RESUMEN
Although nicotine is generally considered to be the main compound responsible for addictive properties of tobacco, experimental data indicate that nicotine does not exhibit all the characteristics of other substances of abuse. We recently showed that a pretreatment with mixed irreversible monoamine oxidases inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and allows maintenance of behavioral sensitization to nicotine in rats. Moreover, we showed by microdialysis in mice that behavioral sensitization induced by compounds belonging to main groups of drugs of abuse, such as amphetamine, cocaine, morphine, or alcohol, was underlain by sensitization of noradrenergic and serotonergic neurons. Here, this neurochemical sensitization was tested after nicotine, tranylcypromine, or a mixture of both compounds. Data indicate that, whereas neither repeated nicotine nor repeated tranylcypromine alone has any effect by itself, a repeated treatment with a mixture of nicotine and tranylcypromine induces both behavioral sensitization and sensitization of noradrenergic and serotonergic neurons. The development of neurochemical and behavioral sensitizations is blocked by prazosin and SR46349B [(1Z,2E)-1-(2-fluoro-phenyl)-3-(4-hydroxyphenyl)-prop-2-en-one-O-(2-dimethylamino-ethyl)-oxime hemifumarate], two antagonists of alpha1b-adrenergic and 5-HT(2A) receptors, respectively, but not by SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], a D(1) receptor antagonist. Finally, we found that pretreatments with WAY 100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexane carboxamide trihydrochloride], a 5-HT(1A) receptor antagonist, can also induce a behavioral and neurochemical sensitization to repeated nicotine. Complementary experiments with 8-OHDPAT (8-hydroxy-dipropylamino-tetralin), a 5-HT(1A) receptor agonist, and analysis of 5-HT(1A) receptors expression in the dorsal raphe nucleus after a tranylcypromine injection indicate that MAOIs contained in tobacco desensitize 5-HT(1A) autoreceptors to trigger the strong addictive properties of tobacco.
Asunto(s)
Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Monoaminooxidasa/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Autorreceptores/metabolismo , Combinación de Medicamentos , Fluorobencenos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidores de la Monoaminooxidasa/farmacología , Fenoles/farmacología , Piperazinas/farmacología , Prazosina/farmacología , Piridinas/farmacología , Núcleos del Rafe/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Tranilcipromina/farmacologíaRESUMEN
RATIONALE: Although locomotor response to d-amphetamine is considered as mediated by an increased release of dopamine in the ventral striatum, blockade of either alpha1b-adrenergic or 5-HT2A receptors almost completely inhibits d-amphetamine-induced locomotor response in mice. In agreement with this finding, mice lacking alpha1b-adrenergic receptors hardly respond to d-amphetamine. However, we show here that, paradoxically, mice lacking 5-HT2A receptors (5-HT2A-R KO) exhibit a twofold higher locomotor response to d-amphetamine than wild-type (WT) littermates. OBJECTIVES: To explore why there is a discrepancy between pharmacological and genetic 5-HT2A receptor blockade. MATERIALS AND METHODS: Locomotor response and behavioral sensitization to d-amphetamine were measured in presence of prazosin and/or SR46349B, alpha1b-adrenergic, and 5-HT2A receptor antagonists, respectively. RESULTS: Repeating amphetamine injections still increases 5-HT2A-R KO mice locomotor response to d-amphetamine at a level similar to that of sensitized WT mice. SR46349B (1 mg/kg) has, as expected, no effect in 5-HT2A-R KO mice. One milligrams per kilogram of prazosin completely blocks d-amphetamine-induced locomotor response in 5-HT2A-R KO naïve animals but 3 mg/kg is necessary in sensitized 5-HT2A-R KO mice. CONCLUSIONS: Because naïve 5-HT2A-R KO mice exhibit an increased cortical noradrenergic response to d-amphetamine, our data suggest that repeated d-amphetamine modifies noradrenergic transmission in 5-HT2A-R KO mice. Stimulation of specific 5-HT2A receptors would inhibit noradrenergic neurons. Dramatic decrease in SR46349B efficiency in sensitized WT mice indicates that a disruption of the regulating role of 5-HT2A receptors on noradrenergic transmission occurs during sensitization and thus represents the physiological basis of behavioral sensitization to d-amphetamine.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dextroanfetamina/farmacología , Receptor de Serotonina 5-HT2A/fisiología , Antagonistas de Receptores Adrenérgicos alfa 1 , Animales , Conducta Animal/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Relación Dosis-Respuesta a Droga , Fluorobencenos/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fenoles/farmacología , Prazosina/farmacología , Receptor de Serotonina 5-HT2A/deficiencia , Receptor de Serotonina 5-HT2A/genéticaRESUMEN
Using a microsuperfusion method in vitro, the effects of the NK1, NK2, and NK3 tachykinin receptor antagonists SR140333, SR48968, and SR142801, respectively, on the NMDA-evoked release of [3H]-acetylcholine were investigated after both acute and chronic suppression of dopamine transmission in striosomes and matrix of the rat striatum. NMDA (1 mm) alone or with D-serine (10 microm) in the presence of alpha-methyl-p-tyrosine (100 microm) markedly enhanced the release of [3H]-acetylcholine through a dopamine-independent inhibitory process. In both conditions, as well as after chronic 6-OHDA-induced denervation of striatal dopaminergic fibers, SR140333, SR48968, or SR142801 (0.1 microm each) reduced the NMDA-evoked release of [3H]-acetylcholine in the matrix but not in striosome-enriched areas. These responses were selectively abolished by coapplication with NMDA of the respective tachykinin agonists, septide, [Lys5,MeLeu9,Nle10]NKA(4-10), or senktide. Distinct mechanisms are involved in the effects of the tachykinin antagonists because the inhibitory response of SR140333 was additive with that of either SR48968 or SR142801. In addition, the SR140333-evoked response remained unchanged, whereas those of SR48968 and SR142801 were abolished in the presence of N(G)-monomethyl-l-arginine (nitric oxide synthase inhibitor). Therefore, in the matrix but not in striosomes, the acute or chronic suppression of dopamine transmission unmasked the facilitatory effects of endogenously released substance P, neurokinin A, and neurokinin B on the NMDA-evoked release of [3H]-acetylcholine. Whereas substance P and neurokinin A are colocalized in same efferent neurons, their responses involve distinct circuits because the substance P response seems to be mediated by NK1 receptors located on cholinergic interneurons, while those of neurokinin A and neurokinin B are nitric oxide-dependent.
Asunto(s)
Acetilcolina/metabolismo , Cuerpo Estriado/metabolismo , N-Metilaspartato/farmacología , Sustancia P/análogos & derivados , Transmisión Sináptica/fisiología , Taquicininas/metabolismo , Animales , Benzamidas/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina/farmacología , Fragmentos de Péptidos/farmacología , Piperidinas/farmacología , Ácido Pirrolidona Carboxílico/análogos & derivados , Quinuclidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Taquicininas/antagonistas & inhibidores , Sustancia P/farmacología , Transmisión Sináptica/efectos de los fármacos , Taquicininas/agonistas , Factores de TiempoRESUMEN
Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.
Asunto(s)
Ansiedad/metabolismo , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Receptores de Glucocorticoides/metabolismo , Alienación Social , Aislamiento Social , Estrés Psicológico/metabolismo , Animales , Miedo , Ratones , Ratones Mutantes , Receptores Dopaminérgicos/metabolismo , Receptores de Glucocorticoides/genéticaRESUMEN
BACKGROUND: In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists months after the last administration. It has been shown that behavioral sensitization to amphetamine develops parallel to an increased release of norepinephrine (NE) in the prefrontal cortex (PFC). METHODS: Rats and mice were repeatedly treated with amphetamine (1 or 2 mg/kg intraperitoneally, respectively) to obtain sensitized animals. The NE release in the PFC was measured by microdialysis in freely moving mice (n = 55). Activity of locus coeruleus (LC) noradrenergic neurons was determined in anaesthetized rats (n = 15) by in vivo extracellular electrophysiology. The α2A-adrenergic autoreceptor (α2A-AR) expression was assessed by autoradiography on brain slices, and Gαi proteins expression was measured by western blot analysis of LC punches. RESULTS: In sensitized rats LC neurons had a higher spontaneous firing rate, and clonidine-an α2A-adrenergic agonist-inhibited LC neuronal firing less efficiently than in control animals. Clonidine also induced lower levels of NE release in the PFC of sensitized mice. This desensitization was maintained by a lower density of Gαi1 and Gαi2 proteins in the LC of sensitized mice rather than weaker α2A-AR expression. Behavioral sensitization was facilitated by α2A-AR antagonist, efaroxan, during amphetamine injections and abolished by clonidine treatment. CONCLUSIONS: Our data indicate that noradrenergic inhibitory feedback is impaired for at least 1 month in rats and mice repeatedly treated with amphetamine. This work highlights the key role of noradrenergic autoreceptor signaling in the persistent modifications induced by repeated amphetamine administration.
Asunto(s)
Anfetamina/farmacología , Autorreceptores/metabolismo , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Autorreceptores/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/efectos de los fármacos , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Although nicotine is generally considered as the main compound responsible for addictive properties of tobacco, some experimental data indicate that nicotine does not exhibit all the characteristics of other substances of misuse such as psychostimulants and opiates. For example, nicotine generally fails to induce locomotor response in mice and self-administration of nicotine is difficult to obtain in rats. We have shown recently that a pretreatment with mixed irreversible monoamine oxidase inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and induces a robust self-administration of nicotine in rats. We show here that when mice were pretreated with enhancers of extracellular levels of noradrenaline, dopamine or serotonin (D-amphetamine, GBR12783 or para-chloro-amphetamine, respectively) and injected with nicotine (1 mg/kg), only those animals pretreated with para-chloro-amphetamine exhibited a specific locomotor response to nicotine. These data indicate a critical role of serotonin in nicotine-induced locomotor activity in mice. This was further confirmed in microdialysis experiments showing that nicotine induces an increase in extracellular serotonin levels in the ventral striatum in mice pretreated with tranylcypromine. This effect of nicotine on extracellular serotonin levels was absent in mice lacking the beta2-subunit of the nicotinic acetylcholine receptor. Our data suggest that mixed irreversible MAOIs contained in tobacco facilitate the effects of nicotine on serotonin release, thus allowing the locomotor and rewarding effects of nicotine.
Asunto(s)
Monoaminooxidasa/metabolismo , Actividad Motora/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Serotonina/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Química Encefálica/efectos de los fármacos , Interacciones Farmacológicas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Microdiálisis/métodos , Inhibidores de la Monoaminooxidasa/farmacología , Receptores Nicotínicos/deficiencia , Serotoninérgicos/farmacología , Factores de Tiempo , Tranilcipromina/farmacología , p-Cloroanfetamina/farmacologíaRESUMEN
Striatal cholinergic interneurons play a crucial role in the control of movement as well as in motivational and learning aspects of behaviour. Neuropeptides regulate striatal cholinergic transmission and particularly activation of mu opioid receptor (MOR) inhibits acetylcholine (ACh) release in the dorsal striatum. In the present study we investigated whether this cholinergic transmission could be modulated by an enkephalin/MOR direct process. We show that mRNA and protein of MORs are expressed by cholinergic interneurons in the limbic/prefrontal territory but not by those in the sensorimotor territory of the dorsal striatum. These MORs are functional because potassium-evoked release of ACh from striatal synaptosomes was dose-dependently reduced by a selective MOR agonist, this effect being suppressed by a MOR antagonist. The MOR regulation of cholinergic interneurons presented a diurnal variation. (i) The percentage of cholinergic interneurons containing MORs that was 32% at the beginning of the light period (morning) increased to 80% in the afternoon. (ii) The MOR-mediated inhibition of synaptosomal ACh release was higher in the afternoon than in the morning. (iii) While preproenkephalin mRNA levels remained stable, enkephalin tissue content was the lowest (-32%) in the afternoon when the spontaneous (+35%) and the N-methyl-d-aspartate-evoked (+140%) releases of enkephalin (from microsuperfused slices) were the highest. Therefore, by acting on MORs present on cholinergic interneurons, endogenously released enkephalin reduces ACh release. This direct enkephalin/MOR regulation of cholinergic transmission that operates only in the limbic/prefrontal territory of the dorsal striatum might contribute to information processing in fronto-cortico-basal ganglia circuits.