RESUMO
CP-96,345, a nonpeptide substance P antagonist, is selective for the tachykinin NK1 receptor. The compound binds to a single population of sites in guinea pig brain and potently inhibits substance P-induced excitation of locus ceruleus neurons. CP-96,345 should be a useful tool for studying the action of substance P in the central nervous system.
Assuntos
Compostos de Bifenilo/metabolismo , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Receptores de Neurotransmissores/antagonistas & inibidores , Receptores de Neurotransmissores/metabolismo , Potenciais de Ação , Animais , Autorradiografia , Sítios de Ligação , Ligação Competitiva , Compostos de Bifenilo/farmacologia , Encéfalo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Cobaias , Concentração de Íons de Hidrogênio , Masculino , Cintilografia , Receptores da Neurocinina-1 , Receptores de Taquicininas , Espectrofotometria , Substância P/metabolismo , Taquicininas/metabolismoRESUMO
N-demethylation of the selective serotonin reuptake inhibitor sertraline to desmethylsertraline yields a compound with 10- to 20-fold less potency at blocking serotonin (5-HT) reuptake as measured in vitro. In the present study desmethylsertraline (DMS) was examined in two in vivo models of reuptake inhibition--elevation of extracellular 5-HT in the corpus striatum as measured by microdialysis and inhibition of firing of serotonin-containing dorsal raphe neurons. Whereas sertraline (1, 3.2, and 10 mg/kg s.c.) produced a dose-dependent increase in extracellular 5-HT and a decrease in 5-HIAA in rat striatum, desmethylsertraline was without effect on either parameter. In similar fashion, desmethylsertraline had no effect on dorsal raphe cell firing at a dose (1,000 micrograms/kg i.v.) nearly 20-fold the ED50 for sertraline (52 micrograms/kg). Taken together, these data suggest that DMS does not contribute to the blockade of central 5-HT reuptake produced by sertraline in vivo and therefore would be expected to play a negligible role in its clinical activity.
Assuntos
1-Naftilamina/análogos & derivados , Receptores de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , 1-Naftilamina/metabolismo , 1-Naftilamina/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sertralina , Fatores de TempoRESUMO
The synthesis of a highly potent and selective NK1 receptor antagonist radioligand, [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine (6a) is described. The in vitro binding pharmacology and autoradiographic distribution of 6a in guinea pig brain following peripheral administration are also reported.
Assuntos
Neurocinina A/antagonistas & inibidores , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Piperidinas/farmacologia , Sequência de Aminoácidos , Animais , Autorradiografia , Encéfalo/metabolismo , Cobaias , Masculino , Dados de Sequência Molecular , Piperidinas/metabolismo , Ensaio Radioligante , Estereoisomerismo , Substância P/químicaRESUMO
The design and synthesis of a series of potential atypical antipsychotic agents based on the structure of 1-naphthylpiperazine are described. The incorporation of dopamine antagonist activity into the parent structure was achieved with heterocyclic surrogates for the catechol moiety of dopamine. Compound 4b from this series showed a biochemical profile that translated to behavioral activity in the rat predictive of an antipsychotic agent with a low propensity to cause extrapyramidal side effects in man.
Assuntos
Antipsicóticos , Piperazinas/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina , Anfetaminas/farmacologia , Animais , Apomorfina/farmacologia , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina , Haloperidol/farmacologia , Ketanserina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Prazosina/metabolismo , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/metabolismoRESUMO
The synthesis and in vitro and in vivo characteristics of 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1, CP-93,129) are described. This rotationally restricted phenolic analogue of RU-24,969 is a potent (15 nM) and selective (200x vs the 5-HT1A receptor, 150x vs the 5HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of 1 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regulating feeding behavior in rodents. 3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1) has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. The source of the selectivity of 1 appears to lie in the ability of a pyrrolo[3,2-b]pyrid-5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.
Assuntos
Indóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Serotonina/fisiologia , Inibidores de Adenilil Ciclases , Animais , Fenômenos Químicos , Química , Colforsina/farmacologia , Ciclização , Ingestão de Alimentos/efeitos dos fármacos , Cobaias , Hipocampo/enzimologia , Estrutura Molecular , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiologia , Piridinas/síntese química , Piridinas/metabolismo , Pirróis/síntese química , Pirróis/metabolismo , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Serotonina/farmacologia , Substância Negra/metabolismoRESUMO
A novel structural class of highly potent and selective 5-HT3 receptor antagonists is described. The compounds in this new series contain a thiazole moiety linking an aromatic group and a nitrogen-containing basic region; the thiazole group appears to be acting as a carbonyl bioisostere in this system. An optimized member of this series, 4-(2-methoxyphenyl)-2-[[4(5)-methyl-5(4)-imidazolyl]methyl]thiazole (5), exhibits oral activity in the Bezold-Jarisch reflex paradigm comparable to or better than the standard agents ondansetron (1) and ICS-205-930 (2). Several of the structure-activity relationships are rationalized in terms of a computer pharmacophore model for 5-HT3 receptor binding.
Assuntos
Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Tiazóis/farmacologia , Administração Oral , Animais , Gráficos por Computador , Técnicas In Vitro , Camundongos , Modelos Moleculares , Neurônios/metabolismo , Ensaio Radioligante , Ratos , Receptores de Serotonina/classificação , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade , Tiazóis/administração & dosagem , Tiazóis/química , Células Tumorais CultivadasRESUMO
Sertraline is a member of a new class of psychotherapeutic agents that selectively inhibit serotonin reuptake in the brain. Animal studies have demonstrated that inhibition of serotonin reuptake leads to enhanced serotonergic neurotransmission and indirectly results in a down-regulation of beta-adrenoceptors. The preclinical pharmacology of sertraline predicts antidepressant activity without accompanying anticholinergic, cardiotonic, or sedative side effects. Recent laboratory and clinical observations pertaining to body weight and obsessive compulsive disorder suggest the possibility of broader clinical indications for selective serotonin reuptake blockers such as sertraline.
Assuntos
1-Naftilamina/farmacologia , Naftalenos/farmacologia , Antagonistas da Serotonina/farmacologia , 1-Naftilamina/análogos & derivados , 1-Naftilamina/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Humanos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Ratos , Antagonistas da Serotonina/uso terapêutico , SertralinaRESUMO
The effects of phasic auditory or visual stimuli upon the single unit activity of serotonergic neurons within the dorsal raphe nucleus (DRN) were studied in freely moving cats. The predominant response to auditory stimulation (86% of the cells) was excitation, with a mean latency of 40 +/- 3 ms (S.E.M.) and a mean duration of 64 +/- 4 ms. This was typically followed by a longer period (206 +/- 32 ms) with unit activity below the baseline level. This did not appear to be a stimulus-induced inhibition of unit activity, however, since its duration closely corresponded to the normal interspike interval for that particular neuron. The response to repetitive auditory stimulation showed no evidence of habituation and was even present during sleep. A similar response, although generally of lesser magnitude, was evoked by a phasic visual stimulation in 64% of the cells tested. The mean latency for the response to visual stimulation was 53 +/- 4 ms, the mean duration of excitation was 76 +/- 7 ms, and the mean duration of the subsequent suppressed period was 239 +/- 37 ms. The response to the visual stimulus also showed no evidence of habituation. These data indicate that serotonergic neurons of the DRN are driven, with similar temporal characteristics, by stimuli in two different sensory modalities. We hypothesize that these similar effects are attributable to a common excitatory input.
Assuntos
Tronco Encefálico/fisiologia , Neurônios/fisiologia , Núcleos da Rafe/fisiologia , Estimulação Acústica , Animais , Gatos , Estimulação Elétrica , Potenciais Evocados Auditivos , Potenciais Evocados Visuais , Feminino , Movimento , Estimulação LuminosaRESUMO
Serotonergic neurons within nucleus raphe pallidus (NRP) of freely moving cats initially were distinguished by their slow (less than 8 Hz), regular discharge and long duration (mean = 2.3 ms) action potentials. The activity of serotonergic NRP neurons was highest during active waking (mean = 4.85 +/- 0.37 spikes/s) and gradually slowed, with little change in firing pattern, during the transition from waking through slow wave sleep (middle of SWS: mean = 3.76 +/- 0.36 spikes/s). In REM sleep there was a precipitous decrease in firing rate (mean = 0.92 +/- 0.23 spikes/s) and loss of discharge regularity. Although there was no significant difference in firing rate between active and quiet waking, discharge rates were significantly increased during transient elevations of the EMG, but these rate increases usually were associated with specific motor behaviors only. The activity of serotonergic NRP neurons during SWS was not related to the occurrence of either sleep spindles in the cortical EEG or PGO waves recorded from the lateral geniculate nucleus. These neurons also were relatively unresponsive to phasic auditory or visual stimuli, with most of the neurons examined showing weak excitatory responses. Activity of all serotonergic NRP neurons tested was suppressed (mean = -81.3 +/- 4.3%) by the serotonergic agonist 5-methoxy-N,N-dimethyltryptamine (250 micrograms/kg, i.m.). The results of this study are compared with those previously reported for serotonergic neurons in the dorsal raphe nucleus of freely moving cats and the issue of homogeneity in central serotonergic systems is discussed.
Assuntos
Tronco Encefálico/fisiologia , Neurônios/fisiologia , Núcleos da Rafe/fisiologia , Serotonina/fisiologia , Estimulação Acústica , Potenciais de Ação , Animais , Gatos , Feminino , Corpos Geniculados/fisiologia , Metoxidimetiltriptaminas/farmacologia , Atividade Motora , Movimento , Estimulação Luminosa , Sono , VigíliaRESUMO
The hypothesis that the action of hallucinogenic drugs is mediated by a depression of the activity of brain serotonergic (raphe) neurons was tested by examining the behavioral effects of several hallucinogenic drugs while concurrently monitoring the activity of raphe neurons in freely moving cats. LSD produced a dose-dependent decrease in raphe unit activity and a dose-dependent increase in certain behaviors (e.g. limb flick and abortive groom), and the peak of the behavioral and unit changes were temporally correlated. However, there were three important dissociations between the behavioral and electrophysiological effects of LSD. Firstly, low doses of LSD produced only small decreases in raphe unit activity but significant behavioral changes. Secondly, the duration of LSD-induced behavioral changes significantly outlasted the depression of raphe unit activity. And thirdly, raphe neurons were at least as responsive to LSD during tolerance as they were in the nontolerant condition. Psilocin produced a dose-dependent decrease in raphe unit activity, while the behavioral changes were not dose-related. However, the peak behavioral changes corresponded to the maximal depression of raphe unit activity. The phenylethylamine hallucinogens, DOM and mescaline, both produced large behavioral changes but no overall effect on raphe neurons. Following administration of DOM or mescaline, some raphe units showed a significant increase, while some showed a significant decrease, and others showed no change in activity. Therefore, the phenylethylamine hallucinogens may exert a depressant effect upon a subset of serotonin-containing neurons, and an amphetamine-like excitatory effect upon another subset of these neurons. Consistent with previous studies, all hallucinogens produced a high concentration of slow waves in the cortical EEG. Following administration of LSD or psilocin, the appearance of slow waves in the EEG was often associated with a transitory decrease in unit activity, while this was not observed for the phenylethylamine hallucinogens. The present data, in conjunction with recent data from other laboratories, suggest that the serotonin hypothesis of hallucinogenic drug action should be re-evaluated.
Assuntos
Anfetaminas/farmacologia , Comportamento Animal/efeitos dos fármacos , Tronco Encefálico/fisiologia , 2,5-Dimetoxi-4-Metilanfetamina/farmacologia , Dietilamida do Ácido Lisérgico/análogos & derivados , Dietilamida do Ácido Lisérgico/farmacologia , Mescalina/farmacologia , Psilocibina/análogos & derivados , Núcleos da Rafe/fisiologia , Animais , Gatos , Condutividade Elétrica , Feminino , Cinética , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Psilocibina/farmacologia , Núcleos da Rafe/efeitos dos fármacosRESUMO
The influence of chloral hydrate anesthesia on the spontaneous activity and responsiveness of serotonergic neurons was examined by administering chloral hydrate (300 mg/kg, i.p.) to freely moving cats from which serotonergic unit activity in the dorsal raphe nucleus (DRN) was being recorded. Although chloral hydrate administration produced a surgical level of anesthesia within 15 min following injection, it produced only a small decrease (approximately 20%) in the spontaneous activity of DRN serotonergic neurons. In contrast, the responsiveness of these same neurons was greatly altered by chloral hydrate administration. By examining the same neuron before and after chloral hydrate injection, it was found that chloral hydrate anesthesia completely abolished the excitatory responses of DRN serotonergic neurons to auditory and visual stimuli, as well as their excitatory response to electrical stimulation of the gigantocellular tegmental field (FTG) in the pontine reticular formation. On the other hand, the inhibition of serotonergic neuron firing resulting from systemic administration of WB 4101 (1.0 mg/kg, i.p.), a selective alpha 1 adrenergic receptor antagonist, was greatly potentiated by chloral hydrate anesthesia. Therefore, these data indicate that chloral hydrate anesthesia produces profound changes in the physiological and pharmacological responses of central serotonergic neurons which are not predictable by examination of spontaneous activity alone. Furthermore, as discussed, it it not clear to what extent these confounding influences might generalize to other anesthetized or immobilized preparations. Thus, beyond the obvious advantage which allows for the study of relationships between neuronal activity and behavior, single unit studies conducted in awake, freely moving animals also may be of greater value for basic physiological and pharmacological studies.
Assuntos
Anestesia Geral , Tronco Encefálico/fisiologia , Hidrato de Cloral , Núcleos da Rafe/fisiologia , Serotonina/fisiologia , Animais , Gatos , Estimulação Elétrica , Potenciais Evocados Auditivos , Potenciais Evocados Visuais , Tegmento Mesencefálico/fisiologiaRESUMO
Single unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats was recorded in experiments which manipulated central or peripheral motor systems. Unilateral microinjections of the cholinomimetic agent, carbachol, into the pontine tegmentum, produced muscle atonia. During these periods of drug-induced atonia, the activity of serotonergic neurons was reduced 97% below pre-drug baseline rates. In experiments where microinjections of carbachol did not produce muscle atonia, no significant change occurred in serotonergic unit discharge rate. Muscle tonus was also altered by systemic injections of mephenesin, a centrally acting muscle relaxant. A low dose of mephenesin (50 mg/kg) produced mild atonia which was correlated with a 16% reduction in serotonergic neuron discharge rate relative to pre-drug baseline. A higher dose of mephenesin (150 mg/kg) produced complete atonia, during which serotonergic unit activity was reduced by 68% below baseline firing rate. To distinguish between centrally and peripherally induced atonia, we injected either succinylcholine or dantrolene, systemically. These are both drugs whose muscle relaxant properties are known to be mediated by peripheral mechanisms. In neither case was a change in serotonergic unit discharge rate seen following drug-induced atonia. These data demonstrate that manipulation of central, but not peripheral, motor systems can profoundly affect the activity of serotonergic neurons of the dorsal raphe nucleus. Alternate hypotheses are also discussed.
Assuntos
Tronco Encefálico/fisiologia , Atividade Motora/fisiologia , Músculos/inervação , Núcleos da Rafe/fisiologia , Transmissão Sináptica , Animais , Nível de Alerta/fisiologia , Carbacol/farmacologia , Gatos , Relação Dose-Resposta a Droga , Eletromiografia , Potenciais Evocados/efeitos dos fármacos , Feminino , Mefenesina/farmacologia , Mesencéfalo/fisiologia , Tono Muscular/efeitos dos fármacos , Ponte/fisiologia , Serotonina/fisiologia , Sono REM/fisiologia , Transmissão Sináptica/efeitos dos fármacosRESUMO
The response of dopaminergic neurons of the substantia nigra pars compacta to auditory clicks continuously presented across the sleep-wake cycle was studied in cats. The initial excitatory followed by inhibitory response to the click which occurred during quiet waking diminished as the cat progressed into slow-wave sleep and was absent during REM sleep. Upon awakening from REM sleep, dopamine neurons once again displayed an excitatory/inhibitory response to the clicks, implying that the decrease across the sleep-wake cycle was not attributable to long-term habituation.
Assuntos
Percepção Auditiva/fisiologia , Dopamina/fisiologia , Fases do Sono/fisiologia , Substância Negra/fisiologia , Animais , Apomorfina/farmacologia , Vias Auditivas/fisiologia , Gatos , Eletrofisiologia , Feminino , Inibição Neural , Serotonina/fisiologia , Sono REM/fisiologiaRESUMO
Single unit activity of dopaminergic neurons in the substantia nigra was recorded in freely moving cats under a variety of conditions. These neurons displayed their highest discharge rate during active waking (3.68 +/- 0.30 spikes/s), which was 20% greater than their discharge rate during quiet waking (3.07 +/- 0.20). Although these cells fired somewhat faster during active waking, their activity displayed no correlation with phasic EMG changes, and, in general, their activity showed little relationship to overt behavioral changes. As the cat progressed from quiet waking through slow-wave sleep and REM sleep there was no significant change in either the rate or pattern of firing of dopaminergic neurons. In addition, no correlation was observed between the activity of these neurons and either sleep spindles or PGO waves. These neurons did respond, however, to the repeated presentation of a click or light flash with excitation followed by inhibition, with no evidence of habituation. One of the most impressive changes in dopaminergic unit activity was a large decrease in association with orienting responses. This was seen in over 50% of the cells in which this relationship was examined. As the behavioral orientation habituated with repeated stimulus presentation, so did the associated dopaminergic unit suppression. In conclusion, dopaminergic neurons maintain a remarkably constant rate and pattern of firing across a variety of behaviors and states. However, this stability can be dramatically altered under special circumstances, such as during and following orienting responses.
Assuntos
Comportamento Animal , Dopamina/fisiologia , Atividade Motora , Neurônios/fisiologia , Substância Negra/fisiologia , Animais , Apomorfina/farmacologia , Gatos , Feminino , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Sono/fisiologia , Sono REM/fisiologia , Vigília/fisiologiaRESUMO
The nonpeptide substance P receptor antagonist CP-96,345 was found to displace binding to Ca2+ channel binding sites labelled with either [3H]desmethoxyverapamil or [3H]diltiazem and to enhance [3H]nitrendipine binding. Unlike the substance P receptor antagonist activity of CP-96,345, these effects on Ca2+ channel binding sites were neither stereoselective nor species-dependent. It is concluded that CP-96,345 may act as an antagonist of L-type Ca2+ channels in addition to being a potent NK1 receptor (substance P) antagonist.
Assuntos
Compostos de Bifenilo/farmacologia , Canais de Cálcio/efeitos dos fármacos , Receptores de Neurotransmissores/antagonistas & inibidores , Substância P/metabolismo , Animais , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Diltiazem/farmacologia , Interações Medicamentosas , Cobaias , Coração/efeitos dos fármacos , Nitrendipino/farmacologia , Ensaio Radioligante , Ratos , Receptores da Neurocinina-1 , Trítio , Verapamil/análogos & derivados , Verapamil/farmacologiaRESUMO
Although central serotonergic systems appear to be linked importantly to the mechanism of action of a variety of hallucinogenic drugs, the nature of this interaction has remained unclear. In the present study, the question of whether the critical link is presynaptic or postsynaptic was examined in cats. Behaviorally inactive doses (1.0 mg/kg) of the serotonin receptor antagonists mianserin, ketanserin or metergoline effectively blocked behavior, as measured by the cat limb flick response, elicited by either LSD (50 micrograms/kg) or DOM (250 micrograms/kg) but not that resulting either from lisuride (50 micrograms/kg) or a high dose of apomorphine (4 mg/kg). Pretreatment with 1.0 mg/kg of mianserin, which completely attenuated LSD's behavioral effect, failed to alter LSD-induced depression of mesencephalic serotonergic neuron discharge. These results demonstrate that at least some of the behavioral effects of LSD can be blocked by pharmacological antagonism of postsynaptic serotonin receptors which leaves LSD's presynaptic effect unaffected. Thus, the behavioral, and possibly psychoactive, effects of hallucinogens appear to be attributable to an action at 5HT2 receptors, presumably located postsynaptically.
Assuntos
Comportamento Animal/efeitos dos fármacos , Alucinógenos/farmacologia , Receptores de Serotonina/efeitos dos fármacos , 2,5-Dimetoxi-4-Metilanfetamina/farmacologia , Animais , Apomorfina/farmacologia , Gatos , Relação Dose-Resposta a Droga , Feminino , Ketanserina , Lisurida/farmacologia , Dietilamida do Ácido Lisérgico/antagonistas & inibidores , Dietilamida do Ácido Lisérgico/farmacologia , Metergolina/farmacologia , Mianserina/farmacologia , Piperidinas/farmacologia , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , SinapsesRESUMO
A comparison was made of the effects of 5-MeoDMT or LSD on serotonergic unit activity in the dorsal raphe nucleus (DRN) and nucleus raphe pallidus (NRP) of freely moving cats. NRP neurons were substantially less responsive than DRN neurons to both drugs. NRP neurons were unresponsive to behaviorally effective low doses of these drugs whereas the activity of DRN neurons was strongly depressed. These data are discussed in terms of autoregulatory control of serotonergic neurons.
Assuntos
Dietilamida do Ácido Lisérgico/farmacologia , Bulbo/metabolismo , Metoxidimetiltriptaminas/farmacologia , Neurônios/efeitos dos fármacos , Serotonina/análogos & derivados , Serotonina/fisiologia , Animais , Gatos , Feminino , Núcleos da Rafe/efeitos dos fármacosRESUMO
Administration of d-amphetamine sulfate (7.5 mg/kg i.p.) twice daily to cats produces an initial large increase in both locomotion and behavioral stereotypy. As this regimen continues beyond three days, however, both measures show large significant decreases. We hypothesize that this tolerance to the behavioral effects of amphetamine is attributable to the concomitant decrease (approx. 70%) in presynaptic stores of dopamine and norepinephrine.
Assuntos
Dextroanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Animais , Química Encefálica/efeitos dos fármacos , Gatos , Dopamina/metabolismo , Tolerância a Medicamentos , Feminino , Humanos , Norepinefrina/metabolismoRESUMO
Previous work has suggested that central noradrenergic neurons may have an important influence on the activity of serotonergic neurons located in the dorsal raphe nucleus. Pharmacological studies have indicated that an alpha -adrenergic input is necessary to maintain the activity of these raphe cells. This issue was examined in freely moving cats by studying the effects of adrenergic drugs on raphe unit activity. Systemic administration of the selective alpha 1-antagonists WB4101 (0.5 and 1.0 mg/kg) or prazosin (10 mg/kg), or the non-competitive antagonist phenoxybenzamine (10 mg/kg), produced strong behavioral effects but had little effect on raphe unit activity. A low dose of the alpha -agonist clonidine (0.05 mg/kg), which decreases adrenergic transmission, produced similar results. These same drugs also had negligible effects on the evoked responses of raphe units to auditory or visual stimulation. Administration of d-amphetamine, a catecholamine releaser, produced behavioral stereotypy but had no significant effect on the discharge of raphe units. These data suggest that the adrenergic influence on serotonergic raphe neurons is very small in the freely moving cat. This is in contrast to the reported complete suppression of unit activity produced by alpha -adrenergic blockade in the chloral hydrate anesthetized rat.
Assuntos
Tronco Encefálico/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Simpatomiméticos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Nível de Alerta/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Gatos , Clonidina/farmacologia , Dextroanfetamina/farmacologia , Dioxanos/farmacologia , Eletroencefalografia , Feminino , Núcleos da Rafe/citologia , Núcleos da Rafe/fisiologia , Receptores Adrenérgicos/fisiologia , Receptores de Serotonina/fisiologiaRESUMO
Significant negative correlations were obtained between the spontaneous discharge rate during waking and the neural response to systemic injections of either 5-MeODMT or LSD for serotonergic neurons in the dorsal raphe nucleus, nucleus centralis superior, and nucleus raphe pallidus of unanesthetized and unrestrained cats. These data are discussed in terms of an hypothesis which accounts for both the rate of spontaneous activity of serotonergic neurons and the magnitude of their response to serotonin agonist drugs in terms of autoreceptor density on individual neurons.