RESUMEN
RATIONALE: Fear conditioning is an important factor in the etiology of anxiety disorders. Previous studies have demonstrated a role for serotonin (5-HT)1A receptors in fear conditioning. However, the relative contribution of somatodendritic 5-HT1A autoreceptors and post-synaptic 5-HT1A heteroreceptors in fear conditioning is still unclear. OBJECTIVE: To determine the role of pre- and post-synaptic 5-HT1A receptors in the acquisition and expression of cued and contextual conditioned fear. METHODS: We studied the acute effects of four 5-HT1A receptor ligands in the fear-potentiated startle test. Male Wistar rats were injected with the 5-HT1A receptors biased agonists F13714 (0-0.16 mg/kg, IP), which preferentially activates somatodendritic 5-HT1A autoreceptors, or F15599 (0-0.16 mg/kg, IP), which preferentially activates cortical post-synaptic 5-HT1A heteroreceptors, with the prototypical 5-HT1A receptor agonist R(+)8-OH-DPAT (0-0.3 mg/kg, SC) or the 5-HT1A receptor antagonist WAY100,635 (0-1.0 mg/kg, SC). RESULTS: F13714 (0.16 mg/kg) and R(+)-8-OH-DPAT (0.03 mg/kg) injected before training reduced cued fear acquisition. Pre-treatment with F15599 or WAY100,635 had no effect on fear learning. In the fear-potentiated startle test, F13714 (0.04-0.16 mg/kg) and R(+)-8-OH-DPAT (0.1-0.3 mg/kg) reduced the expression of cued and contextual fear, whereas F15599 had no effect. WAY100,635 (0.03-1.0 mg/kg) reduced the overall startle response. CONCLUSIONS: The current findings indicate that activation of somatodendritic 5-HT1A autoreceptors reduces cued fear learning, whereas 5-HT1A receptors seem not involved in contextual fear learning. Moreover, activation of somatodendritic 5-HT1A autoreceptors may reduce cued and contextual fear expression, whereas we found no evidence for the involvement of cortical 5-HT1A heteroreceptors in the expression of conditioned fear.
Asunto(s)
Autorreceptores/metabolismo , Señales (Psicología) , Miedo/fisiología , Miedo/psicología , Receptor de Serotonina 5-HT1A/metabolismo , Reflejo de Sobresalto/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Autorreceptores/agonistas , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Miedo/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Ratas , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacos , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas de la Serotonina/farmacologíaRESUMEN
Cocaine is a highly abused drug, and cocaine addiction affects millions of individuals worldwide. Cocaine blocks normal uptake function at the dopamine transporter (DAT), thus increasing extracellular dopamine. Currently, no chemical therapies are available to treat cocaine abuse. Previous works showed that the selective inhibitors of protein kinase Cß (PKCß), enzastaurin and ruboxistaurin, attenuate dopamine overflow and locomotion stimulated by another psychostimulant drug, amphetamine. We now test if ruboxistaurin similarly affects cocaine action. Perfusion of 1 µM ruboxistaurin directly into the core of the nucleus accumbens via retrodialysis reduced cocaine-stimulated increases in dopamine overflow, measured using microdialysis sampling, with simultaneous reductions in locomotor behavior. Because cocaine activity is highly regulated by dopamine autoreceptors, we examined whether ruboxistaurin was acting at the level of the D2 autoreceptor. Perfusion of 5 µM raclopride, a selective D2-like receptor antagonist, before addition of ruboxistaurin, abrogated the effect of ruboxistaurin on cocaine-stimulated dopamine overflow and hyperlocomotion. Further, ruboxistaurin was inactive against cocaine-stimulated locomotor activity in mice with a genetic deletion in D2 receptors as compared to wild-type mice. In contrast, blockade or deletion of dopamine D2 receptors did not abolish the attenuating effect of ruboxistaurin on amphetamine-stimulated activities. Therefore, the inhibition of PKCß reduces dopamine overflow and locomotor activity stimulated by both cocaine and amphetamine, but the mechanism of action differs for each stimulant. These data suggest that inhibition of PKCß would serve as a target to reduce the abuse of either amphetamine or cocaine.
Asunto(s)
Autorreceptores/metabolismo , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Dopamina/metabolismo , Líquido Extracelular/metabolismo , Indoles/administración & dosificación , Maleimidas/administración & dosificación , Animales , Autorreceptores/agonistas , Inhibidores Enzimáticos/administración & dosificación , Líquido Extracelular/efectos de los fármacos , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismoRESUMEN
Psychoactive substances affecting the dopaminergic system induce locomotor activation and, in high doses, stereotypies. Network mechanisms underlying the shift from an active goal-directed behavior to a "seemingly purposeless" stereotypic locomotion remain unclear. In the present study we sought to determine the relationships between the behavioral effects of dopaminergic drugs and their effects on local field potentials (LFPs), which were telemetrically recorded within the ventral tegmental area (VTA) of freely moving rats. We used the D2/D3 agonist quinpirole in a low, autoreceptor-selective (0.1 mg/kg, i.p.) and in a high (0.5 mg/kg, i.p.) dose, and a moderate dose of cocaine (10 mg/kg, i.p.). In the control group, power spectrum analysis revealed a prominent peak of LFP power in the theta frequency range during active exploration. Cocaine alone stimulated locomotion, but had no significant effect on the peak of the LFP power. In contrast, co-administration of low dose quinpirole with cocaine markedly altered the pattern of locomotion, from goal-directed exploratory behavior to recurrent motion resembling locomotor stereotypy. This behavioral effect was accompanied by a shift of the dominant theta power toward a significantly lower (by â¼15%) frequency. High dose quinpirole also provoked an increased locomotor activity with signs of behavioral stereotypies, and also induced a shift of the dominant oscillation frequency toward the lower range. These results demonstrate a correlation between the LFP oscillation frequency within the VTA and a qualitative aspect of locomotor behavior, perhaps due to a variable level of coherence of this region with its input or output areas.
Asunto(s)
Autorreceptores/metabolismo , Ondas Encefálicas/fisiología , Cocaína/farmacología , Locomoción/fisiología , Receptores de Dopamina D2/metabolismo , Área Tegmental Ventral/metabolismo , Animales , Autorreceptores/agonistas , Ondas Encefálicas/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Microelectrodos , Ratas , Ratas Wistar , Receptores de Dopamina D2/agonistas , Área Tegmental Ventral/efectos de los fármacosRESUMEN
BACKGROUND: The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D2 receptors, where its degree of efficacy as a partial agonist remains controversial. METHODS: We examined the properties of aripiprazole at D2-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2 mM K(+), low dopaminergic tone) and a stimulated condition (15 mM K(+), where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions. RESULTS: Aripiprazole under the basal condition acted as an agonist at D2-like autoreceptors and fully activated them at about 10 nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D2-like autoreceptor activation. Under the stimulated (15 mM K(+)) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole. CONCLUSIONS: Under high dopaminergic tone, aripiprazole acts as a D2-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D2-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D2R ligand.
Asunto(s)
Aripiprazol/farmacología , Autorreceptores/metabolismo , Agonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Dopamina/biosíntesis , Receptores de Dopamina D2/metabolismo , Animales , Autorreceptores/agonistas , Autorreceptores/antagonistas & inhibidores , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Piperidinas/farmacología , Potasio/metabolismo , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Quinpirol/farmacología , Ratas Sprague-Dawley , Receptores de Dopamina D2/agonistasRESUMEN
GABAB autoreceptors inhibit release of GABA from GABAergic nerve terminals. Agonists of these receptors (e.g. baclofen) inhibit, whereas antagonists (e.g. (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; Sch 50911) enhance release of the transmitter. The actions of thymol (2-isopropyl-5-methylphenol) and the structurally related compound 2-tert-butyl-4-methylphenol, (4MP) on the release of [(3) H]-GABA were examined in rat neocortical slices where the GABAergic nerves had been preloaded with [(3) H]-GABA and subsequently stimulated electrically on two occasions (S1 and S2 ). Test agents, baclofen and Sch 50911 were added to the superfusion medium prior to the second period of stimulation (S2 ). Stimulation-induced overflow (SIO) of [(3) H]-GABA as a consequence of these stimulations (SIO1 and SIO2 ) were calculated and the effects of agents determined by comparing the SIO2 /SIO1 ratio in the presence of each agent with that in control tissue. Thymol potentiated the release of [(3) H]-GABA (EC50 170 µmol/L), an action reversed by baclofen (2 µmol/L). Baclofen alone had little effect on GABA release. Release of [(3) H]-GABA was inhibited by 4MP (IC50 3 µmol/L) and this effect was blocked by Sch 50911 (10 µmol/L). Alone, Sch 50911 markedly potentiated the release of GABA. These results imply that 4MP is an agonist of GABAB autoreceptors; however, further studies are needed to confirm that thymol is indeed a GABAB autoreceptor antagonist. Of interest are structural differences in these agents. Thymol has a propyl group in the ortho position relative to the phenolic hydroxyl, whereas in 4MP this is a butyl group and the methyl group moves from position 5 to 4. Whether one or both of these changes was responsible for the above actions is unknown.
Asunto(s)
Autorreceptores/agonistas , Autorreceptores/antagonistas & inhibidores , Antagonistas de Receptores de GABA-B/farmacología , Receptores de GABA-B/metabolismo , Timol/farmacología , Ácido gamma-Aminobutírico/metabolismo , Animales , Baclofeno/farmacología , Hidroxitolueno Butilado/análogos & derivados , Hidroxitolueno Butilado/química , Hidroxitolueno Butilado/farmacología , Relación Dosis-Respuesta a Droga , Agonistas del GABA/farmacología , Antagonistas de Receptores de GABA-B/química , Masculino , Morfolinas/farmacología , Neocórtex/efectos de los fármacos , Neocórtex/metabolismo , Fenoles/farmacología , Ratas , Timol/químicaRESUMEN
Selective serotonin reuptake inhibitors (SSRI) are aimed at increasing brain 5-HT tone; however, this expected effect has a slow onset after starting SSRI treatment because of initial activation of 5-HT(1A) autoreceptor-mediated negative feedback of 5-HT release. After chronic SSRI treatment, 5-HT(1A) autoreceptors desensitize, which allows 5-HT tone elevation. Because 5-HT(1A) receptor (5-HT(1A)R) internalization has been proposed as a possible mechanism underlying 5-HT(1A) autoreceptor desensitization, we examined whether this receptor could internalize under well controlled in vitro conditions in the LLC-CPK1 cell line and in raphe or hippocampal neurons from rat embryos. To this goal, cells were transfected with recombinant lentiviral vectors encoding N-terminal tagged 5-HT(1A)R, and exposed to various pharmacological conditions. Constitutive endocytosis and plasma membrane recycling of tagged-5-HT(1A)R was observed in LLC-PK1 cells as well as in neurons. Acute exposure (for 1 h) to the full 5-HT(1A)R agonists, 5-HT and 5-carboxamido-tryptamine, but not the partial agonist 8-OH-DPAT, triggered internalization of tagged 5-HT(1A)R in serotonergic neurons only. In contrast, sustained exposure (for 24 h) to all agonists induced tagged-5-HT(1A)R endocytosis in raphe serotonergic neurons and a portion of hippocampal neurons, but not LLC-PK1 cells and partial agonist displayed an effect only in serotonergic neurons. In all cases, agonist-induced tagged 5-HT(1A)R endocytosis was prevented by the 5-HT(1A)R antagonist, WAY-100635, which was inactive on its own. These data showed that agonist-induced 5-HT(1A)R internalization does exist in neurons and depends on agonist efficacy and neuronal phenotype. Its differential occurrence in serotonergic neurons supports the idea that 5-HT(1A)R internalization might underlie 5-HT(1A) autoreceptor desensitization under SSRI antidepressant therapy.
Asunto(s)
Autorreceptores/agonistas , Autorreceptores/metabolismo , Neuronas/metabolismo , Fenotipo , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/metabolismo , Animales , Endocitosis/efectos de los fármacos , Endocitosis/fisiología , Femenino , Células LLC-PK1 , Neuronas/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT1/farmacología , PorcinosRESUMEN
Psychostimulant conditioning and sensitization effects have proven to be difficult to eliminate using behavioral methods. We used a low autoreceptor dose of apomorphine in counter-conditioning and memory re-consolidation protocols to modify conditioned and sensitized responses induced by a high dose of apomorphine. Rats received five daily treatments of apomorphine (2.0mg/kg) and were tested in an arena for 30 min to induce conditioning and sensitization. Conditioning was validated in a brief 5 min non-drug conditioning test and sensitization by a 2.0 apomorphine challenge test. Next, the counter-conditioning and memory re-consolidation protocols were initiated. In counter-conditioning, vehicle or 0.05 mg/kg apomorphine was given either 15 min or immediately before a 5 min arena test. In the memory re-consolidation protocol, the vehicle and 0.05 apomorphine treatments were administered post-trial either immediately after or 15 min after the 5 min arena test. Effects were assessed with a 5 min saline conditioning test and a second 2.0mg/kg apomorphine challenge test. The counter-conditioning protocol induced hypolocomotion and but did not induce a conditioned hypo-locomotion and did not alter the sensitized response. The 15 min post-trial treatment did not affect either the conditioned or the sensitized responses. The immediate post-trial treatment eliminated sensitization and induced a conditioned hypoactivity response. These results highlight the memory re-consolidation period as a critical target for drug memory substitution and suggest the potential utility of the pharmacological inhibition of dopamine activity given as a therapeutic drug memory replacement during addictive drug memory re-consolidation.
Asunto(s)
Apomorfina/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Agonistas de Dopamina/farmacología , Memoria/efectos de los fármacos , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Animales , Apomorfina/administración & dosificación , Autorreceptores/agonistas , Agonistas de Dopamina/administración & dosificación , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Noradrenaline, essential for the modulation of memory, is released in various parts of the brain from nerve terminals controlled by the locus coeruleus (LoC). Noradrenaline release consequent upon input from higher brain areas also occurs within the LoC itself. We examined the effect of noradrenaline on adrenergic receptors in the LoC on memory processing, using colored bead discrimination learning in the young domestic chick. We have shown previously that the release of noradrenaline in the hippocampus and cortex (mesopallium) is essential for acquisition and consolidation of short-term to intermediate and to long-term memory. Noradrenaline release within the LoC is triggered by the glutamatergic input from the forebrain. Inhibition by LoC injection of NMDA or AMPA receptor antagonists is rescued by injection of ß2-and ß3-adrenoceptor (AR) agonists in the hippocampus. We show that inhibition of α2A-ARs by BRL44408 in the LoC up to 30 min post-training consolidates weakly-reinforced learning. Conversely activation of α2A-ARs in the LoC at the times of consolidation between short-term and intermediate and long-term memory caused memory loss, which is likely to be due to a decreased release of noradrenaline within these two time windows. The α2A-AR antagonist will block presynaptic inhibitory receptors leading to an increase in extracellular noradrenaline. This interpretation is supported by the actions of noradrenaline uptake blockers that produce the same memory outcome. BRL44408 in the mesopallium also caused memory enhancement. ß2-ARs are important in the first time window, whereas α1-, α2C-and ß3-ARs are important in the second time window. The results reveal that for successful memory formation noradrenaline release is necessary within the LoC as well as in other brain regions, at the time of consolidation of memory from short-term to intermediate and from intermediate to long-term memory.
Asunto(s)
Locus Coeruleus/metabolismo , Memoria/fisiología , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa/fisiología , Receptores Adrenérgicos beta/fisiología , Inhibidores de Captación Adrenérgica/farmacología , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Autorreceptores/agonistas , Autorreceptores/fisiología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Pollos , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Locus Coeruleus/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Receptores Adrenérgicos alfa 2/fisiología , Receptores de Glutamato/fisiología , Receptores Presinapticos/agonistas , Receptores Presinapticos/fisiologíaRESUMEN
Dystonia is a neurological disorder characterized by involuntary movements. We examined striatal dopamine (DA) function in hyperactive transgenic (Tg) mice generated as a model of dystonia. Evoked extracellular DA concentration was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in striatal slices from non-Tg mice, Tg mice with a positive motor phenotype, and phenotype-negative Tg littermates. Peak single-pulse evoked extracellular DA concentration was significantly lower in phenotype-positive mice than in non-Tg or phenotype-negative mice, but indistinguishable between non-Tg and phenotype-negative mice. Phenotype-positive mice also had higher functional D2 DA autoreceptor sensitivity than non-Tg mice, which would be consistent with lower extracellular DA concentration in vivo. Multiple-pulse (phasic) stimulation (five pulses, 10-100 Hz) revealed an enhanced frequency dependence of evoked DA release in phenotype-positive versus non-Tg or phenotype-negative mice, which was exacerbated when extracellular Ca(2+) concentration was lowered. Enhanced sensitivity to phasic stimulation in phenotype-positive mice was reminiscent of the pattern seen with antagonism of nicotinic acetylcholine receptors. Consistent with a role for altered cholinergic regulation, the difference in phasic responsiveness among groups was lost when nicotinic receptors were blocked by mecamylamine. Together, these data implicate compromised DA release regulation, possibly from cholinergic dysfunction, in the motor symptoms of this dystonia model.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Distonía/metabolismo , Animales , Autorreceptores/agonistas , Autorreceptores/fisiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Distonía/genética , Distonía/fisiopatología , Estimulación Eléctrica , Técnicas In Vitro , Ratones , Ratones Transgénicos , Antagonistas Nicotínicos/farmacología , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/fisiologíaRESUMEN
BACKGROUND AND PURPOSE: F15599, a novel 5-hydroxytryptamine (5-HT)(1A) receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT(1A) heteroreceptors. EXPERIMENTAL APPROACH: In vivo single unit and local field potential recordings and microdialysis in the rat. KEY RESULTS: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 microg x kg(-1) i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 microg x kg(-1) i.v.). Both effects were reversed by the 5-HT(1A) antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (approximately 1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT(1A) receptors) with an ED(50) of 30 microg x kg(-1) i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT(1A) autoreceptor activation) with an ED(50) of 240 microg x kg(-1) i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (+/-)WAY100635. CONCLUSIONS AND IMPLICATIONS: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT(1A) receptors in PFC rather than somatodendritic 5-HT(1A) autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT(1A) receptor agonists, which preferentially activate somatodendritic 5-HT(1A) autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.
Asunto(s)
Encéfalo/efectos de los fármacos , Piperidinas/farmacología , Células Piramidales/efectos de los fármacos , Pirimidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Sinapsis/efectos de los fármacos , Potenciales de Acción , Animales , Antidepresivos/farmacología , Antipsicóticos/farmacología , Autorreceptores/agonistas , Autorreceptores/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Ciclohexanos/farmacología , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inyecciones Intraperitoneales , Masculino , Microdiálisis , Piperazinas/farmacología , Piperidinas/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Células Piramidales/metabolismo , Pirimidinas/administración & dosificación , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/administración & dosificación , Sinapsis/metabolismo , Factores de TiempoRESUMEN
The development of an immune reaction in CBA mice during activation and blockade of serotonin 1A (5-HT(1A)) autoreceptors with highly selective agents has characteristic features depending on the behavioral stereotype formed. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.1 mg/kg 15 min before immunization) did not alter the number of IgM antibody-forming cells in the spleen at the peak of the immune reaction (day 4) in aggressive mice, but increased the number in submissive mice, in which the immune response without treatment was lower than that in aggressive animals. Blockade of the same receptor type with WAY-100635 (0.1 mg/kg 30 min before immunization) led to a decrease in the immune response in animals with aggressive behavior and an increase in submissive animals. The question of the influences of agents acting on presynaptic 5-HT(1A) somatodendritic autoreceptors on the immune response, depending on the functional state of 5-HT(1A) receptors and the balance of activities in the serotoninergic and dopaminergic systems as a whole, is discussed.
Asunto(s)
Agresión/fisiología , Células Productoras de Anticuerpos/inmunología , Autorreceptores/fisiología , Conducta Animal/fisiología , Neuroinmunomodulación , Receptor de Serotonina 5-HT1A/fisiología , Receptores Presinapticos/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Formación de Anticuerpos , Autorreceptores/agonistas , Dominación-Subordinación , Inmunoglobulina M/inmunología , Factores Inmunológicos/farmacología , Masculino , Ratones , Ratones Endogámicos CBA , Piperazinas/farmacología , Piridinas , Receptores Presinapticos/agonistas , Agonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT1 , Bazo/citología , Bazo/inmunologíaRESUMEN
Development of depressive-like state in mice of the C57BL/6J strain is accompanied by a considerable decrease in the immune response. A selective activation of presynaptic 5-HT1A-receptors (8-OH-DPAT, 0.1 mg/kg, for 15 min before immunization) markedly increased the immune response tested with the number of IgM-antibody-forming cells, and stimulation of postsynaptic 5-HT1A-receptors (8-OH-DPAT, 1.0 mg/kg, for 30 min before immunization twice) produced an immune suppression in control animals (mice without experience of victories and defeats). On the other hand, there were no changes in the immune response level following 8-OH-DPAT administration (0.1 and 1.0 mg/kg) in mice with depressive-like state. The role of pre- and postsynaptic 5-HT1A-receptors in immunomidulation in mice with depressive-like behaviour is discussed.
Asunto(s)
Autorreceptores/agonistas , Depresión/inmunología , Receptor de Serotonina 5-HT1A/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Formación de Anticuerpos , Depresión/etiología , Depresión/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Psicológico/complicacionesRESUMEN
G protein-coupled receptor kinase 5 (GRK5) deficiency has been linked recently to early Alzheimer disease (AD), but the mechanism by which GRK5 deficiency may contribute to AD pathogenesis remains elusive. Here we report that overexpression of dominant negative mutant of GRK5 (dnGRK5) in a cholinergic neuronal cell line led to decreased acetylcholine (ACh) release. This reduction was fully corrected by pertussis toxin, atropine (a nonselective muscarinic antagonist), or methoctramine (a selective M2/M4 muscarinic receptor antagonist). Consistent with results in cultured cells, high potassium-evoked ACh release in hippocampal slices from young GRK5 knock-out mice was significantly reduced compared with wild type littermates, and this reduced ACh release was also fully corrected by methoctramine. In addition, following treatment with the nonselective muscarinic agonist oxotremorine-M, M2, and M4 receptors underwent significantly reduced internalization in GRK5KO slices compared with wild type slices, as assessed by plasma membrane retention of receptor immunoreactivity, whereas M1 receptor internalization was not affected by loss of GRK5 expression. Moreover, Western blotting revealed no synaptic or cholinergic degenerative changes in young GRK5 knock-out mice. Altogether, these results suggest that GRK5 deficiency leads to a reduced hippocampal ACh release and cholinergic hypofunction by selective impairment of desensitization of presynaptic M2/M4 autoreceptors. Because this nonstructural cholinergic hypofunction precedes the hippocampal cholinergic hypofunction associated with structural cholinergic degeneration and cognitive decline in aged GRK5 knock-out mice, this nonstructural alteration may be an early event contributing to cholinergic degeneration in AD.
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Acetilcolina/metabolismo , Quinasa 5 del Receptor Acoplado a Proteína-G/metabolismo , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M4/metabolismo , Animales , Autorreceptores/agonistas , Autorreceptores/genética , Autorreceptores/metabolismo , Western Blotting , Línea Celular , Endocitosis/efectos de los fármacos , Quinasa 5 del Receptor Acoplado a Proteína-G/deficiencia , Quinasa 5 del Receptor Acoplado a Proteína-G/genética , Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Inmunohistoquímica , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Oxotremorina/análogos & derivados , Oxotremorina/farmacología , Toxina del Pertussis/farmacología , Potasio/farmacología , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/genética , Receptor Muscarínico M4/agonistas , Receptor Muscarínico M4/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sinapsis/metabolismo , TransfecciónRESUMEN
The development of the immune reaction after the activation or blockade of presynaptic 5-HT1A receptors, respectively, with a selective agonist or antagonist depends on specific behavioral patterns. Agonist of 5-HT1A receptors 8-OH-DPAT (0.1 mg/kg 15 min prior to immunization) did not change the number of IgM plaque-forming cells in the spleen of aggressive mice at the peak of the immune response (the 4-th day after immunization) but increased their number in submissive animals, in which the baseline immune response was lower than in aggressive animals. Administration of WAY-100635 (0.1 mg/kg 30 min prior to immunization) resulted in a decrease in the immune reaction in aggressive mice and led to its increase in submissive animals. It is suggested that the immunomodulatory effects of drugs affecting the activity of presynaptic 5-HT1A receptors are related to changes in the functional state of these receptors and the interaction between serotonin- and dopaminergic systems.
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Agresión/fisiología , Células Productoras de Anticuerpos/inmunología , Autorreceptores/fisiología , Conducta Animal/fisiología , Neuroinmunomodulación , Receptor de Serotonina 5-HT1A/fisiología , Receptores Presinapticos/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Formación de Anticuerpos , Autorreceptores/agonistas , Dominación-Subordinación , Inmunoglobulina M/inmunología , Factores Inmunológicos/farmacología , Masculino , Ratones , Ratones Endogámicos CBA , Piperazinas/farmacología , Piridinas/farmacología , Receptores Presinapticos/agonistas , Agonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT1 , Bazo/citología , Bazo/inmunologíaRESUMEN
Many studies have demonstrated that GABAergic inhibition within the basolateral amygdala (BLA) plays an integral role in the regulation of anxiety, an important behavioral component in the etiology of alcoholism. Although ethanol has recently been shown to enhance BLA GABAergic inhibition via two distinct populations of inhibitory cells, local and lateral paracapsular (lpcs) interneurons, little is known about the mechanisms underlying ethanol potentiation of these two inhibitory pathways. Ethanol is known to enhance GABAergic inhibition in many brain regions via a complex array of pre- and postsynaptic mechanisms. In addition, ethanol's presynaptic effects are often subject to GABA(B) autoreceptor (GABA(B)-R) modulation. Therefore, in this study, we characterized GABA(B)-R function and modulation of ethanol actions at local and lpcs GABAergic synapses. At local synapses, we found significant paired-pulse depression (PPD, 250 ms inter-pulse interval) which was abated by SCH-50911 (GABA(B)-R antagonist). No significant PPD was detected at lpcs synapses, but SCH-50911 significantly potentiated lpcs-evoked IPSCs. Baclofen (GABA(B)-R agonist) had similar depressant effects on local- and lpcs-evoked IPSCs, however baclofen pretreatment only reduced ethanol potentiation at local synapses. Ethanol also significantly enhanced the frequency of spontaneous and miniature IPSCs, and these effects were also sensitive to GABA(B)-R modulators. Collectively, these data suggest that stimulus-independent inhibitory responses recorded from BLA principal neurons primarily reflect the activity of local GABAergic interneurons and provide additional evidence that ethanol potentiates local BLA inhibitory synapses primarily via a presynaptic enhancement of GABA release that is tightly regulated by GABA(B)-Rs. In contrast, ethanol potentiation of lpcs GABAergic synapses is not sensitive to GABA(B)-R activation and does not appear to involve increased presynaptic GABA release.
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Amígdala del Cerebelo/efectos de los fármacos , Autorreceptores/agonistas , Etanol/farmacología , Agonistas de Receptores GABA-B , Sinapsis/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Animales , Baclofeno/farmacología , Moduladores del GABA/farmacología , Antagonistas de Receptores de GABA-B , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores , Interneuronas/efectos de los fármacos , Interneuronas/fisiología , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
RATIONALE: The effect of manipulation of the serotonin (5-HT) system on conditioned gaping (presumably reflective of nausea in rats) was evaluated. OBJECTIVE: The potential of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (which produces nausea in the clinic), to produce conditioned gaping in rats and of the 5-HT(3) antagonists (ondansetron and palonosetron) and the 5-HT(1A) autoreceptor agonist (8-OH-DPAT) to reverse this effect were evaluated. MATERIALS AND METHODS: In each of four experiments, rats received three pairings of intraorally delivered 17% sucrose solution and fluoxetine (0, 2, 10 or 20 mg/kg) and 72 h later were given a drug-free test trial. In experiment 2, rats were pretreated with the 5-HT(3) antagonists, ondansetron (0, 0.1 or 1.0 mg/kg) or the longer acting palonosetron (0.1 mg/kg), 30 min before each of three sucrose-fluoxetine (20 mg/kg) pairings. In experiment 3, rats were injected with palonosetron (0.1 mg/kg) 2 h before each of three sucrose-fluoxetine (20 mg/kg) or sucrose-lithium chloride (LiCl, 25 mg/kg) pairings. In experiment 4, rats were pretreated with the 5-HT(1A) autoreceptor agonist, 8-OH-DPAT (DPAT, 0.1 mg/kg) 30 min before each of three sucrose-fluoxetine (20 mg/kg) pairings. RESULTS: After two sucrose-fluoxetine pairings, the highest dose of fluoxetine tested (20 mg/kg) produced conditioned gaping reactions. These conditioned gaping reactions were prevented by pretreatment with DPAT, but not with the 5-HT(3) antagonists. On the other hand, palonosetron administered 2 h prior to sucrose-LiCl pairings attenuated conditioned gaping reactions. CONCLUSIONS: These results suggest that the conditioned nausea produced by SSRIs, but not LiCl, may be resistant to treatment with 5-HT(3) antagonists, but not 5-HT(1A) autoreceptor agonists.
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Antieméticos/farmacología , Fluoxetina/farmacología , Náusea/prevención & control , Agonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT3 , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/uso terapéutico , Animales , Antieméticos/uso terapéutico , Autorreceptores/agonistas , Condicionamiento Psicológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Cloruro de Litio/farmacología , Masculino , Náusea/inducido químicamente , Ondansetrón/farmacología , Ondansetrón/uso terapéutico , Palonosetrón , Quinuclidinas/farmacología , Quinuclidinas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
Temperature-induced changes of affinity and efficacy of the alpha2-adrenoceptor full agonist UK14,304 and the partial agonists clonidine and guanfacine were investigated to elucidate the mechanism of partial agonism at the terminal alpha2-autoreceptor. The effect of temperature on the efficacy of the substances was tested in 3H-noradrenaline release experiments at 37 degrees C and at room temperature. Human neocortical slices were prelabeled with 3H-noradrenaline, superfused, and stimulated electrically under autoinhibition-free conditions. Furthermore, saturation binding experiments with human neocortical synaptosomes were performed at 37 degrees C and 17 degrees C to evaluate the influence of temperature on the affinity of 3H-clonidine and 3H-UK14,304. Temperature-induced changes of the association and dissociation rate constants of 3H-UK14,304 and 3H-clonidine were assessed in corresponding kinetic binding experiments. Our experiments reveal that clonidine and guanfacine lose efficacy when the temperature is lowered, whereas no change was noted for the full agonist UK14,304. Moreover, the affinity of clonidine and guanfacine was shown to decrease at lower temperature. Kinetic experiments indicated that the loss of affinity observed for 3H-clonidine at 17 degrees C is due to a marked reduction of the association rate. The loss of efficacy of the partial agonists is most likely related to the short binding duration; partial agonists do not bind long enough to the receptor to mediate a maximum response. The discrepancy between the time required to elicit a maximum response and the actual binding time may be greater for partial agonists at lower temperatures, thus, causing the intrinsic activity to decline.
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Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacología , Autorreceptores/agonistas , Temperatura , Adolescente , Adulto , Anciano , Autorreceptores/metabolismo , Tartrato de Brimonidina , Niño , Preescolar , Clonidina/farmacología , Femenino , Guanfacina/farmacología , Humanos , Técnicas In Vitro , Lactante , Masculino , Persona de Mediana Edad , Neocórtex/efectos de los fármacos , Neocórtex/metabolismo , Unión Proteica , Quinoxalinas/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Factores de Tiempo , Adulto JovenRESUMEN
RATIONALE: Recent theories posit an important role for the noradrenergic system in attentional selection in the temporal domain. In contrast, the spatially diffuse topographical projections of the noradrenergic system are inconsistent with a direct role in spatial selection. OBJECTIVES: To test the hypotheses that pharmacological attenuation of central noradrenergic activity should (1) impair performance on the attentional blink task, a task requiring the selection of targets in a rapid serial visual stream of stimuli; and (2) leave intact the efficiency of the search for a target in a two-dimensional visuospatial stimulus array. MATERIALS AND METHODS: Thirty-two healthy adult human subjects performed an attentional blink task and a visual search task in a double-blind, placebo-controlled, between-subject study investigating the effects of the alpha2 adrenoceptor agonist clonidine (150 microg, oral dose). RESULTS: No differential effects of clonidine vs placebo were found on the attentional blink performance. Clonidine slowed overall reaction times in the visual search task but did not impair the efficiency of the visual search. CONCLUSIONS: The attentional blink results are inconsistent with recent theories about the role of the noradrenergic system in temporal filtering and in mediating the attentional blink. This discrepancy between theory and data is discussed in detail. The visual search results, in combination with previous findings, suggest that the noradrenergic system is not directly involved in spatial attention processes but instead can modulate these processes in an indirect fashion.
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Agonistas alfa-Adrenérgicos/farmacología , Atención/efectos de los fármacos , Parpadeo/efectos de los fármacos , Clonidina/farmacología , Tiempo de Reacción/efectos de los fármacos , Percepción Espacial/efectos de los fármacos , Adolescente , Adulto , Autorreceptores/agonistas , Señales (Psicología) , Método Doble Ciego , Femenino , Fijación Ocular/efectos de los fármacos , Humanos , Locus Coeruleus/metabolismo , MasculinoRESUMEN
Aberrant glutamatergic neurotransmission may underlie the pathogenesis of schizophrenia and metabotropic glutamate receptors (mGluRs) have been implicated in the disease. We have established the localization of the group III mGluR subtype, mGluR8, in the human body and investigated the biological effects of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) in schizophrenia-related animal models. The mGlu8 receptor has a widespread CNS distribution with expression observed in key brain regions associated with schizophrenia pathogenesis including the hippocampus. (S)-3,4-DCPG inhibited synaptic transmission and increased paired-pulse facilitation in rat hippocampal slices supporting the role of mGluR8 as a presynaptic autoreceptor. Using the rat Maximal Electroshock Seizure Threshold (MEST) test, (S)-3,4-DCPG (30 mg/kg, i.p.) reduced seizure activity confirming the compound to be centrally active following systemic administration. (S)-3,4-DCPG did not reverse (locomotor) hyperactivity induced by acute administration of phenylcyclidine (PCP, 1-32 mg/kg, i.p.) or amphetamine (3-30 mg/kg, i.p.) in Sprague-Dawley rats. However, 10 nmol (i.c.v.) (S)-3.4-DCPG did reverse amphetamine-induced hyperactivity in mice although it also inhibited spontaneous locomotor activity at this dose. In addition, mGluR8 null mutant mouse behavioral phenotyping revealed an anxiety-related phenotype but no deficit in sensorimotor gating. These data provide a potential role for mGluR8 in anxiety and suggest that mGluR8 may not be a therapeutic target for schizophrenia.
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Encéfalo/metabolismo , Receptores de Glutamato Metabotrópico/fisiología , Esquizofrenia/metabolismo , Anfetamina/farmacología , Animales , Anticonvulsivantes/farmacología , Ansiedad/genética , Ansiedad/metabolismo , Autorreceptores/agonistas , Autorreceptores/biosíntesis , Autorreceptores/fisiología , Benzoatos/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Giro Dentado/efectos de los fármacos , Giro Dentado/fisiología , Modelos Animales de Enfermedad , Electrochoque , Glicina/análogos & derivados , Glicina/farmacología , Humanos , Masculino , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Fenciclidina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/genética , Esquizofrenia/fisiopatología , Convulsiones/etiología , Convulsiones/prevención & control , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacosRESUMEN
OPC-14523 (OPC) is a novel compound with high affinity for sigma and 5-HT1A receptors that shows 'antidepressant-like' effects in animal models of depression. We have previously demonstrated that OPC produces an increase in 5-HT neurotransmission and a decreased response of 5-HT neurons to the acute administration of paroxetine in the DRN, an effect that appears to be mediated by OPC's 5-HT1A receptor affinity. The current study sets out to investigate more specifically the effects of OPC on 5-HT1A pre- and post-synaptic receptors, to assess whether it acts as an agonist or antagonist. Using an electrophysiological model of in vivo extracellular recordings in anaesthetized rats, the effects of OPC was assessed on pre-synaptic DRN 5-HT1A autoreceptors and post-synaptically on hippocampal 5-HT1A receptors of CA3 pyramidal neurons. OPC applied by microiontophoresis, produced a significant decrease in the firing activity of 5-HT neurons of the DRN and of quisqualate-activated CA3 pyramidal neurons of the dorsal hippocampus. The effects of OPC on 5-HT1A receptors were significantly reduced by the co-application of the 5-HT1A antagonist WAY-100635. In addition, the effects of OPC were not blocked by the injection of the sigma antagonists NE-100 or haloperidol. Therefore, OPC is acting as an agonist on both pre- and post-synaptic 5-HT1A receptors. The current findings combined with previous data on OPC suggest a pharmacological profile that warrants further investigation.