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.     

Effect of intranigral dosage with delta-sleep-inducing peptide and its analogs on movement and convulsive activity in rats

Studies were carried out in rats on the effects of the administration of delta-sleep-inducing peptide (DSIP) and its analogs (1–4) into the reticular part of the substantia nigra on movement and convulsive activity. Intranigral microinjection of DSIP, and of DSIP-1 and DSIP-4, reduced horizontal and vertical movement activity as well as excursions to the center of the open field. DSIP, DSIP-2, and DSIP-3 had anticonvulsant effects, consisting of increases in the latent periods of the first convulsion and clonicotonic convulsions induced by picrotoxin, and reductions in the mean intensity of convulsions. It is suggested that changes in the structure of DSIP are accompanied by alterations in the strength of the effects of this peptide on horizontal and convulsive activity after dosage into the reticular part of the substantia nigra. The results indicating that these peptides have protective activity in experimental convulsive syndrome suggest that a relationship exists between DSIP-induced reductions in movement activity and the anticonvulsive efficacy of DSIP analogs when administered intranigrally, this being one of the components of the nigrodependent mechanisms of inhibition of convulsions. Department of Normal Physiology (Director A. A. Shandra), N. I. Pirogov Medical Institute, Odessa, Ukraine. Laboratory of Peptide Chemistry (Director I. I. Mikhaleva), M. M. Shemyakov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow. Translated from Fiziologicheshkii Zhurnal imeni I. M. Sechenova, Vol. 81, No. 2, pp. 1–6, February, 1995.     

Role of nuclear transcription factor kappa B (NF-kappaB) for MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine)-induced apoptosis in nigral neurons of mice

The biochemical and cellular changes that occur following treatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine) are remarkably similar to that seen in idiopathic Parkinson's disease. In this study, we investigated the time course changes of NF-kappaB (Nuclear factor kappa B) p65 protein and apoptosis in the substantia nigra after MPTP treatment in mice. Four administrations of MPTP at 2 h intervals showed a significant and severe decrease of the number of TH (tyrosine hydroxylase) immunopositive neurons in the substantia nigra of mice from 5 h up to 21 days posttreatment. Densities of DAT (dopamine transporter) immunoreactivity were also significantly decreased in nigral neurons of mice from 1 up to 21 days after MPTP treatment. GFAP (glial fibrillary acidic protein) immunopositive cells were increased significantly in the substantia nigra from 5 h up to 21 days after MPTP treatment. In contrast, isolectin B₄ positive microglia were increased markedly in the substantia nigra only 3 and 7 days after MPTP treatment. On the other hand, a significant increase of NF-kappaB p65 immunoreactivity was observed mainly in glial cells of the substantia nigra from 5 h to 3 days after MPTP treatment. A significant increase of ssDNA (single stranded DNA) immunopositive apoptotic neurons was also observed in the substantia nigra from 5 h to 3 days after MPTP treatment. These results demonstrate that dopaminergic neuronal loss may be caused by apoptosis due to increased cytokines and apoptosis-related proteins via the activation of NF-kappaB in reactive astrocytes of the substantia nigra after MPTP treatment in mice. Thus our findings suggest that the inhibition of NF-kappaB activation in astrocytes may be useful intervention in Parkinson's disease and other neurogenerative disorders where apoptosis or inflammation plays a key role in disease pathogenesis.     

Activity of substantia nigra neurons in the cat brain during a self-initiated behavioral act

Cats were trained to perform a self-initiated behavioral act in the form of an operant food-obtaining reflex with defined time requirements. Activity was recorded from 50 dopaminergic neurons (identified in terms of their low frequency of background activity and long action potentials) and 67 nondopaminergic neurons of the substantia nigra and adjacent region. Dopaminergic neurons were the more responsive. Prior to EMG activation, the activity of 33 (66%) of these cells changed, and 44 (88%) showed changes in activity on movement. Dopaminergic neurosn showed increased activity during the period of waiting for the conditioned stimulus, predicting the release of reinforcement or its absence. These cells were more frequently activated in response to a positive signal and reinforcement and were more frequently inhibited in the absence of reinforcement. The high reactivity of dopaminergic neurons during execution of a movement task could be explained by the involvement of a cognitive component, i.e., determining the point at which the movement should start. Department of Human and Animal Physiology and Biophysics, Simferopol' State University, 4 Yaltinskaya, 333036 Simferopol', Ukraine. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova Vol. 83, No. 1–2, pp. 28–34, January–February, 1997. Original article     

Microelectrophysiological Studies of the Ratio of Excitatory to Inhibitory Synaptic Processes in the Corticonigral Projection in a Model of Parkinson’s

Neuroscience and Behavioral Physiology - Experiments on 23 white male rats (250 g) analyzed the spike activity of individual neurons in the substantia nigra pars compacta (SNc, 242 neurons, n = 11)...     

Synaptic contacts in schizophrenia: Studies using immunocytochemical identification of dopaminergic neurons

Immunocytochemical identification of dopaminergic neurons was performed using an immunoperoxidase method employing antibodies to tyrosine hydroxylase. The ultrastructure of synaptic contacts on dopaminergic (tyrosine hydroxylase immunopositive (TP) cells) neurons was investigated in the substantia nigra in the brains of four patients with schizophrenia and three mentally healthy subjects (controls). The substantia nigra of schizophrenia patients differed from control material in showing the following changes in the ultrastructure of presynaptic terminals contacting TP neurons: reductions in the size of terminals with dense matrix and poorly distinguished vesicles; swelling of terminals with small numbers of vesicles displaced from the active zone of the synapse; hyperplasia of mitochondria in some presynaptic boutons; appearance of membranous lamellar structures within or adjacent to presynaptic boutons. These changes to terminals were located mostly on the distal (small and intermediate) TP dendrites in the compact zone of the substantia nigra, where nearly all the dendrites detected belonged to dopaminergic neurons and the altered terminals formed asymmetrical contacts with short active zones. In the reticular part of the substantia nigra of schizophrenic patients, changes in the ultrastructure of presynaptic terminals were relatively rare; altered terminals contacted both tyrosine hydroxylase immunopositive as well as with the tyrosine hydroxylase immunonegative dendrites located in this structure. Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 97, No. 12, pp. 39–43, December, 1997.     

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.     

Spatial organization of amygdaloid, nigral, and tegmental projections in the dog neostriatum

Axonal transport of retrograde markers was used to study the distribution of projections from functionally diverse subcortical structures (the substantia nigra, the ventral tegmental area, and the amygdaloid body) in the caudate nucleus and putamen of the dog. Striatal structures were found to contain regions receiving projections from limbic structures or formations involved largely in motor acts. These structures also contained regions with concordant terminal fields from neurons of these and other functional structures. These results provide a morphological basis for interactions of information currents of different functional significance in the striatum, as well as providing a foundation for their functional heterogeneity. These allow a deeper understanding of their roles in the systems organization of behavior and integrative brain activity. Laboratory for the Physiology of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Makarov Bank, 199034 St. Petersburg, Russia. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 83, No. 1–2, pp. 53–61, January–February, 1997.     

Topographic and functional neuroanatomical study of GABAergic disinhibitory striatum-nigral inputs and inhibitory nigrocollicular pathways: neural hodology recruiting the substantia nigra, pars reticulata, for the modulation of the neural activity in the inferior colliculus involved with panic-like emotions

Considering the influence of the substantia nigra on mesencephalic neurons involved with fear-induced reactions organized in rostral aspects of the dorsal midbrain, the present work investigated the topographical and functional neuroanatomy of similar influence on caudal division of the corpora quadrigemina, addressing: (a) the neural hodology connecting the neostriatum, the substantia nigra, periaqueductal gray matter and inferior colliculus (IC) neural networks; (b) the influence of the inhibitory neostriatonigral-nigrocollicular GABAergic links on the control of the defensive behavior organized in the IC. The effects of the increase or decrease of activity of nigrocollicular inputs on defensive responses elicited by either electrical or chemical stimulation of the IC were also determined. Electrolytic or chemical lesions of the substantia nigra, pars reticulata (SNpr), decreased the freezing and escape behaviors thresholds elicited by electrical stimulation of the IC, and increased the behavioral responses evoked by the GABAA blockade in the same sites of the mesencephalic tectum (MT) electrically stimulated. These findings were corroborated by similar effects caused by microinjections of the GABAA-receptor agonist muscimol in the SNpr, followed by electrical and chemical stimulations of the IC. The GABAA blockade in the SNpr caused a significant increase in the defensive behavior thresholds elicited by electrical stimulation of the IC and a decrease in the mean incidence of panic-like responses induced by microinjections of bicuculline in the mesencephalic tectum (inferior colliculus). These findings suggest that the substantia nigra receives GABAergic inputs that modulate local and also inhibitory GABAergic outputs toward the IC. In fact, neurotracing experiments with fast blue and iontophoretic microinjections of biotinylated dextran amine either into the inferior colliculus or in the reticular division of the substantia nigra demonstrated a neural link between these structures, as well as between the neostriatum and SNpr.     

The influence of the delta-sleep-inducing peptide on convulsive activity

Data are presented in this paper on the influence of the delta-sleep-inducing peptide (DSIP) on various forms of convulsive activity. The capacity of this peptide to suppress convulsive activity in foci created in the cerebral cortex by the application of strychnine has been demonstrated in experiments on cats. It has been established in experiments on rats that DSIP determines the later development of the convulsive kindling syndrome, and prevents the development of convulsions in mice induced by bicuculline, picrotoxin, and corazol, but is devoid of such action in relation to thiosemicarbazide and strychnine. It was demonstrated that the anticonvulsant action of DSIP is associated with its influence on the reticular portion of the substantia nigra. The lowest level of this peptide itself has been discovered. in the reticular portion of the substantia nigra at the late stages of pharmacological kindling. It is inferred that DSIP may represent one of the factors of the endogenous control of the excitability of the brain.Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 78, No. 5, pp. 17–23, May, 1992. Original article submitted July 22, 1991.     

Serotonin imatates several of the neuronal effects of nociceptive sensitization in the common snail

Experiments on defensive behavior command neurons in common snails showed that synaptic facilitation in the responses of nerve cells to sensory stimulation occurs 50–60 min after the onset of application of serotonin (10 μM) to the CNS. The properties of neuron electrogenic membranes (membrane potential, membrane excitability) did not change after exposure to serotonin. Along with synaptic facilitation, serotonin (100 μM) increased the excitability and produced minimal depolarization of the membranes of command neurons. Serotonin had selective effects on the reactions of neurons to different sensory stimuli: facilitation of neuron responses to tactile stimulation of the head lasted 1 h, while responses to application of dilute quinine solution lasted 2–3 h; serotonin facilitated neuron responses to tactile stimulation only of the snail’s head, and did not alter the responses to stimulation of the foot or the mantle ridge. The time course of the electrophysiological effects of serotonin coincided with changes in bound calcium (Ca_b) levels in command neurons. This set of serotonin-induced neurophysiological effects is simular to the effects resulting from the development of nociceptive sensitization. It is suggested that serotonin is involved in the mechanisms of transient changes and consolidation of long-term plastic rearrangements in command neurons which underlie sensitization. P. K. Anokhin Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow. Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 47, No. 3, pp. 532–542, May–June, 1997.     

Relative involvement of globus pallidus and subthalamic nucleus in the regulation of somatodendritic dopamine release in substantia nigra is dopamine-dependent

Previously, we have shown that GABA(A) receptors and glutamate receptors in substantia nigra play distinct roles in the regulation of somatodendritic dopamine release. GABAergic input to substantia nigra was found to be the primary determinant of the level of spontaneous somatodendritic dopamine release. In contrast, acute blockade of dopamine receptors by systemic haloperidol administration produced an increase in somatodendritic dopamine release in substantia nigra that was found to be dependent exclusively upon activation of nigral glutamate receptors. The focus of the present study was to identify anatomical structures that may participate in the differential regulation of somatodendritic dopamine release by GABA and glutamate under these two conditions. To this end, we pharmacologically inhibited the activity of either globus pallidus or subthalamic nucleus using microinfusion of the GABA(A) receptor agonist muscimol. The effects of these manipulations on spontaneous efflux of somatodendritic dopamine and on increases in this measure produced by systemic haloperidol administration were determined in ipsilateral substantia nigra using in vivo microdialysis. As observed previously, administration of haloperidol (0.5 mg/kg, i.p.) significantly increased extracellular dopamine in substantia nigra. Microinfusion of muscimol (400 ng/200 nl) into globus pallidus also produced a significant increase in somatodendritic dopamine efflux. When haloperidol was administered systemically in conjunction with microinfusion of muscimol into globus pallidus, an increase in nigral dopamine efflux was observed that was significantly greater than that which was produced singly by muscimol microinfusion into globus pallidus or by systemic haloperidol administration. The additive nature of the increases in somatodendritic dopamine release produced by these two manipulations indicates that independent neural circuitries may be involved. Inactivation of subthalamic nucleus by microinfusion of muscimol (200 ng/100 nl) had no effect on spontaneous somatodendritic dopamine efflux. Muscimol application into subthalamic nucleus, however, completely abolished the stimulatory effect of systemic haloperidol on dendritic dopamine efflux in substantia nigra.The present data extend our previous findings by demonstrating: 1) an important involvement of globus pallidus efferents in the GABAergic regulation of somatodendritic dopamine efflux in substantia nigra under normal conditions and, 2) an emergent predominant role of subthalamic nucleus efferents in the glutamate-dependent increase in somatodendritic dopamine efflux observed after systemic haloperidol administration. Thus, the relative influence of globus pallidus and subthalamic nucleus in the determination of the level of somatodendritic dopamine release in substantia nigra qualitatively varies as a function of dopamine receptor blockade. These findings are relevant to current models of basal ganglia function under both normal and pathological conditions, e.g. Parkinson's disease.     

Structural basis of the interaction of the limbic and motor systems in the striopallidum

The results regarding the topical organization of the projections from the nuclei of the amygdaloid body, the ventral tegmental area, and the substantia nigra in the striopallidum were generalized and compared in a study carried out on 125 cats, using the method of retrograde axonal transport of horseradish peroxidase and fluorochromes. Limbic and motor areas were identified in the basal ganglia with a predominance of projections, respectively, from the subcortical structures belonging to the limbic system, or from formations relating to a greater degree to motoric activity. In addition to this, the overlapping of terminals of the fields of the initial neurons of these and other structures was established in substantial areas of the striopallidum. The data obtained regarding the organization of projections of functionally varied subcortical formations to the striopallidum suggest that it may be regarded as the structural basis of the functional heterogeneity of the basal ganglia and of the interaction of the motor and limbic systems in them. 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. 4, pp. 17–22, April, 1994.     

Increasing the activity of the neostriatum cholinergic system alters an established type of motor behavior in animals

Chronic experiments on four dogs were performed to study the effects of bilateral, microinjection of the choline receptor agonist carbacholine and the blocking agent scopolamine into the dorsolateral part of the head of the caudate nucleus on the performance of an operant defensive reflex involving maintenance of a specified amount of flexion and on the differentiation of meaningful signals. Bilateral microinjection of carbacholine (0.1–0.4 μg in 1.5 μl of solvent) reduced the phasic component and amplified the tonic component of the operant responses, inhibited intersignal leg lifts, normalized posture, and calmed the animals, and also led to a sharp improvement in the differentiation of meaningful signals. These changes were expressed as increases of three-fold or more in the latent priod of movement initiation when the differentiation signal was used, as compared with the baseline latent period before the injections. Microinjection of the choline receptor blocker scopolamine into the striatum had the opposite effects. Unilateral microinjection of these substances produced changes mainly only on the day of dosage and had no effect on subsequent behavior, while bilateral microinjection altered the established motor behavior for a longer period of time. This affected both the motor and the sensory components of the operant response. Laboratory for the Physiology of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Makarov Bank, 199034 St. Petersburg, Russia. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni, I. M. Sechenova, Vol. 83, No. 1–2, pp. 35–43, January–February, 1997.     

Responses of rat pallidum cells to cortex stimulation and effects of altered dopaminergic activity

The aim of the study was to investigate the influences of dopamine on oligosynaptic corticopallidal neurotransmission. Different cortical areas were electrically stimulated and the responses in the pallidum were recorded by single-cell electrophysiology. Out of 377 pallidal neurons, 192 (51%) responded to stimulation of at least one of the cortical areas investigated. Convergence between frontal cortex and at least one of the other cortical areas was seen in 59 of 110 (54%) pallidal neurons responding to frontal cortex stimulation. Nearly three-quarters (73%) of all responsive pallidal neurons showed a short latency reduction of activity following the stimulus, the rest responded with pure activation or an activation-depression sequence. The dopaminergic influences on this corticopallidal impulse transmission were assessed by the systemic administration of the dopamine receptor-blocking neuroleptics, haloperidol and fluphenazine, as well as by conditioning electrical stimulation of the substantia nigra. Neuroleptic administration augmented the responses to cortical stimulation in 12 of 34 pallidal neurons. Stimulation of the substantia nigra diminished the responses in 24 and augmented them in 6 of 63 of the tested neurons. We propose from the present results, and in agreement with data from conceptually different studies done by others, that dopaminergic influences reduce the flow of information from the cortex to the pallidum. This may constitute a focussing mechanism by which only information form the strongest cortical inputs would pass to the pallidum while less prominent activity would be lost.     

Synaptic organization of GABAergic inputs from the striatum and the globus pallidus onto neurons in the substantia nigra and retrorubral field which project to the medullary reticular formation.

Anatomical tract-tracing and immunohistochemical techniques involving correlated light and electron microscopy were used to determine whether the descending striatal and pallidal afferents to the substantia nigra pars reticulata converge onto individual neurons projecting to the pontomedullary and medullary reticular formation in the rat. Injections of biocytin into the ventrolateral region of the striatum and Phaseolus vulgaris-leucoagglutinin into the ventrolateral and caudal regions of the globus pallidus led to overlapping anterogradely labelled terminal fields within the dorsolateral substantia nigra pars reticulata. These terminal fields were punctuated by neurons which had been retrogradely labelled following injections of wheatgerm agglutinin conjugated to horseradish peroxidase into the lateral pontomedullary reticular formation. The anterogradely labelled striatal and pallidal terminals displayed different morphological characteristics; the striatal terminals were small and diffusely distributed throughout the neuropil without any particular neuronal association whereas the pallidal terminals were large and formed pericellular baskets around the perikarya of retrogradely and non-retrogradely labelled nigral neurons. In areas of the substantia nigra where there was an overlap between the two terminal fields, individual retrogradely labelled nigroreticular neurons were found to be apposed by both sets of anterogradely labelled terminals. Electron microscopic analysis revealed that the striatonigral and pallidonigral terminals displayed different ultrastructural features, the striatal terminals were small, contained few mitochondria and formed symmetric synaptic contacts predominantly with the distal dendrites of nigroreticular neurons whereas the pallidal terminals were large, contained numerous mitochondria and formed symmetric synaptic contacts preferentially with perikarya and proximal dendrites of nigroreticular neurons. Post-embedding immunohistochemical staining revealed that both striatonigral and pallidonigral terminals, some which formed synaptic contact with nigroreticular neurons, displayed GABA immunoreactivity. Examination of twelve retrogradely labelled neurons in the electron microscope revealed that all received synaptic inputs from both sets of anterogradely labelled terminals. In addition to the substantia nigra pars reticulata, neurons of the retrorubral field were also retrogradely labelled following injections of wheatgerm agglutinin conjugated to horseradish peroxidase into pontomedullary reticular formation. These retrorubroreticular neurons were part of a continuum of labelled cells which extended from the dorsolateral substantia nigra pars reticulata caudally into the retrorubral field. When combined with anterograde tracing methods it was found that the retrorubroreticular neurons received synaptic inputs from pallidal terminals which were morphologically similar to the pallidonigral terminals and formed symmetric synapses with the neuronal somata and proximal dendrites. In contrast to nigroreticular neurons, the stratonigral terminals were not seen in contact with retrorubroreticular cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Electrophysiological analysis of dopamine cells from the substantia nigra pars compacta of circling rats

Summary Extracellular single unit recordings were obtained from dopamine cells in the substantia nigra pars compacta during forced locomotion on a circular turntable treadmill. Stainless steel wire electrodes, 18 m diameter, insulated with Parylene C were used. During the entire recording session the rat was in the treadmill apparatus. The device was stopped while a cell was being sought. A cell was identified as dopaminergic by a frequency of 3 to 10 Hz and a biphasic or triphasic action potential of greater than 2 ms in duration. An attempt was made to record from cells under the following conditions: animal at rest, animal turning in one direction, at rest again, turning in the opposite direction and finally, at rest. If the cell was still firing after these recordings, haloperidol was injected i.p. to see that the presumed dopamine cell increased its firing rate. A cell was held for all the observations in 4 animals. In an additional 10 rats, recordings were made before, during and after movement in one direction. Three animals were recorded only before and during movement. In 6 of the total of 17 animals haloperidol was administered. Results showed that firing patterns of cells in awake animals were similar to those reported from dopamine cells of anesthetized rats. During either contralateral or ipsilateral turning the firing frequency and burst activity significantly increased. These results indicate that the activity of dopamine cells in substantia nigra is increased bilaterally during circling.     

Neuroleptic suppression of feeding and oral stereotypy following microinjections of carbachol into substantia nigra

A large dose of carbachol (5 μg/0.5 μl) unilaterally microinjected into the rostral substantia nigra of rats induced stereotypy characterized by biting, gnawing and licking. A lower dose (0.5 μg/0.5 μl) of the cholinomimetic potentiated normal food intake in satiated animals. Both the cholinergically induced feeding and stereotypy were severely attenuated by subcutaneous administration of haloperidol 0.4 mg/kg. This particular dose of neuroleptic had no significant effect on locomotor activity. These data are consistent with the hypothesis that cholinergic neurotransmission in the rostral substantia nigra mediating oral responses is afferent to the dopamine systems arising from this area.     

Reserpine-induced up-regulation of dopamine D2 receptors in the rat striatum is enhanced by denervation but not by chronic receptor blockade

Compensatory increases in the density of dopamine (DA) D2 receptors in the rat striatum occur following chronic interruption of dopaminergic neurotransmission. Substantia nigra lesions, DA depletion with reserpine and D2 receptor blockade by neuroleptics increase the number of striatal D2 receptors as identified with the D2 ligand, [3H]spiperone [( 3H]SPIP). Chronic administration of haloperidol to substantia nigra-lesioned rats causes an additive increase in binding over levels obtained with one treatment alone. In this study we have found a similar response when lesioned animals are treated with reserpine. However, compensatory increases in the number of [3H]SPIP binding sites found after combined administration of reserpine and haloperidol to intact rats do not exceed levels obtained following administration of either drug alone. The data suggest that up-regulation of striatal D2 binding sites occurring after substantia nigra lesions is unique relative to other forms of up-regulation and may involve the loss of a presynaptic regulatory factor other than DA.     

Circling behavior induced by intranigral administration of ruthenium red and 4-aminopyridine in the rat.

We have studied the effects of the unilateral intranigral microinjection of Ruthenium Red and 4-aminopyridine in the rat, as compared with that of muscimol. The three drugs produced contralateral turning when injected into the central nigra reticulata. Muscimol was the most effective but its effect disappeared in 3-4 h, whereas that of Ruthenium Red lasted for up to 3 days. When injected into the caudoventromedial nigra, Ruthenium Red produced intense ipsiversive turning, 4-aminopyridine weak ipsiversive turning and muscimol intense contraversive turning. Pretreatment with haloperidol (i.p.) abolished the effect of Ruthenium Red after injection into the caudoventromedial nigra but only partially reduced it after administration into the central nigra. The effect of muscimol, when injected into either of the nigral regions studied, was only slightly diminished by haloperidol. The release of [3H]GABA in slices of the Ruthenium Red-injected substantia nigra was not altered. Histological examination showed that the microinjected Ruthenium Red was located mainly inside the soma of nigral neurons. It is concluded that alterations of transmitter release are probably responsible for the circling behavior induced by 4-aminopyridine, but the effects of Ruthenium Red seem to be secondary to its penetration into the neuronal somas. Dopaminergic neurons seem to play an important role in the ipsilateral turning induced by Ruthenium Red when injected into the caudoventromedial nigra.