RESUMO
Activation of sigma1 (σ1) receptors contributes to the behavioral and toxic effects of (-)-cocaine. We studied a key step, the ability of (-)-cocaine to occupy σ1 receptors in vivo, using CD-1(®) mice and the novel radioligand [(125) I]E-N-1-(3'-iodoallyl)-N'-4-(3",4"-dimethoxyphenethyl)-piperazine ([(125) I]E-IA-DM-PE-PIPZE). (-)-Cocaine displayed an ED50 of 68 µmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 µmol/kg for heart, lung, and spleen. For comparison, an ED50 of 26 µmol/kg for (-)-cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [(125) I]3ß-(4-iodophenyl)tropan-2ß-carboxylic acid isopropyl ester ([(125) I]RTI-121) binding. A chief finding is the relatively small potency difference between (-)-cocaine occupancy of σ1 receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (-)-cocaine with σ1 receptors were assessed further using [(125) I]E-IA-DM-PE-PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (-)-Cocaine binding to cerebral σ1 receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E-IA-DM-PE-PIPZE gave an ED50 of 0.23 µmol/kg for occupancy of cerebral σ1 receptors, and a 3.16 µmol/kg (i.p.) dose attenuated (-)-cocaine-induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E-IA-DM-PE-PIPZE is a probable σ1 receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the σ1 and σ2 receptors expressed in CD-1(®) mouse brain.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cocaína/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Receptores sigma/metabolismo , Animais , Autorradiografia , Ligação Competitiva , Cocaína/farmacocinética , Inibidores da Captação de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Receptor Sigma-1RESUMO
Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (σ1) receptors. Selective σ1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity σ1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated σ1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for σ1 sites (Ki 0.46 nM) and 3596-fold selectivity over σ2 sites (Ki 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (Ki >100 µM), and the DAT interaction was weak (Ki 9.0 µM). In vivo, PD144418 bound to central and peripheral σ1 sites in mouse, with an ED50 of 0.22 µmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 µmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 µmol/kg) attenuated cocaine-induced hyperactivity in a dose-dependent manner in mice. There was good correlation (r(2) = 0.88) of hyperactivity reduction with increasing cerebral σ1 receptor occupancy. The behavioral ED50 of 0.79 µmol/kg corresponded to 80% occupancy. Significant σ1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 µmol/kg dose of PD144418.
Assuntos
Cocaína/farmacologia , Isoxazóis/farmacologia , Córtex Motor/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacocinética , Piridinas/farmacologia , Receptores sigma/metabolismo , Animais , Sítios de Ligação , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Cobaias , Hipercinese/metabolismo , Isoxazóis/química , Isoxazóis/farmacocinética , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Córtex Motor/metabolismo , Antagonistas de Entorpecentes/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Piridinas/química , Piridinas/farmacocinética , Receptores sigma/antagonistas & inibidores , Receptores sigma/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Receptor Sigma-1RESUMO
Cocaine functions, in part, through agonist actions at sigma-1 (σ1 ) receptors, while roles played by sigma-2 (σ2 ) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.
Assuntos
Benzamidas/farmacologia , Cocaína/farmacologia , Isoquinolinas/farmacologia , Locomoção/efeitos dos fármacos , Receptores sigma/antagonistas & inibidores , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Ligantes , Camundongos , Ligação Proteica , Receptores sigma/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Receptor Sigma-1RESUMO
Physical inactivity is positively associated with anxiety and depression. Considering physical inactivity, anxiety, and depression each have a genetic basis for inheritance, our lab used artificial selectively bred low-voluntary running (LVR) and wild type (WT) female Wistar rats to test if physical inactivity genes selected over multiple generations would lead to an anxiety or depressive-like phenotype. We performed next generation RNA sequencing and immunoblotting on the dentate gyrus to reveal key biological functions from heritable physical inactivity. LVR rats did not display depressive-like behavior. However, LVR rats did display anxiogenic behavior with gene networks associated with reduced neuronal development, proliferation, and function compared to WT counterparts. Additionally, immunoblotting revealed LVR deficits in neuronal development and function. To our knowledge, this is the first study to show that by selectively breeding for physical inactivity genes, anxiety-like genes were co-selected. The study also reveals molecular insights to the genetic influences that physical inactivity has on anxiety-like behavior.
Assuntos
Ansiedade/genética , Comportamento Sedentário , Seleção Artificial/genética , Animais , Ansiedade/patologia , Ansiedade/fisiopatologia , Giro Denteado , Depressão/genética , Depressão/patologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , RNA-Seq , Ratos , Ratos Wistar , Corrida/fisiologiaRESUMO
Vesicular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline (1) is a potent antagonist at alpha4beta2 * nicotinic acetylcholine receptors, has moderate affinity (K(i)=5.46microM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2-20 of lobeline were synthesized and evaluated for interaction with alpha4beta2 * and alpha7 * neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at alpha7 * nAChRs. Similar to lobeline (K(i)=4nM), sulfonic acid esters had high affinity at alpha4beta2 * (K(i)=5-17nM). Aromatic carboxylic acid ester analogs of lobeline (2-4) were 100-1000-fold less potent than lobeline at alpha4beta2 * nAChRs, whereas aliphatic carboxylic acid ester analogs were 10-100-fold less potent than lobeline at alpha4beta2 *. Two representative lobeline esters, the 10-O-benzoate (2) and the 10-O-benzenesulfonate (10) were evaluated in the (36)Rb(+) efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC(50) values of 0.85microM and 1.60microM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13-45-fold greater potency compared to lobeline) for inhibiting DAT and SERT, respectively, and like lobeline, had moderate affinity (K(i)=1.98-10.8microM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at alpha4beta2 * nAChRs (K(i)=19.3microM) and was equipotent with lobeline, at VMAT2 (K(i)=2.98microM), exhibiting a 6.5-fold selectivity for VMAT2 over alpha4beta2 nAChRs. Thus, esterification of the lobeline molecule may be a useful structural modification for the development of lobeline analogs with improved selectivity at VMAT2.
Assuntos
Ésteres/farmacologia , Lobelina/farmacologia , Neurônios/efeitos dos fármacos , Proteínas de Transporte de Neurotransmissores/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Animais , Ésteres/síntese química , Ésteres/química , Ligantes , Lobelina/síntese química , Lobelina/química , Masculino , Estrutura Molecular , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
RATIONALE: The N-phenylpropyl-N'-substituted piperazines SA-4503 (N-phenylpropyl-N'-(3,4-dimethoxyphenethyl)piperazine) and YZ-185 (N-phenylpropyl-N'-(3-methoxyphenethyl)piperazine) bind to sigma (σ) receptors and block the development of cocaine-induced conditioned place preference at concentrations that inhibit cocaine-induced hyperactivity. YZ-067 (N-phenylpropyl-N'-(4-methoxyphenethyl)piperazine) also binds to sigma receptors and attenuates cocaine-induced hyperactivity in mice. OBJECTIVES: The present study determined the effect of YZ-067 on the development and expression of cocaine (66 µmol/kg or 33 µmol/kg) conditioned place preference (CPP) and locomotor sensitization in mice. RESULTS: YZ-067 (10 or 31.6 µmol/kg) did not have intrinsic effects on place preference or place aversion. Interestingly, the 31.6 µmol/kg YZ-067 dose enhanced the development of cocaine place preference, while 10 µmol/kg YZ-067 attenuated the development of cocaine-induced locomotor sensitization. However, YZ-067 did not alter the expression of cocaine place preference nor cocaine-induced locomotor sensitization. In follow-up studies, YZ-067 did not affect performance in the zero maze or rotarod, indicating that sigma receptors probed by this ligand do not regulate anxiety-like or coordinated motor skill behaviors, respectively. CONCLUSION: Overall, these results are consistent with previous studies demonstrating a role for sigma receptors in the behavioral effects of cocaine. However, the present findings also indicate that N-phenylpropyl-N'-substituted piperazines do not strictly block cocaine's behavioral effects and that sigma receptor may differentially mediate cocaine-induced hyperactivity and place conditioning.
Assuntos
Cocaína/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Piperazinas/metabolismo , Receptores sigma/agonistas , Receptores sigma/metabolismo , Recompensa , Animais , Cocaína/farmacologia , Condicionamento Psicológico/fisiologia , Inibidores da Captação de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologiaRESUMO
Spinal cord injury (SCI) is a deliberating disorder with impairments in locomotor deficits and incapacitating sensory abnormalities. Harpagophytum procumbens (Hp) is a botanical widely used for treating inflammation and pain related to various inflammatory and musculoskeletal conditions. Using a modified rodent contusion model of SCI, we explored the effects of this botanical on locomotor function and responses to mechanical stimuli, and examined possible neurochemical changes associated with SCI-induced allodynia. Following spinal cord contusion at T10 level, Hp (300 mg/kg, p.o.) or vehicle (water) was administered daily starting 24 h post-surgery, and behavioral measurements made every-other day until sacrifice (Day 21). Hp treatment markedly ameliorated the contusion-induced decrease in locomotor function and increased sensitivity to mechanical stimuli. Determination of Iba1 expression in spinal cord tissues indicated microglial infiltration starting 3 days post-injury. SCI results in increased levels of 4-hydroxynonenal, an oxidative stress product and proalgesic, which was diminished at 7 days by treatment with Hp. SCI also enhanced antioxidant heme oxygenase-1 (HO-1) expression. Concurrent studies of cultured murine BV-2 microglial cells revealed that Hp suppressed oxidative/nitrosative stress and inflammatory responses, including production of nitric oxide and reactive oxygen species, phosphorylation of cytosolic phospholipases A2, and upregulation of the antioxidative stress pathway involving the nuclear factor erythroid 2-related factor 2 and HO-1. These results support the use of Hp for management of allodynia by providing resilience against the neuroinflammation and pain associated with SCI and other neuropathological conditions.
Assuntos
Harpagophytum/química , Hiperalgesia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/uso terapêutico , Traumatismos da Medula Espinal/complicações , Aldeídos/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/biossíntese , Heme Oxigenase (Desciclizante)/genética , Hiperalgesia/etiologia , Inflamação , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Ácido Nítrico/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Método Simples-Cego , TatoRESUMO
RATIONALE: Previous research indicates that the selective sigma-1 receptor ligand PD144418 and the selective sigma-2 ligands YUN-252 can inhibit cocaine-induced hyperactivity. The effects of these ligands on other stimulants, such as methamphetamine, have not been reported. OBJECTIVES: The present study examined the effects of PD144418 and YUN-252 pretreatment on methamphetamine-induced hyperactivity after acute treatment. METHODS: Mice (n = 8-14/group) were injected with PD144418 (3.16, 10, or 31.6 µmol/kg), YUN-252 (0.316, 3.16, 31.6 µmol/kg), or saline. After 15 min, mice injected with 2.69 µmol/kg methamphetamine or saline vehicle, where distance traveled during a 60-min period was recorded. Additionally, the effect of PD144418 on the initiation and expression of methamphetamine sensitization was determined by treating mice (n = 8-14/group) with PD144418, methamphetamine or saline repeatedly over a 5-day period, and testing said mice with a challenge dose after a 7-day withdrawal period. RESULTS: Results indicate that both PD144418 and YUN-252, in a dose-dependent manner, attenuated hyperactivity induced by an acute methamphetamine injection. Specifically, 10 µmol/kg or 31.6 µmol/kg of PD144418 and 31 µmol/kg of YUN-252 suppressed methamphetamine-induced hyperactivity. In regard to methamphetamine sensitization, while 10 µmol/kg PD144418 prevented the initiation of methamphetamine sensitization, it did not have an effect on the expression. CONCLUSIONS: Overall, the current results suggest an intriguing potential for this novel sigma receptor ligand as a treatment for the addictive properties of methamphetamine. Future analysis of this novel sigma receptor ligand in assays directly measuring reinforcement properties will be critical.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Isoxazóis/metabolismo , Locomoção/efeitos dos fármacos , Metanfetamina/farmacologia , Piridinas/metabolismo , Receptores sigma/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Isoxazóis/farmacologia , Ligantes , Locomoção/fisiologia , Masculino , Camundongos , Piridinas/farmacologia , Receptores sigma/antagonistas & inibidores , Reforço Psicológico , Receptor Sigma-1RESUMO
Sigma-1 (σ1) receptors have been investigated for their involvement in learning, rewarding and motivational processes. PD144418, a σ1 receptor antagonist, has been found to produce a dose-dependent attenuation of locomotor activity induced by cocaine, and by itself, does not suppress basal locomotor activity in mice. Moreover, PD144418 decreases the motivational effort of a food-reinforced behavior in male rats, without altering appetite or food palatability. It remains unknown whether the PD144418 can alter the motivational effort of a food-reinforced behavior in response to altered energy homeostasis, as is the case under 24â¯-h food deprivation. Additionally, while the previous experiments indicate effects in male rats, there has been no research examining the effects of PD144418, or any other σ1 receptor antagonist, on motivational aspects of feeding in females. The present study examined the effects of PD144418 on motivational aspects of feeding in male and female rats using an operant task under sated or food deprived conditions. Results indicated that when animals are sated, at the highest dose (10⯵mol/kg), under a progressive ratio (PR) reinforcement schedule, PD144418 significantly attenuated the breakpoint and the number of active lever responses for sucrose pellets in both males and females. When animals are in a state of energy deficit, as is the case following 24-hr food deprivation, PD144418 does not alter motivationally driven operant responding as measured by the breakpoint in either sex but does alter the number of earned reinforcers responses in females.
Assuntos
Comportamento Alimentar/fisiologia , Motivação/efeitos dos fármacos , Receptores sigma/metabolismo , Animais , Apetite/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Alimentos , Privação de Alimentos/fisiologia , Isoxazóis/farmacologia , Masculino , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores sigma/antagonistas & inibidores , Esquema de Reforço , Reforço Psicológico , Recompensa , Fatores Sexuais , Receptor Sigma-1RESUMO
Sigma-1 (σ1) receptors have been investigated for their involvement in learning, rewarding and motivational processes, particularly as it relates to substances of abuse. Few studies have examined the effects of σ1 receptor agonists and antagonists on the rewarding and motivational properties of natural reinforcers, such as food. Studies that have investigated σ1 receptor agonists and antagonists has produced conflicting results. σ1 receptor antagonist PD144418 has been found to produce a dose-dependent attenuation of locomotor activity induced by cocaine, and by itself, does not suppress basal locomotor activity in mice. However, its effects on reward and motivation as it relates to food are unknown. The present study examined the involvement of σ1 receptors in mediating the rewarding and motivational properties of food using an operant task. The results indicated that at the highest dose (10 µmol/kg), PD144418 significantly attenuated the number of active lever responses for chow pellets but did not decrease the number of active lever responses for sucrose pellets under a fixed ratio (FR2) schedule of reinforcement. However, under a progressive ratio (PR) reinforcement schedule, 10 µmol/kg of PD14418 significantly reduced the breakpoint, a measure indicative of effort or motivation, for both chow and sucrose pellets. When ad libitum chow or sucrose pellets were made freely available (i.e. no lever press required) inside the operant chamber, 10 µmol/kg, PD144418 did not have an effect on number of pellets consumed. These findings indicate that PD144418 reduces the motivational effort of a food reinforced behavior.
Assuntos
Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Isoxazóis/farmacologia , Piridinas/farmacologia , Receptores sigma/antagonistas & inibidores , Animais , Cocaína/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Motivação/efeitos dos fármacos , Ratos Sprague-Dawley , Reforço Psicológico , Recompensa , Receptor Sigma-1RESUMO
Nicotine evokes dopamine release through activation of nicotinic acetylcholine receptors, and tobacco cigarette smoking is more prevalent among individuals diagnosed with schizophrenia. Blockade of ionotropic glutamate (NMDA) receptors can induce changes in central dopamine and glutamate circuits, which models the symptoms of schizophrenia. The effect of the NMDA receptor antagonist, ketamine, on the effect of nicotine in rat prefrontal cortex was examined using a slice superfusion assay in which cortical slices were preloaded with [(3)H] dopamine. A wide range of ketamine concentrations (0.1-300 microM) did not evoke [(3)H] overflow from slices, indicating that NMDA receptor blockade did not induce dopamine release. Ketamine, at concentrations that model the symptoms of schizophrenia (1-10 microM), augmented the effect of nicotine (1-100 microM) to evoke [(3)H] overflow from slices and decreased the threshold nicotine concentration to evoke [(3)H] overflow. This indicates that NMDA receptor blockade increased the potency and efficacy of nicotine to evoke dopamine release from prefrontal cortex slices, suggesting that ketamine induced hypersensitivity to nicotine. The present results support a role for nicotinic acetylcholine receptors in the pathophysiology and treatment of schizophrenia.
Assuntos
Dopamina/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Ketamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Trítio/metabolismoRESUMO
The symptoms of schizophrenia can be modeled in rats through blockade of ionotropic glutamate receptors, which induces changes in central dopamine circuits. These circuits also contain nicotinic acetylcholine receptors that are activated by nicotine. A role for nicotine in the etiology of schizophrenia is supported by clinical observations of high tobacco use rates in individuals experiencing the psychopathology. The present study investigated the effect of the ionotropic glutamate receptor antagonist ketamine on the function of striatal nicotinic acetylcholine receptors to understand better the potential role of these receptors in schizophrenia. Ketamine (0.1-300 microM) was ineffective to evoke [3H] overflow from rat striatal slices preloaded with [3H]dopamine. Application of psychotomimetic ketamine concentrations (1-10 microM) to striatal slices augmented nicotine-evoked [3H] overflow. Finally, rats received ketamine (30-50 mg/kg) injections for 30 days, to model the development of the disorder, and hyperactivity was observed, although repeated ketamine treatment did not significantly alter nicotine-evoked [3H]dopamine overflow. These data indicate that the function of nicotinic acetylcholine receptors that mediate dopamine release are altered by ketamine, and support a role for nicotinic acetylcholine receptors in schizophrenia pathology.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipercinese/induzido quimicamente , Ketamina/farmacologia , Neostriado/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Dopamina/metabolismo , Dopamina/fisiologia , Relação Dose-Resposta a Droga , Hipercinese/psicologia , Masculino , Atividade Motora/efeitos dos fármacos , Neostriado/citologia , Neostriado/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Ethanol preconditioning (EtOH-PC) refers to a phenomenon in which tissues are protected from the deleterious effects of ischemia/reperfusion (I/R) by prior ingestion of ethanol at low to moderate levels. In this study, we tested whether prior (24 h) administration of ethanol as a single bolus that produced a peak plasma concentration of 42-46 mg/dl in gerbils would offer protective effects against neuronal damage due to cerebral I/R. In addition, we also tested whether reactive oxygen species (ROS) derived from NADPH oxidase played a role as initiators of these putative protective effects. Groups of gerbils were administered either ethanol or the same volume of water by gavage 24 h before transient global cerebral ischemia induced by occlusion of both common carotid arteries for 5 min. In some experiments, apocynin, a specific inhibitor of NADPH oxidase, was administered (5 mg/kg body wt, i.p.) 10 min before ethanol administration. EtOH-PC ameliorated behavioral deficit induced by cerebral I/R and protected the brain against I/R-induced delayed neuronal death, neuronal and dendritic degeneration, oxidative DNA damage, and glial cell activation. These beneficial effects were attenuated by apocynin treatment coincident with ethanol administration. Ethanol ingestion was associated with translocation of the NADPH oxidase subunit p67(phox) from hippocampal cytosol fraction to membrane, increased NADPH oxidase activity in hippocampus within the first hour after gavage, and increased lipid peroxidation (4-hydroxy-2-nonenal) in plasma and hippocampus within the first 2 h after gavage. These effects were also inhibited by concomitant apocynin treatment. Our data are consistent with the hypothesis that antecedent ethanol ingestion at socially relevant levels induces neuroprotective effects in I/R by a mechanism that is triggered by ROS produced through NADPH oxidase. Our results further suggest the possibility that preconditioning with other pharmacological agents that induce a mild oxidative stress may have similar therapeutic value for suppressing stroke-mediated damage in brain.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Etanol/farmacologia , Precondicionamento Isquêmico , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Western Blotting , Isquemia Encefálica/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Gerbillinae , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Peroxidação de Lipídeos , Masculino , NADPH Oxidases/antagonistas & inibidores , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/fisiologia , Transporte Proteico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Traumatismo por Reperfusão/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
Modafinil is a mild psychostimulant used for the treatment of sleep and arousal-related disorders, and has been considered a pharmacotherapy for cocaine and amphetamine dependence; however, modafinil's mechanism of action is largely unclear. The present study investigated modafinil using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64-128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) augmented the discriminative stimulus properties of cocaine (1.6 mg/kg dose group) and amphetamine. In neurochemical experiments, modafinil (100-300 microM) evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. The dopamine transporter inhibitor nomifensine (10 microM) blocked modafinil-evoked [(3)H]overflow, and concentrations of modafinil (<100 microM) that did not have intrinsic activity attenuated amphetamine (1 and 3 microM)-evoked [(3)H]overflow. Modafinil-evoked [(3)H]overflow was not altered by the nicotinic acetylcholine receptor antagonist mecamylamine, and modafinil did not alter nicotine-evoked [(3)H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil's mechanism of action. The present results indicate that modafinil evokes dopamine release from striatal neurons and is a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine.
Assuntos
Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Anfetamina/farmacologia , Animais , Cocaína/farmacologia , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Masculino , Modafinila , Nicotina/farmacologia , Nomifensina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of lobeline and the endogenous opioid system. In guinea pig brain homogenates, lobeline displaced (K(i)=0.74 microM) the binding of [(3)H]DAMGO [(D-Ala(2), N-ME-Phe(4), Gly(5)-ol)-enkephalin]. In a functional assay system comprised of MOR-1 mu opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, lobeline had no effect on the resting current, but maximally inhibited (IC(50)=1.1 microM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, lobeline-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was not blocked by naltrexone. Importantly, concentrations of lobeline (0.1-0.3 microM) that did not have intrinsic activity attenuated ( approximately 50%) morphine-evoked [(3)H]overflow. Overall, the results suggest that lobeline functions as a mu opioid receptor antagonist. The ability of lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and lobeline could be investigated as a treatment for opiate addiction.
Assuntos
Encéfalo/efeitos dos fármacos , Lobelina/farmacologia , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Analgésicos Opioides/farmacocinética , Animais , Ligação Competitiva , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacocinética , Cobaias , Técnicas In Vitro , Mecamilamina/farmacologia , Naltrexona/farmacologia , Nicotina/farmacologia , Oócitos , Ensaio Radioligante , Receptores Opioides/metabolismo , Receptores Opioides mu/metabolismo , Xenopus laevisRESUMO
Nicotine, the main psychoactive ingredient in tobacco, plays a key role in the development of cigarette smoking addiction. The endocannabinoid system has been demonstrated to have an important role in the motivational and reinforcing effects of drugs. The present study used behavioral and neurochemical techniques to study the interaction of cannabinoid receptors and nicotine pharmacology. In a locomotor activity experiment in rats, the CB(1)/CB(2) cannabinoid receptor agonist WIN-55,212-2 (0.28-2.8 mg/kg) attenuated nicotine (0.4 mg/kg)-induced hyperactivity, but did not alter nicotine (1.0 mg/kg)-induced hypoactivity. In contrast, the selective CB(1) cannabinoid receptor antagonist SR-141716A (1.0 mg/kg) diminished nicotine-induced hypoactivity, but did not alter nicotine-induced hyperactivity. In a neurochemical experiment, rat striatal slices preloaded with [(3)H]dopamine were superfused with WIN-55,212-2 or SR-141716A. A high concentration (100 microM) of WIN-55,212-2 evoked [(3)H]overflow, but this effect was not blocked by the cannabinoid receptor antagonist AM-251. SR-141716A did not evoke [(3)H]overflow, and neither WIN-55,212-2 nor SR-141716A altered nicotine-evoked [(3)H]overflow. Overall, these results indicate a behavioral interaction between cannabinoid receptors and nicotine pharmacology. Likely, WIN-55,212-2 and SR-141716A block nicotine-induced changes in behavior through an indirect mechanism, such as alteration in endocannabinoid regulation of motor circuits, rather than directly through blockade of nicotinic acetylcholine receptors.
Assuntos
Analgésicos/farmacologia , Antagonistas de Receptores de Canabinoides , Dopamina/metabolismo , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Naftalenos/farmacologia , Nicotina/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Animais , Benzoxazinas , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , Rimonabanto , TrítioRESUMO
The CB(1) cannabinoid receptor antagonist SR-141716A (Rimonabant) markedly diminishes the behavioral effects of opiates and nicotine and has been an important tool to ascertain the role of cannabinoid receptors in drug addiction. The present goal was to determine the less-explored interaction of SR-141716A and d-amphetamine in neurochemical and behavioral assays. Additionally, the effect of the substituents and substitution patterns on the phenyl ring located at the 5 position of SR-141716A (4-chlorophenyl), and of the CB(1)/CB(2) cannabinoid receptor agonist WIN-55,212-2, was determined. SR-141716A, AM-251 (4-iodophenyl) and NIDA-41020 (4-methoxyphenyl) did not alter amphetamine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine. MRI-8273-30-1 (4-fluorophenyl; 0.1-10 microM) attenuated amphetamine (3 microM)-evoked [(3)H]overflow, and MRI-8273-59 (3,4-dichlorphenyl; 0.01-10 microM) augmented amphetamine (0.3-3 microM)-evoked [(3)H]overflow. WIN-55,212-2 was without effect. In a locomotor activity experiment, SR-141716A and MRI-8273-30-1 did not alter amphetamine-induced hyperactivity. However, MRI-8273-59 (1-3 mg/kg) dose-dependently attenuated amphetamine (1 mg/kg)-induced hyperactivity. The present results suggest that SR-141716A is less efficacious to alter amphetamine effects than its reported efficacy to diminish the effects of opiates and nicotine. Modification of the 5-phenyl position of SR-141716A affords compounds that do interact with amphetamine in vitro and in vivo.
Assuntos
Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Hipercinese/induzido quimicamente , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Cocaína/farmacologia , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Hipercinese/metabolismo , Hipercinese/fisiopatologia , Masculino , Piperidinas/química , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Rimonabanto , Fatores de Tempo , TrítioRESUMO
Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular and plasmalemmal monoamine transporters. Moreover, lobeline has been shown to alter the neurochemical and behavioral effects of psychostimulants. The present study determined the effect of lobeline and drugs selective for nicotinic receptors on the discriminative stimulus properties of low doses of cocaine (1.6 or 5.0 mg/kg) or d-amphetamine (0.3 mg/kg) in rats, using a standard two-lever drug discrimination procedure with food reinforcement. Nicotine substituted for both amphetamine and cocaine. The nicotinic receptor antagonists mecamylamine and hexamethonium did not substitute for or block the cocaine or amphetamine stimulus. In contrast, lobeline substituted for cocaine, but did not substitute for amphetamine. In antagonism tests, lobeline doses that did not substitute for cocaine decreased responding on the cocaine-paired levers. Surprisingly, lobeline did not alter the discriminative stimulus properties of amphetamine. This research further supports the supposition that nicotine, cocaine and amphetamine produce similar, but distinct subjective states. Furthermore, the present findings suggest that lobeline has a complex mechanism of action to disrupt the behavioral effects of drugs of abuse.
Assuntos
Anfetamina/administração & dosagem , Anfetamina/metabolismo , Cocaína/administração & dosagem , Cocaína/metabolismo , Discriminação Psicológica , Lobelina/farmacologia , Entorpecentes/administração & dosagem , Entorpecentes/metabolismo , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Hexametônio/administração & dosagem , Hexametônio/farmacologia , Ligantes , Masculino , Mecamilamina/administração & dosagem , Mecamilamina/farmacologia , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Reforço PsicológicoRESUMO
Lobeline has high affinity for nicotinic receptors and alters presynaptic dopamine storage and release in brain. Moreover, lobeline decreases the reinforcing and locomotor-activating properties of methamphetamine, suggesting that lobeline may be a pharmacotherapy for psychostimulant abuse. This study determined if lobeline alters cocaine-induced hyperactivity and if lobeline alters the induction and/or expression of sensitization to cocaine. On Days 1-12, male rats were administered lobeline (0.3 or 1.0 mg/kg) or saline, placed in an automated activity monitor for 20 min, administered cocaine (10, 20 or 30 mg/kg) or saline and returned to the monitor for 60 min. On Day 13, the effect of lobeline on the induction and expression of sensitization to cocaine was determined. Lobeline did not alter the effect of cocaine after acute injection. However, 1.0 mg/kg lobeline attenuated cocaine (10 and 20 mg/kg)-induced hyperactivity after repeated administration and prevented the development of sensitization to these cocaine doses. Interestingly, 0.3 mg/kg lobeline augmented cocaine (10 mg/kg)-induced hyperactivity after repeated administration. Lobeline did not alter the effect of 30 mg/kg cocaine. The present results indicate a complex interaction of lobeline with cocaine and support other research indicating a role for nicotinic receptors in the development of sensitization to psychostimulants.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/complicações , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cocaína/farmacologia , Lobelina/administração & dosagem , Lobelina/farmacologia , Agitação Psicomotora/tratamento farmacológico , Animais , Esquema de Medicação , Interações Medicamentosas , Masculino , Atividade Motora/efeitos dos fármacos , Agitação Psicomotora/etiologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/fisiologiaRESUMO
This study examined the effect of the N-phenylpropyl-N'-substituted piperazine ligands SA4503 (3.4-dimethoxyphenethyl), YZ-067 (4-methoxyphenethyl), YZ-185 (3-methoxyphenethyl) and Nahas-3h (4-methoxybenzyl) on methamphetamine-induced hyperactivity in mice. In a previous study in rats, SA4503 increased methamphetamine-induced hyperactivity at a lower ligand dose and enhanced it at a higher dose. The other ligands have not been investigated in this assay. Presently, mice were administered sigma ligands, and specific [125I]E-IA-DM-PE-PIPZE and [125I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively. Mice were also administered sigma ligands followed by methamphetamine, and locomotor activity was measured. Each of the ligands occupied σ1 sigma receptors (ED50=0.2-0.6µmol/kg) with similar potency, but none occupied the transporter (ED50>10µmol/kg). At the highest dose tested (31.6µmol/kg) all four sigma ligands significantly attenuated methamphetamine-induced hyperactivity. Interestingly, SA4503, YZ-067 and Nahas-3h, but not YZ-185, enhanced methamphetamine-induced hyperactivity at lower ligand doses (1-3.16µmol/kg). These results suggest that these ligands function as stimulant agonists at lower doses and as antagonists at higher does, with subtle changes in the substitution pattern at the 3- and 4-positions of the phenethyl group contributing to the nature of the interactions. Overall, these data indicate a complex role for σ1 sigma receptor ligands in methamphetamine's behavioral effects.