RESUMO
The effects of the cannabinoid receptor agonist WIN 55,212-2 (0.1-5 mg/kg i.p.) on endogenous extracellular gamma-aminobutyric acid (GABA) levels in the cerebral cortex of the awake rat was investigated by using microdialysis. WIN 55,212-2 (1 and 5 mg/kg i.p.) was associated with a concentration-dependent decrease in dialysate GABA levels (-16% +/- 4% and -26% +/- 4% of basal values, respectively). The WIN 55,212-2 (5 mg/kg i.p.) induced-inhibition was counteracted by a dose (0.1 mg/kg i.p.) of the CB(1) receptor antagonist SR141716A, which by itself was without effect on cortical GABA levels. These findings suggest that cannabinoids decrease cortical GABA levels in vivo, an action that might underlie some of the cognitive and behavioral effects of acute exposure to marijuana.
Assuntos
Morfolinas/farmacologia , Naftalenos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Droga/agonistas , Ácido gama-Aminobutírico/metabolismo , Animais , Benzoxazinas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Microdiálise , Piperidinas/farmacologia , Córtex Pré-Frontal/metabolismo , Pirazóis/farmacologia , Ratos , Receptores de Canabinoides , Rimonabanto , VigíliaRESUMO
The effects of the cannabinoid receptor agonist WIN 55,212-2 on endogenous extracellular glutamate levels in the prefrontal cortex of the awake rat and in primary cultures of rat cerebral cortex neurons were investigated. In the prefrontal cortex WIN 55,212-2 (0.1 and 1 mg/kg i.p.) increased dialysate glutamate levels from of the awake rat, while the lower (0.01 mg/kg) and the higher (2 mg/kg) doses were ineffective. Furthermore, the WIN 55,212-2 (0.1 mg/kg)- induced increase of dialysate glutamate levels was counteracted by pretreatment with the selective CB(1) receptor antagonist SR141716A (0.1 mg/kg i.p.) and by the local perfusion with a low-calcium Ringer solution (Ca(2+) 0.2 mM). In primary cultures of rat cerebral cortex neurons, WIN 55,212-2 (0.01--100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration-response curve. The facilitatory effect of WIN 55,212-2 (1 nM) was fully counteracted by SR141716A (10 nM), by the replacement of the normal Krebs Ringer-bicarbonate buffer with a low Ca(2+) medium (0.2 mM) and by the IP(3) receptor antagonist xestospongin C (1 microM). These in vivo and in vitro findings suggest an increase in cortical glutamatergic transmission by CB(1) receptors, an effect that may underlie some of the psychoactive and behavioural actions of acute exposure to marijuana.
Assuntos
Canabinoides/farmacologia , Córtex Cerebral/efeitos dos fármacos , Ácido Glutâmico/fisiologia , Morfolinas/farmacologia , Naftalenos/farmacologia , Receptores de Droga/agonistas , Transmissão Sináptica/efeitos dos fármacos , Animais , Benzoxazinas , Cálcio/fisiologia , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Canabinoides/antagonistas & inibidores , Células Cultivadas , Córtex Cerebral/metabolismo , Meios de Cultura , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Microdiálise , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Canabinoides , Receptores de Droga/antagonistas & inibidores , RimonabantoRESUMO
Modafinil did not affect spontaneous and K(+)-evoked [3H]5-HT efflux from cortical synaptosomes while it increased K(+)-evoked tritium efflux from cortical slices, an action that became stronger in the presence of paroxetine. In contrast, DL-fenfluramine and fluoxetine were able to enhance spontaneous and/or K(+)-evoked tritium efflux from synaptosomes and slices. These results suggest that modafinil does not affect 5-HT transmission from cortical synaptosomes and that its 5-HT releasing action is different from that of DL-fenfluramine and fluoxetine.
Assuntos
Compostos Benzidrílicos/farmacologia , Lobo Frontal/metabolismo , Fármacos Neuroprotetores/farmacologia , Serotonina/farmacocinética , Animais , Fenfluramina/farmacologia , Fluoxetina/farmacologia , Técnicas In Vitro , Masculino , Modafinila , Paroxetina/farmacologia , Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sono/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , TrítioRESUMO
Dual-probe microdialysis in the awake rat was employed to investigate the effects of intranigral perfusion with the tridecapeptide neurotensin on local dialysate glutamate and GABA levels in the substantia nigra pars reticulata and on dialysate GABA levels in the ventral thalamus. Intranigral neurotensin (10-300nM, 60min) dose-dependently increased (+29+/-3% and +46+/-3% vs basal for the 100 and 300nM concentrations, respectively) local dialysate glutamate levels, while the highest 300nM concentration of the peptide exerted a long-lasting and prolonged reduction in both local and ventral thalamic (-20+/-4% and -22+/-2%, respectively) GABA levels. Intranigral perfusion with the inactive neurotensin fragment neurotensin(1-7) (10-300nM, 60min) was without effect. Furthermore, the non-peptide neurotensin receptor antagonist SR 48692 (0.2mg/kg) and tetrodotoxin (1microM) fully counteracted the intranigral neurotensin (300nM)-induced increase in local glutamate. SR 48692 (0.2mg/kg) also counteracted the decreases in nigral and ventral thalamic GABA release induced by the peptide. In addition, intranigral perfusion with the dopamine D(2) receptor antagonist raclopride (1microM) fully antagonized the neurotensin (300nM)-induced decreases in nigral and ventral thalamic GABA levels. The ability of nigral neurotensin receptor activation to differently influence glutamate and GABA levels, whereby it increases nigral glutamate and decreases both nigral and ventral thalamic GABA levels, suggests the involvement of neurotensin receptor in the regulation of basal ganglia output at the level of the nigra.
Assuntos
Ácido Glutâmico/metabolismo , Vias Neurais/efeitos dos fármacos , Neurotensina/farmacologia , Receptores de Neurotensina/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Núcleos Ventrais do Tálamo/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Estado de Consciência/fisiologia , Antagonistas de Dopamina , Masculino , Microdiálise , Vias Neurais/citologia , Vias Neurais/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Neurotensina/metabolismo , Substância Negra/citologia , Substância Negra/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tetrodotoxina/farmacologia , Núcleos Ventrais do Tálamo/citologia , Núcleos Ventrais do Tálamo/metabolismoRESUMO
We employed dual probe microdialysis in the nucleus accumbens and ipsilateral ventral pallidum of the halothane anaesthetized rat to investigate the effect of intra-accumbens perfusion with the sulphated octapeptide cholecystokinin (CCK-8S, 10-1000 nM, 60 min) alone and in the presence of the selective CCK1 and CCK2 receptor antagonists L-364,718 (10 and 100 nM) and PD134308 (10 nM), tetrodotoxin (TTX, 1000 nM) and the GABA(A) receptor antagonist bicuculline (1000 nM), on dialysate GABA levels in the ventral pallidum. Intra-accumbens perfusion with the 100 and 1000 nM concentration of CCK-8S was associated with a significant decrease (-16+/-3% and -23+/-3% vs basal, respectively) in ventral pallidum GABA levels. The CCK-8S (1000 nM) induced decrease in ventral pallidal dialysate GABA levels was abolished when PD134308, TTX and bicuculline, but not L-364,718, were included into the perfusion medium of the accumbens probe. The data indicate that nucleus accumbens CCK-8S exerts a CCK2 receptor mediated inhibition of ventral pallidal GABA levels. Furthermore, the TTX and bicuculline sensitivity of this effect suggests that this is possibly mediated via CCK2 receptors probably located on local GABA interneurons.