RESUMEN
S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties. In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats. Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Benzamidas/farmacología , Agonismo Inverso de Drogas , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Acetilcolina/metabolismo , Animales , Cognición/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Histamina/metabolismo , Masculino , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Sueño/efectos de los fármacos , Conducta Social , Aprendizaje Espacial/efectos de los fármacosRESUMEN
There is growing evidence to show that atypical antipsychotic quetiapine might exert an anxiolytic effect in patients. Nevertheless, the mechanism underlying this effect has not yet been fully explored. Like other anxiolytic drugs, quetiapine exhibits partial agonistic activity toward serotonergic 1A (5HT1A) receptors. The involvement of the serotonin system in anxiety, particularly of 5HT1A receptors, has been widely documented. In this study we have investigated whether different doses of quetiapine (5, 10, and 30 mg/kg, oral gavage) administered to C57BL6/N mice could produce an anxiolytic effect in the Vogel conflict test, a classical model of anxiety, and whether or not the selective 5HT1A antagonist WAY100635 (0.1 mg/kg, subcutaneously) might prevent such an effect. Our results show that 10 mg/kg quetiapine exhibits an anxiolytic effect, that is, at least in part, 5HT1A-mediated, because it is completely eliminated by WAY100635.
Asunto(s)
Ansiedad/tratamiento farmacológico , Dibenzotiazepinas , Agonistas del Receptor de Serotonina 5-HT1 , Animales , Ansiolíticos/farmacología , Antipsicóticos/farmacología , Ansiedad/fisiopatología , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/fisiopatología , Investigación Conductal , Conflicto Psicológico , Dibenzotiazepinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Fumarato de Quetiapina , Ratas , Ratas Wistar , Serotonina/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas del Receptor de Serotonina 5-HT1/farmacologíaRESUMEN
Clinically important differences exist between antipsychotic agents and formulations in terms of safety and tolerability. Features of the biochemical interaction between the antipsychotic and the D2-receptor may underlie these differences. This article reviews current information on the relationship between antipsychotic receptor occupancy and clinical response. A literature search was performed using the keywords 'antipsychotic or neuroleptic', 'receptor' and 'occupancy' and 'dopamine' and 'D2' supplemented by the authors' knowledge of the literature. Imaging and clinical data have generally supported the hypotheses that optimal D2-receptor occupancy in the striatum lies in a 'therapeutic window' between approximately 65 and approximately 80%, however, pharmacokinetic and pharmacodynamic properties of a drug should also be taken into account to fully evaluate its therapeutic effects. Additional research, perhaps in preclinical models, is needed to establish D2-receptor occupancy in various regions of the brain and the optimal duration of D2-receptor blockade in order to maximise efficacy and tolerability profiles of atypical antipsychotics and thereby improve treatment outcomes for patients with schizophrenia.
Asunto(s)
Antipsicóticos/uso terapéutico , Encéfalo/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/farmacocinética , Antipsicóticos/toxicidad , Enfermedades de los Ganglios Basales/inducido químicamente , Enfermedades de los Ganglios Basales/fisiopatología , Encéfalo/fisiopatología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Preparaciones de Acción Retardada , Dopamina/metabolismo , Humanos , Tomografía de Emisión de Positrones , Receptores de Dopamina D2/fisiología , Esquizofrenia/fisiopatología , Tomografía Computarizada de Emisión de Fotón Único , Resultado del TratamientoRESUMEN
Quetiapine is a novel atypical antipsychotic drug with multi-receptorial affinity. Using in vivo microdialysis, we investigated if quetiapine modulates extracellular noradrenaline and dopamine in brain areas generally believed to be involved in the pathophysiology of schizophrenia and in the action of antipsychotic drugs. Quetiapine (5, 10 and 20 mg/kg, i.p.) increased levels of noradrenaline in both the prefrontal cortex and the caudate nucleus, while it increased dopamine levels mainly in the prefrontal cortex. It is argued that the marked increase of dopaminergic transmission in the prefrontal cortex induced by quetiapine might be relevant to its therapeutical action.
Asunto(s)
Antipsicóticos/farmacología , Dibenzotiazepinas/farmacología , Dopamina/metabolismo , Norepinefrina/metabolismo , Corteza Prefrontal/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Masculino , Corteza Prefrontal/efectos de los fármacos , Fumarato de Quetiapina , Ratas , Ratas Sprague-DawleyRESUMEN
The novel antidepressant mirtazapine has been shown to increase extracellular noradrenaline and dopamine in the medial prefrontal cortex. Our previous studies indicate that extracellular dopamine in the cerebral cortex originates largely from noradrenergic terminals, such release being controlled by alpha(2)-adrenoceptors. Because mirtazapine inhibits alpha(2)-adrenoceptors, the possibility that it might corelease dopamine and noradrenaline was investigated. By means of microdialysis, the effect of mirtazapine on extracellular dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline in the medial prefrontal cortex, densely innervated by dopaminergic and noradrenergic neurons, and in the occipital cortex, receiving equal noradrenergic but scarce dopaminergic projections, was compared. Basal extracellular concentration of noradrenaline was similar in both cortices, while dopamine in the occipital cortex was only about 50% lower than in the medial prefrontal cortex, reflecting noradrenergic rather than dopaminergic projections. The intraperitoneal (i.p.) administration of mirtazapine (5 and 10 mg/kg) increased extracellular dopamine, DOPAC and noradrenaline to approximately the same extent in both cortices, an effect totally suppressed by the alpha(2)-adrenoceptors agonist clonidine (0.15 mg/kg, i.p.). To exclude the possibility that mirtazapine-induced increase in dopamine might result from reduced dopamine removal from extracellular space, noradrenaline and dopamine uptake mechanisms were blocked by perfusing 100 microM desipramine into either cortex. The combined i.p. administration of mirtazapine (5 mg/kg) and the local perfusion of desipramine produced an additional increase in extracellular dopamine, DOPAC and noradrenaline in the medial prefrontal cortex and occipital cortex compared with the increase produced by either drug given alone. The results suggest that mirtazapine by inhibiting alpha(2)-adrenoceptors produces a corelease of noradrenaline and dopamine from noradrenergic terminals in the cerebral cortex.
Asunto(s)
Antidepresivos/farmacología , Dopamina/metabolismo , Mianserina/análogos & derivados , Mianserina/farmacología , Neuronas/metabolismo , Norepinefrina/metabolismo , Lóbulo Occipital/metabolismo , Corteza Prefrontal/metabolismo , Sistema Nervioso Simpático/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Animales , Clonidina/farmacología , Desipramina/farmacología , Inyecciones Intraperitoneales , Masculino , Microdiálisis , Mirtazapina , Neuronas/efectos de los fármacos , Lóbulo Occipital/citología , Lóbulo Occipital/efectos de los fármacos , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Previous results suggest that extracellular dopamine (DA) in the rat cerebral cortex originates from dopaminergic and noradrenergic terminals. To further clarify this issue, dialysate DA, dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) were measured both in the medial prefrontal cortex (mPFC) and in the occipital cortex (OCC), with dense and scarce dopaminergic projections, respectively. Moreover, the effect of the alpha2-adrenoceptor antagonist RS 79948 and the D2-receptor antagonist haloperidol on extracellular DA, DOPAC and NA was investigated. Extracellular DA and DOPAC concentrations in the OCC were 43% and 9%, respectively, those in the mPFC. Haloperidol (0.1 mg/kg i.p.) increased DA and DOPAC (by 35% and 150%, respectively) in the mPFC, but was ineffective in the OCC. In contrast, RS 79948 (1.5 mg/kg i.p.) increased NA, DA and DOPAC, both in the mPFC (by approximately 50%, 60% and 130%, respectively) and the OCC (by approximately 50%, 80% and 200%, respectively). Locally perfused, the DA transporter blocker GBR 12909 (10 micro m) was ineffective in either cortex, whereas desipramine (DMI, 100 micro m) markedly increased extracellular NA and DA in both cortices. The weak haloperidol effect on DA efflux was not enhanced after DA- and NA-transporter blockade, whereas after DMI, RS 79948 markedly increased extracellular NA, and especially DA and DOPAC in both cortices. The results support the hypothesis that most extracellular DA in the cortex is co-released with NA from noradrenergic terminals, such co-release being primarily controlled by alpha2-adrenoceptors.
Asunto(s)
Corteza Cerebral/citología , Dopamina/metabolismo , Indometacina/análogos & derivados , Neuronas/metabolismo , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2 , Animales , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Interacciones Farmacológicas , Espacio Extracelular/metabolismo , Haloperidol/farmacología , Indometacina/farmacología , Masculino , Microdiálisis/métodos , Neuronas/efectos de los fármacos , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Our recent studies suggest that extracellular dopamine (DA) in the cerebral cortex not only originates from dopaminergic terminals but is also coreleased with noradrenaline (NA) from noradrenergic terminals [Devoto et al. (2001) Mol Psychiatry 6:657-664]. To further clarify this issue, the concentrations of extracellular DA, its deaminated metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and NA were compared by microdialysis in the medial prefrontal cortex (mPFC), an area densely innervated by NA and DA neurons, and in the occipital cortex (OCC), equally innervated by NA but receiving scarce DA projections. Moreover, the effect of the alpha(2)-adrenoceptor agonist clonidine locally perfused into the locus coeruleus (LC) on extracellular NA, DA, and DOPAC in the mPFC, OCC, and ventral striatum was investigated. Consistent with the homogeneous NA innervation, extracellular NA concentration was similar in both cortices, while extracellular DA in the OCC, in spite of the scarce DA afference in this area, was only 37% lower than in the mPFC; extracellular DOPAC in the OCC was 81% lower than in the mPFC. Consistent with its ability to inhibit NA neurons, clonidine (10 microM) reduced extracellular NA by about 65 and 80% in the OCC and the mPFC, respectively, but also reduced extracellular DA by 70 and 50% in the OCC and the mPFC, respectively. Clonidine reduced DOPAC in the OCC (by about 40%) but not in the mPFC. In the ventral striatum clonidine reduced NA (by 30%) but not DA and DOPAC. After inhibition of the DA and NA transporter, by perfusing 100 microM desmethyl-imipramine into the mPFC, clonidine perfusion into the LC reduced extracellular NA and DA in the mPFC by about 50%. The results indicate that most of extracellular DA in the OCC and a significant portion in the mPFC reflect the activity of NA neurons and support the hypothesis that extracellular DA in the cerebral cortex may originate not only from DA but also from NA neurons.
Asunto(s)
Dopamina/metabolismo , Neuronas/metabolismo , Norepinefrina/metabolismo , Lóbulo Occipital/metabolismo , Corteza Prefrontal/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Clonidina/farmacología , Cuerpo Estriado/metabolismo , Locus Coeruleus/efectos de los fármacos , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
RATIONALE: Clozapine has been shown to increase extracellular dopamine (DA) and noradrenaline (NA) in the medial prefrontal cortex (mPFC). A recent study of ours suggested that extracellular DA in the PFC originates not only from dopaminergic but also from noradrenergic terminals, its release being controlled by alpha(2)-adrenoceptors. OBJECTIVES: Since clozapine binds to alpha(2)-adrenoceptors, the possibility that it might co-release DA and NA was studied. METHODS: By means of microdialysis coupled to HPLC with electrochemical detection, the effect of clozapine on extracellular DA and NA in the mPFC, densely innervated by DA and NA, was compared to that in the occipital cortex, equally innervated by NA but receiving few DA projections. RESULTS: Extracellular NA was found to be the same in the two cortices, consistent with homogeneous NA innervation. On the other hand, extracellular DA in the occipital cortex was only 29% lower than in the mPFC, in spite of the scarce dopaminergic innervation in the occipital cortex. Clozapine (10 mg/kg IP) increased extracellular DA and NA not only in the mPFC (by about 320% and 290%, respectively) but also in the occipital cortex (by 560% and 230%, respectively). Administration of the alpha(2)-agonist clonidine (0.15 mg/kg) reversed the effect of clozapine in both cortices, while the D(2)-agonist quinpirole (0.1 mg/kg IP) was ineffective. CONCLUSIONS: The results suggest that clozapine, by inhibiting alpha(2)-adrenoceptors, co-releases DA and NA from noradrenergic terminals in the occipital cortex and that the same mechanism might be responsible for the concomitant increase of the two monoamines in the mPFC.
Asunto(s)
Antipsicóticos/farmacología , Corteza Cerebral/efectos de los fármacos , Clozapina/farmacología , Dopamina/metabolismo , Neuronas/metabolismo , Norepinefrina/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Corteza Cerebral/metabolismo , Cromatografía Líquida de Alta Presión , Clonidina/farmacología , Agonistas de Dopamina/farmacología , Espacio Extracelular/metabolismo , Inmunohistoquímica , Masculino , Microdiálisis , Neuronas/efectos de los fármacos , Lóbulo Occipital/efectos de los fármacos , Lóbulo Occipital/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Quinpirol/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Cannabinoid modulation of prefrontal cortex and hippocampus neuronal functioning has been correlated to the disruptive action of marijuana on memory tasks. This study investigates the effects of delta(9)-tetrahydrocannabinol (delta(9)-THC) on dopamine, glutamate and GABA levels in vivo by brain microdialysis in the prefrontal cortex. Delta(9)-THC (1 mg/kg, i.v.) significantly increased extracellular dopamine and glutamate levels and decreased GABA levels. These effects were prevented by the cannabinoid antagonist SR141716A (1 mg/kg, i.v.), which per se was ineffective. These results suggest that delta(9)-THC disrupt the normal interplay between neurotransmitters in this area and may bear relevance in understanding neuronal mechanisms underlying cannabinoid-induced cognitive deficits.
Asunto(s)
Dopamina/metabolismo , Dronabinol/farmacología , Espacio Extracelular/metabolismo , Corteza Prefrontal/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Dopamina/análisis , Dronabinol/antagonistas & inhibidores , Espacio Extracelular/química , Espacio Extracelular/efectos de los fármacos , Ácido Glutámico/análisis , Ácido Glutámico/metabolismo , Masculino , Microdiálisis , Piperidinas/farmacología , Corteza Prefrontal/efectos de los fármacos , Psicotrópicos/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Droga/antagonistas & inhibidores , Rimonabant , Ácido gamma-Aminobutírico/análisisRESUMEN
RATIONALE: Acute morphine and abstinence from chronic morphine have been shown to increase and to decrease extracellular dopamine (DA) in the nucleus accumbens, respectively. In contrast, extracellular DA in the prefrontal cortex (PFC) is not modified by acute morphine and is markedly increased during abstinence syndrome. OBJECTIVES: We investigated whether the peculiar behaviour of PFC DA might depend on the fact that extracellular DA originates not only from DA but, mainly, noradrenaline (NA) terminals. Accordingly, we studied if the effect of acute morphine and morphine-abstinence was modified by the inhibition of DA or NA neurons. METHODS: Extracellular DA and noradrenaline (NA) concentrations were determined by microdialysis in the PFC (densely innervated by DA) and in the parietal cortex (lacking DA afferents) both after acute morphine and in morphine-dependent rats during naloxone-precipitated abstinence syndrome. Dialysate catecholamine levels were evaluated by high performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: Acute morphine (5 mg/kg IP) reduced extracellular NA (by 30%) and failed to modify extracellular DA level in the PFC, but reduced both amines by 40% in the parietal cortex. The co-administration of morphine and the D(2) agonist quinpirole (0.5 mg/kg IP) decreased both extracellular DA and NA by 40% in the PFC. In morphine dependent rats the administration of naloxone (1.0 mg/kg, SC) precipitated a typical abstinence syndrome associated with a concomitant dramatic increase in extracellular DA and NA by about 200 and 100%, respectively, in the PFC. The alpha(2)-adrenoceptor agonist clonidine (0.15 mg/kg IP) suppressed naloxone precipitated abstinence symptoms and brought both NA and DA output in the PFC to <50% baseline values. In contrast, quinpirole was totally ineffective. CONCLUSIONS: The results suggest that: a) morphine-stimulated DA release from DA terminals is compensated by reduced DA release from NA terminals; b) morphine abstinence-induced inhibition of DA release from DA terminals is overshadowed by a marked increase in DA released from NA terminals. Thus, the paradoxical response of PFC DA to morphine and morphine abstinence may be explained by the fact that extracellular DA in the PFC mainly represents the amine co-released from NA terminals.
Asunto(s)
Dopamina/metabolismo , Morfina/administración & dosificación , Morfina/efectos adversos , Narcóticos/administración & dosificación , Narcóticos/efectos adversos , Norepinefrina/metabolismo , Lóbulo Parietal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacología , Animales , Clonidina/farmacología , Agonistas de Dopamina/farmacología , Espacio Extracelular/metabolismo , Locus Coeruleus/efectos de los fármacos , Masculino , Naloxona , Lóbulo Parietal/metabolismo , Corteza Prefrontal/metabolismo , Quinpirol/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/agonistas , Corteza Somatosensorial , Factores de Tiempo , Área Tegmental VentralRESUMEN
The effect of repeated administration of imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, was studied on the stress-induced increase in the extracellular concentration of norepinephrine in the prefrontal cortex of freely moving rats. Exposure to footshock in control rats induced a marked increase in extracellular norepinephrine concentrations in the prefrontal cortex (+120%). Long-term administration with imipramine or mirtazapine (10 mg/kg, i.p., twice or once a day, respectively, for 14 days) reduced (+50%) the effect of stress on basal norepinephrine output. Acute administration of FG7142 (30 mg/kg, i.p.), an anxiogenic benzodiazepine receptor inverse agonist, induced a marked increase in norepinephrine output (+90%) in control rats. In rats chronically treated with imipramine or mirtazapine this effect was completely antagonized. On the contrary, acute administration of these antidepressant drugs failed to reduce stress- and FG7142-induced increase in norepinephrine output. The plastic changes in the sensitivity of norepinephrine neurons to footshock stress and drug-induced anxiogenic stimuli may reveal a new important neuronal mechanism involved in the long-term modulation of emotional state. This action might be relevant for the anxiolytic and antidepressant effect of antidepressant drugs.