mechanisms. Recent results have furnished encouraging indications that changes in synaptic efficiency and plasticity are integrated to a considerable degree. At present, the pharmacological manipulation of clinical symptoms and impaired functions is the basis for rational strategies in the development of drugs for the treatment of SD. On the basis of present knowledge, the following strategies can be considered: (1) drugs to prevent underlying etiopathogenetic processes (antioxidants, aluminium chelating agents, etc.); (2) enhancers of cerebral neurotransmission; (3) cerebral metabolic enhancers (nootropics and related drugs); (4) modulators of synaptic efficiency and plasticity; (5) nooanaleptics; (6) regulators of cerebral circulation; and (7) symptomatic therapy of associated functional mental disorders. The improvement of neuronal metabolism and synaptic transmission are presently the most important strategies in drug development. Nootropics and related drugs fulfill two aspects in the pharmacotherapy of SD: they are cerebral metabolic enhancers and they improve cerebral synaptic transmission processes. In eight of these functions, the relationship between lipid metabolism and cellular Ca++ homeostasis also may be of special functional importance. For the development of further strategies, more detailed knowledge about the pathogenesis of SD and further experimental modeling of the etiopathogenetic and neuropathological processes underlying SD of different origins are required.
Vinpocetine facilitates noradrenaline release in rat brain cortex slices
Authors: Schlicker E. , Betz R. , Göthert M.
Published: January 2005

Rat brain cortex slices preincubated with 3H‐noradrenaline were superfused with physiological salt solution, and the effect of vinpocetine on the electrically (3 Hz) evoked 3H overflow was studied. Vinpocetine at 10–100 μmol/liter facilitated the evoked overflow; at 32 and 100 μmol/liter, basal efflux was slightly increased. The facilitatory effect of vinpocetine on the evoked overflow was not altered by desipramine, rolipram (an inhibitor of cAMP phosphodiesterase), or ICS 205‐930 ([3α‐tropanyl]‐1H‐indole‐3‐carboxylic acid ester; an antagonist at 5‐HT3 (M) receptors); it was strongly attenuated by phentolamine. In turn, vinpocetine moderately decreased the facilitatory effect of phentolamine on the evoked overflow. The concentrationresponse curve of noradrenaline (obtained in the presence of desipramine) for its inhibitory effect on the evoked overflow was not shifted to the right by vinpocetine at 32 and 100 μmol/liter. The present results show that vinpocetine facilitates noradrenaline release. This effect may be related to the blockade of presynaptic α2‐adrenoceptors (although evidence is not unequivocal), but does not appear to involve inhibition of noradrenaline uptake or cAMP phosphodiesterase nor activation of 5‐HT3 (M) receptors. The facilitatory effect of vinpocetine on noradrenaline release occurs at concentrations higher than those obtained under treatment with this drug.
Immune dysfunctions: New targets of drug discovery for alzheimerapos;s disease and other cognitive disorders
Authors: Lal Harbans , Forster Michael J. , Retz Konrad C. , Reisberg Barry
Published: January 2005

The development of treatments applicable to Alzheimerapos;s disease and other age‐associated dementias represents a serious challenge to biomedical research. It is suggested that advances in the understanding of basic etiologic mechanisms in these disorders would provide the most direct avenues to discovery of preventive and arrestive treatments. An overview of research relating to the potential involvement of immune dysfunctions in the etiology of Alzheimerapos;s and other central nervous system (CNS) diseases is reviewed as this was presented and discussed in a recent satellite symposium, “Autoimmunity: Its Role in Alzheimerapos;s Disease and Other Behavioral Dysfunctions,” held at the 17th Annual Meeting of The Society for Neuroscience. It is predicted that some future research may focus on immunological dysfunctions as targets for the discovery and development of drugs for treatment of Alzheimerapos;s dieseas and other cognitive disorders.
Structural and functional relationships between the immune and central nervous systems in Alzheimer's disease
Authors: Kozlowski Gerald P. , Nilaver Gajanan
Published: January 2005

An intact blood–brain barrier (BBB) is a prerequisite to maintaining functional compartmentalization between the neural and immune systems. Only small amounts of immunoglobulins access the internal milieu of the brain, probably via so‐called “functional leaks” existing in the region of the circumventricular organs. However, with aging and disease, globular and other proteins can be found within the cerebrospinal fluid (CSF) because of disruption of perhaps both the BBB and the blood–CSF barrier. There is an increase of lgG, IgA, albumin, and prealbumin in CSF of patients with Alzheimerapos;s disease. The presence of these proteins is taken to be pathognomonic for neuronal impairment, and they are believed to be associated with the amyloid deposits of senile plaques. Our studies have shown that albumins may occur naturally in some CNS neurons. Immunocytochemical studies with antibodies to rat serum albumin have shown the uptake of this serum protein by nerve endings with retrograde transport to perikarya of their cells of origin. Likewise, we have also shown than an endogenous albuminoid substance occurs in arcuate nucleus neurons of the hypothalamus that immunoreact with antibodies to bovine serum albumin. The arcuate nucleus neurons are neurosecretory and have neurohemal endings in contact with blood vessels of the hypothalamohypophysial vasculature. These neurohemal contacts are capable of taking up albumins from the blood for retrograde transport. We, therefore, hypothesize that immunoglobulins may be similarly incorporated by neurons having neurohemal contacts and access the CNS in this and several other ways. We have localized endogenous gammaglobulins in brains of both immunized and nonimmunized rabbits with antisera against rabbit lgG generated in sheep, goat, and mouse. However, serum proteins are also found in neurons without neurohemal contacts. Taken together, albumins, globulins, and other substances may reach the interior milieu of the CNS via: (1) endothelial transcytosis, (2) neurohemal contacts whereby neurons take up blood‐borne substances and retrogradely transport them to their perikarya, (3) circumventricular organs (inter‐ and intraependymal transport), (4) functional leaks at the interface of the circumventricular organs and the brain, (5) a nose–brain pathway, (6) a meningeal pathway, and (7) transsynaptic transport, i.e., substances passed from a neurohemal cell to other connecting neurons.
Antibodies recognizing cholinergic neurons and thyroglobuline are found in the cerebrospinal fluid of a subgroup of patients with Alzheimer's disease
Authors: McRae‐Degueurce Amanda , Haglid Kenneth , Rosengren Lars , Wallin Anders , Blennow Kaj , Gottfries C.‐G. , Dahlström Annica
Published: January 2005

The presence of cholinergic neuron specific lgG in the CSF of a subgroup of patients with Alzheimerapos;s disease (AD) was demonstrated by immunocytochemistry. The lgG labeled cholinergic nerve cell bodies in the medial septum of rat brains, perfusion fixed with glutaraldehyde/allyl alcohol to fix small transmitter molecules. Many of the patient CSFs also recognized thyroglobuline in an ELISA assay. Antithyroglobuline furthermore recognized the same cholinergic neurons in the rat brain as the CSF and antiacetylcholine, as did anti‐T3 and anti‐T4. The results indicated that in a subgroup of AD patients autoimmune mechanisms may play a role in the pathogenesis of dementia, and that disturbances in the handling of thyroid hormone in the CNS may be involved in the disease process.
Nzb mouse: Hippocampal mossy fiber patterns and behavioral profiles of young and older animals
Authors: Schwegler H. , Lipp H.‐P. , Crusio W. E.
Published: January 2005

New Zealand Black mice (NZB) are widely used as a model for presenile dementia, because an autoimmune disease induces early senescence in these animals. Since some of the behavioral properties of NZB might also be related to normal, nonpathologic variations in brain morphology, NZB of different age groups were tested in a number of hippocampus‐dependent tasks. As control strain we used the non‐autoimmune strain C57BL/6. In addition to behavioral testing, we measured the sizes of the hippocampal regio inferior (CA3 + CA4) and the intra‐ and infrapyramidal mossy fiber terminal fields. NZB mice were inferior to C57BL/6 in active one‐way avoidance and performed poorly in a radial maze. For learning scores in other behavioral paradigms NZB mice showed performance levels comparable to other fair‐ to well‐performing strains. Slight age‐related declines in NZB, but not in C57BL/6, mice could be observed in most learning tasks. The hippocampal regio inferior is larger in NZB than in C57BL/6, whereas the latter mice have much larger infrapyramidal mossy fiber (iip‐MF) terminal fields. From this and from previous data it appears that at least some of the behavioral differences between NZB and C57BL/6 may reflect an influence of a factor related to the iip‐MF projection. The inclusion of strain DBA/2 in future studies is suggested.
Renal, cardiac, and systemic hemodynamic effects of the dopamine receptor agonist SK&F 85174 in anesthetized dogs
Authors: Dlewati Abdallah , Lokhandwala Mustafa F. , Chelly Jacques E. , Doursout Marie‐Francoise
Published: January 2005

SK&F 85174 is a mixed DA‐1/DA‐2 receptor agonist which is shown to inhibit sympathetic neurotransmission and cause hypotension in anesthetized animals. In this study, we have determined the regional and systemic hemodynamic effects of an intravenous infusion of SK&F 85174 (5 μg/kg/min for 5 min) in pentobarbital‐anesthetized dogs and attempted to identify the dopamine receptor subtype(s) involved in the cardiac as well as vascular effects of this compound. SK&F 85174 produced significant decreases in mean blood pressure (MBP), left ventricular pressure (LVP), left ventricular dp/dt, total peripheral resistance (TPR) and renal vascular resistance (RVR), and a significant increase in renal blood flow (RBF). There were no significant changes in heart rate, cardiac output, coronary blood flow, or coronary vascular resistance. Prior treatment with SCH 23390 (DA‐1 receptor antagonist) significantly attenuated the effects of SK&F 85174 on MBP, LVP, TPR, RBF, and RVR. In a second group of dogs S‐sulpiride (DA‐2 receptor antagonist) significantly antagonized the effects of SK&F 85174 on MBP, LVP, and dp/dt, but did not influence its effects on RBF, TPR, and RVR. These results show that (a) a decrease in total peripheral resistance and not the cardiac output accounts for the hypotensive action of SK&F 85174, (b) the renal hemodynamic effects of SK&F 85174 are mediated primarily via the activation of DA‐1 receptors, and (c) whereas DA‐1 receptors are involved primarily with the hypotensive action of this compound, it appears that activation of DA‐2 receptors also contributes to the hypotension.
Discriminative and contextual stimuli produced by drugs: History of discussion groups and meetings
Authors: Overton Donald A. , Lal Harbans
Published: January 2005

Systematic research on the stimulus properties of drugs began about 25 years ago. Informal discussion groups and scientific meetings contributed a great deal to developing this area of research into a scientific discipline. A brief history of these discussions and meetings is described.
Effects of reinforcement on stimulus control of drug discrimination behavior
Authors: Mathis D. A. , Emmett‐Oglesby M. W.
Published: January 2005

The present study was designed to examine the disruptive effects of reinforcement during stimulus onset/offset in drug‐discrimination tasks. Rats were trained on a two‐lever task to discriminate either pentylenetetrazole (PTZ, 20 mg/kg) or cocaine (CN, 10 mg/kg) from saline, with food used as a reinforcer. Tests for onset of the drug stimulus were conducted immediately after an i.p. injection of the training stimulus. In order to test drug offset, rats trained to discriminate PTZ were tested immediately after an injection of diazepam (DZP, 5 mg/kg) given 15 min after an injection of PTZ. Responses on either lever were reinforced throughout the 20‐min session. Although the onset or offset of a drug stimulus significantly changed lever selection, consistent change in lever selection was obtained from approximately 30% of the subjects. For both the CN and PTZ onset groups, lever changing occurred after either (1) a disruption in responding, which produced a period of no reinforcement, or (2) very early in the session, which provided only brief exposure to reinforcement for responding on the other lever. Drug‐induced disruption of behavior was much more apparent during PTZ onset than during CN onset. For animals that continued to be reinforced for nondrug responding after onset of the drug stimulus, discrimination of the training stimulus during subsequent training was not disrupted by the testing procedure.
Limitations of existing theory in explaining state‐dependent performance of rats on the maier three‐table reasoning problem
Authors: Stahl Jeanne Marsh , Pieper Walter Alan
Published: January 2005

The three‐table reasoning problem was developed by Norman Maier in 1929 to test the ability of rats to combine the essentials of two isolated experiences to reach a goal. The purpose of this paper is to describe the test situation and the performance of rats that were given each experience in a different chemical state prior to testing. Rats given morphine, methadone, or naloxone for both experiences and the test performed well on this task, whereas rats given the first experience in an undrugged or saline condition and given the second experience in a morphine, methadone, or naloxone condition performed poorly. Similarly, rats given experience 1 in a undrugged condition, experience 2 in a morphine or methadone condition, and the test in a naloxone condition performed poorly. Although these results cannot be explained by most theories of state‐dependent learning, an interpretation is presented, with suggestions for further research.
Yohimbine and serotonergic agonists: Stimulus properties and receptor binding
Authors: Winter J. C. , Rabin R. A.
Published: January 2005

The present investigation was designed to compare the discriminative stimulus properties of yohimbine and purported agonists at the serotonin (5‐HT)1A receptor. To that end, groups of rats were trained with yohimbine, 8‐OH‐DPAT, and ipsapirone, respectively. Tests of generalization were then conducted, and the interaction between clonidine and yohimbine was examined. Drugs examined behaviorally were also characterized in terms of their relative affinities at the 5‐HT1A, 5‐HT1B, and 5‐HT2 receptors by means of standard radioligand binding techniques. A high degree of generalization was observed between each of the training drugs and in tests of gepirone and buspirone. Comparisons of the behavioral and receptor binding data argue against stimulus control mediated solely by a 5‐HT1A‐based mechanism. The observed pattern of interaction of clonidine with yohimbine in rats trained with the latter drug suggests that clonidine may function as a partial agonist. Whatever the mechanistic basis for the present discrimination data, we are left with the puzzle of why yohimbine, widely regarded as anxiogenic, should share stimulus properties with anxiolytic drugs.
Discriminative stimulus properties of ICSS in rats: Effects of ethanol and RO 15‐4513
Authors: Schaefer Gerald J. , Michael Richard P.
Published: January 2005

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle–lateral hypothalamus and trained in a discrete trial procedure to make a differential response (right or left lever press) in the presence or absence of brain stimulation. When animals reached 95% accuracy in this discrimination, testing with vehicle, ethanol (0.1, 0.3, 0.56, 1.0, g/kg), and ethanol plus RO 15‐4513 (1.0 mg/kg) began. During test sessions intermediate stimulus currents were programmed and the data comprised the number of trials completed on the stimulation‐appropriate lever as a function of intermediate currents. The stimulus current at which 50% of the trials were completed was defined as the detection threshold. Ethanol, at 1.0 g/kg, increased the detection threshold but also increased the time to complete the session and decreased the total number of lever presses. RO 15‐4513 reversed the increase in the detection threshold and reduced the increase in time to complete the session and reduced the decreases in lever presses. However, RO 15‐4513 alone, like ethanol, increased the time to complete the session and decreased the total number of lever presses. Thus, while RO 15‐4513 reverses some of the behavioral effects of ethanol, it also has its own behavioral effects, even at low doses.
6‐Hydroxydopamine lesions of the nucleus accumbens attenuate the discriminative stimulus effects of d‐amphetamine
Authors: Dworkin Steven I. , Bimle Cindy
Published: January 2005

Ten rats were trained with a standard two‐lever procedure to discriminate d‐amphetamine (1.0 mg/kg i.p.) from saline. Training was continued until the rats emitted three or less responses on the incorrect lever before the first food presentation and more than 95% of the responses during a session occurred on the correct lever for five consecutive sessions.

A descending range of doses from 1.0 to 0.17 mg/kg d‐amphetamine and saline were resulted to determine a drug‐dose generalization gradient including a threshold dose that resulted in drug‐appropriate responding. Following the determination of the threshold dose, the rats were lesioned with 6‐hydroxydopamine (6‐OHDA) or its vehicle. Three days were allowed for recovery from the lesion. The animals were then again tested starting with the threshold dose. A postlesion generalization gradient was then determined by testing the rats with increasing doses of the drug. Saline test sessions were randomly scheduled during the postlesion testing.

The vehicle lesion produced a slight change in the generalization gradients. The 6‐OHDA lesion, however, resulted in a much larger attenuation in the discriminative stimulus function of the drug. Thus, it appears that destruction of the dopaminergic input into the accumbens only moderately alters the discriminative stimulus properties of d‐amphetamine.
Linogliride fumarate, an oral hypoglycemic agent, improves oral glucose tolerance in a rat model of non‐insulin‐dependent diabetes mellitus (NIDDM)
Authors: Marchione Carol S. , Tuman Robert W.
Published: January 2005

Linogliride fumarate, a structurally novel oral hypoglycemic compound, was tested in the neonatal streptozotocin‐induced rat model of non‐insulin‐dependent diabetes mellitus (NIDDM) [Weir et al.: Diabetes 30:590–595, 1981], and its antihyperglycemic effects were compared to those of representative first and second generation sulfonylureas. Two‐day‐old male Sprague‐Dawley rats (STZ) were injected with the beta cell toxin, streptozotocin (90 mg/kg i.p.); male littermates injected with citrate buffer served as controls (CTL). By 8 weeks of age, blood glucose of fed STZ rats was significantly elevated compared to that of CTL animals (>300 mg/dl vs.<110 mg/dl, respectively) and, in response to an oral glucose (1 g/kg) challenge, 18 hr fasted STZ rats exhibited marked glucose intolerance. Linogliride fumarate (10–100 mg/kg p.o.) significantly lowered blood glucose in 18 hr fasted STZ rats and produced a dose‐dependent improvement of oral glucose tolerance. Linogliride fumarate (ED30 = 12.5 mg/kg) was approximately six times as potent as tolbutamide (ED30 = 72.1 mg/kg) in improving oral glucose tolerance in STZ rats, while glyburide (0.5–2.5 mg/kg p.o.) and glipizide (2.5 mg/kg) were ineffective. This rat model of NIDDM may be useful for evaluating new hypoglycemic compounds.
Attenuation of morphine withdrawal syndrome by macromolecular synthesis inhibitors in rats
Authors: Copeland Robert L. , Pradhan S. N.
Published: January 2005

Attenuation of the morphine withdrawal syndrome by the combination treatment of morphine and protein/nucleic acid synthesis inhibitors was investigated in rats. Groups of rats were treated twice daily with gradually increasing doses of morphine (4–28 mg/kg) in combination with a protein/nucleic acid synthesis inhibitor (actinomycin D, chloramphenicol, cycloheximide, cytarabine, or tetracycline) for 14 days. Withdrawal was precipitated by naloxone on day 15 and the withdrawal manifestations were scored on a weighted basis for mild, moderate, and severe signs. The mild withdrawal signs were significantly decreased by cytarabine and tetracyline whereas the other combination‐treated groups were only slightly decreased. The moderate and serve withdrawal signs for all combination‐treated groups were significantly suppressed compared to the morphine‐treated group. Therefore, attenuation of the morphine withdrawal syndrome by these protein/nucleic acid synthesis inhibitors supports an involvement of macromolecules in the development of physical dependence.
Prevention of “learned helplessness” in the rat by hydroxyzine
Authors: Porsolt Roger D. , Martin Patrick , Lenégre Antoine , Fromage Sylvie , Giurgea Corneliu E.
Published: January 2005

The effects of hydroxyzine (8, 16, and 32 mg/kg i.p.), administered either 30 min before exposing rats to a series of inescapable shocks (preventive treatment) or during the subsequent acquisition of a shuttle box avoidance response (curative treatment), wereinvestigated. In these conditions untreated rats, previously exposed to inescapable shocks (“stress” ), show a marked increase in escape failures in the shuttle box when compared with nonshocked control animals (“ learned helplessness” ). Control experiments examined the effects of hydroxyzine on memory (passive avoidance test) and on electric shock sensitivity. Diazepam (2 mg/kg i.p.) was used as a reference compound. Hydroxyzine, when administered before “ stress,” clearly decreased at 8 and 32 mg/kg the number of escape failures observed but was without effect when administered after “stress” during the subsequent shuttle box avoidance learning. Similar results were observed with diazepam. Unlike diazepam, hydroxyzine at 32 mg/kg−1 induced no amnesia in the passive avoidance test, whereas clear amnesia was observed with diazepam. Neither compound altered the rats' sensitivity to shock. These results suggest that hydroxyzine decreases the effects of “ stress” and that these effects cannot be attributed either to impaired memory for the aversive stimulation or to diminished shock sensitivity.