Rat Hindbrain Research Articles

Presence of S-100 beta in cholinergic neurones of the rat hindbrain.

The double staining of S-100 beta and choline acetyltransferase (ChAT) revealed that S-100 beta immunoreactivity was localized in most, but not in all, cholinergic neurones in the somatomotor nuclei of the cranial nerves and in the ambiguus nucleus. S-100 beta was present in almost all cholinergic neurones in the brain stem reticular, red, vestibular (excluding medial), mesencephalic trigeminal and cerebellar nuclei. However, S-100 beta immunoreactivity was lacking in cholinergic neurones in the parabrachial complex, the dorsal motor nucleus of the vagal nerve and most sensory nuclei. No S-100 beta-positive neurones lacked ChAT immunoreactivity. Taken together with the fact that the vulnerability of motoneurones to axotomy is markedly reduced in the first 3 postnatal weeks, during which period neuronal S-100 beta appears and increases, a possible effect of S-100 beta on the survival of cholinergic motoneurones may be suggested.

Appearance of neuronal S-100β during development of the rat brain

In addition to being an astroglial protein, S-100β is localised in distinct populations of neurons in the adult rat hindbrain. We report, here, the expression of S-100β in both neurons and glia of the rat brain during development. Prenatally, S-100β immunoreactivity was confined to glial cells close to the germinal zone. After birth, S-100β positive glial cells were seen mainly in the brainstem and cerebellum, while only a few were detected in cerebral cortex and hippocampus. The number of S-100β containing glial cells increased steadily during the first 2 postnatal weeks after which the adult pattern was attained. No S-100β containing neurons were present prenatally. The first S-100β containing neurons were seen in the mesencephalic trigeminal nucleus at postnatal day 1 (P1), and in the motor trigeminal nucleus at P3. Neuronal S-100β immunoreactivity in other nuclei was mostly attained from the 10th to the 21st postnatal day. The neuronal S-100β immunoreactivity was first detected in the cell nuclei during development, then increased in the cytoplasm with ages. A nuclear staining in many immunoreactive neurons persisted until the adult. It usually took 1 to 2 weeks for neuronal S-100β to attain the adult staining pattern, i.e., heavy staining of the cytoplasm and processes, after its appearance. The forebrain never contained S-100β positive neurons. The S-100β is first expressed in glial cells, suggesting it is primarily of the glial origin. Coupled with neurotrophic effects of the protein, the time course of neuronal S-100β expression during the critical period of neuronal development implies that it may be involved in neuronal differentiation and maturation.

Ontogeny of Cholecystokinin Binding Sites in the Hindbrain of the Laboratory Rat

Studies in our laboratory have revealed a robust, transient expression of cholecystokinin binding sites in the facial motor nucleus during development in the Brazilian opossum, Monodelphis domestica. To investigate the ubiquity of this phenomenon, we have performed receptor autoradiography on the hindbrains of embryonic and neonatal rat pups. Cholecystokinin binding sites are present at very low levels in the embryonic day-16 rat hindbrain, but binding sites are abundant prior to birth. The greatest increase in labelled nuclei occurs prior to 5 days of postnatal age. Binding levels are heavy in the nucleus of the solitary tract, medial vestibular nucleus, posterior dorsal tegmental nucleus, area postrema, and caudal spinal trigeminal nucleus by 30 days postnatal. Both A-type and B-type receptors are present in the neonatal brainstem, although most labelled areas appear to be B-type. A-type binding sites are present in the ventral cochlear nucleus, the nucleus of the solitary tract, the dorsal motor nucleus of the vagus, the area postrema, the spinal nucleus of the trigeminal, and the cuneate and gracile nuclei by 5 days postnatal. As reported for the Brazilian opossum, cholecystokinin binding sites are expressed in the facial motor nucleus of neonatal rats and are transient. In this study of the brainstem in laboratory rats, a transient expression is also observed in the rubrospinal tract, parvocellular reticular nucleus, raphe obscurus, cuneate and gracile nuclei, and the ventral median fissure of the spinal cord. As vasopressin binding sites and estrogen receptors have also been shown to be expressed transiently in the laboratory rat facial motor nucleus, the physiological and developmental significance of transient binding site expression remains to be elucidated.

S-100β has a neuronal localisation in the rat hindbrain revealed by an antigen retrieval method

The localisation of S-100 in mammalian CNS neurons has been under debate for more than two decades. We address the question with two polyclonal and two new monoclonal antibodies. The specificity and the distribution in rat brain is based on an antigen retrieval method. We present evidence that aldehyde fixatives mask S-100β in neurons, and that the immunoreactivity is retrieved after trypsinisation. Neuronal S-100β is also detected in unfixed and ethanol fixed sections. The neuronal immunoreactivity is partly solubilised from unfixed tissue sections with 2.5 mM EDTA and is completely extracted with 2.5 mM EDTA and 1% Triton X-100. Most of the glial S-100β is washed out from unfixed tissue sections with saline. S-100β has distinct distribution in neurons of the hindbrain, i.e., the brainstem and cerebellum, but is not observed in the forebrain. One of the monoclonal antibodies immunostained neither neurons nor glia when it had been absorbed with S-100 crosslinked to nitrocellulose membranes. The distribution of neuronal S-100β differed from that of other neuronal calcium binding proteins, such as calbindin and parvalbumin. It was confined mainly to cholinergic neurons of the hindbrain. The presence of S-100β in distinct neuronal populations may indicate neurotrophic effects of S-100β. The notion is supported by the capability of S-100 to cause neurite outgrowth in vitro.

S-100 beta immunoreactivity in neurones of the rat peripheral sensory ganglia.

S-100 beta, which is capable of exerting neurotrophic effects on cultured neurones and promoting the survival of motor neurones in vivo, has recently been found in distinct neurones of the rat hindbrain. Here we report that S-100 beta, as well as being present in satellite and Schwann cells, is also present in neurones of sensory ganglia (dorsal root ganglion, trigeminal, petrosal, jugular and nodose ganglia) but absent from neurones of the superior cervical ganglion. In the sensory ganglia, many neurones were immunoreactive, while the staining intensity varied among the neurones. Neuronal S-100 beta appeared in developing rats as early as postnatal day 1. No immunoreactive neurones were observed in the superior cervical ganglion during development. The results are suggestive of selective neurotrophic effects of S-100 beta.

Chemorepulsion of developing motor axons by the floor plate

In the developing nervous system, motor axons grow away from the ventral midline floor plate, suggesting that the latter might be a source of repulsive axonal guidance cues. In donor to host transplantation experiments, ectopic pieces of floor plate were positioned between chick hindbrain motor neurons and their exit points. Immunohistochemistry and retrograde axonal labeling techniques demonstrated that motor axons diverted from their normal pathways to avoid grafted floor plate, often traversing abnormally long circuitous trajectories to reach exit points. When ventral explants of rat hindbrain and spinal cord were cocultured at a distance from floor plate explants within collagen gel matrices, the outgrowth of motor axons was dramatically reduced from explant borders that faced the floor plate. Thus, the floor plate secretes diffusible repulsive cues in vitro that may exclude motor axons from the midline during development.

Cellular expression of glycine transporter 2 messenger RNA exclusively in rat hindbrain and spinal cord

High-affinity transporters mediate the removal of released neurotransmitters from synapses, thereby terminating their synaptic action. A novel glycine transporter has recently been cloned from a rat brain complementary DNA library. In this study we examined, by means of in situ hybridization with 35S-labelled oligodeoxynucleotide probes, the distribution of messenger RNAs encoding glycine transporter 2 in the rat CNS. Moreover, adjacent series of sections were labelled with [3H]strychnine to reveal the regional distribution of strychnine-sensitive glycine receptors. A very discrete pattern of distribution of the transcripts was found exclusively at the level of the brainstem/cerebellum and spinal cord. In the cerebellum, Golgi cells in the granule cell layer as well as a subpopulation of neurons in the interposed nuclei were consistently labelled. In the brainstem, where the bulk of the labelling was concentrated, several nuclei showed a high level of transcript expression, including the superior olivary complex, nucleus of the trapezoid body and the ventral nucleus of the lateral lemniscus. In the spinal cord, many neurons throughout all layers were labelled, including putative Renshaw cells and a few large neurons at the border of layers 7 and 9. No labelled cells were detected at the levels of the fore- and midbrain. The distribution of glycine transporter 2 messenger RNA-containing cell bodies was very different to that of other glycine transporter messenger RNAs (glycine transporter 1a and glycine transporter 1b), but similar to that of known glycine-immunoreactive neurons and correlated very well with that of strychnine-sensitive glycine receptors in most CNS regions except cerebellum. Our results show that glycine transporter 2 (but not glycine transporter 1) in the brainstem, spinal cord and cerebellum is probably involved in the reuptake of glycine from synapses containing classical strychnine-sensitive glycine receptors. Our findings also suggest that glycine acts as a neurotransmitter in cerebellar Golgi neurons. Whether the synaptic concentration of glycine, as co-agonist at NMDA receptors, is regulated (if at all) by transaminase activity or by a glycine transporter (GLYT1a?) distinct from that described here is not yet known.

Labelling of 5-HT 3 receptor recognition sites in the rat brain using the agonist radioligand [ 3H]meta-chlorophenylbiguanide

The binding of the tritiated derivative of the 5-HT 3 receptor agonist meta-chlorophenylbiguanide ([ 3H]mCPBG) to rat cortical homogenates and whole rat brain sections was assessed in an attempt to further investigate the binding of agonists to the 5-HT 3 receptor. In crude homogenates of rat cortex, no reproducible specific [ 3H]mCPBG (1.0 nM) binding (defined by either 10 μM granisetron, 100 μM 5-HT or 100 nM ‘cold’ mCPBG) was detected. Using autoradiographic techniques, in rat hindbrain sections, [ 3H]mCPBG (1.0 nM) labelled a differential distribution of specific binding sites (defined by the inclusion of granisetron, 1.0 μM). Specific binding was only detected within the dorsal vagal complex (nucleus tractus solitarius, area postrema and dorsal motor nucleus of the vagus nerve). An identical distribution of specific binding was detected in adjacent sections incubated with the selective 5-HT 3 receptor radioligand, [ 3H](S)-zacopride (0.5 nM; non-specific binding defined by the inclusion of granisetron, 1.0 μM). No reproducible specific [ 3H]mCPBG (1.0 nM) binding (defined by the inclusion of granisetron, 1.0 μM) was detected within the rat forebrain. In contrast, [ 3Hl(S)-zacopride (0.5 nM) labelled specific sites (defined by the inclusion of granisetron, 1.0 μM) in some limbic brain structures (e.g. cerebral cortex, hippocampus, amygdala). These studies indicate that [ 3H]mCPBG labels the 5-HT 3 receptor in rat brain tissue. However, the relatively high level of non-specific binding associated with this radioligand appears to mask the specific binding in regions which do not express relatively high densities of the 5-HT 3 receptor.

Central effects of endothelin on baroreflex of spontaneously hypertensive rats

To study the contribution made by central endothelin to cardiovascular regulation in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls. Central endothelin binding was measured with receptor autoradiography. The baroreceptor heart rate reflex was measured by sigmoidal curve-fitting of the mean arterial pressure and heart rate responses evoked by alternating intravenous injections of nitroprusside or phenylephrine. The baroreflex gain was derived as a function of the heart rate range and the curvature coefficient. Autoradiographic experiments with [125I]-endothelin-1 showed low to moderate binding in various medullary nuclei involved in cardiovascular regulation, such as the nucleus tractus solitarius and the ventrolateral medulla. A moderate binding density was found in regions such as the hypoglossal nucleus and the spinal trigeminal nucleus, whereas a high binding density was observed in the molecular layer of the cerebellum. The binding density was significantly lower in the ventrolateral medulla of SHR than in that of WKY rats, but there were no differences in other medullary regions. Compared with WKY rats, the SHR had higher mean arterial pressures and heart rates but tended to have a reduced baroreceptor heart rate reflex gain. This latter change was entirely attributed to a significantly lower heart rate range, caused by an elevated lower heart rate plateau in SHR. The intracisternal injection of endothelin-1 at 25 pmol/kg did not influence the resting mean arterial pressure or heart rate, but it caused a significant increase in baroreflex gain, in both SHR and WKY rats. The extent of the effect was similar in the two strains and was attributed to a significant increase in the curvature coefficient of the sigmoidal baroreflex curve. Consequently, the range over which blood pressure changes evoked reflex changes in the heart rate was reduced by endothelin-1 treatment in both SHR and WKY rats. The heart rate range was not affected and remained different between SHR and WKY rats after the endothelin-1 injection. The intracisternal injection of endothelin-3 at 25 pmol/kg, but not at 2.5 pmol/kg, had effects similar to those of endothelin-1 on the baroreflex. These results show that binding sites for endothelin-1 are present in various regions of the hindbrain of SHR and WKY rats and that central administration of endothelin-1 sensitizes the baroreceptor heart rate reflex. However, this latter effect is similar in SHR and WKY rats and is mediated by a mechanism which is distinct from that underlying the difference in reflex sensitivity between these strains.

Immunohistochemical localization of calretinin in the rat hindbrain

The localization of calretinin in the rat hindbrain was examined immunohistochemically with antiserum against calretinin purified from the guinea pig brain. Calretinin immunoreactivity was found within neuronal elements. The distribution of calretinin-immunoreactive cell bodies and fibers is presented in schematic drawings and summarized in a table. Major calretinin-immunoreactive neurons were found in the lateral and medial geniculate nuclei, substantia nigra, ventral tegmental area, interpeduncular nucleus, periaqueductal gray, mesencephalic trigeminal nucleus, superior and inferior colliculi, pontine nuclei, parabrachial nucleus, dorsal and laterodorsal tegmental nuclei, cochlear nuclei, vestibular nuclei, medullary reticular nuclei, nucleus of the solitary tract, area postrema, substantia gelatinosa of the spinal trigeminal nucleus, and cerebellum. These results show that distinct calretinin-immunoreactive neurons are widely distributed in the rat hindbrain.

Expression of gap junction genes during postnatal neural development.

The timing of appearance of mRNAs encoding gap junction proteins was examined during development of the rat and mouse brain. Complementary DNAs (cDNAs) specific for the mRNA for the liver-type gap junction protein, connexin32, and the heart-type gap junction protein, connexin43, were used to probe Northern blots of total RNA isolated from the forebrain and hindbrain of mice and rats at various times before and after birth. Prior to postnatal day 10, connexin32 mRNA is detectable only at low levels. By postnatal days 10 to 16, a sharp increase occurs in the level of this mRNA. This increase is detectable first in the hindbrain, and subsequently in the forebrain. In contrast, connexin43 mRNA is readily detectable at birth, and the level of this mRNA also increases during subsequent development. The developmental appearance of the gap junction proteins, connexin32 and connexin43, was similar to that of their respective mRNAs. These results indicate that the genes encoding connexin32 and connexin43 are differentially expressed during neural development.

Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat

Previous studies have demonstrated that insulin receptors are widely distributed throughout areas of the forebrain in the adult rat that are involved in modulating neuroendocrine functions and feeding behaviour. In addition, a recent investigation showed that there is a good correlation between the presence of the insulin receptor and phosphotyrosine-containing proteins in these regions, indicating a possible functional activity of insulin receptors in vivo. It is unknown whether neural connections between specific brainstem nuclei to forebrain regions may also be under direct regulation of insulin or related factors. In order to test this possibility, the distribution of insulin receptors and phosphotyrosine was mapped throughout the hindbrain of the adult rat by immunocytochemistry, using specific antibodies against the β -subunit of the insulin receptor as well as against phosphotyrosine. Both markers showed a high degree of overlap throughout numerous distinct anatomical regions of the hindbrain. In the mesencephalon, insulin receptor and phosphotyrosine-positive neurons were found in the precommissural nucleus, the lateral and dorsal part of the central gray, the mammillary bodies and the interpeduncular nucleus. In addition, immunoreactivity was found in the subependymal layer around the aqueduct along fibres and nerve cells possibly contacting the cerebrospinal fluid. In the pons and medulla, dense immunoreactivity was seen in the lateral superior olive, nucleus of the solitary tract, spinal trigeminal nucleus and nucleus ambiguus. Scattered cells were found in the pontine and vestibular nuclei, as well as in the reticular formation. The cerebellum contained moderately dense immunoreactivity in the granule cell and molecular cell layer of the cortex, as well as in the deep cerebellar nuclei. Dense immunoreactivity was also observed in circumventricular organs, such as subcommissural organ and area postrema. Ultrastructural analysis of the area postrema demonstrated a distinct localization of insulin receptor immunoreactivity within neuronal perikarya, whereas phosphotyrosine immunoreactivity was homogeneously distributed throughout the cytosol. Although the functional significance of insulin receptors in numerous brainstem nuclei is not understood, the excellent correlation with phosphotyrosine-containing proteins suggests that insulin receptors may be active in these regions in vivo and may be involved in several mechanisms, such as regulation of central autonomie activity and/or communication between peripheral endocrine and central nervous system via circumventricular organs.

Differential effect of μ, δ, and κ ligands on G protein α subunits in cultured brain cells

Rat and guinea pig fetal brain cell cultures and immunoblotting techniques were used to study the effect of receptor selective opioids on the level of the membrane-bound alpha i and alpha o GTP binding protein subunits. Incubation of rat hindbrain cultures with the mu selective peptide DAGO decreased the amount of both alpha proteins. The reduction observed was equivalent to 36% in alpha o and 41% in alpha i. On the other hand, incubation of rat forebrain cultures with this peptide had an opposite effect, increasing the alpha o and alpha i levels by 66% and 68%, respectively. This differential effect of the peptide on the G proteins at the two brain areas may reflect the selective interaction at the receptor level; DAGO induced a fast and effective receptor down-regulation (50% decrease in Bmax) in hindbrain but not in forebrain cultures. Moreover, delta and mu selective ligands differed in their effect, as indicated by the finding that the delta selective peptide DPDPE increased the amount of both alpha proteins in hindbrain cultures by 40%. Similar experiments conducted with guinea pig brain aggregate cultures indicated that the kappa selective agonist U50,488 decreased the amount of the membrane bound alpha i protein subunit by 56%. The results thus indicate that opioid agonists, interacting selectively with the three types of opioid receptors, induce a complex repertoire of changes in the immunoreactive levels of the membrane-bound alpha GTP binding protein subunits in various CNS structures.

Differential Distribution of Immunoreactive Angiotensinogen in the Hind-Brain and Spinal Cord of Neonatal and Adult Rats

The present communication deals with the cytochemical localization of angiotensinogen (ATG) immunoactivity in the hind-brain and spinal cord of neonatal (1-day-old) and adult (3-month-old pregnant) female rats. In the neonatal hind-brain, the immunoreactive cells were more numerous than in that of adult rats. In the adult rat hind-brain, the number of ATG-positive cells was quite limited in each nucleus. Further, in some nuclei, only neurons or neuroglia were positive, while in others the immunoactivity was observed in both the components. Spinal cords of neonatal rats showed a few undifferentiated ATG-positive cells in the grey matter. Contrary to this, the spinal cord of adult animals contained numerous immunoreactive glial cells in the grey matter, fasciculus cuneatus and fasciculus gracilis. Immunoactivity in the neurons was localized in the Nissl bodies.

Immunohistochemical localisation of a gastrin-releasing peptide-like material in area postrema, nucleus of the solitary tract and vagal motor nucleus in the brainstem of rat

The presence of an endogenous gastrin-releasing peptide (GRP)-like peptide in the hindbrain of rat was demonstrated immunohistochemically using antisera directed against the N-terminus and C-terminus of GRP. N-terminal and C-terminal-like immunoreactive material were distributed throughout the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus (DMV) and tractus solitarius (TS), as well as in area postrema (AP) and substantia gelatinosa separating AP from NTS. Positive immunostaining was localised to a dense network of nerve fibres which project longitudinally along the neuraxis. Immunolabelled cell bodies were observed rostral to the obex, principally in the mediolateral subnucleus of NTS. These immunopositive neurones project their axons caudally and longitudinally towards the commissural subnucleus of the NTS. Immunolabelled cell bodies also were found in AP; they projected their axons caudally and ventrally towards NTS. Positive immunostaining was blocked by pre-adsorbing antisera with either GRP (1 nmol/ml) or bombesin (3 nmol/ml), but was unaffected by substance P (30 nmol/ml) and spared by capsaicin pretreatments which deplete sensory nerves of their peptide content. The results indicate that NTS neurons containing a GRP-like peptide connect the rostral and caudal regions of the dorsal vagal complex by way of longitudinal nerve tracts descending NTS and TS. Some neurons in AP also contain a GRP-like peptide and appear to connect with the dorsal vagal complex.

Vesicle-mediated delivery of membrane to growth cones during neuritogenesis in embryonic rat primary neuronal cultures.

Single cell suspensions from 15-day embryonic rat hindbrain plated on collagen formed large clumps by day 1 in culture. Neurite outgrowth was visible within 2 days. By day 14, morphological synapses were observed in nearly all instances of contact of a neurite ending with another cell. At day 3 in culture, the Golgi apparatus consisted of relatively few, broad lamellae. By contrast, at day 7 in culture this organelle consisted of tightly packed lamellar stacks with a considerable increase in vesicles budding from lamellae. Electron-lucent vesicles, ranging in size from 60 to 180 nm, similar to those generated by the Golgi apparatus were noted in neurite shafts and growth cones, with fusion of these vesicles virtually exclusively at the growth cone leading edge. Monensin resulted in the loss of these vesicles in cell somata and neuritic profiles. The electron-dense marker horseradish peroxidase was not incorporated into these vesicles following its addition to the culture medium, indicating that the vesicles were exocytotic. The number of total vesicles increased during the first 7 days of neurite outgrowth with no further increase up to day 14. This increase was due entirely to vesicles not labeled with the impermeable electron-dense stain ruthenium red, indicating that this increase represents actual vesicular elements and not increased surface convolutions. These data suggest that the 60- to 180-nm electron lucent vesicles are derived from the Golgi apparatus and, by fusion with the growth cone plasmalemma, provide new membrane required for neuritic outgrowth and maintenance.

The taste system encodes stimulus toxicity

Attempts to define the organization of the taste system in terms of the physical characteristics of stimuli have been largely unsuccessuful. We recorded taste-evoked neural activity in the rat's hindbrain and determined that stimuli could be effectively organized along a physiological dimension which corresponds to stimulus toxicity. Taste is a visceral sense that mediates between the external and internal chemical environments. Its responsiveness to a wide range of chemicals and its organization along a dimension which promotes the organism's physiological welfare ideally suit it to that purpose.

Fore- and hindbrain mediation of gastric hypoacidity after intracerebral bombesin.

Three experiments assessed possible roles of the rat forebrain and hindbrain in the mediation of the gastric hypoacidity induced by intracerebrally administered bombesin. Experiment 1 found that bilateral electrolytic destruction of the paraventricular nucleus of the hypothalamus, which contains numerous bombesin receptors and which is immediately adjacent to the ventricular system, did not alter gastric hypoacidity after intracisternally administered bombesin (500 ng). Experiment 2, done in rats with complete coronal transections of the brain at the superior colliculus, showed that no forebrain structure is absolutely required for intracisternally administered bombesin (0, 30, 100, or 300 ng) to inhibit gastric acid secretion. Experiment 3 determined that bombesin infusions (500 ng) restricted to either the forebrain or the hindbrain by aqueductal plugs are equally effective in inhibiting acid secretion. In sum, these data suggest that both forebrain and hindbrain mechanisms exist that can mediate the inhibition of acid secretion by intracranially administered bombesin; the hindbrain mechanism does not require the forebrain to produce its effect; and lesions of forebrain structures cannot be expected to block bombesin-induced hypoacidity if bombesin reaches the hindbrain.

Blood glucose level affects perceived sweetness intensity in rats

Electrophysiological data indicate that hyperglycemia is associated with decreased neural taste responsiveness to 1.0 M glucose, but not to 0.01 M quinine HCl, in the rat's hindbrain. The present behavioral experiment was conducted to determine whether this suppression of neural activity is manifested in a reduced intensity perception to glucose, but not quinine. Each rat learned to avoid 1.0 M glucose through development of a conditioned taste aversion. Perceived intensity was then measured in control and in hyperglycemic rats by the extent to which they generalized to each test concentration of glucose. Experimental subjects treated moderate glucose concentrations (0.6–2.0 M) as if their intensity perceptions were reduced by 47%. This is consistent with the mean reduction of 43% in taste-evoked neural activity associated with hyperglycemia. A corresponding experiment gave no indication of a change in intensity perception to quinine as a function of hyperglycemia, again in accord with earlier electrophysiological results. We conclude that nutritional state may selectively affect gustatory sensitivity in the rat.

Different effects of long-term haloperidol administration on GABAA and benzodiazepine receptors in various parts of the brain

The data described in this paper are evidence that long-term administration of haloperidol has an opposite effect on the density of GABA/sub A/ and benzodiazepine receptors in the fore- and hindbrain. These changes are reflected at the molecular level as reversal of behavioral effect of the GABA/sub A/ agonist muscimol and the benzodiazepine agonist Ro15-1788. By means of parallel behavioral tests, binding of /sup 3/H-muscimol in the fore- and hindbrain of rats was investigated in experiments in vitro. /sup 3/H-flunitrazepam binding experiments were carried out in vivo on mice. Parallel with reversal of the behavioral effects of muscimol and Ro15-1788, the number of binding sites both for /sup 3/H-muscimol and for /sup 3/H-flunitrazepam in the forebrain was reduced; in the hindbrain the opposite process took place.