RESUMO
Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or ß2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ß2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in â¼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.
Assuntos
Anticonvulsivantes/farmacologia , PPAR alfa/agonistas , Pirimidinas/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Epilepsia do Lobo Frontal/diagnóstico , Epilepsia do Lobo Frontal/tratamento farmacológico , Fenofibrato/administração & dosagem , Fenofibrato/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Nicotina/efeitos adversos , Técnicas de Patch-Clamp , Fosforilação/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Pirimidinas/administração & dosagem , Ratos , Receptores Nicotínicos/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológicoRESUMO
Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.
Assuntos
Clofibrato/farmacologia , Avaliação Pré-Clínica de Medicamentos/psicologia , Hipolipemiantes/farmacologia , Nicotina/farmacologia , Recompensa , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Clofibrato/uso terapêutico , Modelos Animais de Doenças , Dopamina/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Indóis/farmacologia , Masculino , Neurônios/fisiologia , Nicotina/administração & dosagem , Nicotina/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , PPAR alfa/agonistas , PPAR alfa/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Saimiri , Prevenção Secundária , Autoadministração , Tabagismo/tratamento farmacológico , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
The rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area (VTA), is an important site involved in aversion processes. The RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding dopamine (DA) neurons in the VTA. Here, we studied how RMTg neurons regulate both spontaneous firing of DA cells and their response to the cannabinoid agonist WIN55212-2 (WIN), morphine, cocaine, and nicotine. We utilized single-unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to study RMTg-induced inhibition of DA cells and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of caudal afferents, respectively. The electrical stimulation of the RMTg elicited a complete suppression of spontaneous activity in approximately half of the DA neurons examined. RMTg-induced inhibition correlated with firing rate and pattern of DA neurons and with their response to a noxious stimulus, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA cells. Both morphine and WIN depressed RMTg-induced inhibition of DA neurons in vivo and IPSCs evoked by RMTg stimulation in brain slices with presynaptic mechanisms. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results further support the role of the RMTg as one of the main inhibitory afferents to DA cells and suggest that cannabinoids and opioids might disinhibit DA neurons by profoundly influencing synaptic responses evoked by RMTg activation.
Assuntos
Potenciais de Ação/fisiologia , Neurônios Dopaminérgicos/fisiologia , Inibição Neural/fisiologia , Tegmento Mesencefálico/citologia , Área Tegmentar Ventral/citologia , Potenciais de Ação/efeitos dos fármacos , Análise de Variância , Animais , Benzoxazinas/farmacologia , Canabinoides/agonistas , Canabinoides/antagonistas & inibidores , Cocaína/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Estimulação Elétrica , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Morfina/farmacologia , Morfolinas/farmacologia , Naloxona/farmacologia , Naftalenos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Inibição Neural/efeitos dos fármacos , Vias Neurais/fisiologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Estimulação Física , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Rimonabanto , Fatores de TempoRESUMO
BACKGROUND: Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine. METHODS: We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats. RESULTS: The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886). CONCLUSIONS: These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.
Assuntos
Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , PPAR alfa/metabolismo , Reforço Psicológico , Recompensa , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Masculino , Microdiálise/métodos , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Oligossacarídeos/farmacologia , Proliferadores de Peroxissomos/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Saimiri , Autoadministração , Área Tegmentar Ventral/citologiaRESUMO
The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme that degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single-unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptor. URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system.