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1.
J Neurochem ; 129(4): 721-31, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24422997

RESUMO

Chronic nicotine administration increases the density of brain α4ß2* nicotinic acetylcholine receptors (nAChRs), which may contribute to nicotine addiction by exacerbating withdrawal symptoms associated with smoking cessation. Varenicline, a smoking cessation drug, also increases these receptors in rodent brain. The maintenance of this increase by varenicline as well as nicotine replacement may contribute to the high rate of relapse during the first year after smoking cessation. Recently, we found that sazetidine-A (saz-A), a potent partial agonist that desensitizes α4ß2* nAChRs, does not increase the density of these receptors in brain at doses that decrease nicotine self-administration, increase attention in rats, and produce anxiolytic effects in mice. Here, we investigated whether chronic saz-A and varenicline maintain the density of nAChRs after their up-regulation by nicotine. In addition, we examined the effects of these drugs on a measure of anxiety in mice and weight gain in rats. After increasing nAChRs in the rodent brain with chronic nicotine, replacing nicotine with chronic varenicline maintained the increased nAChR binding, as well as the α4ß2 subunit proteins measured by western blots. In contrast, replacing nicotine treatments with chronic saz-A resulted in the return of the density of nAChRs to the levels seen in saline controls. Nicotine, saz-A and varenicline each demonstrated anxiolytic effects in mice, but only saz-A and nicotine attenuated the gain of weight over a 6-week period in rats. These findings suggest that apart from its modest anxiolytic and weight control effects, saz-A, or drugs like it, may be useful in achieving long-term abstinence from smoking.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/prevenção & controle , Azetidinas/uso terapêutico , Química Encefálica/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/uso terapêutico , Piridinas/uso terapêutico , Receptores Nicotínicos/biossíntese , Síndrome de Abstinência a Substâncias/prevenção & controle , Tabagismo/tratamento farmacológico , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/farmacologia , Ansiedade/induzido quimicamente , Azetidinas/administração & dosagem , Azetidinas/farmacologia , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/genética , Abandono do Uso de Tabaco , Tabagismo/metabolismo , Regulação para Cima/efeitos dos fármacos , Vareniclina , Aumento de Peso/efeitos dos fármacos
2.
Neurosci Lett ; 721: 134825, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32036029

RESUMO

Morbidity and mortality attributed to type 2 diabetes have exponentially increased in the US. At exceptionally high risk is a subpopulation of persons with type 2 diabetes who smoke, which are shown to have decreased success rates of smoking cessation than euglycemic smokers. Preclinical research in our laboratory has shown that the rewarding effects of nicotine are enhanced in the streptozotocin and high-fat diet rodent model of diabetes. It is presently unclear whether this enhancement of nicotine reward can be demonstrated in other insulin resistant rat models. This study aimed to determine if a similar increase in nicotine reward is found in Goto-Kakizaki (GK) rats, a model of the spontaneous formation of insulin resistance in an inbred sub-strain of Wistar rat. Nicotine conditioned place preference (CPP) was examined in Sprague-Dawley (SD), Wistar, and GK rats. A robust nicotine CPP was found in SD and Wistar rats, but nicotine CPP was not detected in GK rats. Locomotor activity was also evaluated in all three strains, and GK rats demonstrated significantly less activity as compared to SD and Wistar rats. To further assess reward behavior in GK rats, consumption of saccharin solution was measured over a 48 -h period. GK rats showed a significant increase in saccharin intake compared to SD rats. These findings suggest that GK rats experience an enhanced hedonic processing as compared to SD rats. The lack of nicotine CPP in GK rats may be due to deficits in learning and memory, thus hindering their ability to acquire or express a place preference.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Nicotina/administração & dosagem , Recompensa , Sacarina/administração & dosagem , Animais , Condicionamento Psicológico/fisiologia , Diabetes Mellitus Tipo 2/genética , Masculino , Agonistas Nicotínicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Autoadministração , Especificidade da Espécie , Edulcorantes/administração & dosagem
3.
Brain Res ; 1658: 36-41, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28089665

RESUMO

Sex differences in the analgesic effects of morphine have been previously reported in various models that represent the sensory component of pain. However, pain sensation is a complex process that consists of both sensory and affective components. It is presently unclear whether the analgesic effects of morphine between the sensory and affective components of pain are sexually dimorphic. Moreover, differences in morphine dose-response in the two components of pain have not been examined in male and female rats. Therefore, we examined the analgesic effects of morphine on the sensory and affective components of formalin-induced pain behaviors in male and female rats. To discern the sensory component, rats were pretreated with varying doses of morphine and then intraplantar formalin-induced paw flinches were measured. Morphine reduced the number of formalin-induced paw flinches at a treatment dose of 4.0mg/kg. Morphine analgesia was similar across the sexes in the early (phase 1) and late phase (phase 2) of the formalin test. To examine the affective component, rats were pretreated with varying doses of morphine, and then intraplantar formalin-induced conditioned place aversion (CPA) was examined. Formalin produced CPA, which was blocked by morphine at doses of 1.0mg/kg and higher in male and female rats. Lastly, formalin-induced cFos expression and the effects of systemic morphine were examined in the superficial dorsal horn of the spinal cord. Intraplantar formalin produced robust expression of cFos; however, morphine did not attenuate the cFos expression. These results demonstrate a notable dissociation of the analgesic effects of morphine by detecting a fourfold shift in the minimum effective dose between the sensory and affective components of formalin-induced spontaneous pain, that were similar between male and female rats. The findings further suggest disparate mechanisms involved in systemic morphine-induced analgesia in the two components of formalin-induced pain.


Assuntos
Afeto/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Morfina/farmacologia , Percepção da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/fisiopatologia , Afeto/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Relação Dose-Resposta a Droga , Feminino , Formaldeído , Imuno-Histoquímica , Vértebras Lombares , Masculino , Dor/patologia , Dor/psicologia , Medição da Dor , Percepção da Dor/fisiologia , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/metabolismo , Células do Corno Posterior/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Caracteres Sexuais , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia
4.
Drug Alcohol Depend ; 140: 205-7, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24774962

RESUMO

BACKGROUND: Tobacco use among persons with Type II diabetes exponentially increases negative health consequences and mortality rates. It is especially troubling that diabetic persons who smoke have a greater difficulty with tobacco cessation as compared to non-diabetic smokers. Diabetes is a metabolic syndrome that consists of insulin resistance due to disruptions in insulin signaling. We have previously shown that insulin depletion enhances the motivational effects of nicotine. METHODS: The present study expands our previous work by examining whether insulin resistance, produced by a high-fat diet (HFD) regimen, enhances the rewarding effects of nicotine, as measured by the conditioned place preference (CPP) paradigm. Rats were placed on either a regular diet (RD) or a HFD for 5 weeks, after which they were assessed for insulin resistance via blood glucose measurements after an insulin challenge. Rats then underwent a nicotine CPP study. RESULTS: The findings revealed that HFD produced insulin resistant and non-insulin resistant animals. Interestingly, the magnitude of nicotine CPP was larger in insulin resistant rats versus RD rats. Nicotine CPP was absent in non-insulin resistant animals. A similar increase in body weight was observed in insulin resistant and non-insulin resistant rats as compared to RD rats. These findings suggest that neither the increased body weight nor the HFD per se in the insulin resistant rats contributed to the enhanced nicotine reward. CONCLUSION: These present study suggests that insulin resistant rats undergo unique neurobiological changes related to a disruption in insulin signaling that promotes the rewarding effects of nicotine.


Assuntos
Resistência à Insulina/fisiologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Condicionamento Operante , Sinais (Psicologia) , Dieta , Masculino , Ratos , Ratos Sprague-Dawley
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