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1.
Pharmacol Biochem Behav ; 204: 173157, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33647274

RESUMO

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (µ), kappa- (κ), and delta- (δ) opioid receptors and functions as a µ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DAext) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DAext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DAext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.


Assuntos
Dopamina/metabolismo , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Anfetamina/farmacologia , Animais , Cocaína/farmacologia , Etanol/farmacologia , Humanos , Masculino , Microdiálise/métodos , Naltrexona/farmacologia , Núcleo Accumbens/metabolismo , Oxicodona/farmacologia , Ratos , Ratos Wistar , Receptores Opioides mu/metabolismo , Autoadministração/métodos
2.
J Alzheimers Dis Rep ; 2(1): 169-179, 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30480260

RESUMO

Strategies to achieve a therapy for Alzheimer's disease (AD) aimed at reducing the effects of amyloid-ß (Aß) have largely involved inhibiting or modifying the activities of the ß- or γ-secretases or by the use of monoclonal antibodies (MAb). We previously offered the potential for a new, early and effective approach for the treatment of AD by a strategy that does not target the secretases. We showed that a family of peptides containing the DEEEDEEL sequence and another independent peptide, all derived from the amino terminus of PS-1, are each capable of markedly reducing the production of Aß in vitro and in mThy1-hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-ß protein precursor (AßPP) and did not affect the catalytic activities of ß- or γ-secretase, or the level of AßPP. Critical to the development of any therapeutic for AD is the requirement that it is stable and can be delivered to the brain. We report here data on the metabolic stability and delivery to the rat brain of our lead candidate P8 by intravenous (IV), intranasal (IN), and subcutaneous (SC) administration. Pharmacokinetics (PK) of P8 in rat plasma and CSF following a single dose of P8 demonstrate that SC administration gives better absorption compared to IN and is the delivery method of choice for the further development of P8 as a clinical candidate.

3.
J Med Chem ; 58(2): 1005-11, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25493909

RESUMO

A leading nicotine conjugate vaccine was only efficacious for one-third of clinical trial participants, likely due in part to its use of racemic nicotine hapten, (±)-3'-AmNic. Immunization of male Wistar rats with (+)-, (-)-, or (±)-3'-AmNicSucTT and subsequent antibody immunoassays suggest that a vaccine using enantiopure (-)-3'-AmNic hapten imparts superior capacity to bind (-)-nicotine. Future nicotine vaccine clinical candidates must incorporate this design consideration (i.e., hapten enantiopurity) in order to maximize efficacy.


Assuntos
Haptenos/imunologia , Nicotina/imunologia , Vacinas Conjugadas/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Masculino , Nicotina/metabolismo , Ratos , Ratos Wistar , Estereoisomerismo
4.
J Pharmacol Exp Ther ; 350(1): 171-80, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24817033

RESUMO

A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-[(4'-trimethylfluoro)benzamido]morphinan-hydrochloride--(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 µg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 µg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development.


Assuntos
Etanol/administração & dosagem , Morfinanos/farmacologia , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Alanina Transaminase/sangue , Alanina Transaminase/efeitos dos fármacos , Animais , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Condicionamento Operante/efeitos dos fármacos , Masculino , Morfinanos/efeitos adversos , Morfinanos/farmacocinética , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos , Antagonistas de Entorpecentes/farmacocinética , Ratos , Ratos Endogâmicos , Autoadministração , Tioamidas/antagonistas & inibidores
5.
Vaccine ; 30(47): 6665-70, 2012 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-22963803

RESUMO

Despite being consistently ranked as the leading cause of preventable death in the United States, about 20% of the population continues to smoke. Current smoking cessation therapies offer limited success, show high rates of relapse, and have potentially dangerous side effects, consequently emphasizing the need for alternative therapies. Immunopharmacotherapy aims to use highly specific antibodies to sequester nicotine in the bloodstream thus blunting passage into the brain and minimizing positive reinforcing effects. A successful vaccination strategy is dependent upon the appropriate hapten design, carrier protein and adjuvant which affect both the magnitude and affinity of the immune response elicited. Our laboratory previously demonstrated the use of molecular constraint as a means to increase the intrinsic immunogenicity and antigenicity of a nicotine vaccine. The present study expands upon those initial results and explores the protective effects of vaccination with both constrained hapten CNI and its unconstrained counterpart NIC. Our results demonstrate how immunization with CNI-KLH produces large amounts of moderate affinity anti-nicotine antibodies even when formulated with ALUM adjuvant, making it particularly relevant for human use. In contrast, vaccination with NIC-KLH produced moderate amounts of high affinity anti-nicotine antibodies. These differential responses proved critical in offering protecting effects. Vaccination with CNI, but not NIC, resulted in an increase of self-administration responding on a progressive ratio schedule using a high nicotine dose (0.03 mg/kg/infusion; ≈ 2 cigarettes in human) as compared to KLH-controls. Furthermore, vaccination with CNI was able to antagonize the analgesic effects of a heavy bolus dose of nicotine (0.35 mg/kg). These results support our hypothesis that molecular constraint can be advantageously utilized to increase the immunogenicity of a nicotine vaccine. Furthermore in correlating the behavioral effects with the differential responses elicited, we shed light on the distinct roles of antibody concentration and affinity.


Assuntos
Nicotina/imunologia , Tabagismo/terapia , Vacinas/uso terapêutico , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos/sangue , Anticorpos/imunologia , Afinidade de Anticorpos , Haptenos/farmacologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Nicotina/farmacologia , Ratos , Ratos Wistar , Abandono do Hábito de Fumar/métodos , Vacinas/imunologia
6.
Psychopharmacology (Berl) ; 223(1): 17-25, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22418732

RESUMO

RATIONALE: Despite increased education regarding its dangers, cigarette smoking remains a significant public health concern due to serious associated health consequences such as cancer and respiratory and cardiovascular diseases. Most smokers fail in their attempts to quit smoking, and current pharmacological interventions have relatively low levels of efficacy and are associated with significant adverse events. We have previously reported that combinations of metyrapone and oxazepam, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats while not affecting food-maintained responding during the same sessions. OBJECTIVES: The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats. METHODS: Several dose combinations of metyrapone (12.5, 25 or 50 mg/kg) and oxazepam (5 or 10 mg/kg) were tested in rats trained to intravenously (IV) self-administer nicotine (0.03 mg/kg/infusion) during 1-h self-administration sessions using both fixed-ratio and progressive-ratio (PR) schedules of reinforcement. RESULTS: The administration of low doses of metyrapone and oxazepam in combination significantly decreased IV nicotine self-administration in rats. At the lowest doses of 12.5 mg/kg of metyrapone and 5 mg/kg of oxazepam, the drugs alone did not decrease IV nicotine self-administration, but the combination was effective. Varenicline was also tested using the fixed-ratio schedule, and reductions in nicotine intake were similar to those seen with the moderate dose of the combination. CONCLUSIONS: The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans.


Assuntos
Metirapona/farmacologia , Nicotina/administração & dosagem , Oxazepam/farmacologia , Abandono do Hábito de Fumar/métodos , Animais , Benzazepinas/farmacologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Infusões Intravenosas , Masculino , Metirapona/administração & dosagem , Oxazepam/administração & dosagem , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Esquema de Reforço , Autoadministração , Vareniclina
7.
Psychopharmacology (Berl) ; 221(4): 637-48, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22218454

RESUMO

RATIONALE: Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported. OBJECTIVES: We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats. METHODS: Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03 mg/kg/infusion in 0.1 ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5-25 mg/kg, i.p., 30 min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11. RESULTS: Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED(50) values 4 and 2.8 mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian α4ß2- or α7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds. CONCLUSION: The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved.


Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Imidazóis/farmacologia , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Animais , Condicionamento Operante/efeitos dos fármacos , Citocromo P-450 CYP2A6 , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Masculino , Ratos , Ratos Wistar , Autoadministração
8.
Mol Pharm ; 7(2): 431-41, 2010 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-20104903

RESUMO

(S)-Nicotine is a psychostimulant legal drug responsible for causing addiction to tobacco smoking. Tobacco smoking has been irrevocably linked to a number of serious diseases and at present is considered the leading cause of preventable death in the United States. Despite well-documented adverse medical consequences, nicotine addiction has historically been one of the hardest to break. Current therapies have offered limited success and show high rates of relapse, emphasizing the need to engineer alternative therapies to aid nicotine cessation. The current study presents a protein-based immunopharmacotherapy approach for the treatment of nicotine addiction. Immunopharmacotherapy aims to use highly specific antibodies to blunt passage of drug into the brain thus minimizing reinforcing effects on the reward pathways of the central nervous system. Generation of a successful vaccine heavily relies on appropriate optimization of hapten design, immunogenic carrier and adjuvant. Modification of a classical nicotine hapten in conjugation with three distinct carrier proteins allowed for priming of a nicotine vaccine able to elicit significant amounts of nicotine-specific antibodies. Increased self-administration with use of a high drug dose (0.03 mg/kg/infusion; approximately 2 cigarettes in human) was observed in the vaccinated versus control animals suggesting a compensatory pattern and possibly reduced passage of nicotine to the brain. These results support the hypothesis that proper optimization of vaccine formulations could lead to successful nicotine vaccines for human use.


Assuntos
Nicotina/imunologia , Tabagismo/tratamento farmacológico , Vacinas/uso terapêutico , Animais , Anticorpos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Imunoconjugados/imunologia , Infusões Intravenosas , Masculino , Camundongos , Modelos Teóricos , Ratos , Tabagismo/imunologia , Vacinas/imunologia
9.
Bioorg Med Chem ; 17(18): 6671-81, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19683449

RESUMO

A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (mu), delta (delta) and kappa (kappa) opioid and nociceptin (NOP) receptors. Binding assays showed that 4-10 had subnanomolar K(i) values for mu and kappa opioid receptors. Functional assays for stimulation of [(35)S]GTPgammaS binding showed that several compounds acted as partial or inverse agonists and antagonists of the mu and delta, kappa opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4-9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5-8 to have very potent efficacy (ED(50) values 19-50 microg/kg).


Assuntos
Dissuasores de Álcool/química , Dissuasores de Álcool/uso terapêutico , Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Receptores Opioides/metabolismo , Dissuasores de Álcool/metabolismo , Dissuasores de Álcool/farmacologia , Animais , Humanos , Fígado/metabolismo , Masculino , Camundongos , Naltrexona/química , Naltrexona/metabolismo , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Ligação Proteica , Ratos , Ratos Wistar , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade , Receptor de Nociceptina
10.
Psychopharmacology (Berl) ; 206(4): 699-714, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19462162

RESUMO

RATIONALE: Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties. OBJECTIVES: The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone. MATERIALS AND METHODS: Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01-0.3 mg/kg s.c.), Apo-PPI (0.001-0.3 mg/kg s.c.), DNMTP (0.01-0.1 mg/kg s.c.), and 5-CSR (0.003-0.3 mg/kg s.c.). RESULTS: Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03-0.3 mg/kg; and risperidone, 0.01-0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05). CONCLUSIONS: Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.


Assuntos
Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Anfetamina/toxicidade , Animais , Antipsicóticos/administração & dosagem , Apomorfina/toxicidade , Atenção/efeitos dos fármacos , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacologia , Dibenzocicloeptenos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Masculino , Olanzapina , Transtornos Psicóticos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Risperidona/administração & dosagem , Risperidona/farmacologia
11.
J Med Chem ; 51(6): 1913-24, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18298057

RESUMO

Substituted aryl and aliphatic amide analogues of 6-naltrexamine were synthesized and used to characterize the binding to and functional activity of human mu-, delta-, and kappa-opioid receptors. Competition binding assays showed 11-25 and 27-31 bound to the mu (K(i) = 0.05-1.2 nM) and kappa (K(i) = 0.06-2.4 nM) opioid receptors. Compounds 11-18 possessed significant binding affinity for the delta receptor (K(i) = 0.8-12.4 nM). Functional assays showed several compounds acted as partial or full agonists of delta or kappa receptors while retaining an antagonist profile at the mu receptor. Structure-activity relationship for aryl amides showed that potent compounds possessed lipophilic groups or substituents capable of hydrogen bonding. Metabolic stability studies showed that 11, 12, and 14 possessed considerable stability in the presence of rat, mouse, or human liver preparations. The ED 50 of inhibition of 10% ethanol self-administration in trained rats, using operant techniques for 11, was 0.5 mg/kg.


Assuntos
Alcoolismo/tratamento farmacológico , Morfinanos/síntese química , Morfinanos/uso terapêutico , Naltrexona , Consumo de Bebidas Alcoólicas , Amidas/química , Animais , Ligação Competitiva , Avaliação Pré-Clínica de Medicamentos , Etanol/administração & dosagem , Humanos , Ligação de Hidrogênio , Fígado/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Morfinanos/química , Naltrexona/análogos & derivados , Naltrexona/síntese química , Naltrexona/uso terapêutico , Ratos , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade
12.
Proc Natl Acad Sci U S A ; 104(43): 17198-203, 2007 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-17921249

RESUMO

Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF(1) receptors. Overactivation of the CRF-CRF(1) system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Nicotina/administração & dosagem , Nicotina/farmacologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade , Comportamento Aditivo , Comportamento Animal/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Mecamilamina/farmacologia , Nicotina/efeitos adversos , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Autoadministração
13.
Eur J Neurosci ; 24(12): 3532-40, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17229101

RESUMO

Although nicotine is considered to be responsible for the addictive properties of tobacco, growing evidence underlines the importance of non-nicotine components in smoking reinforcement. It has been shown that tobacco smoke contains monoamine oxidase (MAO) A and B inhibitors and decreases MAO-A and MAO-B activity in smokers. Here, we investigated the effects of clorgyline hydrochloride (irreversible MAO-A inhibitor; 2 mg/kg/day), selegiline (irreversible MAO-B inhibitor; 4 mg/kg) and the beta-carboline norharmane hydrochloride (reversible MAO-B inhibitor; 5 mg/kg/day) treatments on nicotine self-administration (30 microg/kg/infusion, free base) in rats. Independent of the responsiveness to novelty and locomotor activity stimulation, only clorgyline hydrochloride treatment increased the intake of nicotine in a fixed-ratio schedule (FR5) of reinforcement. When a progressive-ratio schedule was implemented, both clorgyline hydrochloride and norharmane hydrochloride treatments potentiated the reinforcing effects of nicotine, whereas selegiline had no effect. Taken together, these results indicate that MAO-A inhibition interacts with nicotine to enhance its rewarding effects in rats and suggest that other compounds present in tobacco, such as beta-carboline, may also play an important role in sustaining smoking behavior in humans.


Assuntos
Monoaminoxidase/fisiologia , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Reforço Psicológico , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cotinina/sangue , Interações Medicamentosas , Masculino , Inibidores da Monoaminoxidase/sangue , Inibidores da Monoaminoxidase/farmacologia , Atividade Motora/efeitos dos fármacos , Nicotina/sangue , Agonistas Nicotínicos/sangue , Ratos , Ratos Wistar , Esquema de Reforço , Autoadministração/métodos , Fatores de Tempo
14.
J Neurosci ; 25(38): 8593-600, 2005 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-16177026

RESUMO

Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats. These effects were more prominent in rats selected for high responsiveness to novelty than in rats with low responsiveness to novelty. The results suggest that the inhibition of MAO activity by compounds present in tobacco smoke may combine with nicotine to produce the intense reinforcing properties of cigarette smoking that lead to addiction.


Assuntos
Comportamento Aditivo/enzimologia , Inibidores da Monoaminoxidase/farmacologia , Motivação , Nicotina/administração & dosagem , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Monoaminoxidase/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Autoadministração
15.
Int J Pharm ; 283(1-2): 35-44, 2004 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-15363499

RESUMO

Pharmacotherapy treatment for alcoholism is limited by poor compliance, adverse effects, and fluctuating drug levels after bolus administration. A long-term delivery system would improve upon these limitations. The current study describes the characterization of a sustained release implant containing nalmefene, an opioid antagonist, for treatment of alcoholism. Nalmefene was blended with ethylene vinyl acetate (EVA), extruded into 2.8 mm x 27 mm rods, and coated with EVA to optimize release. In vitro release was determined by HPLC, and in vivo release characteristics after subcutaneous implantation into rats were determined by LC-MS/MS analyses. Extrusion produced rods containing 80.09 +/- 6.0 mg nalmefene. In vitro release was high from the uncoated rods, and they were depleted of drug fairly quickly; however EVA coatings maintained release over longer periods. The 25 wt.% coated rods provided in vitro release of 0.36 mg/day/rod, and in vivo release of 0.29 mg/day/rod over 6 months, and showed dose-dependent nalmefene plasma concentrations (one rod: 3.33 +/- 0.56 ng/ml, three rods: 10.19 +/- 2.31 ng/ml). After explantation, nalmefene plasma concentrations were undetectable by 6 h. A sustained release nalmefene rod provides 6 months of drug with no adverse effects.


Assuntos
Alcoolismo/tratamento farmacológico , Bombas de Infusão Implantáveis , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Tecnologia Farmacêutica , Animais , Área Sob a Curva , Preparações de Ação Retardada , Desenho de Equipamento , Humanos , Masculino , Naltrexona/administração & dosagem , Naltrexona/farmacocinética , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacocinética , Ratos , Ratos Wistar
16.
Psychopharmacology (Berl) ; 170(1): 42-50, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12783156

RESUMO

RATIONALE: Conditioned place aversion (CPA) is known to be a sensitive measure of the aversive motivational state produced by opioid withdrawal in rats made chronically dependent on opioids. OBJECTIVE: The purpose of the present study was to examine the sensitivity of the CPA model in detecting a possible aversive state associated with naloxone-precipitated withdrawal from acute treatment with morphine. METHODS: Doses of morphine and naloxone, as well as number of conditioning trials, were systematically varied to determine the minimum conditions that would result in a detectable CPA in male Wistar rats. Naloxone (0.003-16.7 mg/kg) was administered 4 h after an injection of vehicle or morphine (1.0, 3.3, or 5.6 mg/kg) and immediately prior to confinement to one compartment of the conditioning apparatus; rats received either one or two such naloxone-conditioning trials (separate by 48 h). RESULTS: Morphine (5.6 mg/kg) followed 4 h later by vehicle produced no significant preference or aversion. In morphine-naive rats, 10 mg/kg naloxone was required to produce a significant CPA with two cycles of conditioning. When increasing doses of morphine were administered (1.0, 3.3, 5.6 mg/kg), significant increases in naloxone potency to elicit a CPA were observed (16-, 211-, and 1018-fold potency shifts, respectively). Naloxone potency after two pretreatments with 5.6 mg/kg morphine was comparable to its potency to elicit a CPA after chronic exposure to morphine. Although naloxone was still effective in producing a CPA after a single conditioning cycle (and hence a single morphine exposure), its effects were dramatically reduced relative to those seen with two conditioning cycles. CONCLUSIONS: CPA is a reliable and sensitive index of the aversive motivational state accompanying withdrawal from acute opioid dependence.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Dependência de Morfina/psicologia , Síndrome de Abstinência a Substâncias/psicologia , Doença Aguda , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Morfina/administração & dosagem , Morfina/farmacologia , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/administração & dosagem , Entorpecentes/farmacologia , Ratos , Ratos Wistar
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