RESUMEN
Our previous studies on conscious rabbits showed that stimulation of the median cervical nucleus (MCN) decreases the extent and frequency of oscillatory theta activity in the septohippocampal system, while functional blockade of the nucleus by administration of the anesthetic lidocaine produces a stage high-frequency theta rhythm. The present study addresses the nature of the serotoninergic influences of the MCN (which also contains cells of other chemical natures) on the septohippocampal system. Experiments on conscious rabbits involved recording of the hippocampal EEG in control conditions and after microinjection of fluoxetine, a serotonin reuptake blocker which increases the levels of this transmitter in the brain. In all experiments, bilateral intracerebroventricular administration of fluoxetine hydrochloride (Sigma, St. Louis, MO; 15 microg in 5 microl of physiological saline) induced decreases in the magnitude of the hippocampal theta rhythm. In 15 of 18 (83.3%) of experiments, suppression of the oscillator activity by at least 50% of control was seen. The amplitude of the theta band in the spectral density histogram decreased by an average of 56 +/- 5.8% compared with control values (decreases in different experiments were from 7% to 90% of control p < 0.001). The latent period of these changes averaged 3.5 +/- 0.11 min (range: 2.9-4.1 min). The effect lasted 64.8 +/- 3.2 min (varying from 45.3 to 90 min in different experiments). There were no significant changes in the theta rhythm frequency, as compared with controls; this averaged 5.25 +/- 0.5 Hz (range: 4.5-6.5 Hz). The decrease in the magnitude of theta oscillations in the hippocampus after administration of fluoxetine provided evidence of the inhibitory control of rhythmic theta activity by the serotoninergic system of the brain.
Asunto(s)
Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Ritmo Teta/efectos de los fármacos , Análisis de Varianza , Animales , Conejos , Factores de TiempoRESUMEN
The modulation of the firing discharge of medial septal neurons and of the hippocampal electroencephalogram (EEG) mediated by actions on alpha2-adrenoreceptors (ARs) was investigated in awake rabbits. Bilateral i.c.v. infusion of a relatively low dose (0.5 microg) of the alpha2-AR agonist clonidine produced a reduction in the theta rhythmicity of both medial septal neurons and the hippocampal EEG. In contrast, a high dose of clonidine (5 microg) increased the percentage and degree of rhythmicity of theta bursting medial septal neurons as well as the theta power of the hippocampal EEG. On the other hand, administration of alpha2-AR antagonist idazoxan produced the opposite dose-dependent effect. While a low dose of the antagonist (20 microg) produced an increase in both the theta rhythmicity of medial septal neurons and the theta power of the hippocampal EEG, a high dose (100 microg) caused a reduction of theta rhythmicity in both the medial septum and hippocampus. These results suggest that low doses of alpha2-ARs agents may act at autoreceptors regulating the synaptic release of noradrenaline, while high doses of alpha2-ARs drugs may have a predominant postsynaptic action. Similar results were observed after local injection of the alpha2-AR drugs into the medial septum suggesting that the effects induced by the i.c.v. infusion were primarily mediated at the medial septal level. We suggest that noradrenergic transmission via the postsynaptic alpha2-ARs produces fast and strong activation of the septohippocampal system in situations that require urgent selective attention to functionally significant information (alert, aware), whereas the action via the presynaptic alpha2-ARs allows a quick return of the activity to the initial level.
Asunto(s)
Hipocampo/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Tabique del Cerebro/fisiología , Ritmo Teta , Vigilia/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Clonidina/administración & dosificación , Clonidina/farmacología , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Idazoxan/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Conejos , Núcleos Septales/efectos de los fármacos , Tabique del Cerebro/efectos de los fármacos , Factores de TiempoRESUMEN
The influence of the alpha 2-adrenoreceptors agonist clonidine on the neuronal activity of the medial septal area (MS) and hippocampal EEG was studied in unanaesthetized rabbits. A slight and short-term decrease in the theta-rhythm modulation in the MS neuronal activity and/or EEG was revealed in 30.4% of tests after the bilateral intraventricular injection of a small dose of clonidine (0.5 microgram/5 microliters of water). On the contrary, a high dose of clonidine (5 micrograms/5 microliters) substantially enhanced the theta modulation in 100% of tests. The frequency of the theta bursts in the MS increased, on average, by 1.6 +/- 0.18 Hz (from 5.25 +/- 0.19 to 6.8 +/- 0.17 Hz). The regularity of the theta modulation became almost twice higher: the time constant of damping increased from 0.34 +/- 0.04 to 0.60 +/- 0.08 s. Increase in the neuronal activity in the MS produced by the high dose of clonidine was always accompanied by appearance of continuous stable theta waves in the EEG; the spectral power in the theta range increased, on average, by 480 +/- 98%. This strong effect arose suddenly but was relatively short-lasting (12 +/- 3.5 min) and usually abruptly terminated. It is concluded that the noradrenergic system has a double control over the theta oscillations through the alpha 2-adrenoreceptors agonist. In low concentrations the agonist clonidine acts on the high affinity inhibitory presynaptic autoreceptors reducing the noradrenaline release and suppressing the theta activity. In a high dose clonidine predominantly acts on postsynaptic (low affinity) adrenoreceptors substantially increasing the frequency and regularity of the theta bursts in the activity of septal neurons. Presumably, different types of alpha 2-adrenoreceptors participate in regulation of the theta oscillations in different functional states. It is suggested that the noradrenergic locus coeruleus is a functional synergist of the activating reticular formation participating in the urgent phasic activation of the septohippocampal system during the action of sudden strong stimuli.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacología , Clonidina/farmacología , Hipocampo/efectos de los fármacos , Animales , Hipocampo/fisiología , ConejosRESUMEN
The control of theta rhythm in neuronal activity of the medial septal area and hippocampal electroencephalogram by the brainstem structures was investigated in waking rabbits. In the first series of experiments stimulating electrodes were implanted into the midbrain reticular formation and median raphe nucleus. The standard frequency of theta-bursts in medial septal area neurons and in the electroencephalogram was uniformly and chronically decreased in all rabbits with electrodes implanted into the median raphe nucleus (4.7 +/- 0.5 Hz versus 5.2 +/- 0.19 Hz in animals without electrodes in median raphe nucleus). Weak electrical stimulation of the median raphe nucleus resulted in additional decrease of theta expression in the medial septal area neurons and its disappearance from the hippocampal electroencephalogram, where it was substituted by delta-waves and spindles. Stimulation of the reticular formation had the opposite effect, with an increase in theta frequency, regularity and expression in medial septal area neuronal activity and hippocampal electroencephalogram. In the second series of experiments reversible functional blockade of the median raphe nucleus by local microinjection of lidocaine was performed. This resulted in expression of theta-bursts in an additional group of medial septal area neurons, an increase in theta-burst frequency (by 0.5-2 Hz) and regularity with concomitant changes in the electroencephalogram. The effects of sensory stimuli on the background of increased theta activity were suppressed or significantly decreased. It is concluded that, in accordance with the data of other authors, the median raphe nucleus can be regarded as a functional antagonist of the reticular formation, powerfully suppressing theta-bursts of the medial septal area neurons and hippocampal theta rhythm. It is suggested that, in combination with the theta-enhancing influences of reticular formation, the median raphe nucleus may participate in termination of attention, its switching to other stimuli and stabilization of the effects of learning.