Dopaminergic modulation of the neuron activity in the cerebral cortex of the wakeful animal.

Specific effects of the dopamine synaptic transmission modulator on the activity of sensomotor cortical neurons in a wakeful animal, performing a conditioned reflex are discussed. First, specific responses in the neocortical neurons after application of glutamate agonists and antagonists and gamma aminobutyric acid are described and then the effect of dopamine, its agonists and antagonists and amantadine, a dopamine releaser, on the background and induced pulse activities in the cortical neurons, as well as on specific characteristics of conditioned reflex motor responses, such as latency and intensity are analyzed in detail.

Dopaminergic modulation of spike activity in sensorimotor cortex neurons in a conditioned reflex.

Changes in the spike conditioned reflex reactions of sensorimotor cortex neurons during microiontophoretic application of agonists and antagonists of glutamatergic and GABAergic transmission and their modulation by dopamine were studied. A paradoxical reaction is described, consisting of facilitation of spike responses evoked by antagonists of ionotropic glutamate transmission, which was blocked by GABA. This is evidence for the active involvement of inhibition in organizing the excitatory responses of neurons in the conditioned reflex. Application of the metabotropic glutamate transmission antagonist MCPG was accompanied by sharp suppression of the baseline and evoked activity of cortical neurons, along with increases in the latency of spike responses and conditioned reflex movement. Dopamine was found to reverse the effect of blocking metabotropic glutamate receptors and to normalize neuron activity, which is evidence for the stabilizing role of dopamine in the functioning of neocortical neurons.

[Effect of dopamine on activity of brain sensory-motor cortex neurons during conditioned reflex]. / Vplyv dofaminu na aktyvnist' neironiv sensomotornoï kory holovnoho mozku pry umovnomu refleksi.

A changes of background and evoked activity of deep cortical layers neurons and latency of the movement in the response to the conditioned stimuli were investigated in cats chronical experiments during microelectrode iontophoretic local aplication of dopamine, its antagonists and antagonists ofglutamatergic and gabaergic transmission. It was shown, that application of dopamine and others synapticaly active substances near soma of pyramidal neurons moderately increased their background and evoked activity and did not sygnificantly change their latency. Application of dopamine antagonists sulpiride and SCH 23390 depressed the background and evoked impulse activity and increased the latency of neuronal reaction and conditioned movements. These effects were completely removed by the aplication of the same antagonists together with dopamine. Dopamine removed the depressing influence on the background and evoked impulse activity and latency of the conditioned reflexes evoked by application of antagonists of glutamate ionotropic and metabotropic transmission (AP-4 and MCPG). The same stabilized influences were evoked by the iontophoretic application of GABA antagonist bicuculline. It was concluded that effects of dopamine are connected with its local inhibitory influences on the inhibitory interneurons and their synaptic endings on soma of pyramidal neurons.

[Dopaminergic modulation of impulse activity of sensorymotor cortex neurons during conditioned reflex]. / Dofaminérgicheskaia moduliatsiia impul'snoi aktivnosti neironov sensomotornoi kory pri uslovnom reflekse.

Changes of conditioned impulse reaction of cortical neurons wer studied during microiontophoretic application of agonist and antagonists of glutamate and GABA transmission and their modulation by dopamine. It was shown paradoxal reaction of facilitation of impulse activity during iontophoretic application of ionotropic glutamate antagonist and depressive influences of metabotropic antagonist. Local iontophoretic application of dopamine increased background and evoked impulse activity of pyramidal neurons of deep layers of cortex and eliminated inhibitory influences of glutamate metabotropic antagonist MCPG. It is concluded that DA has stabilizing effects on activity of cortical neurons. It is suppose that these effects of DA realize through system of inhibitory interneurons.

Dopamine modulation of glutamate metabotropic receptors in conditioned reaction of sensory motor cortex neurons of the cat.

The dopamine modulation of microiontophoretic application of antagonists of glutamate metabotropic synaptic transmission was studied in the sensory motor cortex of awake cats during instrumental conditioned reflex. The substances depressed the background and intensity of evoked impulse activity of pyramidal neurons of the sensory-motor cortex and provoked significant increases in the latency of impulse reaction and corresponding conditioned movements of animals. Simultaneous application of the antagonists and dopamine (DA) eliminated their depression of the background and evoked activity of neurons and decreased the latency of the impulse reactions and movements. Similar qualitative effects were observed in experiments with simultaneous application of biccuculine and (RS)-alpha-methyl-4-carboxyphenylglycine. It is supposed that the DA modulation in the brain consists in stabilizing the background and evoked activity of cortical neurons during reduced intensity of metabotropic glutamatergic synaptic transmission. Such modulation can be important when considering some pathological disorders of glutamatergic transmission.

The effects of activation of glutamate ionotropic connections of neurons in the sensorimotor cortex in a conditioned reflex.

Changes in conditioned reflex spike activity of neurons in the sensorimotor cortex were studied during microiontophoretic application of agonists and antagonists of glutamate and GABAergic transmission. The results of these experiments showed that the glutamate ionotropic receptors (AMPA and NMDA) of neurons in the sensorimotor cortex were intensely activated by the arrival of a conditioned signal in the cortex. This response included not only large pyramidal neurons of the deep cortical layers, but also the surrounding inhibitory interneurons. The existence of constant tonic inhibitory regulation of the activity of large pyramidal neurons by the surrounding inhibitory cells was demonstrated, along with the active involvement of this inhibition in organizing the excitatory responses of neurons in the sensorimotor cortex during a conditioned reflex.

Dopamine modulation of activity of cat sensorimotor cortex neurons during conditioned reflexes.

The effects of iontophoretic application of dopamine and selective D1 or D2 dopamine receptor agonists and antagonists on impulse activity of neurons of the deep layers of the sensorimotor cortex of cat were investigated during performance of a conditioned paw movement task. The application of dopamine, Quinpirole (selective D2 receptor agonist) or SKF 38393 (selective D1 receptor agonist) increased both background (P<0.001) and evoked impulse activity (P<0.05 for selective agonists). Selective D2 and D1 receptor antagonists (Sulpiride and SKF 83566, respectively) both increased the latency of neural responses and significantly increased the latency of the conditioned paw movements (P<0.01). These data suggest that during natural physiological functions subcortical dopamine neurons provide facilitation of activity pyramidal neurons of sensorimotor cortex.

[Activation of glutamate ionotropic connections of sensorimotor cortex neurons during conditioning]. / Effekty aktivatsii glutamatnykh ionotropnykh sviazei neironov sensomotornoi kory pri uslovnom reflekse.

Changes in conditioned impulse reactions of neurons in sensorimotor cortex were studied during microiontophoretic application of glutamatergic and GABA ergic agonistic and antagonistic drugs. It was shown that ionotropic glutamate receptors (AMPA and NMDA) are activated by a conditioned stimulus. Not only large pyramidal neurons of deep cortical layers but surrounding short-axon inhibitory interneurons are involved in the reaction. It was shown that the activity of pyramidal neurons is under a constant inhibitory control from surrounding interneurons. This inhibition is involved in organization of excitatory cortical responses during conditioning.

The effect of Psilocybe cubensis extract on hippocampal neurons in vitro.

The action of P. cubensis mushroom extract, containing psilocybin (PCB) and psilocin, on spike activity of hippocampal CA1 pyramidal neurons was studied in in vitro rat brain slices. In 38 (76%) out of 50 investigated neurons spike activity was decreased, in 2 (4%) cells it increased. There was no response 10 (20%) neurons. Application of the extract caused short burst firing in 12 (24%) neurons. All neurons showing inhibition during PCB-containing extract application, were also inhibited by serotonin (5-HT). Usually inhibitory reaction did not last over 4-5 min upon 3 min extract application and could be prolonged up to 10-43 min up on serotonin application. Part of neurons were inhibited by serotonin and did not react to extract application. Inhibitory reactions induced by extract application were blocked by ritanserin in half of the tested units and were induced due to activation of 5-HT2 serotonin receptors. The extract suppressed excitative spike reactions caused by application of L-glutamic acid. It is concluded, that application of PCB-containing extract in most cases reduced spike activity in hippocampal CA1 pyramidal neurons and suppressed glutamate transmission.

Modulation of the spike activity of neocortex neurons during a conditioned reflex.

Experiments were conducted on cats to study the effects of iontophoretic application of glutamate and a number of modulators on the spike activity of neurons in the sensorimotor cortex during a conditioned reflex. These studies showed that glutamate, as well as exerting a direct influence on neuron spike activity, also had a delayed facilitatory action lasting 10-20 min after iontophoresis was finished. Adrenomimetics were found to have a double modulatory effect on intracortical glutamate connections: inhibitory and facilitatory effects were mediated by beta1 and beta2 adrenoceptors respectively. Although dopamine, like glutamate, facilitated neuron spike activity during the period of application, the simultaneous facilitatory actions of glutamate and L-DOPA were accompanied by occlusion of spike activity, and simultaneous application of glutamate and haloperidol suppressed spike activity associated with the conditioned reflex response. Facilitation thus appears to show a significant level of dependence on metabotropic glutamate receptors which, like dopamine receptors, are linked to the intracellular medium via Gi proteins.

[The modulation of the pulse activity of neocortical neurons during a conditioned reflex]. / Moduliatsiia impul'snoi aktivnosti neironov neokorteksa pri uslovnom reflekse.

Spontaneous and evoked activity of neurons in the sensorimotor cortex was recorded in cats with learned conditioned placing reaction before, during, and after the iontophoretic application of synaptically active substances. It was shown that apart from direct excitatory effect on the cortical neurons during its application, glutamate (Glu) exerted some modulatory influence on unit activity in subsequent 20 min. Noradrenaline suppressed the background and evoked activity through beta 1 adrenoreceptors. Activation of beta 2 adrenoreceptors by metaproterenol was accompanied by facilitation of the background and evoked activity during application and 10-20 min after. The joint application of Glu and metaproterenol improved facilitation of neuronal responses evoked by conditioned stimuli. Application of levodopa, like Glu, increased the background and evoked activity of many sensorimotor cortical neurons. The joint effect of Glu and levodopa was not substantially more intensive than the changes produced by the isolated application of any of these substances. A nonselective blocker of DA1 and DA2 receptors haloperidol either increased or did not change the background and evoked activity of some cortical neurons. In contrast to isolated application of Glu, simultaneous application of Glu and haloperidol to neocortex suppressed the neuronal responses associated with conditioned movements. The results suggest that the Glu-induced potentiation is substantially realized through molecular mechanisms common for Glu and dopamine, probably, through Gi-proteins. The conclusion is drawn that the adrenergic and dopaminergic inputs to neocortical neurons are involved in the Glu-mediated plastic changes in the cortex during conditioning.

Interaction between dopamine and glutamate in the sensorimotor cortex during conditioned placing reaction.

Changes in impulse activity of sensorimotor cortex neurons associated with interaction of glutamate and dopamine during conditioned placing reaction were investigated in experiments on cats. Application of either glutamate or levodopa as a dopamine precursor increased background and evoked impulse activity in many of sensorimotor cortex neurons. It occurred occasionally that an increased impulse activity of cortical neurons produced by joint application of glutamate and levodopa could be much more intense than that produced by one of these substances. Amphetamine acted on cortical neurons in a similar way as levodopa. Haloperidol, a non-selective blocker of dopamine1 and dopamine2 receptors, increased or did not change background and evoked impulse activity in some cortical neurons. In contrast to application of glutamate alone, simultaneous application of glutamate and haloperidol to the neocortex depressed neuronal responses connected with conditioned movement. Thus, glutamate cannot exert its potentiating effect on evoked neuronal activity due to the depressing action of haloperidol. This means that glutamate potentiation is realized to a great extent through molecular mechanisms common for glutamate and dopamine, possibly through G-proteins which are common for glutamate metabotropic and dopamine receptors.

Interaction of glutamatergic and adrenergic inputs of cortical neurons during conditioning.

Background and evoked activities of sensorimotor cortex neurons have been examined on learning cats with conditioned placing reaction before, during and after iontophoretic application of synaptically active drugs. It was shown that glutamate exerted not only a direct excitatory effect on the cortical neurons during its application, but also developed modulatory influences on background and evoked impulse activity after cessation of application in the subsequent 10-20 min. Adrenergic influences on the activity of neocortical neurons evoked by application of adrenomimetic drugs were complex and consisted of at least two different types. Noradrenaline depressed background and particularly evoked activity of many neurons through beta1-adrenoreceptors. At the same time, activation of beta2-adrenoreceptors was accompanied by facilitation of background and evoked activity during application and 10-20 min after its cessation, as was shown in experiments with alupent. Co-application of glutamate and alupent improved facilitation of impulse response evoked by conditioned stimuli. It was concluded that beta1- and beta2-adrenergic inputs to neocortical neurons are involved in plasticity changes of glutamate inputs of some cortical neurons.

Dependence of sensorimotor cortex neuron activity on noradrenergic and serotoninergic transmission in unspecific thalamic nuclei.

Background and evoked impulse activity of sensorimotor cortex neurons and conditioned reflex of trained cats were changed by blockers of noradrenaline and serotonin receptors applied through chemitrodes to thalamic complex of the centrum medianum and nucleus parafascicularis neurons. Application of obzidan, an antagonist of beta-adrenoreceptor to the complex of the centrum medianum and nucleus parafascicularis induced an initial increase and following decrease of the motor activity of cats. After obzidan application conditioned reflex remained unchanged at the initial, excitatory phase and started to decrease later. Lisergamide applied to the complex of the centrum medianum and nucleus parafuscicularis produced an initial decrease of movement activity and then drowsiness of the animals. Responses to conditioned stimuli were gradually decreased. The background impulse activity of the sensorimotor cortex neurons increased after obzidan application and decreased rapidly after lisergamide injection into the complex of the centrum medianum and nucleus parafascicularis. The responses of cortical neurons to conditioned stimuli were reduced, sometimes completely eliminated in both cases. Background and evoked impulse activity greatly increased by application of 5-hydroxytryptamine after preliminary lisergamide-induced depression of the impulse activity. It was concluded that under natural conditions the noradrenergic system exerts indirect inhibitor effects on the neocortex neurons through the centrum medianum and nucleus parafascicularis thalamic complex, whereas the serotoninergic system acting via the same complex increases the background and evoked impulse activity of the sensorimotor cortical neurons.

[Neocortex neuronal reactions induced by substantia innominata stimulation in cats]. / Reaktsii neironov neokorteksa, vyzvannye stimuliatsiei bezymiannoi substantsii, u koshek.

Neuronal impulse activity in the sensorimotor cortex after Substantia Innominata (SI) stimulation has been studied in cats during conditioned placing with food reinforcement. SI stimulation was delivered 1 or 3 seconds before the conditioned sound stimuli. The results of the investigation show that SI stimulation does not change sensorimotor cortex impulse activity but at the same time it inhibits the background activity. Reactions of 32% (after 1 s) and 33% (after 3 s) of the somatosensory cortex neurones were increased to conditioned stimuli and conditioned movement after preliminary SI stimulation. The appearance of impulse responses in some neurones which showed no initial reactions to conditioned stimuli was caused by SI stimulation. Preliminary SI stimulation may cause not only excitatory but also inhibitory effect on somatosensory cortical neurones. In case of 1 s interval between SI stimulation and conditioned stimuli presentation there were only 6% of cells with such inhibition, but in case of 3 s interval there were 33% of such reactions. SI stimulation shortened the latencies of the conditioned movement 2-3 times. Modulatory influence of acetylcholine from SI neurones to neocortical activity is discussed.

[Role of glutamate intracortical connections in conditioned reflex activity]. / Uchastie glutamatnykh vnutrikorkovykh sviazei v uslovnoreflektornoi deiatel'nosti.

The effects of iontophoretic application of glutamate and its blockers on neuronal activity of the sensorimotor cortex were studied in cat during fulfillment of conditioned instrumental placing reflex. 64 neurons were investigated. Application of glutamate caused reliable facilitation of neuronal impulse reactions to the conditioned stimulus. The facilitation appeared some seconds after beginning of the application of glutamate and continued for 5-10 min after cessation of the iontophoretic application. The similar inhibitory effect in neuronal activity was observed with application of APV, kinurenate, ketamine. It is suggested that the NMDA receptors under natural conditions take part in facilitation of the synaptic transmission in glutamatergic intracortical pathways.

Analysis of extrathalamic synaptic influences on reactions of sensorimotor cortical neurons during conditioning.

The effects of iontophoretic application of acetylcholine, noradrenaline, serotonin and their blockers on neuronal activity were studied in the cat before and during fulfillment of conditioned instrumental placing reflex. It was found that acetylcholine increased the background neuronal activity through muscarinic cholinergic receptors and noradrenaline decreased it through beta-adrenoceptors in a considerable proportion of the cortical neurons. Serotonin had no reliable effect on the background activity. At the same time, it facilitated an initial component of the impulse reaction to conditioned stimulus and part of the impulse reaction preceding the start of the conditioned movement. Acetylcholine applied iontophoretically also facilitated the evoked responses in some cortical neurons via nicotinic cholinergic receptors. On the contrary, iontophoretic application of noradrenaline or ephedrine decreased the evoked activity of some neurons. Application of beta-adrenergic receptor blocker, propranolol, led to an increase of neuronal responses to conditioned stimuli. Evidently, noradrenergic projections exert a steady inhibitory influence on the cortical neurons during natural functioning of the cortex. It is concluded that cortical reactions evoked by activation of thalamic projections and intracortical connections are modulated and regulated by extrathalamic projections to the cortex.

Influence of substantia innominata neuronal activity on neocortex neuronal reactions during conditioned reflex.

Impulse activity of substantia innominata (SI) and motor cortex neurons was studied in cats during conditioned placing with food reinforcement. It was shown that SI neurons have been activated first directly by sound stimuli and later by food reward. Stimulation of SI did not change the background activity of neocortex neurons but promoted the modulation of impulse response to conditioned stimuli. The modulating effect of the SI has a mainly excitatory character, that manifested itself either in a change and increase of the impulse responses of cortical neurons which responded initially to sound stimuli, or in the appearance of impulse responses in those neurons which showed no initial reaction to conditioned sound stimuli.