[The influence of intrastriatal and systemic microinjections of nicotine on motor behavior and its motor and postural components in dogs].

In chronic experiments in dogs on a model of instrumental avoidance reflex we have found that intrastriatal and/or systemic injection of nicotine causes a significant prolonged increase of motor excitability. By decrease of latent period of instrumental reflex, an increase of amplitude of reflex was shown and, in some cases, by increase of conditional flexion maintenance time. An interesting feature of instrumental reflex in our investigations was both strengthening of cholinergic influence and strengthening of dopaminergic influence. The former is shown by sharp strengthening of tonic component of answer, the latter--by increase of answer amplitude and decrease of its latency, increase of general excitability.

Comparison of the effects of systemic (intramuscular) and intrastriatal administration of a selective D1 dopamine receptor blocker on motor behavior and postural rearrangement in dogs.

The present study was based on the concept (Shapovalova, 2000) that activation and blockade of different types of muscarinic and dopamine receptors located in different efferent outputs of the neostriatum should have different effects on motor behavior. The aim of the study was to compare the effects of systemic and intrastriatal injections of a selective D(1) dopamine receptor blocker on motor behavior. Experiments were performed on five dogs using a model of an operant defensive reflex associated with maintaining a defined flexor posture. The experiments, with recording, storage, and analysis of data, were performed using an original personal computer program. Systemic (intramuscular) administration of the D(1) dopamine receptor blocker SCH23390 at a dose of 0.025 mg/kg led to a sharp reduction in the amplitude of the operant defensive reflex, with complete refusal to perform it in most cases. The phasic component of the operant response showed the most significant level of inhibition, though the diagonal pattern of the postural rearrangement persisted. Bilateral microinjections of the same D(1) receptor blocker into the neostriatum at doses of 0.1 and 1.0 microg did not alter the proportion of correct solutions of the operant task, though the microinjections did induce a series of changes in motor activity, with significant increases in the latent period of the response, and in some cases increases in response amplitude, decreased phasicity, and complete cessation of intersignal raisings of the limb. These data lead to the following conclusions: 1) the difference in the effects of systemic and intrastriatal administration of SCH23390 evidently results from the fact that systemic administration can also block D(1) receptors in other structures in addition to the neostriatum; 2) the effects of the nigrostriatal dopaminergic system on the neostriatum mediated by D(1) receptors are complex, with activation of motor activity (projection spiny neurons in the direct pathway) and weak modulation of mental processes (large aspiny cholinergic interneurons); 3) regulation of movement and postural rearrangement is mediated by different efferent outputs of the neostriatum.

[Comparison of effects of systemic (intramuscular) and intrastriatal injections of D1-dopamine receptor blocker on motor behavior and postural adjustment in dogs].

The study is based on the concept (Shapovalova, 2000) that activation and blockade of various types of muscarine and dopamine receptors located at various outputs of neostriatum should have different effects on motor behavior. The goal of the study was comparison of effects of systemic and intrastriatal injections of a selective blocker of D1 dopamine receptors on motor behavior. Experiments were carried out on 5 dogs on a model of instrumental defensive reflex (IDR) connected with keeping a certain flexor posture. Performance of the experiments, recording, storage, and analysis of data were accomplished with aid of original programs for PC. Systemic (intramuscular) administration of the blocker of D1 dopamine receptors SCH23390 at a dose of 0.025 mg/kg led to a sharp decrease of the IDR amplitude and in most cases--to the complete refusal of its performance. First of all, the phasic component of the instrumental response was inhibited, the diagonal pattern of the postural adjustment being preserved. Bilateral microinjections into the dog neostriatum of the same blocker of D1 receptors at a dose of 0.1 and 1.0 g did not change the percent of correct solution of the instrumental task, but at the same time produced a great number of changes in motorics: latent period of response increased statistically significantly, in some cases its amplitude rose, phasity decreased, intersignal raisings of limbs ceased completely. The obtained data allow the following conclusions to be made. 1. Difference of effects of systemic and intrastriatal injections of SCH23390 seems to be due to that at its systemic administration, D1 receptors of other structures, not only of neostriatum, can also be blocked. 2. Effect of nigrostriatal dopaminergic system on neostriatum via D1 receptors is complex - activation of motor activity (projectional spine neurons of the direct pathway) and a weak modulation of mental process (large spineless cholinergic interneurons). 3. Regulation of movement and postural adjustment is realized along different efferent neostriatum outputs.

Motor and cognitive functions of the neostriatum during bilateral blockade of its dopamine receptors.

Studies on 60 Sprague-Dawley rats were performed to compare systemic and intrastriate administration of the selective D1 dopamine receptor blocker SCH23390 on the acquisition of a discriminant conditioned active avoidance reflex (CAAR) in a T maze and on behavior in an open field test. Systemic treatment at a dose of 0.025 mg/kg produced several-fold reductions in the proportion of correct performances of the discriminant CAAR and motor activity in the open field test. At the same time, bilateral microinjection of SCH23390 into the rat neostriatum at doses of 0.004-1.0 microg did not induce any deterioration in learning of the discriminant CAAR as compared with intact controls, though there was a sharp inhibition of motor activity in the open field test. Bilateral microinjections of the D2 dopamine receptor blocker raclopride into the rat neostriatum at a dose of 0.004 microg produced a marked and long-lasting degradation of learning of the discriminant CAAR. These data lead to the following conclusions: 1) the differences in the effects of systemic and intrastriate administration of SCH23390 appear to be associated with the fact that the behavioral changes seen after systemic administration may be mediated mainly by structures differing from neostriatal D1 receptors, and 2) the D1-mediated effects of the nigrostriatal dopaminergic system on the neostriatum are complex, with activation of motor activity (projection spiny neurons of the direct pathway) and weak modulation of the learning process (large aspiny cholinergic interneurons). Modulation of the learning process evidently occurs via neostriatal D2 dopaminergic receptors.

Involvement of the transmitter systems of the neostriatum in automation of motor skills in dogs.

Chronic experiments were performed on six dogs to address the influence of automation of a motor skill on the components of an operant defensive reflex, rearrangement of posture, and the characteristics of the projection of the center of mass on a tensometric platform by the forepaws; the effects of activation and blockade of muscarinic and dopamine receptors on the process of automation of the motor skill were also studied. Despite high criteria for execution of the operant reflex, the reproducibility of reflex performance, increases in the tonic component of the response, and the clear diagonal pattern of the postural rearrangement, a local (as opposed to diffuse) projection of the position of the center of mass on the tensometric platform by the forepaws was seen only after prolonged training leading to automation of the skill. The effect of automation of the operant response could be obtained immediately following bilateral microinjection of the muscarinic receptor agonist carbachol into the neostriatum. The same effect, but weaker, was obtained using bilateral microinjections of the dopamine D2 receptor blocker raclopride into the neostriatum. Conversely, bilateral microinjections of the selective muscarinic M1 receptor blocker pirenzepine into the neostriatum gave the opposite result, with increases in the phasic component of the response, impairment of the diagonal pattern of the postural rearrangement, and diffuseness of the projection of the center of mass on the tensometric platform by the forelimbs. It is concluded that the indirect efferent output of the neostriatum has an important role in the process of learning the motor operant reflex involving maintenance of a defined degree of flexion (where the main role is played by the tonic component of the movement) and during the process of automation of the motor skill.

[Motor and cognitive functions of the neostriatum during bilateral blocking of its dopamine receptors].

In experiments on 60 Sprague-Dawley rats, effects of systemic and intrastriatal injections of se-lective blocker of D1 receptors SCH23390 on elaboration of discriminational conditioned reflex of active avoidance (CRAA) were studied in T-maze and on behavior in test of the "open field". Systemic administration of this inhibitor at doses of 0.025 mg/kg produced a several fold decrease of percentage of correct realizations of the discriminational CRAA and of motor activity in the "open field" test. Bilateral microinjections of SCH23390 into the rat neostriatum at a dose of 0.004-1.0 mkg did not deteriorate learning of the discriminational CRAA as compared with intact control, although a marked inhibition of motor activity was observed in the open field, test. Analysis of the data has also shown a statistically significant decrease of percentage of errors in the starting maze compartment in experiments with intrastriatal injection of SCH23390 to rats. At the same time, the intrastriatal injection to rats of raclopride, a blocker of D2 dopamine receptors, at a dose of 0.004 mkg produced a sharp and prolonged deterioration of learning of the discriminational CRAA. The data obtained have allowed the following conclusions to be made: 1. Difference of effects of the systemic and intrastriatal SCH23390 injections seems to be due to that the behavioral changes observed at the systemic administration can be provided predominanantly by structures differing from neostriatal D1 receptors; 2. Effect of nigrostriatal dopaminergic system on the neostriatum through D1 receptors is complex: activation of motor activity (efferent spine cells of the direct pathway) and a poor modulation of the learning process (large aspine cholinergic interneurons); 3. The modulation of the learning process seems to occur through neostriatal D2 receptors (large aspine cholinergic interneurons).

The effects of microinjection of the selective blocker of muscarinic M1 receptors pirenzepine into the neostriatum on the motor behavior of rats.

A discrimination conditioned active avoidance reflex (CAAR) model in a T maze was used in 18 rats to study the effects of bilateral microinjections of the selective muscarinic M1 receptor blocker pirenzepine into the neostriatum on the acquisition of the CAAR and behavior in an open field test. There was sharp degradation of learning of the CAAR and a significant improvement in motor activity both in the open field test and in the maze itself in rats given bilateral microinjections (pirenzepine, 0.004 mg) into the neostriatum as compared with intact controls. This suggests that changes in motor behavior (a sharp increase in locomotor activity) may be among the reasons for difficulty in learning the CAAR in rats after pirenzepine microinjections. Another reason for difficulty in learning the CAAR in these animals may be impairment of the perception of the conditioned signals (a flashing light) and poor differentiation. This is particularly indicated by the delay in the start chamber (double that seen in intact animals) on presentation of conditioned signals despite the high level of motor activity. These results and published data provide evidence for the complex nature of changes induced by blockade of muscarinic M1 receptors in the neostriatum.

[Effect of microinjections of a selective blocker of M1-muscarinic receptors pirenzepine into the neostriatum on the rat motor activity]. / Vliianie mikroin''ektsii selektivnogo blokatora muskarinovykh M1-retseptorov pirenzepina v neostriatum na dvigatel'noe povedenie krys.

In simulated discrimination conditioned reflex of active avoidance (CRAA) in T-maze, the effect of bilateral microinjections of the muscarinic receptor M1 selective blocker pirenzepine on the CRAA formation and behaviour in the "open filed" test, was studied in rats. A sharp worsening of the CRAA learning and a significant increase in the motor activity were shown to occur in rats following the microinjections as compared with control rats. The change in the motor responses seems to account for the worsening of the CRAA learning. Another reason of the phenomenon could involve a disorder in perception of conditioned signals and their poor differentiation. The data obtained and the literature data suggest a complex character of changes induced by the blockade of the M1 muscarinic receptors of the neostriatum.

Operant behavior in conditions of activation and blockade of neostriatal muscarinic receptors.

Chronic experiments were performed on four dogs using a model of an operant defensive reflex associated with maintaining a flexion posture to study the effects of bilateral intraneostriatal microinjection of the non-selective muscarinic receptor agonist carbachol, the selective D2 dopamine receptor blocker raclopride, and the selective M1 muscarinic receptor blocker pirenzipine on the performance of the operant defensive reflex and differentiation of signals. The results show that microinjection of carbachol induced increases in the tonic component and inhibition of the phasic component of the reflex, an ordering rearrangement of the posture, and increases in the amplitudes of its components. Raclopride microinjection gave similar but less marked results. The greatest effects with both substances were seen using differential stimuli. There were sharp increases in the process of differentiation of sound signals. Pirenzipine microinjections gave the opposite result. These data are assessed on the basis of concepts of the existence of two efferent outputs from the neostriatum with opposite effects on their targets and the roles of muscarinic and dopamine receptors in triggering and blocking these effects.

Comparison of the postural and movement components during learning by dogs of an operant defensive reflex.

Chronic experiments on six dogs using a model of an operant defensive reflex associated with maintenance of flexion of the hindlimb of specified amplitude were performed to compare the characteristics of the postural and movement components during the learning process. Dogs were placed standing on four tension platforms. Signals were activated and data were recorded and stored using original PC programs. Original programs running on another PC were used to analyze the data. All dogs showed a series of characteristics for the appearance of a diagonal pattern of conditioned reflex posture rearrangement. During the period of complete formation of the "coordinated" program of the operant reflex (indicated by high performance criteria for execution of the operant task), the diagonal pattern of posture rearrangement was seen extremely rarely, in only occasional performances in calm dogs. It was only during the period of complete automatization of the movement habit that the diagonal pattern of postural rearrangement was seen consistently in all performances. By this time, there was a sharp increase in the tensogram amplitudes for all four limbs, which sharp increases in the correlation coefficients between individual tensogram performances. These results suggest that in the experimental conditions used here, the diagonal pattern of postural rearrangement appeared significantly later than the movement pattern needed for resolving the operant task. These data also lead to the conclusion that dogs can complete operant defensive limb movements associated with maintaining a specified flexor posture in the absence of preliminary rearrangement of the posture having the diagonal pattern.

[Instrumental behavior in the activation or blockade of the neostriatum muscarinic receptors]. / Instrumental'noe povedenie pri aktivatsii ili blokade muskarinovykh retseptorov neostriatuma.

In four dogs, microinjections of carbacholine enhanced the tonic component and inhibited the physical component of the instrumental defence reflex, put in order the posture, and increased its components' amplitude. Microinjections of raclopride yielded a similar though a less obvious result. Differentiation stimuli provided the greatest effect of both substances. A sharp improvement occurred in differentiation of sound signals. Microinjections of pyrenzepine yielded an opposite result. The data obtained are explained proceeding from the idea of a presence of the neostriatum's two efferent outputs exerting opposite effects on their targets, and the role of muscarine and dopamine receptors in their triggering and blockade.

[Muscarinic receptors of the neostriatum -- important targets of regulation of instrumental movement and posture]. / Muskarinovye retseptory neostriatuma -- vazhnye misheni reguliatsii instrumental'nogo dvizheniia i pozy.

Chronic experiments with 10 dogs were conducted to study effects of bilateral microinjections of the nonselective agonist of the muscarinic receptors carbachol, nonselective blocker of the muscarinic receptors scopolamine and selective blocker M1 of the muscarinic receptors pyrensepine on the instrumental defensive reflex in the neostriatum to sustain a given flexion amplitude and posture adjustment. Microinjections of carbachol were found to increase tone and stem the phase of the reflex, make posture adjustment more orderly and amplitudinous. Repeated microinjections gave the instrumental movement a ramp-like form. Chronic carbachol microinjections (over several years) resulted in akinesis and rigidity in dogs. However, these led to impairment of the diagonal pattern of posture adjustment as in pathologic so in normal dogs. These developments were partially meliorated by dopamine, scopolamine and pyrensepine which sharply increased the phase component of the instrumental movement. These findings are interpreted in the light of the concept of two neostriatum efferent outputs with opposite effects on respective targets and the muscarinic and dopamine receptors as their triggers and blockers. Results of the experiment bring to the conclusion that activation or blockage of the muscarinic receptors in the neostriatum can modify an existing motor behavior and compensate motor pathology in dogs.

Muscarinic receptors of the neostriatum--their role in controlling operant behavior in dogs.

Chronic experiments were performed on six dogs to study the effects of bilateral microinjections of muscarinic receptor agonists and blockers into the dorsal striatum on the performance of an operant defensive reflex consisting of maintenance of a specified posture and on the differentiation of stimuli. Microinjections of carbachol, a non-selective agonist of muscarinic receptors, were accompanied by increases in the tonic component of movements, inhibition of phasic movements, ordering of the postural rearrangement, and increases in the amplitudes of its components. Bilateral microinjections of the selective agonist oxotremorine into the neostriatum had significantly weaker effects on the amplitude of postural rearrangement, generally decreasing the amplitude. Although oxotremorine also increased the tonic component of the operant response, this effect was weaker than that seen with carbachol microinjections. In addition, oxotremorine, unlike carbachol increased the number of intersignal limb elevations. These data, along with data published in the literature, are used to suggest the hypothesis that the actions of oxotremorine are mediated not only via muscarinic M2 but also via M1 receptors in the neostriatum. Stronger changes in responses to differential stimuli were also obtained after microinjection of the non-selective agonist carbachol than after microinjection of oxotremorine, and the fact that changes in responses to differential stimuli were significantly greater than changes in those to defensive stimuli suggests that microinjections of muscarinic M1 and M4 receptor agonists into the striatum are also accompanied by improvements in attention to significant stimuli.

[Comparison of postural and motor components in instrumental defense learning in dogs]. / Sopostavlenie poznogo i dvigatel'nogo komponentov pri obuchenii sobak instrumental'noi oboronitel'noi reaktsii.

In 6 dogs, during the period of a complete formation of the "co-ordination" program of defensive reflex associated with maintaining flexion of the left hind-limb, the diagonal pattern of posture readjustment occurred very infrequently. Only during the period of a complete automation of the motor habit, a constant occurrence of the diagonal pattern of posture readjustment was observed in all realisations. These findings suggest that the diagonal pattern of posture readjustment occurs much later than the motor pattern necessary for solving the instrumental task.

[Muscarinic receptors in the neostriatum--participation in the operant behavior regulation in dogs]. / Muskarinovye retseptory neostriatuma--uchastie v reguliatsii instrumental'nogo povedeniia u sobak.

Exposure of the dogs to signals, data collection and processing were accomplished using a special PC software. Bilateral microinjections of the muscarinic receptors agonists (oxotremorine) into the neostriatum enhanced the tonic component of instrumental movements, suppressed the phasic component and increased the postural component's amplitude. These changes were much more obvious in microinjections of the non-selective muscarinic receptor agonist carbachol due, probably, to its effect on both the M1 and M4 muscarinic receptors of the neostriatum efferent neurones.

Activation of the cholinergic system of the striatum improves attention to conditioned reflex stimuli.

Chronic experiments were performed on 16 dogs using a model of an operant defensive reflex associated with maintenance of a flexion pose to study the effects of uni- and bilateral microinjections of the acetylcholine agonist carbacholine (0.05-0.4 microg) and the choline receptor blocker scopolamine (0.5 microg) into the dorsolateral part of the head of the caudate nucleus and CM-Pf intralaminar thalamic nuclei. These experiments produced data showing that the cholinergic system of the striatum has an important role in realizing the sensory and motor components of the learned movement. Activation of the cholinergic system of the dorsal striatum led to general calming of behavior and inhibition of intersignal limb elevation and the phasic components of the movement, along with ordering and stabilizing of the pose and an increase in the tonic component of the operant response. This suggests that the cholinergic system of the striatum receives an indirect efferent output via motor structures and takes part in preparing the motor apparatus needed for transferring attention to significant stimuli. Microinjections of scopolamine had the opposite effects. Use of differential signals in the same behavioral model, along with special tests for attention, showed that the cholinergic system of the striatum plays an important role in the sensory control of attention. Activation of the striatal cholinergic system led to a significant improvement in responses to differential signals and defensive signals of intensity 2-3 times slower than normal signals, and these changes were accompanied by clearer responses in special tests for attention. Scopolamine microinjections had the opposite effects. Carbacholine microinjections into the intralaminar thalamic nuclei potentiated the effects of cholinergic activation of the striatum. These data indicate that the dorsal striatum can be regarded not only as a parallel level of information processing, but also as a control system for passing this information to various levels of both sensory and motor structures. One important result of this type of control may be that of improving attention to significant stimuli.

[Activation of striatum cholinergic system improves attention to conditioned stimuli]. / Aktivatsiia kholinergicheskoi sistemy striatuma uluchshaet vnimanie k uslovnoreflektornym stimulam.

Activation and blockade of the dog striatal cholinergic system yielded data suggesting that the cholinergic system of the striatum takes part in regulation of attention to significant stimuli working through motor structures involved in indirect efferent pathways as well as through sensory systems, too. The two possible mechanisms of sensory regulation of the attention processes by the striatal cholinergic system have been outlined.