Behaviour correlates of neurotransmitter activity.

Most disorders of motor activity including disturbances of muscle tone and of locomotor activity observed in patients with neurological disorders have been reproduced experimentally in animals. Most motor disorders of the extrapyramidal type including those associated with Parkinson's disease and choreiform and athetoid involuntary movements, have been reproduced exclusively in primates. This is most likely related to the highly complex organization of the extrapyramidal and related nervous mechanisms subserving the corresponding peculiar type of motor control in the primate brain. Other types of motor disturbances including cervical and trunkal dystonias, ataxia, hypotonicity, spasticity and intention tremor, however, have been successfully induced in various mammalian species. The latter types of motor disorders are related to disturbances of central nervous mechanisms which show similar patterns in the brains of different animal species. Histopathological and neurochemical changes associated with extrapyramidal disorders have been discovered and more precisely determined as a consequence of the development of new technical approaches. Therefore numerous morphological, physiological and neurochemical data concerning the extrapyramidal system are now available but a better knowledge of their precise and subtle interrelationship is greatly needed in order to develop more efficient therapeutic procedures.

The nigrostriatal nervous pathways in the brain of the cat. An autoradiographic study.

By comparing the findings obtained in these series of cats with injections of 3H-leucine involving different areas of the SN and adjacent neurons of the VTA, some conclusions may be drawn concerning the origins, courses, and terminations of the nigrostriatal fibers. Three main bundles of nigrostriatal fibers originating from different groups of neurons of the SN may be identified. The main cluster of neurons of the compacta type, corresponding to the more abundant and larger neurons of this group in the caudal part of the SN and above (pars dorsalis of the SN), gives rise to fibers that leave the latter structure through its dorsomedial lip. They course successively in the VTA and in the area of Tsai and proceed rostralward through the lateral hypothalamus, subthalamus, and the internal capsule. At the level of the anterior limb of the internal capsule, they undergo an important arborization before ending in the putamen and caudate nucleus. Fibers from the main cluster of compacta neurons terminate more dorsally and those from the dorsal part of the SN end more ventrally in the neostriatum. These findings generally agree with those of VanderMaelen et al. (12) and Szabo (9), who applied the HRP technique, and Usunoff et al. (11), who used a selective silver impregnation method in cat brains. In the caudate nucleus, endings from the compacta type neurons are more abundant in certain areas, forming islands of dense silver grains. These areas of dense endings appear to correspond to the areas of greater cellular density of the striatum as more easily recognizable in the caudate nucleus of the newborn cat (Fig. 9).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative morphology of the substantia nigra and ventral tegmental area in the monkey, cat and rat.

Four types of neurons were identified in the substantia nigra (SN) of the monkey, cat, and rat. The compacta-type neurons, characterized by unevenly distributed and intensely stained Nissl substance, display many shapes and sizes. The reticulata-type neurons, characterized by the presence of discrete Nissl bodies, are triangular or round. The intermediary-type neurons contain less intensely stained but more diffusely distributed Nissl substance. These triangular or fusiform neurons have thinner processes than the compacta- and reticulata-type cells. The globular-type neurons, characterized by a high nuclear/cytoplasmic ratio, are much smaller than the three other types of SN neurons. The total number of neurons of the SN, which is much greater in the macaque (n=73,508) than in the cat (n=38,366) and the rat (n=22,532), is comprised mainly of the compacta type neurons (n=62,624; 22,323; and 9.925 in the three species, respectively). The reticulata-type neurons are more abundant in the cat, and the intermediary and globular types are more numerous in the rat. The compacta-type neurons have a particular distribution in each species. The ventral tegmental area (VTA) contains numerous globular-type neurons and a number of compacta-like or transitional type neurons which constitute the foyer pédiculaire of the central linear nucleus and the paranigral nucleus. The rostral linear nucleus is unique to the cat brain.

Isthmic origin of neurons of the rat substantia nigra.

This study provides new data on the time of origin, the generation site and the migration route of the young neurons of the substantia nigra of the rat during embryogenesis. The neurons of the substantia nigra are generated on day 12, 13, 14 and 15 of gestation. They settle following a light spatiotemporal rostrocaudal gradient from day 12 to 15. The neurons of the substantia nigra are generated at two different points of the basal plate at the level of the fovea isthmi (meso-isthmic junction) and migrate in radial pattern as two definite streams toward the ventral mesencephalon. From this point they move rostralwards along the surface towards their final site. The main findings of this work are the disclosure that the neurons of the substantia nigra are generated in the region of the isthmus rhombencephali and that its cells do not migrate between existing cells of the mesencephalic tegmentum but first migrate ventralwards in a radial pattern and then rostrally towards their definite site. Numerous neurons of the basal mesencephalon and of the midline structures of the caudal mesencephalon are apparently derived from the region of the fovea isthmi.

An autoradiographic study of the striatofugal fibers in the monkey.

Anterograde labelling with 3H-leucine was used to study the course and termination of striatofugal fibers in the monkey. Following injection of the isotope in the most medial part of the head and the body of the caudate nucleus fibers were traced along the ventrolateral part of the internal capsule and within the medial part of the comb bundle before penetrating the rostromedial pole of the substantia nigra (SN). Fiber endings were found along the dorsomedial edge of both divisions of the pallidum and in approximately the medial third of the SN over the whole length of this structure. Injection in the rostromedial part of the putamen resulted in silver grain concentrations representing labelled terminals in the central part of both divisions of the pallidum and in the ventrolateral and central part of the SN. Isotope concentration was equally important in both parts, reticulata and compacta, of the SN. These results favour the existence of rostrocaudal and mediolateral topographical relationships between, on the one end, the neostriatum and, on the other end, the pallidum and the SN.

[Histopathologic and neurochemical correlations as a function of lesions of the locus coeruleus region in the cat (I)]. / Correlations histopathologiques et neurochimiques en fonction de lesions de la region du locus coeruleus chez le chat. (Part I).

Unilateral lesions in the area of the loci coeruleus and subcoeruleus in the cat are associated with a significant and sustained decrease of noradrenaline (NA) in the ipsilateral cerebral cortex without any important change in the concentrations of NA in the contralateral cortex and in the spinal cord of both sides. The serotonin (5-HT) concentrations of the spinal cord and cerebral cortex of both sides remained unchanged in the same groups of animals. Bilateral lesions in the same area result also in a marked decrease of NA in the cerebral cortex of both sides. The latter lesions also result in slight decreases of NA in the hypothalamus and of NA and 5-HT in the spinal cord but the NA and 5-HT concentrations of the striatum and thalamus and the 5-HT concentrations of the cerebral cortex and hypothalamus are unmodified by such lesions. Unilateral lesions of the area immediately rostral to the locus coeruleus (praelocus lesions) result in a very significant decrease of NA in the ipsilateral cerebral cortex without any change of NA in the contralateral cerebral cortex and spinal cord of both sides. Similar lesions produced bilaterally in another group of cats resulted in marked decreases of NA in the cerebral cortex of both sides and a slight decrease of NA in the thalamus without any change of NA in the striatum, hypothalamus and spinal cord and of 5-HT in the cerebral cortex. In the same group of animals with lesions which, however, extended more closely to the midline than in cats with locus coeruleus lesions, 5-HT is markedly decreased in the striatum and thalamus and slightly decreased in the hypothalamus and spinal cord. These results support the view that the noradrenergic coeruleo-cortical pathway is made up of fibers which originate in the loci coeruleus and subcoeruleus and predominantly end ipsilaterally to their origin in the cerebral cortex. Ascending NA fibers ending in the thalamus appear to originate from NA neurons located more laterally in the upper pons and more specifically at the level of the parabrachial nuclei.

Morphological characteristics of acetylcholinesterase-containing neurons in the CNS of DFP-treated monkeys. Part 2. Diencephalic and medial telencephalic structures.

The distribution and morphological characteristics of neurons containing acetylcholinesterase (AChE, EC 3.1.1.7.) in diencephalic and medial telencephalic structures of the rhesus monkey (Macaca mulatta) were studied by means of a pharmaco-histochemical method that involves staining for AChE (Karnovsky-Roots' procedure) at various times after the administration of di-isopropylfluorophosphate (DFP). At medial telencephalic levels, numerous, mostly multipolar, AChE-containing neurons of medium to large size are present in the bed nucleus of the anterior commissure, in the ascending division of the nucleus of the diagonal band of Broca, and in the so-called "substantia innominata". This last structure is composed of medial and lateral AChE cell groups that extend caudad, beneath the lenticular nucleus, for a considerable distance. The AChE neurons lying within the substantia innominata correspond, at least in part, to the basal nucleus of Meynert. Most neurons of the olfactory tubercle are devoid of AChE but lie within a lightly-stained AChE background. In addition, clusters of amorphous and highly reactive AChE material are found within the islands of Cajella and along the ventromedial edge of the olfactory tubercle. At the level of the thalamus, the strongest AChE staining is seen in the periokarya of the anterior dorsal nucleus and of most nuclei located within the fibrous or lamellar thalamic structures--i.e., the reticular nucleus, the intralaminar nuclei, and the midline nuclei except nuclei parataenialis and reuniens. In most of these nuclei the neuronal somata are of medium size and stain moderately for AChE. Their proximal processes are either lightly stained or devoid of AChE. At the level of the hypothalamus of the monkey, intense AChE staining can be seen within the neuronal somata of the supraoptic and paraventrivular nuclei. In the paraventricular necleus, the AChE-positive perikarya are of medium size and have numerous AChE-containing processes. Moderately reactive AChE neurons of smaller size with unstained processes are also present in the paraventricular nucleus. Most perikarya of the main rostral portion of the supraoptic nucleus are moderately stained for AChE, are closely packed, and their processes are difficult to discern. The main cellular aggregate of the supraoptic nucleus extends caudad and is composed of a large group of moderately to intensely stained neurons lying along the optic tract and which constitute the caudal, or infundibular, portion of the supraoptic nucleus. Other moderately to intensely stained AChE neurons were found in the lateral and perifornical areas and most particularly in the dorsal hypothalamic area. These neurons are of medium size and mostly multipolar. Moderately stained AChE neurons were also observed in the supramammillary nucleus, as well as those of the acruate nucleus, however, are only weakly reactive. The median eminence and most neurons of the ventromedial nucleus of the monkey hypothalamus are virtually devoid of AChE...

Morphological characteristics of the acetylcholinesterase-containing neurons in the CNS of DFP-treated monkeys.

The distribution of acetylcholinesterase (AChE, EC3.1.1.7) within extrapyramidal and related structures was studied in 4 monkeys following the i.m. administration of bis-(1-methylethyl) phosphorofluoridate (di-isopropylfluorophosphate: DFP). In 1 animal, sacrificed 4 hr after the injection of 0.43 mg/kg C, AChE is virtually absent in all structures. In the other 3 animals, which received 0.20 mg/kg DFP 10, 12 and 18 hr prior to sacrifice, AChE activity is greatly reduced in the neuropil of those structures which normally show intense AChE activity in pharmacologically unmanipulated monkeys. As a consequence of the lower background AChE activity in the latter 3 DFP-treated monkeys, the perikarya and processes of several groups of neurons can be readily identified. The perikarya and processes of two types of neurons of the neostriatum, representing a small percentage of all neurons in this structure, are intensely stained. They apparently correspond to the chromatic giant aspiny neurons and the achromatic medium-size "spidery aspiny" neurons. Most perikarya and processes of the neurons of the medial and lateral divisions of the pallidum, as well as the morphologically similar neurons of the pars reticulata of the substantia nigra, display light to moderate AChE activity. The pars compacta of the substantia nigra contains a small number of intensely stained elongated and triangular neurons and numerous moderately stained ovoid neurons whose processes are very lightly reactive. The cell bodies of the neurons of the subthalamic nucleus and associated groups of neurons (nucleus ansae peduncularis) are moderately stained whereas the perikarya and processes of the subnucleus compactus of the pedunculopontine tegmental nucleus are intensely and moderately stained, respectively. Numerous large and multipolar neurons associated with the lenticular nucleus (intralamellar groups) or the pallidum (peripallidal groups) including the nucleus ansae lenticularis have somata and processes which show an intense AChE activity. Certain of the latter groups of neurons, partially interspersed with the neurons of the substantia innominata, correspond in part to the nucleus basalis of Meynert. The present data are compatible with the idea that the large AChE neurons of the neostriatum may be the source of the acetylcholinesterasic striatopallidal and strionigral fibers. The similarity between the neurons of the pallidum and those of the pars reticulata of the substantia nigra suggests that the latter structure may represent a caudal extension of pallidal tissue. Therefore, the nigrothalamic projection, which has been claimed to originate in the pars reticulata of the substantia nigra, would correspond to pallidothalamic projections.

Effects of 1694 and other dopaminergic agents on circling behavior.

One hour after the administration of 40 mg/kg of amineptine chlorydrate (1694) the HVA concentration in the striatum was increased but the concentrations of DA, NA, 5HT and 5-HIAA in the striatum, cortex, thalamus-hypothalamus and pons-midbrain of rats were not significantly altered. Unilateral lesioning at the level of the entopeduncular nucleus in cats and rats resulted in spontaneously occurring ipsiversive circling behavior in the two species. However circling was more sustained in cats than in rats. Apomorphine, d-amphetamine, methamphetamine, L-dopa and piribedil (ET-495) exaggerated the ipsiversive circling. 1694 (amineptine chlorydrate), a new agent, was comparatively more active than L-dopa and ET-495 and less active than apomorphine, d-amphetamine and methamphetamine. Although in higher doses (30--40 mg/kg), 1694 caused increased exploratory activity it was not associated with any stereotypy. Its biochemical and pharmacological effects are comparable to those of d-amphetamine and methamphetamine. Removal of the contralateral (with respect to the side of the entopeduncular lesion) motor cortex in the lesioned cat abolished spontaneous and drug-induced circling movements. The results of this and of previous studies support the idea that these dopaminergic agents act on the striopallidal system of the intact side which is no longer properly counterbalanced by the corresponding system of the lesioned side. Although this experimental model is useful to determine the degree of dopaminergic activity of various chemical agents it does not duplicate the motor disorders encountered in parkinsonism which are associated with a decreased concentration of dopamine.

The effect of capsaïcin on temperature regulation of the rat.

1. Subcutaneous injection of capsaïcin (6-11 mg, or 21-66 mg cumulative), permanently reduced the capacity of rats to withstand a hot environment, as described by Jancsó-Gábor et al. (1970). 2. The treated rats thermoregulatory behaviour was not different from that of control rats, both in hot and cold environments. 3. Saliva secretion was decreased in a hot environment, and the weight of the submaxillary glands was reduced in capsaïcinized rats. 4. It is concluded that hyperthermia present in treated rats when subjected to a warm environment is not due to a disruption of sensu stricto temperature regulation, but rather to a decreased salivary secretion. Whether this decrease has a central or a peripheral origin is not known.

Parkinsonian akinesia, rigidity and tremor in the monkey. Histopathological and neuropharmacological study.

Parkinsonian postural tremor and rigidity most likely involve the disruption of the dopaminergic (DA) nigrostriatal mechanisms and the corresponding rubro-olivo-cerebello-rubral loop without excluding the involvement of related dentato-rubral and dentato-thalamic nervous fascicles. The integrity of the magnocellular division of the red nucleus and of the rubrotegmentospinal pathway, however, is apparently essential for the expression of rigidity. Akinesia most likely results from the bilateral involvement of brain stem catecholaminergic (CA) mechanisms including the DA nigrostriatal pathways. Finally the integrity of the pallidothalamic fibers seems to represent an essential feature for the improvement of these motor disorders by DA agonists, suggesting that certain of these agents, such as apomorphine, exert their main effects through the neostriatal DA receptors.