In studies on superfused slices obtained from the rat hippocampus, we extracellularly recorded field EPSP (fEPSPs), pharmacologically isolated components of these fEPSP, which were related to activation of synaptic NMDA-glutamate receptors, and neuronal responses of the dentate gyrus, which were mediated by activation of extrasynaptic NMDA-glutamate receptors. Recordings were performed in junctions formed by fibers of the medial perforant pathway and dendrites of granular cells of the gyrus dentatus. In the course of the development of behavioral depression in rats, which was caused by zoosocial isolation or chronic injection of dexamethasone, the amplitude of fEPSPs decreased, on average, by 19.8 and 26.0%, respectively, while the NMDA components of fEPSP increased by 28.6 and 33.4%; the rise in the amplitude of neuronal responses recorded in the gyrus dentatus, which were mediated by the activation of extrasynaptic NMDA receptors (by 75.4 and 92.3%), was clearly expressed. In intact rats, chronic (over 14 days) injections of tricyclic antidepressants, imipramine and amitriptyline, as well as of an atypical antidepressant, maprotiline, resulted in an increase in the fEPSP amplitude by 22.1 to 25.9%. At the same time, the amplitude of NMDA components of fEPSP dropped by 27.0 to 29.1%, while the amplitude of responses mediated by the activation of extrasynaptic NMDA-glutamate receptors decreased by 46.1 to 49.8%. Changes in the neuronal responses in the gyrus dentatus, which were mediated by the activation of NMDA-glutamate receptors, are related to an increase or decrease in the number of such receptors. It is supposed that an increase in the total number of NMDA-glutamate receptors under conditions of behavioral depression results in a deterioration of the energy supply of cerebral neurons, while an increase in the extrasynaptic pool of NMDA-glutamate receptors leads to suppression of biosynthesis of neurotrophins and to injury of neurons. As a general result, informational processes in the brain are subjected to significant negative influences. Chronic injections of antidepressants promote a permanent rise in the concentration of noradrenaline and serotonin in extracellular environments and the activation of monoamine receptors positively conjugated with adenylate cyclase; suppression of expression of informational RNAs, which encode subunits of NMDA-glutamate receptors, and a decrease in the number of these receptors. These events improve the functional state of neurons.
In tests of "illuminated area" and the "threatening situation" avoidance by rats, apomorphine and phenamine, administered intraperitoneally, attenuate the state of alarm. A similar effect is observed when sulpiride, a selective blocker of D2-receptors of dopamine, and of picrotoxin, a GABA antagonist, are administered. Sulpiride effectively counteracts the anxiolytic effects of all of the dopaminomimetics investigated and of picrotoxin. Haloperidol, a nonselective blocker of the D1- and D2-receptors of dopamine removes the anxiolytic effect of apomorphine, phenamine, and picrotoxin. The microinjection into the ventral region of the midbrain tegmentum of dopamine, or of sulpiride into the nucleus accumbens of the septum, attenuates the state of alarm formed by aversive influences of various biological modalities. By contrast, sulpiride, introduced locally into the tegmentum, or chemical stimulation of the nucleus accumbens of the septum by dopamine, intensifies the state of alarm in the "illuminated area" avoidance test. The participation of dopaminergic mechanisms of the mesolimbic system of the brain in anxiety of various aversive causations is discussed.
Microinjections of serotonin and glutamic acid into the globus pallidus in conditions of free selection between a light and a dark chamber showed these substances to have antiaversive activity in rats in the "threatening situation" test but not in the "illuminated area" test. Local administration of dopamine and GABA into this basal ganglia formation had no effect on the mechanisms of voluntary movement but countered anxiety states in both behavioral models. These results provide evidence that the neurotransmitter systems of the dorsal pallidum have different degrees of involvement in the operative control of behavior when the modality of the aversive stimulus changes.
In experiments on rats using an "illuminated area" avoidance test and a "threatening situation" avoidance test, preliminary i.p. administration and subsequent microinjection into the ventromedial hypothalamus of various combinations of monoamines, transmitter amino acids, and their agonists and antagonists demonstrated differences in the functional importance of the neurochemical profile of this limbic formation in mediating anxiety states of different origins. The neurochemical analysis with local intrahypothalamic administration of anxiosedative and anxioselective substances showed that the antiaversive actions of Campirone are obtained only in conditions in which the dominant motivation is fear, while chlordiazepoxide, Phenibut, and Indoter are also active in anxiety induced by negatively stressful zoosocial influences; these actions are mediated respectively by serotoninergic and GABAergic types of synaptic switching in the ventromedial hypothalamus.
Microinjections of dopamine, apomorphine, and GABA to the dorsal part of the caudate nucleus decreased the level of anxiety in an illuminated platform avoidance task in rats, while sulpiride and picrotoxin increased it. Intrastriatal injection of serotonin, glutamic acid, yohimbine, and phenylephrine reduced anxiety in threatening situation, but not in the illuminated platform avoidance task. It is suggested that emotional states associated with different kinds of stress are realized through diverse neurochemical systems of the caudate nucleus neuronal network.Key Words: caudate nucleus; anxiety; neurochemical mechanisms Tranquillizers potentiating GABA-ergic transmission are known to suppress fear and deactivate the fearinduced synthesis of catecholaminergic enzymes in the caudate nucleus [4,14]. Aversive stimuli of diverse modalities converging on the caudate nucleus differently change the content of dopamine, GABA, and glutamic acid [8,10,13], or induce asymmetrical changes in their metabolism and synaptic release [11]. Although noradrenaline and serotonin also belong to neostriatal neurotransmitters [2,7,12], their role in the genesis of anxiety is unclear.In this study, the functional role of different neurotransmitters in anxiety caused by different aversive stimuli was investigated by means of local microinjections of GABA, glutamic acid, monoamines, and their agonists and antagonists into the caudate nucleus. MATERIALS AND METHODSExperiments were carried out on 42 outbred adult male rats weighing 250i70 g. The rats were tested in a box consisting of light (200-W light bulb) and dark compartments and a special section for victim rats separated from the dark compartment by a transparent wall. The light and dark compartments were connected through a hole located 6 cm above the floor. The level of anxiety was measured in rats previously trained to avoid illuminated place (test 1, illuminated platform avoidance) and to avoid light compartment in a threatening situation (test 2, threatening situation avoidance). Painful electric stimulation (45 V) applied to 18 victim rats in the special section of the dark compartment served as a model of threatening situation for spectator rats and was automatically switched off, when spectator rat reached a special platform in the dark compartment. After consolidation of the avoidance reactions, the rats (n=24) were anesthetized with ether and chemotrodes for intrastriatal microinjections were implanted in the dorsal part of the caudate nucleus according to stereotaxic coordinates AP=,I.0, L=2.0, and H=3.2. The following drugs (0.5-5%) were used: dopamine GABA, glutamic acid, serotonin creatinine sulphate, agonists of cz 2 adrenoreceptor, D 1 and D 2 dopamine receptors (clonidine, apomorphine), and antagonists of %, a2, D v and D 2 receptors (phentolamine, yohimbine, sulpiride) in doses of 5-50 ~tg. All drugs were administered in a volume of 1 ~tl. Retention of the acquired reactions was tested for 2 days before experiments (5-6 days after surgery). The rats with avoidance l...
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