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.

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.

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.

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.