Jean-Jacques Vanderhaeghen

Reduced cholecystokinin immunoreactivity in the cerebrospinal fluid of patients with psychiatric disorders.

The close relationship of cholecystokinin peptides with some of the dopamine pathways and the limbic system suggests a putative role for these peptides in the pathophysiology of neuropsychiatric disorders such as Parkinsons disease, manic-depression and schizophrenia. By use of radioimmunoassay, we report a significant decrease in cholecystokinin-immunoreactivity in the cerebrospinal fluid of patients with bipolar manic-depression and untreated schizophrenia in comparison to control subjects.

Immunohistochemical evidence for cholecystokinin-like peptides in neuronal cell bodies of the rat spinal cord.

SummaryCholecystokinin-like immunoreactivity has been demonstrated by radioimmunoassay and immunocytochemistry in the spinal cord of various mammals, in particular in nerve fibers of the superficial layers of the posterior column, but had not been detected in neuronal cell bodies. We report immunohistochemical evidence for the presence of a group of cholecystokinincontaining neuronal cell bodies in the lumbar spinal cord of the rat. This group of cells is only visualized after direct injection of colchicine into the spinal cord and is located near the central canal in the intermedio-medial nucleus of area X of Rexed.

A benzodiazepine antagonist, Ro 15-1788, can block the phase-shifting effects of triazolam on the mammalian circadian clock

A single injection of the short acting benzodiazepine, triazolam, can induce permanent phase advances as well as phase delays in the onset of the circadian rhythm of wheel running behavior in hamsters free-running under constant environmental conditions. If the phase shifting effects of triazolam on the circadian system are mediated through the benzodiazepine-GABA receptor complex, then it should be possible to block these effects with RO 15-1788, a selective benzodiazepine antagonist, which acts at the benzodiazepine-GABA receptor level. To test this hypothesis, hamsters free running in constant light received an intraperitoneal injection of various doses of Ro 15-1788 15 min before a single i.p. injection of 0.5 mg of triazolam. This dose of triazolam is known to induce maximal phase shifts in the circadian rhythm of wheel running behavior in hamster. Treatment with Ro 15-1788 totally blocked both the phase advancing and phase delaying effects of triazolam, while the administration of Ro 15-1788 alone did not phase shift the activity rhythm. These results support the hypothesis that the phase shifting effects of triazolam are mediated through the benzodiazepine-GABA receptor complex. The absence of any phase shifting effects of Ro 15-1788 when delivered alone suggests that Ro 15-1788 has no partial agonist properties in this experimental paradigm.

Levels of gastrin-cholecystokinin-like immunoreactivity in the brains of genetically obese and non-obese rats.

Levels of gastrin-cholecystokinin-like immunoreactivity were measured in three brain regions (cortex, diencephalon, brainstem) and the pituitary gland in groups of genetically obese Zucker rats and their non-obese littermates. The obese animals had significantly increased body weights and significantly lowered brain weights. However, levels of gastrin-cholecystokinin-like immunoreactivity were not different between the two groups in any of the regions measured. These results contrast with a recent report [11] in which ob/ob mice were found to have decreased levels of cholecystokinin in their brains.

Transient neurotensin high-affinity binding sites in the human inferior olive during development

High-affinity binding sites for neurotensin 1-13 are found transiently in the human inferior olive during development. An in vitro membrane binding assay demonstrates, in the fetus, a specific binding to a single population of sites (Kd = 561 pM) which are levocabastine-insensitive and possess a Bmax value of 71 fmol/mg protein. No specific binding is present in the adult. Film radioautography shows, in fetuses of 15 weeks, a labelling in the whole inferior olive. At 25 weeks and at 33 weeks, the labelling is concentrated in the ventral lamella of the principal olive and in the caudal accessory olives. At birth and until 1 month of age, the labelling is still detected in the medial part of the ventral lamella of the principal olive. The labelling disappears after 3 months of age, is absent at 4 and 6 months and remains absent in the adults from 55 to 81 years of age. At the light microscopic level, the labelling is located mostly outside olivary neuronal cell bodies suggesting its presence on afferent nerve fibers. This ontogeny and localization of the binding sites in the inferior olive is quite different from that of the neurotensin 1-13 nerve terminals.

Homolateral cerebrocortical changes in neuropeptide and receptor expression after minimal cortical infarction

A cortical infarct of 2 mm diameter was obtained in the parietal cortex after a craniotomy, disruption of the dura mater and topical application of 3 M KCl. It has been shown previously that the presence of a small cortical infarct induces an increase in immediate early gene messenger RNA expression followed by an increase in neuropeptide and glutamic acid decarboxylase messenger RNA expression. Glutamate, acting at N-methyl-D-aspartate receptors, is held responsible for these changes, since they are blocked by pretreatment with dizocilpine. In the present study, we have analysed the consequences of the dramatic changes in messenger RNA expression on the level of immediate early gene products c-fos and zif 268, and on that of neuropeptides by using immunohistochemistry. After just 1 h, an increase in c-fos- and zif 268-like immunoreactivity is observed in the entire cortical hemisphere homolateral to the infarct, and is no longer detected after 6 h. An increase in cholecystokinin octapeptide-, substance P-, neuropeptide Y- and somatostatin-like immunoreactivity is observed in the entire cortical hemisphere homolateral to the infarct after three days, and is no longer detected after 30 days. To investigate if these dramatic increases in neuropeptide immunoreactivities may have functional consequences, we studied the level of cholecystokinin receptors by autoradiographic binding using [125I]cholecystokinin-8S and in situ hybridization for the detection of cholecystokinin-b receptor messenger RNA. A decrease in cholecystokinin binding sites and cholecystokinin-b receptor messenger RNA is observed in the entire cortical hemisphere homolateral to the infarct after three days, and is no longer detected after nine days. This study shows that a topical stimulation has diffuse effects, reaching regions far from the site of the lesion, and some of them are still strongly present after nine days. The increase in neuropeptide messenger RNAs is followed by an increase in the protein products of these genes, which may modify the neurotransmission. As a corollary to this, a decrease in cholecystokinin binding sites occurs. This may have further consequences on signal transduction pathways. This decrease in cholecystokinin binding sites is associated with a decrease in the cholecystokinin-b receptor messenger RNA, and this is the first example of a decrease in messenger RNA levels in this experimental model.

Cholecystokinin distribution in the human striatum and related subcortical structures

The distribution of cholecystokinin immunoreactive nerve cell bodies and processes is reported in the human striatum and adjacent structures such as the claustrum, the pallidum, the bed nucleus of the stria terminalis and the substantia innominata. Cholecystokinin-positive terminals are present in the striatum where they are arranged in a patchy pattern. Cholecystokinin-positive somata are observed in the claustrum and in the bed nucleus of the stria terminalis but not in the striatum, the pallidum or the substantia innominata. Dense networks of cholecystokinin-positive woolly fibres are present in the bed nucleus of the stria terminalis and the substantia innominata. These results suggested that cholecystokinin is involved in the compartmental organization of the human striatum. This compartmentalization has functional and pathological implications. Involvement of the cholecystokinin system in some basal ganglia diseases is therefore expected. Presence of neuronal cholecystokinin in the accumbens nucleus, bed nucleus of the stria terminalis and substantia innominata also suggests that this peptide may interact at different levels in the human limbic system.

Effects of chronic uridine treatment on regional neuropeptide and tyrosine hydroxylase-like immunoreactivities in the brain of 12 month-old male rats

Uridine was administered in the drinking water (0.5 mg/ml) in adult 6 month-old rats for 6 months. The mean daily dose of uridine was 12.5 mg/rat. The effects of this treatment on tyrosine hydroxylase, galanin, somatostatin, neuropeptide Y and cholecystokinin-like immunoreactivities were studied by means of semiquantitative immunocytochemistry using the peroxidase-antiperoxidase procedure in combination with image analysis. A decrease of somatostatin, cholecystokinin and galanin-like immunoreactivities in nerve terminals was observed in various brain areas of 12 month-old animals compared with 3 month-old animals, while the levels of tyrosine hydroxylase-like immunoreactivity were unchanged. Uridine-treated animals showed a decrease of galanin, neuropeptide Y and cholecystokinin-like immunoreactivities in nerve terminals of some diencephalic areas and an increase of cholecystokinin-like immunoreactivity in nerve terminals of most of the telencephalic brain areas in comparison with vehicle treated animals of the same age. It is suggested that the pyrimidine nucleoside uridine can affect the synthesis and/or degradation of mRNAs involved in the synthesis of neuropeptides via direct nuclear actions and/or indirect actions involving effects on receptor activated phosphoinositide metabolism. Uridine offers a new way to modulate central peptide synapses.

Synenkephalin in bovine and human spinal cord.

SummarySynenkephalin, which comprises 70 residues at the aminoterminal of proenkephalin, was studied with immunocytochemical methods in the human and bovine spinal cord. Immunoreactive fibers had the same general distribution as methionine-enkephalin, but not as leucine-enkephalin fibers. They were found in all spinal layers and were most numerous in lamina II (outer zone) and V–VI (lateral portion). Synenkephalin immunoreactivity was overall less dense than that of the enkephalins. These results suggest that proenkephalin is the precursor protein also in enkephalinergic neurons of the human spinal cord.

Transient neurotensin in the cat inferior olive during development.

By immunohistochemistry, a large number of neurotensin immunoreactive nerve terminals are found in the kitten inferior olive of the medulla oblongata. They are present in the dorsal lamella of the principal olive, in the ventrolateral outgrowth and in the medial part of the caudal dorsal accessory olive. They are absent in the medial accessory olive. They disappear in the adult cat. Neurotensin immunoreactivity is absent in the developing rat inferior olive. This localization in the cat suggests a neuronal origin in the mesencephalon, mainly in the red nucleus. These results confirm our recent report on a transient large neurotensinergic innervation of the human developing principal olive.