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[Effects of hypothalamus and globus pallidus lesions and of apomorphine injections into the globus pallidus, caudate nucleus, substantia nigra and septum on the aggressive behavior induced by apomorphine treatment of rats (author's transl)].

Intraspecific apomorphine-induced aggressive behavior in the rat was not affected following electrolytic lesions of the ventromedial hypothalamus. Some inhibition of the aggressive behavior was found after lateral lesions and an almost total suppression after destruction of globus pallidus. These results, as well as those following localized injections of apomorphine into the septum, substantia nigra, caudate nucleus, and globus pallidus suggested that the latter anatomical region may be the major site of the action of apomorphine in the behavior studies. The role of acetylcholine is discussed.

Aggression

The striatal efferents in the globus pallidus and in the substantia nigra.

The radial fibers in the globus pallidus are the striatal efferents. Evidence now indicates that they arise from medium-sized neurons in the striatum. During their transit of the globus pallidus, they give off collaterals in both segments of the globus pallidus and undergo reduction in caliber. It has not been possible to observe the same radial fiber emitting collaterals in both segments of the globus pallidus, and the prospects of ever doing so are not good. The radial fibers in the medial segment of the globus pallidus continue into the substantia nigra by way of the "comb" bundle. The divergence and convergence in the striatal efferent systems is considerable. The afferent plexuses of fine fibers bearing bouton en passant endings, which completely ensheath the long dendrites in the globus pallidus and the substantia nigra and make "longitudinal axodendritic connections," are derived from the convergence of branches off the collaterals of a number of different radial fibers in the globus pallidus and the convergence of "comb" bundle fibers in the substantia nigra. The synaptic endings on these fibers constitute most of the endings in the globus pallidus. They are the endings with large, egg-shaped, synaptic vesicles and form symmetrical synapses.

Animals

Baclofen (beta-p-chlorophenyl-gamma-aminobutyric acid) enhances [3H]gamma-aminobutyric acid (3H-GABA) release from rat globus pallidus in vitro.

The rat globus pallidus has been investigated as a possible model in which to study pre-synaptic GABA mechanisms in vitro. (+/-)-Baclofen (300 micrometer-1 mM) significantly enhanced the release of radioactivity from superfused slices of rat globus pallidus prelabelled with 3H-GABA in vitro. This releasing action was specific to the (+)-isomer of baclofen: neither the (-)-isomer nor another neuronal depressant dl-alpha-epsilon-diaminopimelic acid had any significant effect. The releasing effect of baclofen appeared unrelated to the phenethylamine moiety of its structure as neither beta-phenethylamine nor dopamine evoked release of 3H-GABA from pallidal slices. Baclofen increased the efflux of radioactivity from pallidal slices prelabelled with either [3H]-beta-alanine or [3H]diaminobutyric acid in vitro. The use of specific glial and neuronal GABA uptake blocking compounds (beta-alanine and (+/-)-cis-1,3-amino-cyclohexanecarboxylic acid) did not permit resolution of the elements from which baclofen was evoking [3H]GABA release. Baclofen also inhibited uptake of [3H]GABA into pallidal slices with an IC50 value of 6 x 10(-4) m. The GABA-like properties of baclofen may be related to the (+)-isomer while non-specific neuronal depressant actions are an effect of the (-)-isomer. The potential of the (+)-isomer as an antipsychotic agent while (-)-baclofen remains the effective antispastic drug free from unwanted side-effects, is discussed.

Alanine

The radial fibers in the globus pallidus.

In our Golgi collection of adult monkey brains the striatal efferents, i.e., the radial fibers in the globus pallidus and the "comb" bundle fibers in the internal capsule and in the cerebral peduncle, are well impregnated in the horizontally sectioned brain and in a sagittal sectioned brain. Since collaterals emerging from radial fibers are seen only in the horizontal series and not in the saggittal series, the interpretation is that they proceed anteriorly and posteriorly only, following the curvature of the pallidal segments, and do not run superiorly or inferiorly as they emerge. Although radial fibers emitting collaterals in the lateral segment and in the medial segment of the globus pallidus have been observed, it has not been possible to observe the same radial fiber emitting collaterals in both pallidal segments and the prospects of ever doing so are not good. The radial fibers converging in the globus pallidus pursue many radii and there is little coincidence between the plane of section and the planes in which they travel. At most only severed radial fiber segments 100-150 microns in length can be found in the horizontal sections needed to observe the collaterals. Moreover, sagittal sections trodorsally, as they pass through the internal medullary lamina to enter the medial segment of the globus pallidus. The radial fibers in the medial segment of the globus pallidus are continuous with the "comb" bundle fibers and appear to be thinner than the radial fibers in the lateral segment of the globus pallidus. It is not proved; nonetheless, the view expressed here is that the radial fibers are thinner in the medial segment of the globus pallidus because they may be the same fibers that gave off collaterals in the lateral segment of the globus pallidus. This is discussed in the light of the electrophysiological disclosure of Yoshida et al. ('71, '72) that caudatopallidal fibers are collaterals off caudatonigral fibers. The afferent plexuses of fine, "bouton en passage" fibers, which completely ensheath the long radiating dendrites in the globus pallidus (Fox et al., '66) are well impregnated in the horizontal series. Obviously, they are formed by a number of ultimate branches converging from the collateral brances of a number of different radial fibers. The divergence, too, in this system must be considerable; however, its true extent can only be surmised from the several radial fibers and radial fiber collaterals seen in the incompletely impregnanted Golgi section. Continued.

Animals

[Biometrical fresh volume analysis of nucleus caudatus, putamen and globus pallidus in an ontogenic series of Tupaia belangeri].

The fresh volumes of the nucl. caudatus (including the nucl. accumbens septi), putamen, globus pallidus and of the whole brain of 37 male Tupaia belangeri aged between 36-536 days of ontogenesis have been determined. The growth of these nuclear regions is described by the logistic function. The parameters were approximated by means of an iterative procedure by the least square method. The "ideal" volume of the globus pallidus is 9,6 mm3, of the striatum 113 mm3, and of the whole brain 3 260 mm3. The degrees of maturity of globus pallidus, striatum and the whole brain do not differ significantly from each other concerning the date of birth (43th day of ontogenesis), the growth factors are about 5,5. The nucl. caudatus, including the nucl. accumbens septi, and the putamen demonstrate almost the same course in their degrees of maturity and growth dynamics within the tested age interval. In the course of postnatal development the globus pallidus grows more quickly than the whole brain, and the whole brain, on the other hand, more quickly than the striatum. The half value time of the globus pallidus is about 53 days of ontogenesis, of the whole brain about 56 days of ontogenesis and of the striatum about 58 days of ontogenesis. On the 70th day of ontogenesis, the difference between the degrees of maturity of globus pallidus (93 per cent) and striatum (= nucl. caudatus + nucl. accumbens septi + putamen) (72 per cent) is 21 percent. This complicated growth dynamics can be seen exactly by considering the non-linear logistic functions, the degrees of maturity, and the growth-rate of the degrees of maturity.

Age Factors

Opiate receptor agonists as modulators of gamma-aminobutyric acid turnover in the nucleus caudatus, globus pallidus and substantia nigra of the rat.

The injection of various doses of morphine, subcutaneously, or of beta-endorphin, intraventricularly, changes the turnover rate of gamma-aminobutyric acid (TRGABA) in the substantia nigra, globus pallidus and nucleus caudatus. The TRGABA decreases in N. caudatus but increases in globus pallidus and substantia nigra. These changes are dose related and can be inhibited by naltrexone. The increased TRGABA in globus pallidus elicited by these opioid receptor agonists may be associated with catalepsy since muscimol, a specific GABA receptor agonist, injected into the globus pallidus causes a dose-related catalepsy. Since this GABA receptor agonist injected into the substantia nigra fails to cause catalepsy, one can exclude that the increase in the TRGABA of substantia nigra elicited by opiate receptor agonists is operative in mediating the catalepsy elicited by opioids.

Animals

Hyperactive behavior of rats after lesions of the globus pallidus.

Following bilateral lesions of the globus pallidus, rats living in a residential maze were hyperactive during the 12 hr dark cycle but not during the 12 hr light cycle. Lesioned rats were less exploratory during the light cycle than control rats but not during the dark cycle. Exploratory behavior of rats was photographed for 15 min during the light cycle. The duration of 6 behavior acts was significantly shorter than controls (scratching, grooming, sitting, sniffing, standing and rearing). The number of initiations of grooming, scratching, sniffing and smelling decreased while looking and walking increased in frequency. The linkage of behavior acts into sequences was diminished compared with controls. Similar, but not identical, changes were found when the structure of exploratory behavior of naive rats was compared with the exploratory behavior of experienced rats. It is concluded that naive control rats are hyperactive relative to experienced rats in this exploratory situation and that rats with pallidal lesions display changes in their behavior which are characteristic of hyperactive animals even when other tests under similar conditions, such as exploration during the light cycle in a maze, show the pallidal rats as hypoactive relative to control rats.

Animals

Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra, and interactions with haloperidol or benzodiazepines.

Intranigral injection of muscimol induced hyperactivity in rats and antagonized haloperidol-induced catalepsy. Intranigral injection of gabaculine, an inhibitor of GABA transaminase, induced similar effects 5h after injection, when the nigral GABA content was increased 7-fold. On the other hand, injections of muscimol (30 ng) into the globus pallidus potentiated the cataleptic effect of haloperidol, and muscimol alone in high doses (100 and 200 ng) induced catalepsy. Gabaculine also induced catalepsy of medium intensity and potentiated the effect of haloperidol 24h after injection, when GABA was increased in the globus pallidus as well as in the substantia nigra. Injections of muscimol into either the globus pallidus or substantia nigra increased striatal HVA and enhanced haloperidol-induced elevation of HVA. Three benzodiazepines, nitrazepam, diazepam and chlordiazepoxide administered orally, potentiated the effect of muscimol (30 ng) injected into the globus pallidus and induced catalepsy. A similar effect was not obtained with phenobarbital. It is suggested that stimulation of GABA receptor or increase of GABA content in the sustantia nigra antagonize haloperidol-induced catalepsy by activation of nigral dopaminergic system, and that enhancement of pallidal GABA function induces catalepsy by non-dopaminergic mechanisms. Potentiation of haloperidol-induced catalepsy by benzodiazepines may be due to enhancement of GABA-ergic transmission within the globus pallidus.

4-Aminobutyrate Transaminase

[Connections between the globus pallidus and putamen and the cerebral cortex].

The results are represented on investigation of the projections of the globus pallidus and putamen on the brain cortical fields. In 17 cats a unilateral electrolytic destruction of the exterior and interior globus pallidus, and in 8 cats--unilateral electrolysis of the putamen were performed. The brains were treated after Nauta--Gygax, Fink--Heimer, Kawamura--Niimi. Direct connections between the external globus pallidus with prepiriformic, orbital (field 43), temporal (fields 20, 22), frontal (field 6), precentral (field 4), postcentral (field 2) cortical areas were revealed, and projections of the putamen on the frontal (field 6), precentral (field 4), postcentral (field 2), orbital (field 43) cortical areas were demonstrated. Less fibres connect the putamen with temporal and parietal areas. No convincing evidence was obtained to demonstrate direct connections of the entopedunctular nucleus with the brain cortex.

Animals

In vitro release of [5-methionine]enkephalin and [5-leucine]-enkephalin from the rat globus pallidus.

Endogenous [5-methionine]enkephalin (Metenkephalin) and [5-leucine]enkephalin (Leu-enkephalin) are released from perfused slices of rat globus pallidus by increased K(+) in a Ca(2+)-dependent manner. Tissue perfused for 40 min contained only 26% of the Met-enkephalin and 44% of the Leu-enkephalin found in the freshly dissected tissue. After perfusion, the mean (+/-SEM) ratio (wt/wt) of Met-enkephalin to Leu-enkephalin was 3.4 +/- 0.2 compared with 5.8 +/- 0.2 in the fresh tissue. The degradation of trace amounts of synthetic [(3)H]enkephalins in the perfusing medium during stimulated release seems to reflect the accelerated degradation of enkephalin released from the tissue: 63% of the Met-enkephalin and 23% of the Leu-enkephalin were degraded in a medium containing bacitracin (30 mug/ml). The mean ratio (wt/wt) of the Met-enkephalin to the Leu-enkephalin recovered after release by exposure of slices to 50 mM K(+) was 2.7 +/- 0.3. When perfusates were corrected for degradation, this ratio increased to about 5.5 which is higher than that found in the perfused tissue. The differences in release, tissue loss, and catabolism of the two enkephalins may be reflecting differences in the metabolic systems operating on the pentapeptides, but this interpretation will have to be validated by in vivo release experiments. In any event these observations strongly suggest that both enkephalins can be considered candidate neurotransmitters in the rat globus pallidus.

Animals

[Connections between the globus pallidus and putamen and the hypothalamus and subthalamus].

In 16 adult cats with electrolytically destructed external and internal parts of the globus pallidus and in 8 cats with destructed putamen direct strio-pallido-hypothalamic and strio-pallido-subthalamic pathways have been studied. Degeneration of the axonal preterminals and terminals have been examined in preparations treated after Nauta--Gygax, Nauta--Laidlow, Finck--Heimer with simultaneous additional staining of the nuclei with cresyl violet after Kawamura--Niimi. Direct pallido- and putamen-hypothalamic pathways to nuclei of the grey tubercle, posterior and lateral nuclei of the hypothalamus were stated. Direct pathways from the putamen to the subthalamic nucleus have been revealed, however, these pathways are represented in less degree than those of pallido-subthalamic connections. Direct pathways from the external portion of the globus pallidus and putamen to the subthalamic nucleus are more pronounced and represented by greater numbers of projections than those of strio-pallido-hypothalamic origin.

Animals

A presynaptic action of dopamine on globus pallidus afferents to substantia nigra in the rat.

Dopamine applied iontophoretically onto substantia nigra and adjacent reticular formation units, changed the pattern of response evoked in these cells by stimulation of the globus pallidus. This change was reversible and was sensitive to iontophoretically applied dopamine. It is proposed that this effect is brought about by an interaction of dopamine with dopamine receptors located on afferent fibres coming from the globus pallidus.

Acetylcholine

Effects of interruption of the nigrostriatal pathway and of dopaminergic agents on the spontaneous activity of globus pallidus neurons in the awake monkey.

Interruption of the nigrostriatal pathway has been shown to change parameters of striatal activity. These changes are often difficult to explain because the functional structure of the striatum is not understood sufficiently. The function of the globus pallidus appears to be simpler. It transmits the output of the striatum to the thalamus and to the midbrain. Yet the effects of interruption of the nigrostriatal pathway on the activity of pallidal neurons are unknown. To study these effects the spontaneous activity of globus pallidus neurons was recorded in intact monkeys and in monkeys with lesions of the ventromedial midbrain tegmentum. The two groups of animals were studied with and without administration of dopaminergic agents. In intact monkeys medial pallidal neurons discharge uninterruptedly at high firing rates, while the discharge of most lateral pallidal neurons is interrupted by relatively long periods of silence. Lesions involving the nigrostriatal pathway change the firing patterns but not the mean firing rates of pallidal neurons. In lesioned monkeys pallidal neurons fire in bursts continuously: during movement, rest and sleepiness. Two lines of evidence strongly suggest that the bursting pallidal activities are a consequence of the interruption of the nigrostriatal dopaminergic pathway: (1) the percentage of bursting pallidal neurons is proportional to the amount of degeneration in the pars compacta of the ipsilateral substantia nigra; (2) chronic administration of dopamine antagonists, haloperidol and reserpine, reproduces in intact monkeys the bursting activities observed in lesioned animals. On the other hand, single injections of dopamine agonists, apomorphine and piribedil, silence the medial pallidum and concomittantly abolish the signs of parkinsonism displayed by lesioned monkeys.

Animals

The spontaneous firing patterns of forebrain neurons. IV. Effects of bilateral and unilateral frontal cortical ablations on firing of caudate, globus pallidus and thalamic neurons.

To assess the effects of partial deafferentation of the neostriatum on spontaneous neuronal activity in the basal ganglia and related thalamic nuclei, ablations of frontal cortex were carried out in adult cats. Postoperative measures of interspike intervals of single neurons in the caudate nucleus, globus pallidus and ventral anterior-ventral lateral complex of the thalamus revealed a slowing of neuronal firing in these structures as compared with non-lesioned controls. The fact that deafferentation by cortical damage produces changes in neuronal firing in target neurons of the striatum (globus pallidus) and in thalamic neurons at least two synapses removed from the striatum is noteworthy. The possible extent to which these results might have been influenced by reduction of cortical inputs to or denervation of the thalamus is discussed.

Afferent Pathways

Neuronal depletion in the globus pallidus of heroin addicts.

Decreased neuronal population densities are described in the globus pallidus of narcotic addicts. Toxicologic studies indicate mixed addiction to be frequent, but exposure to parenteral heroin is the only common factor. This permanent brain damage seems more likely to be caused by recurrent episodes of hypoxia during severe reactions to narcotics than to be related to direct neurotoxic effects of heroin. The lesion may account for some of the long term changes observed in addicts.

Adolescent

Projections of the globus pallidus and adjacent structures: an autoradiographic study in the monkey.

Because the globus pallidus gives rise to the principal efferent system of the corpus striatum and is traversed by several fibers systems, attempts were made to study the projections of its cells by autoradiographic technics. Tritiated amino acids (L-leucine, L-proline and L-lysine) were injected into: (1) the medial pallidal segment (MPS), (2) the MPS and the substantia innominata (SI), (3) portions of the MPS and the lateral pallidal segment (LPS) and (4) parts of the putamen. Cells labeled by injections of the MPS transported isotope to thalamic nuclei (ventral anterior, VApc, ventral lateral, VLo and VLm, and the centromedian, CM), the pedunculopontine nucleus (PPN), and the lateral habenular nucleus (Hbl). Labeled cells of the MPS and SI transported isotope to: (1) thalamic nuclei (VLo, VLm and CM), (2) PPN, (3) Hbl, (4) lateral and posterior regions of the hypothalamus, and (5) extensive dorsal regions of the substantia migra (SN). Comparisons of label transported from uptake of isotope by cells of the MPS, and cells of both pallidal segments, suggest that the LPS projects fibers only to the subthalamic nucleus (STN). Not all regions of the STN appear to receive fibers from the LPS. Selectively labeled neurons of the putamen transport isotope to broad regions of both pallidal segments and to the pars reticulata of the SN. This study suggests that cells of the MPS project profusely and topographically to: (1) the rostral ventral tier thalamic nuclei (VApc, VLo and VLm), (2) lateral portions of CM, and (3) the PPN. Fibers of the lenticular fasciculus appear to terminate preferentially in VLo. Cells in sublenticular portions of SI, and those extending into the medullary laminae of the pallidum, appear to project to: (1) HB1 via the stria medullaris, (2) the pars compacta of SN, (3) lateral and posterior regions of the hypothalamus, and (4) the so-called nucleus of the ansa lenticularis. Some fibers from cells of SI appear to join the dorsal stria terminalis, but none enter the inferior thalamic peduncle and none project to any part of the dorsomedial nucleus of the thalamus.

Amygdala