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1.
Neurochem Int ; 60(8): 791-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22426202

RESUMO

The psychostimulant drug amphetamine is often prescribed to treat Attention-Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC). Recent behavioral data suggest that the endocannabinoid system also plays a role in this respect. Here we investigated the role of cannabinoid CB1 receptor activity in amphetamine-induced monoamine release in the NAC and/or mPFC of rats using in vivo microdialysis. Results show that systemic administration of a low, clinically relevant dose of amphetamine (0.5mg/kg) robustly increased dopamine and norepinephrine release (to ∼175-350% of baseline values) in the NAC shell and core subregions as well as the ventral and dorsal parts of the mPFC, while moderately enhancing extracellular serotonin levels (to ∼135% of baseline value) in the NAC core only. Although systemic administration of the CB1 receptor antagonist SR141716A (0-3mg/kg) alone did not affect monoamine release, it dose-dependently abolished amphetamine-induced dopamine release specifically in the NAC shell. SR141716A did not affect amphetamine-induced norepinephrine or serotonin release in any of the brain regions investigated. Thus, the effects of acute CB1 receptor blockade on amphetamine-induced monoamine transmission were restricted to dopamine, and more specifically to mesolimbic dopamine projections into the NAC shell. This brain region- and monoamine-selective role of CB1 receptors is suggested to subserve the behavioral effects of amphetamine.


Assuntos
Anfetamina/farmacologia , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Receptor CB1 de Canabinoide/agonistas , Animais , Masculino , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar
2.
Behav Brain Res ; 217(2): 408-15, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21074574

RESUMO

Cannabinoid CB(1) receptor (CB(1)R) signaling has been shown to play a role in the regulation of addictive behavior. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 could reduce ethanol and nicotine self-administration and cue-induced reinstatement of ethanol and nicotine seeking behavior in Wistar rats. In operant chambers, rats were learned to emit a specific response (nose poke) in order to receive an ethanol solution or intravenous injections of nicotine. Discrete light and tone cues were presented during ethanol and nicotine delivery. These cues are particularly important for drug self-administration behavior and, through Pavlovian conditioning, acquire conditioned reinforcing and motivational properties and are therefore able to generate and maintain drug-seeking behavior. Subsequently, the CB(1)R antagonist SLV330 (doses ranging from 1 to 10mg/kg, given orally, p.o.) was administered to investigate the effects on drug self-administration. In addition, responding for ethanol and nicotine was extinguished. Then, the animals were tested for cue-induced reinstatement of ethanol and nicotine seeking and treated with vehicle or SLV330. Finally, the effects of SLV330 were studied on the number of anticipatory responses in the 5-choice serial reaction time task (5-CSRTT) in order to determine whether this compound could also increase impulse control in Wistar rats. The CB(1) antagonist SLV330 was effective in reducing ethanol self-administration at a lowest effective dose (LED) of 10mg/kg (p.o.) and reinstatement of ethanol seeking at a LED of 3mg/kg (p.o.). SLV330 was also effective in reducing nicotine self-administration and reinstatement of nicotine seeking, although at a LED of 10mg/kg (p.o.). Finally, SLV330 decreased time delay-dependent anticipatory responding (LED of 3.0mg/kg, p.o.), indicating an increased inhibitory control. These findings are in agreement with results reported with other CB(1) antagonists. The combined action of reducing the reinforcing and motivational properties of nicotine and alcohol and the improvement of impulse control supports the idea that the cannabinoid system is a promising target for anti-relapse medication.


Assuntos
Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/efeitos adversos , Nicotina/efeitos adversos , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sulfonamidas/farmacologia , Análise de Variância , Animais , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Masculino , Nicotina/administração & dosagem , Pirazóis/química , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/química , Reforço Psicológico , Autoadministração , Sulfonamidas/química , Fatores de Tempo
3.
Neuropharmacology ; 55(5): 712-6, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18588903

RESUMO

Nicotine-associated paraphernalia such as cigarettes and ashtrays are potent smoking relapse triggers. In addition to these discrete cues, environmental contexts previously associated with smoking elicit strong cigarette craving, indicating that contextual stimuli also contribute to high smoking relapse rates. Nonetheless, little is known about the precise role of these stimuli in smoking relapse and the neuropharmacological mechanisms implicated herein. To address this issue, we determined whether re-exposure to the nicotine self-administration context after long-term extinction reinstates nicotine seeking behavior in rats. Further, we examined the effects of SR141716A (Rimonabant), a selective cannabinoid CB1 receptor antagonist which has been shown to attenuate cue-induced relapse to nicotine seeking, on context-induced reinstatement of nicotine seeking. Rats were trained to self-administer nicotine intravenously (30microg/kg/infusion). Nicotine infusions were paired with an audiovisual compound stimulus. Subsequently, nose poking behavior was extinguished in the presence of this discrete cue in a context different from the self-administration context. Hereafter, rats were injected with 0, 1, or 3mg/kg Rimonabant (i.p.) prior to re-exposure to either the self-administration or the extinction context. Re-exposure to the self-administration context, but not to the extinction context robustly reinstated responding for the discrete nicotine cues, an effect that was dose-dependently attenuated by Rimonabant. This is the first demonstration of contextual renewal of nicotine seeking in rodents after prolonged withdrawal. Further, our results indicate that the endocannabinoid system is involved in context-induced relapse to nicotine seeking, and as such these data provide further evidence for the use of CB1 antagonists in smoking cessation.


Assuntos
Antagonistas de Receptores de Canabinoides , Condicionamento Operante/efeitos dos fármacos , Nicotina/administração & dosagem , Piperidinas/farmacologia , Pirazóis/farmacologia , Tabagismo/psicologia , Análise de Variância , Animais , Comportamento Animal , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Reforço Psicológico , Rimonabanto , Autoadministração , Tabagismo/fisiopatologia
4.
Neuroscience ; 146(4): 1662-76, 2007 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-17467186

RESUMO

Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by N-ethyl-N-nitrosurea (ENU)-driven target-selected mutagenesis. Biochemical characterization revealed that SERT mRNA and functional protein are completely absent in homozygous knockout (SERT-/-) rats, and that there is a gene dose-dependent reduction in the expression and function of the SERT in heterozygous knockout rats. As a result, 5-HT homeostasis was found to be severely affected in SERT-/- rats: 5-HT tissue levels and depolarization-induced 5-HT release were significantly reduced, and basal extracellular 5-HT levels in the hippocampus were ninefold increased. Interestingly, we found no compensatory changes in in vitro activity of tryptophan hydroxylase and monoamine oxidase, the primary enzymes involved in 5-HT synthesis and degradation, respectively. Similarly, no major adaptations in non-serotonergic systems were found, as determined by dopamine and noradrenaline transporter binding, monoamine tissue levels, and depolarization-induced release of dopamine, noradrenaline, glutamate and GABA. In conclusion, neurochemical changes in the SERT knockout rat are primarily limited to the serotonergic system, making this novel rat model potentially very useful for studying the behavioral and neurobiological consequences of disturbed 5-HT homeostasis.


Assuntos
Química Encefálica/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Serotonina/metabolismo , Animais , Animais Geneticamente Modificados , Monoaminoxidase/metabolismo , Mutagênese/efeitos dos fármacos , Mutagênese/fisiologia , Neurotransmissores/metabolismo , Nitrosometiluretano/farmacologia , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Triptofano Hidroxilase/metabolismo
5.
Genes Brain Behav ; 6(6): 579-87, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17116168

RESUMO

The tremendous increase in the use of mouse inbred strains and mutant mice to study the molecular basis of psychiatric disorders urges for a better understanding of attentional performance in mice. To this aim, we investigated possible strain differences in performance and cholinergic modulation of visuospatial attention in three widely used mouse inbred strains (129S2/SvHsd, C57BL/6JOlaHsd and DBA/2OlaHsd) in the five-choice serial reaction time task. Results indicated that after extended training, performance of 129S2/SvHsd mice was superior to that of C57BL/6JOlaHsd and DBA/2OlaHsd mice in terms of attention, omission errors, inhibitory control and latencies to correct choice. Increasing the attentional load resulted in comparable decrements in attention in all strains and inhibitory control impairments that were most pronounced in DBA/2OlaHsd mice. Further pharmacological evaluation indicated that all strains showed attentional impairments after treatment with the muscarinic and nicotinic antagonists scopolamine and mecamylamine, respectively. 129S2/SvHsd mice were less sensitive, whereas DBA/2OlaHsd mice appeared more sensitive to the detrimental effects of mecamylamine. In addition, subchronic, but not acute, nicotine treatment slightly improved attentional performance in all strains to the same extent. In conclusion, our data indicate strain specificity with particularly good performance of 129S2/SvHsd mice and strong cholinergic involvement in visuospatial attention in mice.


Assuntos
Atenção/fisiologia , Comportamento de Escolha/fisiologia , Fibras Colinérgicas/fisiologia , Aprendizagem em Labirinto/fisiologia , Receptores Colinérgicos/fisiologia , Aprendizagem Seriada/fisiologia , Animais , Atenção/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Colinérgicos/farmacologia , Fibras Colinérgicas/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Nicotina/farmacologia , Receptores Colinérgicos/efeitos dos fármacos , Escopolamina/farmacologia , Aprendizagem Seriada/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Especificidade da Espécie
6.
Neuropharmacology ; 51(4): 773-81, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16806307

RESUMO

We examined the occurrence of functional interactions between CB1 cannabinoid and mu opioid receptors in the core of rat nucleus accumbens (NAc core). To that end, receptor-mediated inhibition of depolarization (4-aminopyridine)-induced [3H]glutamate release and glutamate (NMDA) receptor-stimulated [14C]acetylcholine (ACh) and [3H]GABA release was studied in superfused NAc core slices. The inhibitory effects of the mu receptor agonist morphine and the CB1 receptor agonist HU210 on the release of these neurotransmitters were selectively antagonized by the mu receptor antagonist naloxone and the CB1 receptor antagonist SR141716A, respectively. Surprisingly, naloxone prevented the antagonistic action of SR141716A at CB1 receptors and SR141716A abolished that of naloxone at mu receptors mediating inhibition of [3H]glutamate and [3H]GABA release. Therefore, these antagonists seem to allosterically interact, indicating the involvement of physically associated mu opioid and CB1 cannabinoid receptors. Such an interaction between antagonists was not observed at the receptors mediating inhibition of [14C]ACh release. Moreover, dose-response curves of the agonists showed that mu and CB1 receptors mediating inhibition of [3H]glutamate release display a non-additive interaction, whereas these receptors synergistically interact regarding their inhibitory control of [3H]GABA release. Finally, the apparent allosteric interaction between antagonists was also observed regarding the effects of other receptor-selective agonists and antagonists at mu opioid and CB1 cannabinoid receptors (mediating inhibition of NMDA-induced [3H]GABA release) and must therefore be a unique property of the receptors involved. These data suggest the existence of physically associated mu opioid and CB1 cannabinoid receptors, whereby activation of these receptors results in either a non-additive (glutamate release) or a synergistic (GABA release) effect. It is proposed that these allosterically interacting mu and CB1 receptors in the NAc core may represent G-protein coupled heterodimeric receptor complexes.


Assuntos
Inibição Neural/efeitos dos fármacos , Neurotransmissores/metabolismo , Núcleo Accumbens/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/fisiologia , Receptores Opioides mu/fisiologia , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Rimonabanto , Trítio/metabolismo
7.
J Neural Transm (Vienna) ; 113(5): 593-8, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16252076

RESUMO

Anethole dithiolethione (ADT) is a clinically available, pluripotent antioxidant proposed as a neuroprotectant for Parkinson's disease (PD). Here, using extracts from cultured astrocytes, containing both monoamine oxidase (MAO) A and B activity, we demonstrate that ADT concentration-dependently inhibits MAO-B activity in a clinically relevant concentration range (0.03-30 microM, IC-50 = 0.5 microM) without affecting MAO A activity. Considering the alleged contribution of MAO activity in general, and MAO-B in particular, to oxidative stress and neurodegeneration in PD, our data further support the neuroprotective potential of ADT.


Assuntos
Anetol Tritiona/farmacologia , Antioxidantes/farmacologia , Astrócitos/efeitos dos fármacos , Monoaminoxidase/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Gânglios da Base/citologia , Células Cultivadas , Clorgilina/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Ratos
8.
Neuroscience ; 128(1): 121-30, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15450359

RESUMO

Numerous clinical studies have indicated that lifetime anxiety is highly prevalent in drug addicts. In the treatment of drug abuse, dually diagnosed drug addicts may benefit from pharmacological intervention strategies that alleviate the psychiatric symptomatology. We have previously shown that rats with different coping strategies in a stressful environment show strong differences in the motivation to self-administer cocaine. That is, cocaine self-administration under a progressive ratio (PR) schedule of reinforcement was enhanced in high grooming (HG) rats as compared with low grooming (LG) rats. To identify the pharmacological basis of these differences, we tested the acute effects of several anxiolytic drugs on cocaine self-administration in HG and LG rats under a PR schedule of reinforcement. Chlordiazepoxide increased PR responding in both the HG and LG rats, while the selective corticotrophin releasing hormone 1 receptor antagonist R121919 had no effect on cocaine self-administration under the PR schedule. Interestingly, buspirone and fluoxetine decreased PR responding in HG rats only and thereby abolished the individual differences in PR responding between HG and LG rats. In support of the differential effects of the serotonergic drugs on PR responding in HG and LG rats, we found that the in vitro electrically evoked release of [3H]serotonin from mesocorticolimbic brain slices was reduced in the medial prefrontal cortex, substantia nigra and nucleus accumbens core, and increased in the nucleus accumbens shell of HG rats relative to LG rats. These findings show that serotonergic anxiolytics abolish the pre-existing individual differences in cocaine self-administration between HG and LG rats, which show differences in the reactivity of serotonergic neurons. This suggests that the effectiveness of pharmacological interference may depend on the neurochemical and motivational state of the individual.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Aditivo/fisiopatologia , Encéfalo/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Automedicação , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Comportamento Aditivo/complicações , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/complicações , Masculino , Motivação , Neurônios/metabolismo , Ratos , Ratos Wistar , Serotonina/metabolismo
9.
Neuroscience ; 121(4): 829-36, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14580932

RESUMO

Previously, we demonstrated that stress-induced self-grooming behaviour in rats predicted an enhanced motivation to self-administer cocaine as determined under a progressive ratio schedule of reinforcement. The enhanced motivation of high grooming (HG) rats was associated with a reduced reactivity of dopaminergic neurons in the medial prefrontal cortex and amygdala, but not nucleus accumbens. In the present study, we studied the effect of cocaine and saline self-administration on these pre-existing differences in neurochemical profile by determining the electrically evoked release of [3H]dopamine and [14C]acetylcholine from superfused slices of the nucleus accumbens shell and core, medial prefrontal cortex and amygdala of HG and low grooming (LG) rats. Although HG and LG rats did not differ in acquisition of cocaine and saline self-administration, both conditions induced substantially different neuroadaptations in these rats. Differences in depolarisation-induced dopamine and acetylcholine release were maintained in the medial prefrontal cortex, emerged in the nucleus accumbens and dissipated in the amygdala. These results indicate that altered reactivity of mesocorticolimbic dopaminergic and cholinergic neurons due to exposure to cocaine and environmental stimuli (saline) is dependent on pre-existing neurochemical differences and displays region-specificity. These pre-existing differences and the cocaine- and environmental-induced neuroadaptations seem to act in concert to produce an enhanced motivational state to self-administer cocaine.


Assuntos
Acetilcolina/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/farmacologia , Dopamina/metabolismo , Sistema Límbico/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica , Técnicas In Vitro , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatologia , Masculino , Motivação , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , Autoadministração , Cloreto de Sódio/farmacologia , Síndrome de Abstinência a Substâncias/metabolismo
10.
Eur J Neurosci ; 14(9): 1533-8, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11722615

RESUMO

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long-lasting sensitization. The present study was designed to evaluate whether long-lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate-putamen, was assessed. In morphine-pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate-putamen from morphine-pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long-lasting behavioural sensitization and associated neuroadaptations.


Assuntos
Química Encefálica/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Tolerância a Medicamentos/fisiologia , Dependência de Morfina/metabolismo , Morfina/farmacologia , Neurotransmissores/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Acetilcolina/metabolismo , Anfetamina/farmacologia , Animais , Química Encefálica/fisiologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas/fisiologia , Masculino , Dependência de Morfina/fisiopatologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neostriado/fisiopatologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Wistar , Trítio/metabolismo
11.
Nat Med ; 7(10): 1151-4, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11590440

RESUMO

Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction. The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system and has rewarding effects in preclinical models of drug abuse. We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.


Assuntos
Canabinoides/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/metabolismo , Receptores de Droga/metabolismo , Animais , Comportamento Animal , Moduladores de Receptores de Canabinoides , Canabinoides/agonistas , Canabinoides/antagonistas & inibidores , Cocaína/farmacologia , Modelos Animais de Doenças , Dronabinol/análogos & derivados , Dronabinol/metabolismo , Dronabinol/farmacologia , Humanos , Piperidinas/metabolismo , Piperidinas/farmacologia , Pirazóis/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Long-Evans , Ratos Wistar , Receptores de Canabinoides , Receptores de Droga/antagonistas & inibidores , Recidiva , Rimonabanto
12.
Synapse ; 42(2): 87-94, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11574945

RESUMO

Withdrawal from repeated exposure to morphine causes a long-lasting increase in the reactivity of nucleus accumbens nerve terminals towards excitation. The resulting increase in action potential-induced exocytotic release of neurotransmitters, associated with behavioral sensitization, is thought to contribute to its addictive properties. We recently showed that activation of N-methyl-D-aspartate (NMDA) as well as dopamine (DA) D1 receptors in rat striatum causes tetrodotoxin-insensitive transporter-dependent GABA release. Since sustained changes in extracellular GABA levels may play a role in drug-induced neuronal hyperresponsiveness, we examined the acute and long-lasting effect of morphine on this nonvesicular GABA release in rat nucleus accumbens slices. The present study shows that morphine, through activation of mu-opioid receptors, reduces nonvesicular NMDA-induced [(3)H]GABA release in superfused nucleus accumbens slices. Moreover, prior repeated morphine treatment of rats (10 mg/kg, sc, 14 days) caused a reduction in NMDA-stimulated [(3)H]GABA release in vitro until at least 3 weeks after morphine withdrawal. This persistent neuroadaptive effect was not observed studying dopamine D1 receptor-mediated [(3)H]GABA release in nucleus accumbens slices. Moreover, this phenomenon appeared to be absent in slices of the caudate putamen. Interestingly, even a single exposure of rats to morphine (>2 mg/kg) caused a long-lasting inhibition of NMDA-induced release of GABA in nucleus accumbens slices. These data suggest that a reduction in nonvesicular GABA release within the nucleus accumbens, by enhancing the excitability of input and output neurons of this brain region, may contribute to the acute and persistently enhanced exocytotic release of neurotransmitters from nucleus accumbens neurons in morphine-exposed rats.


Assuntos
Benzenoacetamidas , Proteínas de Transporte/efeitos dos fármacos , Morfina/farmacologia , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Analgésicos/farmacologia , Animais , Proteínas de Transporte/metabolismo , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Dependência de Morfina/metabolismo , Dependência de Morfina/fisiopatologia , N-Metilaspartato/farmacologia , Naloxona/farmacologia , Inibição Neural/fisiologia , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Técnicas de Cultura de Órgãos , Pirrolidinas/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides mu/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Trítio/farmacocinética , Ácido gama-Aminobutírico/farmacocinética
13.
Alcohol Clin Exp Res ; 25(7): 960-7, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11505019

RESUMO

BACKGROUND: Research has indicated a close relationship between the P3 event-related potential and the dopamine D2 receptor A1 allele in individuals at high risk for alcoholism. Other research has suggested an association between the dopamine D2 receptor A1 allele and sensation-seeking. In this study, we further examined the relationships between the P3, the A1 allele, and sensation-seeking in a sample of nonalcoholic adult children of alcoholics. METHODS: Participants (n = 57; range, 19-30 years; 41 women), who performed a visual novelty oddball task to elicit the P3, were asked to fill in personality questionnaires, including Zuckerman's Sensation-Seeking Scale, and were classified according to the presence of the dopamine D2 receptor A1 allele. The effects of sex, age, and socioeconomic status were assessed to determine whether these variables affected the relations between the P3, the A1 allele, and sensation-seeking. RESULTS: A small P3 amplitude was associated with high sensation-seeking, particularly with high disinhibition. The presence of the A1 allele was also associated with high disinhibition, but only in men. By contrast, P3 amplitudes and latencies were not associated with the presence of the A1 allele. CONCLUSIONS: Although a small P3 amplitude, high sensation-seeking, and the presence of the A1 allele were all associated with alcoholism risk, these findings indicate that these three characteristics together do not reflect a common risk factor in alcoholism.


Assuntos
Alcoolismo/genética , Alelos , Potenciais Evocados/fisiologia , Comportamento Exploratório/fisiologia , Receptores de Dopamina D2/genética , Adulto , Eletroencefalografia , Feminino , Genótipo , Humanos , Masculino , Personalidade , Polimorfismo Genético/genética
14.
Eur J Neurosci ; 13(10): 1923-30, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11403685

RESUMO

Single administration of the cytokine interleukin-1beta (IL-1) or the psychostimulant amphetamine causes long-term sensitization of the hypothalamus pituitary adrenal (HPA) axis, i.e. enhanced adrenocorticotropine hormone (ACTH) and corticosterone responses weeks later. HPA responses to these stimuli involve activation of hypothalamic corticotropin-releasing hormone (CRH) neurons by noradrenergic projections to the paraventricular nucleus (PVN). In search of the underlying mechanisms, we studied the temporal pattern of HPA sensitization in relation to (1) the reactivity of noradrenergic projections to the PVN and (2) altered secretagogue production in hypothalamic CRH neurons. Single exposure to IL-1 or amphetamine induced cross-sensitization of ACTH and corticosterone responses 11 and 22 days later, but not after 42 days. Amphetamine-induced HPA sensitization was not accompanied by increased costorage of arginine vasopressin (AVP) in CRH terminals, as found previously after IL-1 pretreatment. The reactivity of noradrenergic terminals was assessed by measuring the electrically evoked release of [3H]-noradrenaline from superfused PVN slices. Single administration of amphetamine and IL-1 induced a long-lasting (up to 22 days) increase (up to 165%) of evoked noradrenaline release. This indicates that single exposure to psychostimulants or to cytokines can induce a long-lasting increase in stimulus-secretion coupling in brainstem noradrenergic neurons that innervate the PVN. This common, long-lasting functional change may underlie, at least in part, IL-1- and amphetamine-induced HPA cross-sensitization. In addition, increased AVP signalling by hypothalamic CRH neurons appears to play a role in IL-1-induced, but not in amphetamine-induced, HPA sensitization.


Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Corticosterona/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Interleucina-1/farmacologia , Norepinefrina/metabolismo , Animais , Arginina Vasopressina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Resistência a Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Eminência Mediana/metabolismo , Ratos , Ratos Wistar , Estresse Psicológico/psicologia , Fatores de Tempo
15.
Psychopharmacology (Berl) ; 150(1): 35-44, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10867974

RESUMO

RATIONALE: Mesolimbic dopaminergic neurotransmission plays a critical role in the locomotor effects of psychostimulant drugs, but a general involvement in the induction of long-term psychostimulant sensitization is questionable. By influencing dopaminergic neurotransmission, opioid drugs can alter the behavioral effects of psychostimulants. OBJECTIVES: The effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on the locomotor stimulant and the long-term sensitizing effects of amphetamine and cocaine were investigated in rats. Unlike U69593 and U50488H, bremazocine is also an antagonist at mu- and delta-opioid receptors, as well as an agonist at a subtype of delta-opioid receptors inhibiting dopamine D1 receptor-stimulated adenylate cyclase. METHODS: Bremazocine, U69593, and U50488H were administered prior to amphetamine and cocaine, and locomotor activity was measured. In separate studies, the opioids were co-administered with amphetamine and cocaine for 5 days, and locomotor sensitization was assessed 3 weeks post-treatment. RESULTS: Bremazocine and U69593 attenuated the psychomotor stimulant effects of amphetamine and cocaine. U50488H attenuated the locomotor effect of cocaine and biphasically affected amphetamine-induced locomotion, i.e., suppression followed by stimulation. Bremazocine prevented the development of amphetamine-induced but not cocaine-induced long-term sensitization. Neither U69593 nor U50448H affected the induction of long-term amphetamine or cocaine sensitization. CONCLUSIONS: In agreement with previous studies, the present data suggest that differential mechanisms underlie the acute stimulant versus the long-term sensitizing effects of psychostimulants, and the induction of long-term sensitization by amphetamine versus cocaine. Stimulation of kappa-opioid receptors does not seem to block the induction of long-term psychostimulant sensitization. Thus, bremazocine is likely to block the induction of amphetamine sensitization through a non-kappa-opioid receptor mechanism. We suggest that this effect of bremazocine is the result of its unique agonist action at a subtype of delta-opioid receptors, thereby acting as a functional dopamine D1 receptor antagonist. This would be consistent with the literature showing that the induction of long-term amphetamine sensitization depends on the activation of dopamine D1 receptors. In addition, the present data are in keeping with studies showing that dopamine neurotransmission is not critical for the induction of long-term cocaine sensitization.


Assuntos
Benzenoacetamidas , Estimulantes do Sistema Nervoso Central/farmacologia , Atividade Motora/efeitos dos fármacos , Agitação Psicomotora/tratamento farmacológico , Receptores Opioides kappa/agonistas , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/uso terapêutico , Anfetamina/antagonistas & inibidores , Analgésicos/antagonistas & inibidores , Animais , Benzomorfanos/farmacologia , Benzomorfanos/uso terapêutico , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Cocaína/antagonistas & inibidores , Masculino , Atividade Motora/fisiologia , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Ratos , Ratos Wistar
16.
J Neurosci ; 20(9): 3496-503, 2000 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-10777812

RESUMO

Given the complex interactions between dopamine D1 and glutamate NMDA receptors in the striatum, we investigated the role of these receptors in transporter-mediated GABA release from cultured medium spiny neurons of rat striatum. Like NMDA receptor-mediated [(3)H]-GABA release, that induced by prolonged (20 min) dopamine D1 receptor activation was enhanced on omission of external calcium, was action potential-independent (tetrodotoxin-insensitive), and was diminished by the GABA transporter blocker nipecotic acid, indicating the involvement of transporter-mediated release. Interestingly, lowering the external sodium concentration only reduced the stimulatory effect of NMDA. Blockade of Na(+)/K(+)-ATPase by ouabain enhanced NMDA-induced but abolished dopamine-induced release. Moreover, dopamine appeared to potentiate the effect of NMDA on [(3)H]-GABA release. These effects of dopamine were mimicked by forskolin. mu-Opioid receptor-mediated inhibition of adenylyl cyclase by morphine reduced dopamine- and NMDA-induced release. These results confirm previous studies indicating that NMDA receptor activation causes a slow action potential-independent efflux of GABA by reversal of the sodium-dependent GABA transporter on sodium entry through the NMDA receptor channel. Moreover, our data indicate that activation of G-protein-coupled dopamine D1 receptors also induces a transporter-mediated increase in spontaneous GABA release, but through a different mechanism of action, i.e., through cAMP-dependent inhibition of Na(+)/K(+)-ATPase, inducing accumulation of intracellular sodium, reversal of the GABA carrier, and potentiation of NMDA-induced release. These receptor interactions may play a crucial role in the behavioral activating effects of psychostimulant drugs.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Transportadores de Ânions Orgânicos , Receptores de Dopamina D1/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cardiotônicos/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , AMP Cíclico/metabolismo , Dopamina/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA , Masculino , Proteínas de Membrana/efeitos dos fármacos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo
17.
Acta Neuropsychiatr ; 12(1): 5-8, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26976679

RESUMO

Repeated exposure of rats to cocaine, amphetamine, opiates, nicotine and alcohol causes a very long-lasting (months) increase in the behavioral effects of these addictive drugs and drug-associated environmental stimuli (sensitization). This hypersensitivity is associated with persistent changes in the reactivity of neurons of the motivational (mesocorticolim-bic) system in the brain. Using an animal model for relapse, recent studies in our laboratory show that relapse to drug-seeking behavior (following extinction of intravenous cocaine or heroin self-administration) depends on the occurrence of sensitization. Accordingly, sensitization and conditioning seem to be more important for the persistence of drug and alcohol addiction then the occurrence of withdrawal phenomena. Biochemical research on the molecular and cellular basis of behavioral sensitization and behavioral studies on readjustment of stimulus responsiveness in rats, is of great importance for the development of an adequate pharmacotherapy of addiction.

18.
J Neurosci ; 19(21): 9579-86, 1999 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-10531460

RESUMO

Repeated treatment with psychostimulant drugs causes long-lasting behavioral sensitization and associated neuroadaptations. Although sensitization induced by a single psychostimulant exposure has also been reported, information on the behavioral and neurochemical consequences of a single psychostimulant exposure is sparse. Therefore, to evaluate whether behavioral sensitization evoked by single and repeated psychostimulant pretreatment regimens represent the same neurobiological phenomenon, the time-dependent expression of behavioral, neurochemical, and neuroendocrine sensitization after a single exposure to amphetamine was investigated in rats. A single exposure to amphetamine (5 mg/kg, i.p.) caused context-independent sensitization of the locomotor effects of amphetamine, which intensified over time. Thus, sensitization to amphetamine was marginal at 3 d after treatment and more evident after 1 week, whereas 3 weeks after treatment, profound sensitization, as well as cross-sensitization, to cocaine was observed. Amphetamine pretreatment caused an increase in the electrically evoked release of [(3)H]dopamine from nucleus accumbens, caudate putamen, and medial prefrontal cortex slices and of [(14)C]acetylcholine from accumbens and caudate slices. The hyperreactivity of dopaminergic nerve terminals appeared to parallel the development of locomotor sensitization, i.e., whereas hyperreactivity of accumbens dopaminergic terminals increased between 3 d and 3 weeks after treatment, the hyperreactivity of medial prefrontal dopaminergic terminals decreased. Pre-exposure to amphetamine also sensitized the hypothalamus-pituitary-adrenal axis response to amphetamine at 1 and 3 weeks, but not at 3 d after treatment. Because these data closely resemble those reported previously for repeated amphetamine pretreatment, it is concluded that a single exposure to amphetamine is sufficient to induce long-term behavioral, neurochemical, and neuroendocrine sensitization in rats.


Assuntos
Acetilcolina/metabolismo , Anfetamina/farmacologia , Núcleo Caudado/fisiologia , Dopamina/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Córtex Pré-Frontal/fisiologia , Putamen/fisiologia , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Anfetamina/administração & dosagem , Animais , Benzazepinas/farmacologia , Proteínas de Transporte/agonistas , Proteínas de Transporte/fisiologia , Núcleo Caudado/efeitos dos fármacos , Cocaína/farmacologia , Corticosterona/sangue , Corticosterona/metabolismo , Agonistas de Dopamina/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Técnicas In Vitro , Injeções Intraperitoneais , Masculino , Núcleo Accumbens/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Putamen/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Dopaminérgicos/fisiologia , Receptores de Droga/agonistas , Receptores de Droga/fisiologia , Fatores de Tempo
19.
Neuropsychopharmacology ; 21(4): 550-9, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10481839

RESUMO

Repeated exposure to morphine and amphetamine induces long-lasting sensitization of their psychomotor stimulant properties, whereas pretreatment with morphine causes cross-sensitization of the locomotor effects of amphetamine. Here, we investigated whether pre-exposure to amphetamine also results in cross-sensitization to morphine. Rats pretreated with amphetamine (5 x 2.5 mg/kg, i.p.) displayed neither short-term (3 days post-treatment) nor long-term (3 weeks post-treatment) cross-sensitization of the locomotor effects of morphine (2 or 5 mg/kg, s.c.). Two other amphetamine pretreatment protocols (1 x 5 mg/kg, i.p. and 14 x 2.5 mg/kg, i.p.) also failed to induce cross-sensitization to morphine. In contrast, all amphetamine pretreatment regimens induced sensitization of the locomotor effects of amphetamine (1 mg/kg, i.p.) and pretreatment with morphine (14 x 10 mg/kg, s.c.) induced both short- and long-term sensitization of the locomotor effects of both morphine and amphetamine. These data suggest that the expression of sensitization of the locomotor effects of morphine and amphetamine, at least partially, involves distinct neuroadaptive phenomena.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Análise de Variância , Animais , Interações Medicamentosas , Masculino , Ratos , Ratos Wistar
20.
Neuroscience ; 92(1): 343-52, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10392855

RESUMO

Repeated exposure to drugs of abuse induces long-lasting behavioural sensitization, which is thought to play a role in the persistence of drug-seeking behaviour. Recently, we showed that repeated exposure of rats to cocaine resulted in a long-lasting (weeks) sensitization of the hypothalamus-pituitary-adrenal axis, i.e. hypersecretion of adrenocorticotropic hormone and of the glucocorticoid corticosterone. Moreover, we found that the administration of a glucocorticoid receptor antagonist abolished the expression of psychostimulant-induced behavioural sensitization. In the present study we tested whether stressor- or drug-induced long-term hypersecretion of corticosterone is associated with the long-term expression of behavioural sensitization to psychostimulant drugs. To that end, groups of male Wistar rats were exposed once to interleukin-1beta or to footshocks, treatments that are known to induce long-term sensitization of the hypothalamus-pituitary-adrenal axis, or were treated with amphetamine or morphine, according to protocols known to induce long-lasting behavioural (locomotor) sensitization. Three weeks later, the groups and their controls were challenged with amphetamine or vehicle. Previous exposure to interleukin-1beta or footshocks enhanced adrenocorticotropic hormone and corticosterone responses, but did not affect the long-term locomotor sensitization to amphetamine. Prior amphetamine treatment enhanced the locomotor response and the adrenocorticotropic hormone and corticosterone responses to amphetamine. Prior morphine treatment resulted in long-term locomotor sensitization, whereas the adrenocorticotropic hormone and corticosterone responses to amphetamine were decreased. From these findings and the absence of within-group correlation between corticosterone and locomotor responses in interleukin-1beta and morphine-pretreated rats, we conclude that there is no correlation between sensitization of the corticosterone response and behavioural sensitization to amphetamine. Apparently, sensitization of the corticosterone response is not a prerequisite for the long-term expression of behavioural sensitization, which suggests that drug-induced long-term behavioural sensitization may involve corticosteroid receptor-dependent (central) mechanisms that occur independent of hypothalamus-pituitary-adrenal axis responsiveness.


Assuntos
Anfetamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Corticosterona/metabolismo , Interleucina-1/farmacologia , Estresse Fisiológico/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Eletrochoque , Masculino , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo
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