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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.
Brain Res ; 1740: 146873, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387137

RESUMO

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H3 receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H3 receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H1 receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H1 receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H2 receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H4 receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H3 receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H3 receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H3 receptors, which then bind to the post-synaptic histamine receptor H1 (but not H2 or H4). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Hipercinese/induzido quimicamente , Metanfetamina/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Hipercinese/tratamento farmacológico , Hipercinese/fisiopatologia , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfolinas/administração & dosagem , Piperidinas/administração & dosagem
3.
Curr Drug Res Rev ; 11(2): 85-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31875781

RESUMO

BACKGROUND: The effectiveness of lithium salts in neuropsychiatric disorders such as bipolar disorder, Alzheimer's disease, and treatment-resistant depression has been documented in an extensive scientific literature. Lithium inhibits inositol monophosphatase, inositol polyphosphate 1- phosphatase, and glycogen synthase kinase-3 and decreases expression level of tryptophan hydroxylase 2, conceivably underlying the mood stabilizing effects of lithium, as well as procognitive and neuroprotective effects. However, the exact molecular mechanisms of action of lithium on mood stabilizing and pro-cognitive effects in humans are still largely unknown. OBJECTIVE: On the basis of the known aspects of lithium pharmacology, this review will discuss the possible mechanisms underlying the therapeutic effects of lithium on positive symptoms of methamphetamine abuse and dependence. CONCLUSION: It is possible that lithium treatment reduces the amount of newly synthesized phosphatidylinositol, potentially preventing or reversing neuroadaptations contributing to behavioral sensitization induced by methamphetamine. In addition, it is suggested that exposure to repeated doses of methamphetamine induces hyperactivation of glycogen synthase kinase-3ß in the nucleus accumbens and in dorsal hippocampus, resulting in a long-term alterations in synaptic plasticity underlying behavioral sensitization as well as other behavioral deficits in memory-related behavior. Therefore it is clear that glycogen synthase kinase-3ß inhibitors can be considered as a potential candidate for the treatment of methamphetamine abuse and dependence.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Estimulantes do Sistema Nervoso Central , Compostos de Lítio/farmacologia , Compostos de Lítio/uso terapêutico , Metanfetamina , Animais , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos
4.
Pharmacol Biochem Behav ; 172: 9-16, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30017858

RESUMO

A single administration with morphine (30 mg/kg, i.p.) induced long-lasting hyperlocomotion in male ICR mice. Pretreatment of mice with a benzoquinolizine derivative tetrabenazine (TBZ; a reversible vesicular monoamine transporter-2 inhibitor) (1 mg/kg, i.p.) for 30 min significantly attenuated the hyperlocomotion induced by morphine, as compared with vehicle (saline)-pretreated mice. No significant change in locomotion was observed in mice pretreated with TBZ (1 mg/kg) alone. Mice treated with TBZ (1 mg/kg) showed an increase in immobility time in a tail suspension test, as compared with saline-treated mice. Pretreatment with TBZ (1 mg/kg) had no effect on morphine (1-30 mg/kg)-induced antinociception. TBZ at a dose of 1 mg/kg inhibited dopamine turnover (the ratio of 3,4-dihydroxyphenylacetic acid/dopamine) and 5-hydroxytryptamine turnover (the ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine) in the cerebral cortex of mice challenged with morphine, as compared with saline-pretreated mice challenged with morphine. No stereotypic behavior was observed in mice treated with morphine (30 mg/kg) in combination with TBZ (1 mg/kg), so the reduction in observed locomotion did not result from induction of stereotypical behavior. Moreover, TBZ (1 and 2 mg/kg) pretreatment had no effect on stereotyped behaviors observed in mice challenged with 10 mg/kg methamphetamine. These data support the potential antagonistic actions of TBZ on some opiate actions, and encourage further exploration of potential effects on morphine reinforcement.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Córtex Cerebral/efeitos dos fármacos , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Morfina/farmacologia , Serotonina/metabolismo , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Córtex Cerebral/metabolismo , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos ICR
5.
Biomed Pharmacother ; 100: 116-123, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29427922

RESUMO

A single administration of mice with memantine (1-amino-3,5-dimethyladamantane), a glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, induced stereotyped behaviors in dose- and time-dependent manners. The predominant behavioral component of the stereotypy was a continuous, exaggerated sniffing which was accompanied by persistent locomotion. In contrast, a psychostimulant methamphetamine (METH) predominantly induced a stereotyped biting and other forms of intense stationary stereotypical behaviors. Memantine-induced stereotyped sniffing was attenuated by pretreatment with haloperidol, a dopamine D2 receptor antagonist, in a dose-dependent manner. The memantine-induced stereotyped sniffing was also attenuated by pretreatment with betahistine (2-[2-(methylamino)ethyl]pyridine), an agent which increases histamine turnover and releases histamine in the brain. These observations suggest that memantine might induce stereotypies through neuronal mechanisms that are somewhat different from those of METH, but still overlap to a certain extent, since memantine-induced stereotypies can be attenuated by the mechanisms that also suppress METH-induced stereotypy. Importantly, these data suggests that the effects of memantine may be more limited to the ventral striatum including nucleus accumbens than those of METH, which is associated with dorsal striatal stimulation at high doses. In this respect memantine may also have pharmacological properties such as compartmentation (i.e. brain distribution) and neuronal mechanisms different from those of other NMDA receptor antagonists, such as ketamine, which may have important implications for therapeutic uses of these drugs.


Assuntos
Dopaminérgicos/farmacologia , Memantina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Comportamento Estereotipado/efeitos dos fármacos , Estriado Ventral/efeitos dos fármacos , Animais , Dopaminérgicos/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Memantina/farmacocinética , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/agonistas , Fatores de Tempo , Estriado Ventral/metabolismo
6.
Free Radic Res ; 50(11): 1245-1256, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27629432

RESUMO

Copper/zinc superoxide dismutase (SOD1), a primary anti-oxidative enzyme, protects cells against oxidative stress. We report herein on a comparison of behavioral and neurobiological changes between SOD1 knockout (KO) and wild-type mice, in an attempt to assess the role of SOD1 in brain functions. SOD1 KO mice exhibited impaired motivational behavior in both shuttle-box learning and three-chamber social interaction tests. High levels of dopamine transporter protein and an acceleration of serotonin turnover were also detected in the cerebrums of the SOD1 KO mice. These findings suggest that SOD1 deficiency disturbs monoaminergic neurotransmission leading to a decrease in motivational behavior.


Assuntos
Superóxido Dismutase/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Espécies Reativas de Oxigênio , Estresse Psicológico , Superóxido Dismutase/metabolismo , Transmissão Sináptica
7.
Drug Target Insights ; 10: 1-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26966348

RESUMO

Stereotypical behaviors induced by methamphetamine (METH) overdose are one of the overt symptoms of METH abuse, which can be easily assessed in animal models. Currently, there is no successful treatment for METH overdose. There is increasing evidence that elevated levels of brain histamine can attenuate METH-induced behavioral abnormalities, which might therefore constitute a novel therapeutic treatment for METH abuse and METH overdose. In mammals, histamine N-methyltransferase (HMT) is the sole enzyme responsible for degrading histamine in the brain. Metoprine, one of the most potent HMT inhibitors, can cross the blood-brain barrier and increase brain histamine levels by inhibiting HMT. Consequently, this compound can be a candidate for a prototype of drugs for the treatment of METH overdose.

8.
J Exp Neurosci ; 9(Suppl 1): 1-10, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26525833

RESUMO

Aripiprazole is a third-generation atypical antipsychotic and a dopamine D2 receptor partial agonist. In the present study, we investigated whether a single administration of aripiprazole to mice, either as a pretreatment or as a posttreatment, would affect stereotypy induced by methamphetamine (METH). Pretreatment of male ICR mice with aripiprazole (1 or 10 mg/kg, i.p.) attenuated the incidence of METH-induced stereotypical behavior in a dose-dependent manner. Pretreatment of mice with 1 mg/kg aripiprazole produced an increase in the locomotor activity in mice treated with METH compared with mice treated with vehicle plus METH and with 10 mg/kg aripiprazole plus METH. This increase in locomotion is indicative of a rightward shift in the dose-response curve for METH, consistent with a shift in the type of stereotypical behavior observed from biting to sniffing. Aripiprazole posttreatment, after METH-induced stereotypical behavior, was fully expressed and also significantly attenuated overall stereotypy in an aripiprazole dose-dependent manner. These data suggest that the antagonism of METH effects by aripiprazole should be investigated as a potential treatment for acute METH overdose.

9.
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.

10.
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
11.
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
12.
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
13.
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
14.
Brain Res ; 1429: 155-63, 2012 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-22079320

RESUMO

Repeated intermittent administration of amphetamines acutely increases appetitive and consummatory aspects of motivated behaviors as well as general activity and exploratory behavior, including voluntary running wheel activity. Subsequently, if the drug is withdrawn, the frequency of these behaviors decreases, which is thought to be indicative of dysphoric symptoms associated with amphetamine withdrawal. Such decreases may be observed after chronic treatment or even after single drug administrations. In the present study, the effect of acute methamphetamine (METH) on running wheel activity, horizontal locomotion, appetitive behavior (food access), and consummatory behavior (food and water intake) was investigated in mice. A multi-configuration behavior apparatus designed to monitor the five behaviors was developed, where combined measures were recorded simultaneously. In the first experiment, naïve male ICR mice showed gradually increasing running wheel activity over three consecutive days after exposure to a running wheel, while mice without a running wheel showed gradually decreasing horizontal locomotion, consistent with running wheel activity being a positively motivated form of natural motor activity. In experiment 2, increased horizontal locomotion and food access, and decreased food intake, were observed for the initial 3h after acute METH challenge. Subsequently, during the dark phase period decreased running wheel activity and horizontal locomotion were observed. The reductions in running wheel activity and horizontal locomotion may be indicative of reduced dopaminergic function, although it remains to be seen if these changes may be more pronounced after more prolonged METH treatments.


Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Ritmo Circadiano/efeitos dos fármacos , Metanfetamina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Animais , Escuridão , Luz , Masculino , Camundongos , Camundongos Endogâmicos ICR
15.
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
16.
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
17.
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
18.
Synapse ; 62(9): 689-99, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18566973

RESUMO

Neuronal adaptations have been found to occur in multiple brain regions after chronic intake of abused drugs, and are therefore thought to underlie drug dependence, tolerance, and withdrawal. Pathophysiological changes in drug responsiveness as well as behavioral sequelae of chronic drug exposure are thought to depend largely upon the altered state of heterotrimeric GTP binding protein (G protein)-coupled receptor (GPCR)-G protein interactions. Responsiveness of GPCR-related intracellular signaling systems to drugs of abuse is heterogeneous, depending on the types of intracellular effectors to which the specific Galpha protein subtypes are coupled and GPCR-G protein coupling efficiency, factors influenced by the class of drug, expression levels of G protein subunits, and drug treatment regimens. To enhance understanding of the molecular mechanisms that underlie the development of pathophysiological states resulting from chronic intake of abused drugs, this review focuses on alterations in the expression levels of G protein subunits induced by various drugs of abuse. Changes in these mechanisms appear to be specific to particular drugs of abuse, and specific conditions of drug treatment.


Assuntos
Analgésicos Opioides/farmacologia , Barbitúricos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Química Encefálica/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Tolerância a Medicamentos/fisiologia , Humanos , Síndrome de Abstinência a Substâncias/metabolismo
19.
Neurochem Res ; 33(1): 204-19, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17605106

RESUMO

Chronic abuse of amphetamines, such as d-amphetamine (AMPH) and d-methamphetamine, results in psychological dependence, a condition in which the drug produces a feeling of satisfaction and a drive that requires periodic or continuous administration of the drug to produce overwhelming pleasure or to avoid discomfort such as dysphoria. The dysphoric state of AMPH withdrawal has been recognized as depressive syndromes, such as anhedonia, depression, anxiety, and social inhibition, in early drug abstinence. Medication for treatment of the dysphoric state is important for AMPH abusers to avoid impulsive self-injurious behavior or acts that are committed with unconscious or uncontrolled suicidal ideation. However, successful treatments for AMPH withdrawal remain elusive, since the exact molecular basis of the expression of dysphoria has not been fully elucidated. This review focuses on the molecular aspects of AMPH withdrawal as indexed by neurochemical parameters under a variety of injection regimens (for example, levels of brain monoamines and their metabolites, and gamma-aminobutyric acid, expression of genes and proteins involved in neuronal activity, and monoamine metabolism and availability) in rodent models which exhibit significant phenotypic features relevant to the syndromes of AMPH withdrawal in humans.


Assuntos
Anfetaminas/efeitos adversos , Modelos Animais , Transtornos do Humor/etiologia , Síndrome de Abstinência a Substâncias , Animais , Transtornos do Humor/metabolismo
20.
Pharmacol Biochem Behav ; 87(1): 48-55, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17482247

RESUMO

The effects of topiramate, a structurally novel anticonvulsant, on the methamphetamine (METH)-induced expression of stereotypy and conditioned place preference (CPP) in male ICR mice were investigated. After a single administration of METH (10 mg/kg, i.p.), mice showed stereotyped behaviors with a plateau level 25 min after drug challenge. Pretreatment with topiramate (1, 10, and 100 mg/kg, i.p.) 30 min prior to METH challenge had no effect on the expression frequency of stereotypy, compared with saline challenge. No differential effects of topiramate on METH-induced stereotyped behavior (that is, head-bobbing, circling, continuous sniffing, nail and/or wood-chip biting, and vigorous and compulsive grooming) were observed. In saline-challenged groups, the doses of topiramate examined did not induce any stereotyped behaviors. Although mice showed a significant CPP for METH (0.5 mg/kg, i.p.), pretreatment with subchronic topiramate did not affect the magnitude of CPP. Locomotor activity was not affected by the doses of topiramate tested. Conditioned rewarding or aversive effects of topiramate were not observed as indexed by the place preference procedure. These results suggested the lack of effect of topiramate on METH-induced stereotypy and rewarding property in mice.


Assuntos
Anticonvulsivantes/farmacologia , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Operante/efeitos dos fármacos , Frutose/análogos & derivados , Metanfetamina/antagonistas & inibidores , Metanfetamina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Frutose/farmacologia , Ácido Homovanílico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Recompensa , Topiramato
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