Food-procuring behavior of rats under the conditions of chronic activation and blockade of the neostriatal dopaminergic system

Using the technique of intracerebral microinjections, the features of food-procuring behavior (the realization of a situational instrumental conditioned reflex in a Skinner box) were investigated in rats in experiments under the conditions of a pharmacological influence on the dopaminergic system of the neostriatum. Amphetamine in a dose of 15 and 45 μg and haloperidol in a dose of 5 mg were injected daily over the course of three weeks bilaterally into the rostral division of the neostriatum. A amphetamine dose of 15 μg was ineffective, but a increase in motor hyperactivity, a behavioral stereotypy, and a substantial acceleration of food-procuring movements were observed against the background of the injection of 45 μg of amphetamine. Stimulation of the dopaminergic system of the neostriatum qualitatively altered the behavioral strategy in animals with an initially low level of realization of the reflex; this fostered a stable activation of the instrumental skill enduring even after the cessation of the microinjections. Chronic blockade of dopamine receptors by haloperidol induced the reverse effect. I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg. Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 44, No. 4-5, pp. 731–737, July–October, 1994.     

Effects of microinjection of scopolamine into the neostriatum of rats on performance of a food conditioned reflex at different levels of fixation

Chronic experiments performed on 32 Sprague-Dawley rats using a movement-feeding operant reflex (Skinner box) model showed that microinjection of scopolamine into the neostriatum had effects on this reflex which depended on the stage of learning. In animals with weakly fixed reflexes (prior to reaching the stage of memory consolidation), bilateral microinjection of 0.3 μg of scopolamine into the caudate nucleus completely inhibited the reflex for a prolonged period of time. When the operant habit was well fixed, bilateral microinjection of the same doses of scopolamine into the neostriatum had no effect on the reflex. These results suggest that the neostriatum cholinergic system is critically involved in forming the motor engram. The cholinergic system of the caudate nucleus either takes no part in realizing the well-fixed conditioned reflex movement response and/or other forebrain structures are involved in the reflex, compensating for the disturbance in neostriatal cholinergic function. I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg. Translated from Fiziologicheskii Zhurnal im. I. M. Sechenova, Vol. 81, No. 8, pp. 139–146, August, 1995.     

Sensory and motoric components of various forms of learned movement with change in the activity of the cholinergic system of the neostriatum

The participation of the cholinergic system of the neostriatum in the regulation of sensorily-monitored movements and the differentiation of sensory signals were investigated in 12 Wistar rats, 27 Sprague-Dawley rats, and 6 mongrel dogs, using the following models: 1) the maintenance of learned extension of the forelimb for a specified time (rats); 2) prolonged conditioned reflex flexion of the hind limb (dogs); and 3) active avoidance in a T-maze (rats). It was demonstrated that the injection of carbacholine (0.03 μg) into the dorsolateral division of the caudate nucleus of the rats does not bring about significant changes in the performance of movements associated with the maintenance of tonus of the forelimb, whereas the injection of carbacholine (0.05–0.1 μg) into the same division of the caudate nucleus of the dogs improves the realization of movement associated with the maintenance of tonus of the hind limbs. The injection of a blocker of the cholinergic system (scopolamine in the rats and atropine in the dogs) in both the first and the second instance disturbed the performance of the movement by the animals. Bilateral microinjections of carbacholine (0.03 μg) into the neostriatum of the rats significantly improves the development of a differentiated active avoidance conditioned reflex in a T-maze on the first three days of testing. The differentiation of acoustic signals by dogs also signicicantly improved against the background of the injection of carbacholine (0.05–0.1 μg) into the caudate nucleus. Thus, the data obtained in the various behavioral models and different animals suggest that the cholinergic system of the neostriatum participates in the regulation of both motor and sensory mechanisms in connection with the realization of learned movement. Laboratory of Physiology of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg. Laboratory of the Comparative Physiology and Pathology of the Central Nervous System, I. M. Sechenov Institute of Evolutionary Biochemistry and Physiology, Russian Academy of Sciences, Saint Petersburg. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 80, No. 12, pp. 34–44, December, 1994.     

Participation of glutamatergic and dopaminergic systems of the neostriatum in the organization of alimentary conditioned reflexes

In this study the results of behavioral, neurophysiological, and morphological investigations in relation to the participation of the corticostriatonigral system in the organization of conditioned reflexes are presented. It was demonstrated in experiments on dogs that blockade of N-methyl-D-aspanate receptors of the caudate nucleus disrupts the realization of consolidated conditioned reflexes and renders their development more difficult. The blockade of quisqualate receptors facilitates the process of differentiation. Switching off of the dopaminergic input makes the development of positive conditioned reflexes more difficult. The reversible switching off of the substantia nigra leads to the reorganization of the neuronal activity of the caudate nucleus in response to the presentation of the conditional signal. Inhibitory nigral influences are directed primarily to the ventromedial divisions of the nucleus, while activating influences are directed to its dorsal segments. The topically organized connections of the motor regions of the cortex with the dorsal region of the caudate nucleus, and of the limbic regions with its ventromedial divisions were studied in morphological investigations on cats. A certain distinctiveness was identified of the spatial organization of the nigrostriatal projections. The data obtained are discussed from the point of view from the systemic organization of behavior.Translated from Fiziologicheskii Zhurnal SSSR imeni I. M. Sechenova, Vol. 76, No. 11, pp. 1509–1520, November, 1990.     

Influence of the blockade of D2 dopamine receptors of the cat neostriatum on the baseline activity and saccadic eye movement-associated reactions of neurons of the reticular portion of the substantia nigra

The activity of neurons of the reticular portion of the substantia nigra before and after the microinjection of haloperidol (25 μg/5 μl) into the head of the caudate nucleus on the ipsilateral side was investigated under chronic experimental conditions in cats, using the extracellular microelectrode pickup technique. A significant (p<0.05) increase, from 34 to 61%, of neurons with the burst type of spontaneous activity was established after the injection of haloperidol. A significant increase in the ratio of the number of excitatory responses to inhibitory responses, from 0.04 to 0.4, was identified among the reactions associated with saccadic eye movements following the microinjection of haloperidol. The number of orienting saccades in response to the visual stimulus decreased against this background from 58 to 37%. The identified changes are regarded as a result of the disinhibition of GABAergic neurons of the reticular portion of the substantia nigra under the influence of the blockade of D₂ dopamine receptors of the neostriatum. Department of the Physiology of the Cerebral Cortex and Subcortical Structures, A. A. Bogomolets Institute of Physiology, Academy of Sciences of Ukraine, Kiev. Translated from Fiziologicheskii Zhurnal irneni I. M. Sechenova, Vol. 80, No. 1, pp. 17–22, January, 1994.     

Activation of neostriatal dopaminergic system in rats prevents toxic effects of picrotoxin administered into globus pallidus

Multiple bilateral microinjections of 5 μg picrotoxin (antagonist of chloride channels coupled with GABA_A receptors) into the globus pallidus induced lethal seizures in some rats and impaired conditioned avoidance responses in survivors. Administration of 15 μg amphetamine into the rostral neostriatum prevented picrotoxin-induced lethal seizures and reduced its negative effects on active avoidance behavior. Activation of the neostriatal dopaminergic system in animals receiving no intrapallidal picrotoxin promoted recovery of conditioned responses after implantation procedure. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 8, 144–146, August, 2000     

Role of dopaminoreactive systems of the cortex and the neostriatum in the organization of situational conditioned reflexes

The results of experiments on dogs with dysfunction of the dopaminoreactive system of the brain suggest the nonidenticality of its different divisions (cortical, striatal, mesencephalic) in the organization of situational conditioned reflexes. It was demonstrated that the nigrostriatal system is involved to a greater degree in the spatial analysis of signals, while the mesocortical system is more involved in the analysis of their biological significance. The dopaminoreactive system of the caudate nucleus is associated to a greater degree with the realization of cognitive, while that of the putamen is associated with the realization of motor programs of situational conditioned reflexes. The thesis of the necessity of the coordinated functioning of the DA-reactive systems for the organization of goal-directed behavior is substantiated. Laboratory of Physiology of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 80, No. 1, pp. 65–71, January, 1994.     

Locomotor disturbances in rats induced by repeated picrotoxin microinjections to the globus pallidus and caudal neostriatum

Repeated bilateral microinjections of picrotoxin in doses of 1 and 5 μg in the globus pallidus or caudal neostriatum induce seizures and impair conditioned motor reactions, but not myoclonic hyperkinesis typical of pharmacological block of the rostral neostriatal GABAergic system. Picrotoxin injected in a dose of 15 μg induces significant toxic effects. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 10, pp. 381–383, October, 1998     

The influence of injections of 6-hydroxydopamine into the nucleus accumbens and the substantia nigra on the behavior of rats

Bilateral injections of 6hydroxydopamine into the nucleus accumbens of rats with destroyed dopaminergic neurons of the substantia nigra leads to an increase in the horizontal motoric activity in the open field and accelerates the appearance of conditioned reflex responses in the course of the postoperative restoration of the skill as compared with these indices in rats in which the neurotoxin was injected only into the substantia nigra. Thus, destructions of the dopaminergic system of the nucleus accumbens can compensate to a certain degree for the consequences of nigrostriatal pathology.Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 78, No. 4, pp. 14–20, April, 1992.     

The dopaminergic nigrostriatal system in sleep deprivation in cats

The dynamics of changes in electrophysiological measures of the sleep-waking cycle were analyzed in Wistar rats after 6 h of sleep deprivation by gentle waking and subsequent 9-h post-deprivation sleep. A delayed sleep “overshoot” reaction was observed 2.5–3 h after sleep deprivation, as a moderate increase in the proportions of slow-wave and fast-wave sleep in the sleep-waking cycle. Immunohistochemical studies were performed in relation to changes in the sleep-waking cycle, with the aim of identifying changes in the quantities of immunoreactive dopamine D₁ and D₂ receptor material and tyrosine hydroxylase, the key enzyme in dopamine synthesis in the nigrostriatal system. In conditions of sleep deprivation, the caudate nucleus showed increases in the quantities of dopamine D₁ and D₂ receptor material, while there was a simultaneous decrease in the amount of immunoreactive material in the substantia nigra. Post-deprivation sleep was accompanied by decreases in the quantities of immunoreactive D₁ receptor material and increases in D₂ receptor material in the caudate nucleus, with an increase in the quantity of immunoreactive tyrosine hydroxylase in the substantia nigra. These data provide evidence of the active role of the dopaminergic nigrostriatal system which, along with other CNS transmitter systems, supports telencephalic-diencephalic interactions, in the sleep-waking cycle. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 93, No. 12, pp. 1344–1354, December, 2007.     

Lesions of the substantia nigra retard Pavlovian eye-blink but not heart rate conditioning in the rabbit

Bilateral radio-frequency (RF) lesions of the substantia nigra retarded Pavlovian eye-blink (EB) conditioning without affecting concurrent heart rate (HR) conditioning. Dopamine (DA) depletion occurred only in the caudate nucleus, whereas norepinephrine (NE) depletion was limited to the hypothalamus. Bilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra retarded acquisition of both EB and HR responses. Six-OHDA lesions produced significant NE depletion in the nucleus acumbens/septi, frontal cortices, and hypothalamus, as well as DA depletion in the caudate nucleus. Trials required to reach EB conditioning criterion was significantly correlated with caudate DA levels. The magnitude of conditioned bradycardia was on the other hand significantly correlated with hypothalamic NE levels. These results suggest that interruption of the nigro-striatal dopaminergic pathway retards Pavlovian somatomotor learning without affecting concurrent autonomic learning, although the latter may depend on an intact ascending NE pathway to the hypothalamus, which passes through the tegmentum and thus is also destroyed in some cases by substantia nigra lesions.     

Regional distribution of cholecystokinin binding sites in macaque basal ganglia determined by in vitro receptor autoradiography

Cholecystokinin binding sites were labeled with [3H]cholecystokinin-8, [125I]cholecystokinin-33, and [125I]cholecystokinin-8 in major structures of macaque basal ganglia by in vitro receptor autoradiography. Analysis of autoradiograms revealed areas of heavy cholecystokinin binding in the neostriatum and substantia nigra that were set off, often quite sharply, from the adjacent globus pallidus and subthalamic nucleus where labeling was, by contrast, very light. Heavy label characterized the ventromedial and posterior parts of the caudate nucleus and adjacent putamen, binding was of moderate intensity in central areas of these regions, while, the dorsolateral margin of the head of the caudate and precommissural putamen, the dorsolateral one-third of the body of the caudate, and all but the most medial and ventral portions of the posterior putamen lateral to the pallidum were sparsely labeled. The pattern of cholecystokinin binding within the neostriatum was mottled; patches of reduced label stood out from the background of more prominent binding. However, those patches were only imperfectly correlated with the striosomal organization of both the caudate nucleus and putamen as revealed by acetylcholinesterase staining. Cholecystokinin binding in the substantia nigra was also intricately patterned. Moderately dense, vertically orientated bands of label were found in the dorsal one-third to half of the pars reticulata, providing a marked contrast to the near background levels in the ventral pars reticulata and overlying pars compacta. The present study shows that heavy cholecystokinin binding is confined to particular areas within the primate basal ganglia; the pattern of label within the substantia nigra and neostriatum can be linked to intrinsic and afferent connections of these structures. The confinement of binding sites to the dorsal pars reticulata suggests an association with dendrites of pars compacta neurons which invade this region; this interpretation is consistent with recent evidence of depletion of nigral cholecystokinin binding sites in macaques following chemical lesion of dopaminergic cells of the par compacta. In the neostriatum the distribution of binding shows overlap with its topographically organized corticostriatal innervation; portions of heavily labeled striatum coincide with regions innervated by association cortex of the frontal and temporal lobes, whereas regions of diminished binding correspond to areas innervated mainly by sensory and motor cortex. These latter findings suggest that cholecystokinin may have a particularly strong influence on cognitive aspects of striatal function.     

Expression of early genes in the rat brain after administration of corticoliberin into the neostriatum

In situ hybridization using oligonucleotide probes was used to study the effects of intrastriatal microinjection of corticoliberin on the expression of the early genes c-fos, jun B, c-jun, and NGFIA in the rat brain. Administration of corticoliberin (0.25 g) into the neostriatum induced the expression of mRNA encoded by the early genes c-fos, jun B, and NGFIA in both the neostriatum itself and in its efferent structures, particularly the nucleus accumbens and various parts of the cortex. Intrastriatal microinjection of corticoliberin had no effect on the expression of mRNA for the oncogene c-jun in the brain. These results suggest that neuronal activation in the neostriatum and its projection targets manifest as the expression of early genes is one of the mechanisms underlying the adaptive effects of corticoliberin in stress.     

Role of enkephalinergic brain structures in regulating motivated behavior in rats with lesioned serotoninergic neurons

The behavioral effects of injections of enkephalin into the substantia nigra or dorsal raphe nucleus were studied in rats with lesioned serotoninergic structures. Lesions were produced by intracerebral administration of the neurotoxin 5,7-dihydroxytryptamine. Treated rats showed normalization of conditioned drinking reflex extinction. It is proposed that there is a tight connection between the normalizing effects of enkephalin on rat behavior in conditions of deficient brain serotoninergic system function and increases in the efficiency of presynaptic inhibition of dopaminergic neurons. Laboratory for Conditioned Reflex Morphophysiology, Science Research Institute of the Brain, Russian Academy of Medical Sciences, 5 Obukh Lane, 103064 Moscow, Russia. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 83, No. 1-2, pp. 71–75, January–February, 1997.     

Changes in Sleep during Degeneration of Neurons in the Substantia Nigra Induced by the Proteasome Inhibitor Lactacystin

Decreases in the activity of the ubiquitin-proteasome system lead to the accumulation of toxic forms of proteins and cell degeneration, including dopaminergic neurons in the substantia nigra; these neurons are characterized by proteasomes with low proteolytic activity, such that they are more susceptible, especially during exposure to neurotoxins and the development of Parkinson’s disease (BP). The aim of the present work was to use suppression of proteasome activity to develop an experimental model of the degeneration of substantia nigra cells not accompanied by impairments to motor behavior but leading to changes in the waking-sleep state as a measure of non-motor behavior. The optimum dose of the natural proteasome inhibitor lactacystin (0.4 μg) was determined and a model of the preclinical stage of BP was developed in Wistar rats. On day 14 after two doses (with weekly intervals) of bilaterally administered lactacystin into the substantia nigra, its action consisted of the degeneration of 28 % of dopaminergic neurons in the compact zone of the substantia nigra with no impairment to motor behavior, along with a 37 % increase in the total duration of REM sleep during the second half of the inactive phase of the day. These data, along with an increase in the tyrosine hydroxylase level in surviving cells (this is a key enzyme in dopamine synthesis), with an inverse correlation (r = –0.8, p < 0.01) between the number of surviving neurons and their tyrosine hydroxylase level, suggest the hypothesis that an increase in the duration of REM sleep may be a non-motor sign of the preclinical stage of BP, reflecting preservation of compensatory reserves in the nigrostriatal system.     

Characteristics of the Actions of Neurotensin on Motor Reactions in Rats in Response to Positive and Negative Conditioned Signals

This study addressed the effects of microinjections of neurotensin into the caudate nucleus and substantia nigra on the performance of motor reactions in response to positive and negative conditioned signals, as well as the post-effects of microinjections in subsequent experiments. Neurotensin had positive effects on the extinction of non-reinforced motor reactions. Neurotensin had no effect on the number of motor responses to the non-reinforced signal, though the number decreased in subsequent experiments. There was an increase in the latent period of responses as compared with controls. The effect of neurotensin at the level of the caudate nucleus was more marked than that at the level of the substantia nigra. Neurotensin microinjections had no marked effect on performance of conditioned responses to positive signals. The behavioral effects of neurotensin are associated with normalization of the interactions of the brain's monoaminergic systems. It is suggested that the positive actions of neurotensin on extinction of motor responses to negative signals result from the formation of a contextual conditioned emotional state in the animals, this facilitating optimization of conditioned reflex activity.     

Differences in the neurochemical mechanisms of conditioning to stimuli of different modalities at the caudate nucleus level in rats

Microinjection of noradrenalin into the head of the caudate nucleus in rats did not affect the latent period of avoidance conditioning or muscle tone but inhibited motor activity, reduced the number of taps, and significantly increased the amplitude and latent period of the conditioned food-getting reflex. Local microinjection of serotonin into the neostriatum did not affect the latent period of the conditioned avoidance reflex and did not change the motor activity but it reduced the latent period and the number of taps in the conditioned food-getting response and increased its amplitude significantly. Dopamine inhibited the conditioned food and avoidance reflexes but significantly activated the spontaneous motor activity of the rats. The results are evidence of differences in the neurochemical mechanisms of conditioned reflexes to stimuli of different modalities closed at the caudate nucleus level in rats.     

Participation of the nigro-striatal and mesolimbic dopaminergic systems of the brain in the control of components of learned motor responses in dogs

We studied the role of the striatal and limbic dopaminergic systems in the regulation of instrumentally conditioned avoidance behavior and postural adjustment in chronic experiments on dogs. Dopamine in doses of 3 g was introduced bilaterally into the caudate nucleus head and the nucleus accumbens of the forebrain through implanted cannuli. Predominately unidirectional effects were demonstrated, but a clear acceleration of the initiations of both conditioned-reflex postural adjustment and voluntary movement were obtained from the caudate nucleus; there was a marked degree of expressiveness to this movement. The greatest effects were obtained during simultaneous, bilateral introduction of dopamine into both structures in dogs with an akinetic form of motor pathology. We conclude that the integration of the striatal and limbic dopaminergic systems is of critical necessity for the initiation and regulation of the components of voluntary movement.Translated from Fiziologicheskii Zhurnal SSSR imeni I. M. Sechenova, Vol. 73, No. 5, pp. 579– 589, May, 1987.     

Monoaminergic control by amygdalar nuclei of the reinforcing action of conditional stimuli

The influence of microinfusion of 5-HT, NE, and DA into the amygdalar nuclei on the accomplishment of conditioned reinforcing and conditioned trigger reflexes which are constituents of the CADR was studied in cats with a developed conditioned alimentary discrimination reflex (CADR) in response to two conditional light stimuli set apart on different sides of a box. It was established that 5-HT in doses of 30–50 μg in a volume of 5 μl elicits inhibition; the same doses of NE, by contrast, induces the “hanging-up” of the animals on conditional and conditional—unconditional stimuli which possess the property of reinforcement during the execution of the CADR. The microinfusion of DA in doses of 30–60 μg recalls, from animal to animal, the action of 5-HT and NE. It is hypothesized that the inhibitory functions of 5-HT and the activating actions of NE in the amygdalar nuclei support this structure's control of reinforcing conditional and conditional—unconditional reflexes and the perception of the reinforcing action of conditional stimuli. It is hypothesized that the DAergic innervation of the amygdala does not participate directly in conditioned reflex activity. A. I. Karaev Institute of Physiology, Academy of Sciences of the Azerbaidzhan, Baku. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 44, No. 2, pp. 254–260, March–April, 1994.