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1.
Pharmacol Biochem Behav ; 209: 173257, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418452

RESUMO

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.

2.
J Gastroenterol Hepatol ; 31(6): 1147-53, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26574143

RESUMO

BACKGROUND AND AIM: Inflammatory bowel disease is associated with chronic abdominal pain. Transient receptor potential ankyrin 1 (TRPA1) is a well-known pain sensor expressed in primary sensory neurons. Recent studies indicate that reactive oxygen species such as hydrogen peroxide (H2 O2 ) may activate TRPA1. METHODS: Colonic inflammation was induced by intra-colonic administration of trinitrobenzene sulfate (TNBS) in adult male Sprague-Dawley rats. Visceromotor response (VMR) to colorectal distention (CRD) was recorded to evaluate the visceral hyperalgesia. Rats were sacrificed 1 day after treatment with saline or TNBS; colonic tissues from the inflamed region were removed and then processed to assess the H2 O2 content. H2 O2 scavenger N-acetyl-l-cysteine or a TRPA1 antagonist, HC-030031, was intravenously administrated to the TNBS-treated rats or saline-treated rats. In a parallel experiment, intra-colonic H2 O2 -induced visceral hyperalgesia in naïve rats and the effect of intravenous HC-030031 were measured based on the VMR to CRD. RESULTS: Trinitrobenzene sulfate treatment resulted in significant increase in VMR to CRD at day 1. The H2 O2 content in the inflamed region of the colon in TNBS-treated rats was significantly higher than that of saline-treated rats. N-acetyl-l-cysteine or HC-030031 significantly suppressed the enhanced VMR in TNBS-treated rats while saline-treated rats remained unaffected. Moreover, blockade of TRPA1 activation by HC-030031 significantly reversed the exogenous H2 O2 -induced visceral hyperalgesia. CONCLUSION: These results suggest that H2 O2 content of the colonic tissue is increased in the early stage of TNBS-induced colitis. The increased H2 O2 content may contribute to the visceral hyperalgesia by activating TRPA1.


Assuntos
Dor Abdominal/metabolismo , Colite/metabolismo , Colo/metabolismo , Peróxido de Hidrogênio/metabolismo , Hiperalgesia/induzido quimicamente , Canais de Cátion TRPV/metabolismo , Ácido Trinitrobenzenossulfônico , Dor Visceral/metabolismo , Dor Abdominal/induzido quimicamente , Dor Abdominal/fisiopatologia , Dor Abdominal/prevenção & controle , Acetanilidas/administração & dosagem , Acetilcisteína/administração & dosagem , Administração Intravenosa , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/fisiopatologia , Colo/inervação , Modelos Animais de Doenças , Sequestradores de Radicais Livres/administração & dosagem , Peróxido de Hidrogênio/administração & dosagem , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Limiar da Dor , Purinas/administração & dosagem , Ratos Sprague-Dawley , Transdução de Sinais , Canais de Cátion TRPV/antagonistas & inibidores , Fatores de Tempo , Regulação para Cima , Dor Visceral/induzido quimicamente , Dor Visceral/fisiopatologia , Dor Visceral/prevenção & controle
3.
J Exp Neurosci ; 9: 27-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25987850

RESUMO

In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or ß-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by µ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety.

4.
Behav Pharmacol ; 25(2): 158-65, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24557322

RESUMO

We investigated whether pretreatment with the neurotransmitter/neuromodulator agmatine (decarboxylated L-arginine) affected methamphetamine (METH)-induced hyperlocomotion and stereotypy in male ICR mice. Agmatine pretreatment alone had no effects on locomotion or stereotypy, but it produced a dose-dependent attenuation of locomotion and the total incidence of stereotyped behavior induced by a low dose of METH (5 mg/kg). The stereotypy induced by this dose was predominantly characterized by stereotyped sniffing. By contrast, agmatine did not affect the total incidence of stereotypy induced by a higher dose of METH (10 mg/kg). However, the nature of stereotypy induced by this dose of METH was substantially altered; agmatine pretreatment significantly reduced stereotyped biting but significantly increased stereotyped sniffing and persistent locomotion. Agmatine pretreatment therefore appears to produce a rightward shift in the dose-response curve for METH. Pretreatment of mice with piperazine-1-carboxamidine (a putative agmatinase inhibitor) had no effect on locomotion or stereotypy induced by a low dose of METH, suggesting that endogenous agmatine may not regulate the METH action.


Assuntos
Agmatina/farmacologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Neurotransmissores/farmacologia , Agitação Psicomotora/tratamento farmacológico , Comportamento Estereotipado/efeitos dos fármacos , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Piperazinas/farmacologia , Agitação Psicomotora/etiologia , Fatores de Tempo , Ureo-Hidrolases/antagonistas & inibidores
5.
Brain Res ; 1522: 88-98, 2013 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-23727404

RESUMO

We investigated whether pretreatment with opioid receptor antagonists affected methamphetamine (METH)-induced stereotypy in mice. Pretreatment of male ICR mice with naloxone, a relatively non-selective opioid receptor antagonist, significantly attenuated the total incidence of METH-induced stereotypical behavior compared with saline vehicle-pretreated subjects. Furthermore, the distribution of METH-induced stereotypical behavior was affected by naloxone administration. Thus, METH-induced stereotypical sniffing and persistent locomotion were significantly increased by naloxone treatment while stereotypical biting was reduced. One way to interpret this pattern of effects is that pretreatment with naloxone appeared to produce a shift in the dose-response curve for METH. Thus, while the more intense forms of oral-facial stereotypies were reduced, increased persistent locomotion was observed in mice given naloxone followed by METH. The selective µ opioid receptor antagonist ß-funaltrexamine, but not nor-binaltorphimine (a κ-selective antagonist) nor naltrindole (a δ-selective antagonist), mimicked the effect of naloxone. These observations suggest that opioid receptor antagonists may attenuate METH-induced stereotypical biting in mice via µ opioid receptors, and suggest that antagonism of this system may be a potential therapeutic approach to reducing some deleterious effects of METH use and perhaps in the treatment of some forms of self-injurious behavior.


Assuntos
Comportamento Animal/efeitos dos fármacos , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Comportamento Estereotipado/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/efeitos adversos , Masculino , Metanfetamina/efeitos adversos , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/farmacologia
6.
Brain Res ; 1482: 40-6, 2012 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-22981417

RESUMO

Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific σ receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative σ(1) receptor agonist) and partially by PB 28 (a putative σ(2) receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative σ(1) receptor antagonist), but not SM-21, a putative σ(2) receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective κ-agonist), suggesting that the STR may be mediated by activation of opioid receptor system.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Metanfetamina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Pirimidinas/farmacologia , Reflexo/efeitos dos fármacos , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Analgésicos não Narcóticos/farmacologia , Animais , Antipsicóticos , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos , Morfina/farmacologia , Naloxona/farmacologia , Entorpecentes/farmacologia , Fenazocina/análogos & derivados , Fenazocina/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inibidores , Cauda/efeitos dos fármacos , Fatores de Tempo
7.
Brain Res ; 1439: 15-26, 2012 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-22265332

RESUMO

Nomifensine is a dopamine/norepinephrine reuptake inhibitor. Nomifensine and some of its structural analogues produce behavioral effects indicative of indirect dopaminergic agonist properties, such as hyperlocomotion. By contrast, the deaminated and demethylated nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) is reported to have amphetamine-antagonistic properties, as demonstrated by inhibition of methamphetamine (METH)-induced dopamine release in the nucleus accumbens and METH-induced hyperlocomotion in rats. In the present study, we examined the effect of PTIQ (10mg/kg, i.p.) and nomifensine (3mg/kg, i.p.) on METH (5 or 10mg/kg, i.p.)-induced stereotypical behavior in mice in order to determine whether PTIQ and nomifensine inhibit and augment, respectively, METH-induced stereotypical behavior. Unexpectedly, our observations demonstrated that both PTIQ and nomifensine significantly augmented METH-induced stereotypical behavior and locomotion in mice. This augmentation is likely the result of additive effects on dopaminergic function by METH in combination with PTIQ or nomifensine. These results suggest that, contrary to some reports, PTIQ may display dopaminergic agonist properties in mice.


Assuntos
Dopaminérgicos/farmacologia , Metanfetamina/farmacologia , Nomifensina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Análise de Variância , Animais , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/administração & dosagem , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Distribuição Aleatória
8.
Neurochem Res ; 36(10): 1824-33, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21573995

RESUMO

The effects of the histamine H(3) receptor agonists (R)-α-methylhistamine, imetit and immepip on methamphetamine (METH)-induced stereotypical behavior were examined in mice. The administration of METH (10 mg/kg, i.p.) to male ddY mice induced behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing (1.9%), circling (1.7%), sniffing (14.3%), and biting (82.1%). Pretreatment with (R)-α-methylhistamine (3 and 10 mg/kg, i.p.) significantly decreased stereotypical sniffing, but increased stereotypical biting induced by METH, in a dose-dependent manner. This effect of (R)-α-methylhistamine on behavior was mimicked by imetit or immepip (brain-penetrating selective histamine H(3) receptor agonists; 10 mg/kg, i.p. for each drug). Hypothalamic histamine levels 1 h after METH challenge were significantly increased in mice pretreated with saline. These increases in histamine levels were significantly decreased by pretreatment with histamine H(3) receptor agonists, effects which would appear to underlie the shift from METH-induced stereotypical sniffing to biting.


Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Metanfetamina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Imidazóis/farmacologia , Masculino , Metilistaminas/farmacologia , Camundongos , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacologia , Distribuição Aleatória , Tioureia/análogos & derivados , Tioureia/farmacologia
9.
Neurochem Res ; 35(5): 749-60, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20148307

RESUMO

A variety of drug treatment regimens have been proposed to model the dysphoric state observed during methamphetamine (METH) withdrawal in rats, but little has been established in experiments using mice. In male ICR mice, a fixed-dose injection regimen of METH (1.0 or 2.5 mg/kg, i.p., twice daily for 10 consecutive days) induced a significant decrease in the time spent in open arms in an elevated plus maze after 5 days of drug abstinence. Under an escalating-dose injection regimen (0.2-2.0 mg/kg, i.p., 3 times daily for 4 days, total: 15 mg/kg/animal) or continuous subcutaneous administration with osmotic mini-pumps (15 or 76 mg/kg of METH for 2 weeks), no significant behavioral change was observed after 5 days of drug abstinence, compared with control animals. Reduced gains in body weight were observed during repeated treatment with METH in the fixed-dose injection and mini-pump treatment regimens, but not the escalating-dose injection regimen. HPLC analysis revealed significant decreases in the level of cerebral 3-methoxy-4-hydroxyphenylglycol, a norepinephrine metabolite, and norepinephrine turnover, which may be attributed to the expression of anxiety-related behavior in the elevated plus maze. These observations suggest that the mice treated with a fixed-dose of METH may model the anxiety-related behavior observed in the dysphoric state induced by METH withdrawal in humans.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Metanfetamina/efeitos adversos , Metoxi-Hidroxifenilglicol/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Química Encefálica/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Metanfetamina/administração & dosagem , Camundongos , Camundongos Endogâmicos ICR
10.
Pharmacol Biochem Behav ; 94(3): 464-70, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19895842

RESUMO

The administration of methamphetamine (METH; 10mg/kg, i.p.) to male ICR mice induced bizarre behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing, circling, sniffing, and biting. Pretreatment with l-histidine (750 mg/kg, i.p.) significantly decreased the stereotypical biting induced by METH and significantly increased persistent locomotion. This effect of l-histidine on behavior was completely abolished by simultaneous administration of pyrilamine or ketotifen (brain-penetrating histamine H(1) receptor antagonists; 10mg/kg each, i.p.), but not by the administration of fexofenadine (a non-sedating histamine H(1) receptor antagonist that does not cross the blood-brain barrier; 20mg/kg), zolantidine (a brain-penetrating histamine H(2) receptor antagonist; 10mg/kg), thioperamide, or clobenpropit (brain-penetrating histamine H(3) receptor antagonists; 10mg/kg each). The histamine content of the hypothalamus was significantly increased by l-histidine treatment. These data suggest that l-histidine modifies the effects of METH through central histamine H(1) receptors.


Assuntos
Mordeduras e Picadas , Histidina/farmacologia , Locomoção/efeitos dos fármacos , Metanfetamina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Histamina/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Metilistaminas/metabolismo , Camundongos , Camundongos Endogâmicos ICR
11.
J Psychopharmacol ; 21(7): 757-67, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17606472

RESUMO

Although the mechanism of action of acetaminophen (AAP) is not fully understood, some studies suggest that AAP and phenacetin (PHE) are selective cyclooxygenase (COX)-3 inhibitors. To examine the participation of COX-3 in memory formation, water maze performance was studied in mice treated with AAP, PHE or other COX inhibitors. Mice received intraperitoneal injections of drugs immediately after each training session. Administration of high-dose AAP [302.3 mg/kg (IC50 for COX-2)] or PHE [179.2 mg/kg (IC50 for COX-2)] and of non-specific (indomethacin: 20 mg/kg) or specific COX-2 (NS-398: 10 mg/kg) inhibitor impaired the performance in hidden platform (HP) not visible platform (VP) tasks, whereas low-dose (15.1 mg/kg) AAP facilitated performance in HP and VP tasks. The facilitation of performance by low-dose AAP was reversed by co-administration with a 5-HT(1/2) receptor antagonist (methysergide: 0.47 mg/kg). The middle-dose [69.5 mg/kg (IC50 for COX-3)] of AAP, the PHE [17.9 mg/kg (IC50 for COX-3)] and a specific COX-1 inhibitor (piroxicam: 10-20 mg/kg) did not influence performance in either task. These results suggest that the memory impairment by high-dose AAP and PHE and facilitation of performance by low-dose AAP could involve endogenous COX-2 and serotonergic neuronal activity, but not COX-3, respectively.


Assuntos
Acetaminofen/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/fisiologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Acetaminofen/administração & dosagem , Animais , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/administração & dosagem , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Injeções Intraperitoneais , Masculino , Memória/efeitos dos fármacos , Metisergida/farmacologia , Camundongos , Fenacetina/administração & dosagem , Fenacetina/farmacologia , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia
12.
Eur J Pharmacol ; 560(1): 36-41, 2007 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-17303115

RESUMO

In this study, we investigated the effect of administration of inhibitors of each of the arachidonic acid metabolism pathways and the effect of co-administration of these inhibitors with NC-1900, a fragment analog of arginine vasopressin, on step-through passive avoidance task performance. All drugs were administered just after the acquisition trial in the passive avoidance task. Intracerebroventricular (i.c.v.) administration of nordihydroguaiaretic acid (NDGA, 1 and 10 microg), a phospholipase A2 (PLA2) and lipoxygenase (LOX) inhibitor, and of arachidonyl trifluoromethyl ketone (ATK, 1 and 10 microg), a specific PLA2 inhibitor caused reductions in latency on the retention trial. The i.c.v. administration of either of baicalein (0.1-10 microg), a 12-LOX inhibitor, or AA-861 (0.1-10 microg), a 5-LOX inhibitor, did not influence the latency. Intraperitoneal administration of indomethacin (20 mg/kg), a non-specific COX inhibitor, or NS-398 (10 mg/kg), a specific COX-2 inhibitor, impaired performance on the retention trial in the task, while piroxicam (20 mg/kg), a specific COX-1 inhibitor, did not. Subcutaneous administration of NC-1900 (0.1 ng/kg) ameliorated the reduction of latency caused by NDGA, ATK, indomethacin, or NS-398. These results suggested that the COX-2 pathway of arachidonic acid metabolism may be important for learning and/or memory in the passive avoidance task in mice, and that the ameliorating effect of NC-1900, in part, is due to mimicking of the effects of metabolites of the COX-2 pathway.


Assuntos
Amnésia/tratamento farmacológico , Ácido Araquidônico/metabolismo , Aprendizagem da Esquiva/efeitos dos fármacos , Memória/efeitos dos fármacos , Oligopeptídeos/farmacologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Amnésia/induzido quimicamente , Animais , Ácido Araquidônico/antagonistas & inibidores , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/fisiologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Camundongos , Oligopeptídeos/uso terapêutico , Ácido Pirrolidonocarboxílico/farmacologia , Ácido Pirrolidonocarboxílico/uso terapêutico
13.
J Pharmacol Sci ; 102(3): 296-304, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17072101

RESUMO

We characterized [methyl-(3)H]thymidine ([(3)H]thymidine) and [5-(3)H]uridine ([(3)H]uridine) incorporation into cultured astrocytes and neurons in the presence and absence of hydrogen peroxide (H2O2) in order to define the response to oxidative stress in the central nervous system. [(3)H]Thymidine incorporation into cultured astrocytes was remarkably decreased by N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP), a permeable analogue of cAMP, which induced a morphological change from the polygonal form (undifferentiated astrocytes) to the process-bearing one (differentiated astrocytes). H2O2 induced [(3)H]thymidine, but not [(3)H]uridine, incorporation into cultured astrocytes at only an early time from 24 h after DBcAMP treatment, although the absolute quantities of [(3)H]thymidine incorporation into astrocytes pretreated with DBcAMP were less than those into astrocytes pretreated without DBcAMP. Hydroxyurea, a replicative DNA synthesis inhibitor, suppressed dose-dependently and completely [(3)H]thymidine incorporation into astrocytes pretreated without DBcAMP, but not astrocytes pretreated with DBcAMP. H2O2 did not stimulate [(3)H]thymidine or [(3)H]uridine incorporation into astrocytes pretreated without DBcAMP and neurons. These findings indicate that only astrocytes pretreated with DBcAMP are able to increase thymidine incorporation specifically in the presence of H2O2 for a purpose other than proliferation, including the repair of H2O2-induced DNA injury, for example.


Assuntos
Astrócitos/metabolismo , Peróxido de Hidrogênio/farmacologia , Timidina/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Bucladesina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Hidroxiureia/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Uridina/metabolismo
14.
Peptides ; 26(5): 893-7, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15808920

RESUMO

To examine the relationship between glutamate receptors and the action of NC-1900 on a step-through passive avoidance (PA) task in mice, MK-801, an NMDA receptor blocker, and (S)-4-carboxyphenylglycine (4CPG), a group I metabotropic receptor antagonist, were administered intraventricularly (i.c.v.) singly or as co-injections. The i.c.v. injection of MK-801 (0.8 microg) or 4CPG (2 microg) decreased the latency on the PA task. NC-1900 (1 ng/kg, subcutaneously (s.c.)) alone prolonged the latency on the retention trial in the PA task. MK-801 (0.2 and 0.8 microg) or 4CPG (0.5 and 2 microg) significantly inhibited the action of NC-1900, while the s.c. injection of NC-1900 did not affect latency in mice that received i.c.v. co-injection of MK-801 and 4CPG at any of the doses tested. These results suggest that glutamate receptors participate in the action of NC-1900 on learning and memory in PA task performance.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memória/efeitos dos fármacos , Oligopeptídeos/antagonistas & inibidores , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Benzoatos/farmacologia , Maleato de Dizocilpina/farmacologia , Ácido Glutâmico/fisiologia , Glicina/análogos & derivados , Glicina/farmacologia , Masculino , Camundongos , N-Metilaspartato/farmacologia , Ácido Pirrolidonocarboxílico/antagonistas & inibidores , Receptores de Glutamato/efeitos dos fármacos , Vasopressinas/antagonistas & inibidores
15.
J Pharmacol Sci ; 97(3): 437-42, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15764838

RESUMO

To examine the effect of the arginine-vasopressin fragment, [pGlu(4),Cyt(6)]AVP((4-9)) (AVP4-9), on group II metabotropic glutamate receptor (mGluR2/3) agonist and antagonist induced impairment of passive avoidance (PA) task performance, AVP4-9 or phorbol 12-myristate 13-acetate (PMA) was administered in the presence of mGluR2/3-related drugs that induced the impairment of the step-through-type PA task performance. The PA task performance was evaluated in terms of the latency (the time that elapsed prior to entry into the dark compartment) at 24 h after the electrical stimulation. The subcutaneous injection of AVP4-9 at 1 mug/kg had the greatest facilitative effect on the performance, and the facilitative effect of AVP4-9 was inhibited by NPC-15437, a specific protein kinase C (PKC) inhibitor. The injection of AVP4-9 ameliorated PA task performance impairment induced by DCG-IV, an mGluR2/3 agonist. Intracisternal injection of PMA, a PKC activator, also ameliorated the DCG-IV-induced impairment. High doses of AVP4-9 exacerbated the PA task performance impairment induced by LY341495 (an mGluR2/3 antagonist), and PMA injection (1 mug) also exacerbated the impairment induced by the antagonist. These results suggest that an increase in the activity of the PKC-signaling pathway may not always facilitate PA task performance; therefore, AVP4-9 can either enhance or inhibit memory performance in mice.


Assuntos
Aminoácidos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memória/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Análise e Desempenho de Tarefas , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos , Piperidinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Tempo de Reação/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores
16.
Peptides ; 25(7): 1139-46, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15245873

RESUMO

In order to determine the mechanism of action of a new AVP(4-9) analog, NC-1900, on memory processes, memory retention and retrieval tests were conducted in a step-through passive avoidance (PA) task in mice. The administration of NC-1900 facilitated memory retention and retrieval in the PA task through vasopressin1A (V1A) receptors but not V2 receptors. The effect of NC-1900 on memory retention test performance appeared to be due to activation of the protein kinase C (PKC) signaling pathway via V1A receptors; however, the modulation of PKC was not essential for the facilitative effect of the new peptide in the retrieval test. The facilitation of memory retrieval by NC-1900 may also be mediated by other non-PKC-dependent signaling pathways, such as the phospholipase C-inositol trisphosphate pathway.


Assuntos
Arginina Vasopressina/análogos & derivados , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Oligopeptídeos/farmacologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/farmacologia , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Oligopeptídeos/administração & dosagem , Ésteres de Forbol/farmacologia , Piperidinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ácido Pirrolidonocarboxílico/administração & dosagem , Receptores de Vasopressinas/metabolismo , Estimulação Química , Acetato de Tetradecanoilforbol/farmacologia
17.
Pharmacol Biochem Behav ; 78(2): 309-17, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15219772

RESUMO

In the present study, we investigated the facilitative effect of NC-1900, a new arginine vasopressin (AVP(1-9)) fragment analog, on memory performance in eight-arm radial maze or passive avoidance (PA) tasks in nonamnesic and amnesic (PA tasks only) mice. In the radial maze, all injections (subcutaneous) were given daily 60 min before each trail. NC-1900 (1 ng/kg)-treated animals showed enhancement of performance, and AVP(4-9) (1 microg/kg), an AVP(1-9) fragment, had similar effects, although the effective dose was 1000-fold higher. In the PA task, all drugs were administrated subcutaneously 60 min before the acquisition trial (Acq.), and the amnesic mice were exposed to CO(2) just after the Acq. NC-1900 (1 ng/kg) enhanced the memory performance of nonamnesic mice and ameliorated CO(2)-induced amnesia. AVP(4-9) (1 microg/kg) had a similar effect, although only at higher doses, while AVP(1-9) (0.1-1 microg/kg) had no effect. The facilitating effect of NC-1900 on nonamnesic mice was inhibited by coinjection [Pmp(1)-Tyr(Me)(2)]-AVP (Pmp,Tyr-AVP; 1 microg/kg), a V(1A) antagonist, but not by OPC-31260, a vasopressin(2) (V(2)) antagonist. The effect of NC-1900 on CO(2)-induced amnesia was also decreased by coinjection of Pmp,Tyr-AVP or [deamino-Pen(1), Me-Tyr(2)]-AVP (10 microg/kg), both of which are V(1) antagonists. These results suggested that NC-1900 has a more potent effect on facilitation of memory via the V(1A) receptor than AVP(4-9) in non- and CO(2)-amnesic conditions.


Assuntos
Amnésia/tratamento farmacológico , Dióxido de Carbono/toxicidade , Memória/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/farmacologia , Vasopressinas/farmacologia , Amnésia/induzido quimicamente , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Oligopeptídeos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Ácido Pirrolidonocarboxílico/uso terapêutico , Vasopressinas/química , Vasopressinas/uso terapêutico
18.
Behav Brain Res ; 150(1-2): 33-42, 2004 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-15033277

RESUMO

There is increasing evidence that ovarian steroids and calcium ions are involved in learning and memory. To examine the effect of ovarian steroids on learning and memory under a low-calcium condition, middle-aged female rats were fed either a low-calcium (0.02% Ca) or a normal-calcium (1.25% Ca) diet. All rats were ovariectomized (OVX), and these animals were divided into eight groups: 1) an OVX group with a normal-calcium diet (OVX-normal-Ca group), 2) an OVX group with 17beta-estradiol treatment and a normal-calcium diet (E2 group), 3) an OVX with progesterone treatment and a normal-calcium diet (P4 group), 4) an OVX with 17beta-estradiol and progesterone treatments and a normal-calcium diet (E2 + P4 group), 5) an OVX group with a low-calcium diet (OVX-low-Ca group), 6) an OVX group with 17beta-estradiol treatment and a low-calcium diet (LE2 group), 7) an OVX group with progesterone treatment and a low-calcium diet (LP4 group), and 8) an OVX group with 17beta-estradiol and progesterone treatments and a low-calcium diet (LE2 + LP4). Seventy-seven days after the OVX operation, the learning and memory abilities of the rats were examined by using an eight-arm radial maze task. E2 and E2 + P4 groups learned in fewer trials, and performed better in the radial maze and the working memory task than the other groups under the normal-calcium condition. Rats in the LE2 group learned in fewer trials, and performed better in the maze and working memory task than the other low-calcium groups, but in combination with progesterone under the low-calcium condition (LE2 + LP4 group), the facilitative effect of estradiol in all the tasks was inhibited. Treatment with progesterone alone did not inhibit the learning and memory task performance. These results suggest the possibility that treatment with estradiol under low-calcium conditions cannot improve impaired learning and memory when progesterone is applied simultaneously, and that the intake of adequate calcium may be necessary and effective for patients with learning and memory hypofunction receiving hormone replacement therapy.


Assuntos
Cálcio na Dieta , Cálcio/deficiência , Estradiol/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Progesterona/farmacologia , Animais , Feminino , Memória/fisiologia , Ovariectomia , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar
19.
Physiol Behav ; 80(5): 747-58, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14984810

RESUMO

The cAMP/protein kinase A signaling pathway is negatively modulated by group II metabotropic glutamate receptors (mGluRs), and the cross-talk that occurs between these receptors may modulate learning and memory. To examine the relationship among cAMP/PKA-signaling pathway activity, group II mGluRs, and learning and memory, mice were trained to perform a step-through-type passive avoidance task, and 10 min before each avoidance trial the following drugs were injected intracisternally (i.cist.): vehicle (0.05% dimethylsulfoxide); a specific group II mGluR agonist, DCG-IV (1-50 ng/mouse); a specific group II mGluR antagonist, LY341495 (10-300 ng); a selective inhibitor of cAMP-specific phosphodiesterase, rolipram (100-1000 ng); an activator of adenylyl cyclase, forskolin (25-250 ng); a specific inhibitor of PKA, H-89 (150 or 300 ng) or; an activator of protein kinase C, phorbol 12-myristate 13-acetate (PMA 200 ng). DCG-IV (25 and 50 ng) or LY341495 (150 and 300 ng) reduced the latency in the avoidance task. The reduction of latency by DCG-IV was not observed in mice coinjected with DCG-IV (50 ng) together with rolipram (500 ng) or forskolin (25 ng). Conversely, coinjection of LY341495 with 100 or 1000 ng rolipram, or with 25 or 250 ng forskolin tended to potentiate the LY341495-induced shortening of latency. In addition, the reduction of latency by DCG-IV (50 ng) was not observed in mice coinjected with DCG-IV and PMA together. However, the reduction of latency by LY341495 (300 ng) was potentiated when the drug was coadministered with PMA. These results suggest that changes in the cAMP/PKA-signaling pathway, mediated by group II mGluRs, influence memory in the passive avoidance task, and that both the excessive activation and deactivation of this pathway may induce the impairment of learning and memory.


Assuntos
Aminoácidos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Ciclopropanos/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Memória/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas , Xantenos/farmacologia , Animais , Anticonvulsivantes/farmacologia , Colforsina/farmacologia , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Isoquinolinas/farmacologia , Masculino , Camundongos , Tempo de Reação/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Rolipram/farmacologia , Acetato de Tetradecanoilforbol/farmacologia
20.
Pharmacol Res ; 49(2): 151-9, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14643695

RESUMO

Inhibition of sodium-potassium adenosine 5'-triphosphatase ((Na(+), K(+))-ATPase) activity causes edema and cell death in the central nervous system, and impairment of learning and memory. Several sex steroid hormones have a protective effect against neuronal cell damage and the hypofunction of learning and memory. To examine the possible roles and mechanism of action of steroid hormones against amnesia induced by ouabain, an inhibitor of (Na(+), K(+))-ATPase, gonadectomized male mice were administrated ouabain (0.1 microg per mouse) intracisternally (i.cist.), and the learning and memory abilities of the mice were assessed by a step-through passive avoidance task. Subcutaneous (s.c.) administration of 17beta-estradiol (betaE2; 10 microg kg(-1)) or testosterone (TES; 1 mg kg(-1)) improved the memory impairment induced by ouabain, while administration of dihydrotestosterone (1 mg kg(-1)) or corticosterone (COR) (1 mg kg(-1)) did not. Treatment with the estradiol receptor antagonists, tamoxifen (TAM) (10 mg kg(-1); s.c. or 0.1 microg; i.cist.) and 4-hydroxytamoxifen (10 mg kg(-1); s.c.), or the androgen receptor antagonist, cyproterone (10 mg kg(-1); s.c. or 1 microg; i.cist.), did not influence the protective effect of betaE2 or TES on ouabain-induced amnesia. Moreover, we studied the effects of several free radical scavengers-17alpha-estradiol (10 microg kg(-1); s.c.), alpha-tocopherol (VE: 200 mg kg(-1); per os (p.o.), ascorbic acid (VC: 200 mg kg(-1); p.o.), or VE+VC (200 mg kg(-1) each; p.o.)-on ouabain-induced amnesia, and compared those effects with that of betaE2. The administration of free radical scavengers had no significant effect on memory impairment. These results indicate that betaE2 and TES ameliorate the amnesia induced by inhibition of (Na(+), K(+))-ATPase activity, and that the protective effect of betaE2 is caused by a non-genomic, rather than a genomic effect or a radical scavenging action. Additionally, the ameliorative effect of TES does not appear to involve free radical scavenging, but its aromatization to estrogen could contribute to the non-genomic action of betaE2.


Assuntos
Amnésia/tratamento farmacológico , Aprendizagem da Esquiva/efeitos dos fármacos , Hormônios Esteroides Gonadais/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Amnésia/induzido quimicamente , Antagonistas de Androgênios/farmacologia , Animais , Castração , Inibidores Enzimáticos/farmacologia , Antagonistas de Estrogênios/farmacologia , Sequestradores de Radicais Livres/farmacologia , Hormônios Esteroides Gonadais/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Ouabaína/farmacologia , Substâncias Protetoras/farmacologia , Fatores de Tempo
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