Asunto(s)
Conducta Animal/efectos de los fármacos , Morfina/farmacología , Narcóticos/farmacología , Neostriado/metabolismo , Receptores Dopaminérgicos/metabolismo , Animales , Autorradiografía , Núcleo Caudado/citología , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Neostriado/citología , Neostriado/efectos de los fármacos , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Wistar , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3RESUMEN
The development of behavioural sensitization is thought to depend on the dose and temporal pattern of drug treatment. Previous studies have shown that two distinct morphine pretreatment regimens cause different long-term neuroadaptations in rat striatum. Therefore, in the present study the ability of these pretreatment regimens to induce long-term behavioural sensitization was investigated. One pretreatment regimen, termed "chronic", consisted of three daily injections, for 5 days, with escalating doses (10-50 mg/kg) of morphine, and the other, termed "intermittent", of 14 daily injections with morphine (10 mg/kg). Both intermittent and chronic morphine pretreatment caused sensitization to the locomotor effects of morphine, 3 weeks post-treatment, although the former induced a far greater level of sensitization. Moreover, 3 weeks post-treatment, intermittent, but not chronic, morphine pretreatment induced cross-sensitization to the locomotor stimulant effects of amphetamine. Behavioural sensitization following intermittent morphine pretreatment was clear-cut both 1 day and 3 weeks post-treatment, while after 9 weeks, the locomotor effects of morphine were still slightly augmented. It is concluded that intermittent morphine pretreatment is far more effective in inducing long-term behavioural sensitization than chronic morphine pretreatment.
Asunto(s)
Anfetamina/farmacología , Locomoción/efectos de los fármacos , Morfina/farmacología , Animales , Esquema de Medicación , Masculino , Ratas , Ratas Wistar , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
Glucocorticoid receptor (GR)-mediated facilitation of striatal dopaminergic (DA) neurotransmission has been proposed to play a role in behavioral sensitization induced by intermittent exposure to drugs of abuse or stressors. Searching for possible common neuronal substrates acted upon by drugs of abuse and corticosterone, we addressed the question as to whether such a facilitatory effect is apparent (i.e., persists) in primary cultures of rat striatum subsequent to intermittent (prenatal) morphine administration. As previously observed in striatal slices of morphine-treated rats, intermittent morphine exposure in vivo caused a long-lasting increase in DA D1 receptor-stimulated adenylyl cyclase activity, that appeared to persist in primary cultures of rat striatal gamma-aminobutyric acid (GABA) neurons. Subsequent in vitro exposure of these striatal neurons to corticosterone or dexamethasone, simultaneously activating GR and mineralocorticoid receptors (MR), about doubled this adaptive effect of previous in vivo morphine administration. The selective MR agonist aldosterone was ineffective in this respect. Prior in vivo morphine treatment also enhanced the stimulatory in vitro effect of corticotropin releasing hormone (CRH) on adenylyl cyclase in cultured GABA neurons. However, the enhanced CRH receptor functioning was not potentiated by in vitro corticosterone exposure. Activation of GR by corticosterone did not facilitate the increase in D1 receptor efficacy induced by sustained activation of muscarinic receptors in cultured striatal neurons. These data indicate that previous intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on enhanced striatal DA neurotransmission at the level of postsynaptic D1 receptors. Moreover, the induction of this neuroadaptation seems to display opioid receptor selectivity and its long-term expression may be confined to D1 receptors. Since exposure to drugs of abuse or stressors not only increase striatal DA release but also plasma corticosterone levels, we hypothesize that this adaptive phenomenon in DA-sensitive GABA neurons is involved in the expression of morphine-induced long-term behavioral sensitization to drugs of abuse and stressors.
Asunto(s)
Cuerpo Estriado/fisiología , Corticosterona/farmacología , Morfina/farmacología , Neuronas/fisiología , Receptores de Dopamina D1/fisiología , Ácido gamma-Aminobutírico/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Adenosina Trifosfato/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Células Cultivadas , Cuerpo Estriado/citología , Hormona Liberadora de Corticotropina/farmacología , AMP Cíclico/metabolismo , Dexametasona/farmacología , Sinergismo Farmacológico , Embrión de Mamíferos , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalinas/farmacología , Femenino , Cinética , Neuronas/citología , Neuronas/efectos de los fármacos , Oxotremorina/farmacología , Embarazo , Ratas , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/fisiología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/fisiología , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/fisiologíaRESUMEN
Protracted changes in basal "steady-state" opioid peptide gene expression in the brain may represent adaptations underlying the behavioral effects of drugs of abuse, observed long after drug exposure. Here, we have studied the long-term effects of two distinct regimens of morphine administration ("intermittent" vs "chronic" morphine treatment) on behavioral sensitization and "steady-state" striatal preprodynorphin and preproenkephalin gene expression in rats. Opioid peptide gene expression was investigated using in situ hybridization at three rostrocaudal levels (rostral, intermediate and caudal) of the caudate-putamen and the nucleus accumbens. Behavioral studies showed that the intermittent morphine treatment resulted in a significantly greater enhancement of morphine-induced locomotion than the chronic morphine treatment three weeks after cessation of opiate exposure. The intermittent morphine treatment resulted in an initial decrease of preprodynorphin gene expression of about 5-10% in the caudate-putamen and the nucleus accumbens at the rostral and intermediate levels one day after the last morphine administration. In contrast, a protracted increase of preprodynorphin gene expression of about 20% throughout the caudate-putamen and of about 6% in intermediate sections of the nucleus accumbens was observed 21 days after cessation of intermittent morphine treatment. Although the chronic morphine treatment induced a decrease of preprodynorphin messenger RNA levels one day after the last administration, no significant changes were observed three weeks after cessation of chronic morphine treatment. No long-term changes were observed in preproenkephalin gene expression after either morphine treatment. Since the intermittent morphine administration induced long-term behavioral sensitization much more effectively than the chronic morphine treatment, we tentatively suggest that the protracted increase of preprodynorphin gene expression may play a facilitative role in the long-term character of opiate-induced behavioral sensitization.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cuerpo Estriado/fisiología , Dinorfinas/genética , Expresión Génica/efectos de los fármacos , Morfina/administración & dosificación , Narcóticos/administración & dosificación , Precursores de Proteínas/genética , Animales , Autorradiografía , Encefalinas/genética , Masculino , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Narcóticos/farmacología , Ratas , Ratas Wistar , Factores de Tiempo , Distribución TisularRESUMEN
One month (but not 1-3 days) after intermittent morphine administration, the hyperresponsiveness of rats toward the locomotor effects of morphine and amphetamine was associated with an increase in dopamine (DA) D-1 receptor-stimulated adenylyl cyclase activity and enhanced steady state levels of preprodynorphin gene expression in slices of the caudate/putamen and nucleus accumbens. Such an enduring increase in postsynaptic D-1 receptor efficacy also occurred in cultured gamma-aminobutyric acid (GABA) neurons of the striatum obtained from rats prenatally treated with morphine. Interestingly, in vitro glucocorticoid receptor activation in these cultured striatal neurons by corticosterone potentiated this neuroadaptive effect of prior in vivo morphine exposure. Since activation of glucocorticoid receptors by corticosterone did not affect D-1 receptor functioning in cultured neurons of saline-pretreated rats, prior intermittent exposure to morphine (somehow) appears to induce a long-lasting state of corticosterone hyperresponsiveness in striatal neurons. Therefore, DA-sensitive striatal GABA neurons may represent common neuronal substrates acted upon by morphine and corticosterone. We hypothesize that the delayed occurrence of these long-lasting morphine-induced neuroadaptive effects in GABA/dynorphin neurons of the striatum is involved in the enduring nature of behavioral sensitization to drugs of abuse and cross-sensitization to stressors.
Asunto(s)
Cuerpo Estriado/fisiología , Morfina/farmacología , Neuronas/fisiología , Receptores de Dopamina D1/fisiología , Receptores de Glucocorticoides/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Adenilil Ciclasas/metabolismo , Anfetamina/farmacología , Animales , Núcleo Caudado/fisiología , Células Cultivadas , Cuerpo Estriado/efectos de los fármacos , Corticosterona/farmacología , Dinorfinas/biosíntesis , Embrión de Mamíferos , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Núcleo Accumbens/fisiología , Embarazo , Precursores de Proteínas/biosíntesis , Putamen/fisiología , Ratas , Ratas Wistar , Receptores de Dopamina D1/biosíntesis , Transducción de Señal , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Three weeks following intermittent amphetamine exposure (2.5 mg/kg/day for 5 days), rats showed an enhanced locomotor response to an amphetamine challenge. Mifepristone (20 mg/kg) given 45 min prior to the challenge completely prevented the expression of amphetamine hyperresponsiveness. The glucocorticoid antagonist did not affect the locomotor response to amphetamine in drug-naive rats. These data demonstrate for the first time that glucocorticoid receptor antagonist treatment may prevent long-term hyperreactivity to drugs of abuse in individuals with a drug history.
Asunto(s)
Anfetamina/antagonistas & inhibidores , Antagonistas de Hormonas/farmacología , Mifepristona/farmacología , Actividad Motora/efectos de los fármacos , Anfetamina/farmacología , Animales , Masculino , Ratas , Ratas Wistar , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/fisiologíaRESUMEN
3 weeks following cessation of intermittent morphine administration (10 mg/kg, s.c., once daily for 14 days), [3H]dopamine and [14C]acetylcholine release induced by 10 microM N-methyl-D-aspartate (NMDA) from superfused rat striatal slices appeared to be significantly higher than the release from striatal slices from saline-treated rats. A similar adaptive increase of the NMDA-evoked release of these neurotransmitters was observed in slices of the nucleus accumbens, whereas that of [3H]noradrenaline from hippocampal slices remained unchanged. Blockade of dopamine D2 receptors by 10 microM (--)-sulpiride enhanced NMDA-induced [3H]dopamine and [14C]acetylcholine release from striatal slices from saline-treated animals, but was found to be ineffective in this respect following intermittent morphine treatment. Moreover, morphine administration appeared to cause a profound decrease in the apparent affinity of the full dopamine D2 receptor agonist LY171555 (quinpirole) for these release-inhibitory dopamine D2 receptors, indicating the occurrence of dopamine D2 receptor desensitization. It is suggested that such a desensitization of dopamine D2 receptors on dopaminergic nerve terminals as well as on cholinergic interneurons may play a pivotal role in the long-lasting nature of behavioural sensitization upon cessation of treatment with morphine and possibly other drugs of abuse.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Morfina/farmacología , Narcóticos/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Acetilcolina/metabolismo , Animales , Dopamina/metabolismo , Técnicas In Vitro , Masculino , N-Metilaspartato/farmacología , Ratas , Ratas Wistar , Sulpirida/farmacologíaRESUMEN
Considering the long-lasting neuroadaptations that occur in the brain after exposure to drugs of abuse, we found that the facilitatory effect of an EC50 concentration (0.1 microM) of the acetylcholinesterase inhibitor physostigmine, unlike that of the muscarinic receptor agonist oxotremorine, on K(+)-induced [3H]dopamine release from rat striatal slices was enhanced about 2-fold 1 month after cessation of intermittent morphine treatment. Similarly, the inhibitory effect of physostigmine on K(+)-induced [14C]acetylcholine release from the slices was enhanced subsequent to morphine treatment, whereas that of oxotremorine appeared to be unchanged. Therefore, intermittent morphine administration may cause a very long-lasting increase of muscarinic receptor activation by released endogenous acetylcholine in rat striatum, which may play a pivotal role in the enduring character of stimulus hyperresponsiveness after exposure to drugs of abuse.
Asunto(s)
Acetilcolina/metabolismo , Cuerpo Estriado/efectos de los fármacos , Morfina/farmacología , Narcóticos/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Técnicas In Vitro , Masculino , Ratas , Ratas Wistar , Receptores Muscarínicos/efectos de los fármacosRESUMEN
The present study was designed to evaluate the hypothesis that enhanced corticosterone levels may facilitate the enduring neuroadaptive effects in the brain caused by drugs of abuse. Treatment of primary neuronal cultures of the rat striatal complex (striatum/nucleus accumbens, consisting for more than 90% of gamma-aminobutyric acid neurons) with 10 microM morphine for 2 hr to 3 days, enhanced the maximal stimulatory effect of the dopamine D-1 receptor agonist SKF38393 on adenylyl cyclase activity. This adaptive increase in D-1 receptor efficacy upon long-term mu-opioid receptor activation was about doubled after simultaneous or previous exposure of the neurons to the glucocorticoid receptor agonist dexamethasone (EC50 about 2 nM). A similar facilitation of the effect of morphine was observed upon exposure of the neurons to relatively high (nanomolar) concentrations of corticosterone, whereas the mineralocorticoid receptor agonist aldosterone appeared to be ineffective in this respect, indicating the involvement of glucocorticoid receptors. Interestingly, whereas morphine exposure also enhanced isoprenaline-stimulated adenylyl cyclase activity, this increase of beta adrenoceptor efficacy was not at all affected by dexamethasone. In both morphine-treated and untreated neurons, low concentrations (< .3 nM) of corticosterone or aldosterone, but not dexamethasone, caused a slight (about 20%) reduction of dopamine D-1 receptor-stimulated adenylyl cyclase activity, indicating the involvement of mineralocorticoid receptors. These data show that the morphine-induced adaptive increase of postsynaptic dopamine D-1 receptor efficacy (also observed in striatal slices of rats weeks after repeated treatment with morphine or cocaine) is strongly enhanced after previous or simultaneous glucocorticoid receptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Morfina/farmacología , Narcóticos/farmacología , Neuronas/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Esteroides/agonistas , Ácido gamma-Aminobutírico/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Células Cultivadas , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Dexametasona/farmacología , Activación Enzimática , Neuronas/metabolismo , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/enzimología , Ratas , Receptores de Dopamina D1/agonistas , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/metabolismo , Receptores de Esteroides/metabolismo , Trastornos Relacionados con Sustancias , Factores de TiempoRESUMEN
Intermittent treatment of rats with morphine (10 mg/kg s.c., once daily) caused an increase (of about 30%) of the electrically evoked release of [14C]acetylcholine from cholinergic interneurons of superfused striatal slices 1-21 days after morphine withdrawal. Similarly, chronic treatment with escalating doses of morphine (5-50 mg/kg s.c., 3 times daily), causing physical dependence (unlike intermittent treatment), resulted in an enduring enhanced response of these neurons towards depolarization. Following chronic morphine treatment this adaptive increase of acetylcholine release was associated with a slight but long-lasting decrease of the (delta-opioid receptor-mediated) maximal inhibitory effect of [Met5]enkephalin, whereas upon intermittent drug treatment delta-opioid receptor desensitization was observed 1 day after opiate withdrawal only. Also in slices of the nucleus accumbens both intermittent as well as chronic morphine administration caused a long-lasting increase of the electrically evoked [14C]acetylcholine release. Therefore, we hypothesize that an enhanced (re)activity of striatal and accumbal cholinergic neurons, which are regulated by dopaminergic neurons of the ventral mesencephalon, may represent a long-lasting neuroadaptive effect of morphine (and possibly other drugs of abuse) playing a crucial role in behavioral sensitization associated with enhanced vulnerability to drugs of abuse.
Asunto(s)
Acetilcolina/metabolismo , Cuerpo Estriado/efectos de los fármacos , Morfina/farmacología , Núcleo Accumbens/efectos de los fármacos , Animales , Fibras Colinérgicas/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Cloruro de Sodio/farmacología , Factores de TiempoRESUMEN
Repeated, once daily morphine treatment (14 days) as well as chronic morphine administration (6 days) caused a rebound reduction in the electrically evoked release of [3H]dopamine from superfused rat striatal slices 1 day after the last subcutaneous injection. Interestingly, whereas [3H]dopamine release remained significantly reduced for at least 3 weeks following morphine withdrawal in chronically treated (tolerant/dependent) rats, neurotransmitter release from dopaminergic nerve terminals gradually increased above control values following cessation of repeated morphine administration. Postsynaptically, dopamine D1 receptor-stimulated adenylate cyclase appeared to be sensitized 1-3 days but was unchanged 3 weeks after chronic morphine treatment. In contrast, such an enhanced postsynaptic dopamine D1 receptor efficacy did not occur 1-3 days following repeated morphine administration, but appeared to develop slowly resulting in a profound increase of dopamine-sensitive adenylate cyclase 3 weeks after the last injection. The inhibitory effect of dynorphin A-(1-13) on [3H]dopamine release, as well as that of [Met5]enkephalin on dopamine D1 receptor-stimulated adenylate cyclase appeared to be unchanged subsequent to repeated or chronic morphine treatment. These data indicate that, long after cessation of drug treatment, chronic morphine treatment causes a reduction whereas repeated morphine administration gradually induces an enhancement of opioid receptor-regulated dopaminergic neurotransmission due to local adaptive changes within the rat striatum. Such distinct long-lasting alterations of dopaminergic neurotransmission induced by different temporal patterns of morphine administration in projection areas of mesencephalic dopaminergic neurons may be related to the enduring effects of drug abuse such as behavioural sensitization and drug craving.