Increase in nigral type II benzodiazepine recognition sites following striatonigral denervation

doi:10.1016/0014-2999(85)90507-2

European Journal of Pharmacology

Volume 112, Issue 2, 7 June 1985, Pages 265-267

https://doi.org/10.1016/0014-2999(85)90507-2 Get rights and content

Abstract

In the rat substantia nigra Type II benzodiazepine recognition sites (measured as the portion of [³H]flunitrazepam binding which remain after the addition of 2 × 10⁻⁷ M Cl 218872) represent 50% of the total benzodiazepine recognition sites. The density of Type II sites was increased by 35% following the degeneration of the striatonigral afferents induced by the intrastriatal injection of kainic acid. On the other hand the same lesion failed to change the density of the remaining nigral Type I sites. The results indicate that denervation induces supersensitivity to nigral Type II benzodiazepine recognition sites.

References (10)

G. Biggio et al.
Denervation supersensitivity for benzodiazepine receptors in the rat substantia nigra
Brain Res.
(1981)
C.A. Klepner et al.
Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors
Pharmacol. Biochem. Behav.
(1979)
O.H. Lowry et al.
Protein measurement with the folin phenol reagent
J. Biol. Chem.
(1951)
R.F. Squires et al.
Some properties of brains specific benzodiazepine receptors: new evidence for multiple receptors
Pharmacol. Biochem. Behav.
(1979)
C. Braestrup et al.
³H-propyl-β-carboline-3-carboxylate as a selective radioligand for the BZI benzodiazepine receptor subclass
J. Neurochem.
(1981)

There are more references available in the full text version of this article.

Cited by (8)

Plasticity-related binding of GABA and muscarinic receptor sites in piriform cortex of rat: An autoradiographic study
1989, Experimental Neurology
This study has used the recently developed in vitro quantitative autoradiographic technique to examine the effects of olfactory bulb (OB) removal on receptor-binding sites in the deafferented piriform cortex (PC) of the rat. The γ-aminobutyric acid-benzodiazepine receptor (GABA-BZR)- and muscarinic cholinergic receptor (MChR)-binding sites in layer I of PC were localized using [³H]flunitrazepam and [³H]quinuclidinyl benzilate as ligands, respectively. From the resultant autoradiograms the optical densities were measured using a Drexel-DUMAS image analysis system. The densities of BZR and MChR-binding sites were markedly increased in the PC ipsilateral to the lesion as compared to the contralateral side in those subjects that were operated in adulthood (Postnatal Day 100, PN 100). Comparisons between the unoperated and PN 100 operated animals also showed significant increases in the deafferented PC. In the animals operated on the day of birth (PN 0) no significant differences were seen between the operated and the contralateral PC. The difference between the PN 0 deafferented PC and the unoperated controls shows a slight decrease in BZR density in the former group; however, in case of the MChR there is a slight increase on the side of the lesion. These results demonstrate that deafferentation of PC by OB removal appears to modulate both the BZR-binding sites that are coupled with the GABA-A receptor complex and the MChR-binding sites. The results also suggest the possibility of a role for these neurotransmitter receptor-binding sites in plasticity following deafferentation.
Cerebellar benzodiazepine receptors: cellular localization and consequences of neurological mutations in mice
1988, Brain Research
The distribution of cerebellar [³H]flunitrazepam binding sites was studied autoradiographically in Purkinje cell degeneration (pcd/pcd), weaver (wv/wv), staggerer (sg/sg) and reeler (rl/rl) mutant mice. In the normal 78-day-old C57BL/6J mouse cerebellum, the highest concentration of [³H]flunitrazepam binding sites was observed over the molecular layer. Intermediate grain density was present over the Purkinje cell layer and intermediate to high density over the deep cerebellar nuclei. Low labeling was observed over the granule cell layer. Negligible concentrations of binding sites were seen in the white matter. In 45–49-day-old Purkinje cell degeneration mutants, where essentially all Purkinje cells have disappeared by day 45, there was a small decrease in grain density over the cerebellar cortex. Concomitantly, a substantial increase in grain density was observed over the deep cerebellar nuclei of the pcd/pcd mutants when compared to littermate controls. A significant increase in [³H]flunitrazepam labeling was observed over the cerebellar cortex of 81–86-day-old wv/wv mutants; this was most pronounced in the vermis where the granule cell loss was greatest. Over the hemispheres, where fewer granule cells degenerate, a lower density of binding sites was seen. Grain density over the wv/wv deep cerebellar nuclei was comparable to that of littermates. Substantially lower [³H]flunitrazepam labeling was detected over the cerebellar cortex of 25–27-day-old sg/sg mutants in which the number of granule. Purkinje and Golgi cells is greatly reduced; the labeling over the deep nuclei, however, was significantly increased. In 27–29-day-old rl/rl mutant cerebella, where all classes of cells are malpositioned, labeling density over all areas of the cerebellar cortex, including the Purkinje cell masses. was increased. Our autoradiographic data suggest that a proportion of cerebellar cortical benzodiazepine receptors are associated with Purkinje cells; we propose that the remainder of the receptors are localized on Golgi cells, while granule cells are devoid of receptors. In the deep cerebellar nuclei, the observed increase in benzodiazepine receptors in the pcd/pcd and sg/sg mutants may be a manifestation of denervation supersensitivity subsequent to the loss of innervation by Purkinje cell axon terminals. The finding of a high receptor density in the Purkinje cell masses of the rl/rl mutant, where Purkinje cells are devoid of afferent basket cell input, suggests that benzodiazepine receptors are expressed and maintained in the absence of a full complement of GABAergic afferents.
Functional coupling of γ-aminobutyric acid (GABA)<inf>a</inf> and benzodiazepine type II receptors: Analysis using purified GABA/benzodiazepine receptor complex from bovine cerebral cortex
1987, Neuropharmacology
Possible functional coupling between γ-aminobutyric acid (GABA) and benzodiazepine receptors was examined using a purified GABA/benzodiazepine receptor complex. The purified receptor complex was obtained by 1012-S-acetamide adipic hydrazide Sepharose 4B affinity column chromatography, following the solubilization of synaptic membrane from the bovine cerebral cortex with Nonidet P-40. The binding of [³H]GABA to the purified GABA receptor was displaced significantly by muscimol and bicuculline, GABA_a receptor agonists and antagonists, respectively, but not by baclofen, a GABA_b receptor agonist. On the other hand, the binding of [³H]flunitrazepam to the purified benzodiazepine receptor was found to be displaced by μM ranges of CL 218,872, which is known to be sensitive to the benzodiazepine type II recetor. Furthermore, it was found that the binding of [³H]muscimol to these purified GABA_a receptors was enhanced by benzodiazepines, while the binding of [³H]flunitrazepam to these benzodiazepine type II receptors was increased by GABA receptor agonists. These enhancements by GABA agonists and benzodiazepine agonists were found to be blocked by bicuculline and a benzodiazepine receptor antagonist, Ro 15–1788, respectively. These results strongly suggest that the purified receptor may consist of GABA_a and benzodiazepine type II receptors and possess a functional coupling of these sites, as shown in cerebral synaptic membranes.
Benzodiazepine binding increases in the superficial laminae of the trigeminal subnucleus caudalis following central rhizotomy
1987, Neuroscience Letters
Benzodiazepine (BZ) binding is being studied in the spinal trigeminal nucleus of the cat 3 and 11 days following unilateral retrogasserian rhizotomy using in vitro autoradiography and computer-assisted densitometry. At 3 days following rhizotomy there is an increase in number and decrease in affinity of flunitrazepam binding sites in the superficial laminae of subnucleus caudalis of the spinal trigeminal complex. By 11 days, affinity remains below control values and binding site number shows an insignificant but detectable increase. There is no change in binding site characteristics in deeper laminae at either survival time. The results are discussed in relation to the physiological hyperactivity and synaptic changes which occur following such lesions and to other conditions of deafferentation.
Changes in GABAergic transmission induced by stress, anxiogenic and anxiolytic β-carbolines
1987, Brain Research Bulletin
The cerebral cortex of unstressed (handling-habituated) rats has a higher number of low affinity GABA receptors than stressed (naive) rats. Foot shock stress delivered to unstressed rats decreases the density of cortical low affinity GABA receptors to the level found in the naive animals. The effect of stress on GABA receptors is mimicked by anxiogenic β-carbolines, both after in vitro addition (10⁻⁶ M) to cortical membrane preparations or after the in vivo administration (20 mg/kg IP) to unstressed rats. Vice versa, benzodiazepines or anxiolytic β-carbolines (ZK 93423, 10⁻⁵ M) added to membranes from naive rats increase GABA binding to the level of unstressed rats and remove the decrease in the density of GABA receptors elicited by anxiogenic β-carbolines. Rats chronically treated with the anxiogenic β-carboline, FG 7142 (15 mg/kg IP twice a day for 10 consecutive days) have an enhanced sensitivity to punishment at 5 and 15 days after the last treatment. The behavioural effect is paralleled by a marked decrease in the total number of cortical low affinity GABA receptors. Both biochemical and behavioural effects elicited by chronic FG 7142 are prevented by the concurrent administration of the benzodiazepine antagonist Ro15-1788. These results suggest that (a) anxiolytic β-carbolines, like benzodiazepines, increase the GABAergic transmission, (b) acute and chronic anxiogenic β-carboline administration, like stress, decreases GABAergic transmission. Since all these effects are antagonized by the benzodiazepine receptor blocker Ro15-1788, it is tempting to speculate that stress releases an endogenous ligand for benzodiazepine recognition sites.
The β-carboline ZK 93423 inhibits reticulata neurons: An effect reversed by benzodiazepine antagonists
1987, Life Sciences
A novel β-carboline with benzodiazepine-like properties has recently been synthesized. We compared the effects of the i.v. administration of this drug, ZK 93423, with diazepam on the activity of nigral pars reticulata neurons which are known to be very sensitive to the inhibitory effect produced by GABA-mimetics and benzodiazepines. ZK 93423 (0.05 – 1.0 mg/kg) inhibited reticulata cells in a dose-related manner up to the cessation of their activity. Since the maximal rate-inhibition elicited by diazepam (1.0 mg/kg) was some 55% of baseline, ZK 93423 showed a much greater potency. Moreover, the firing depression by ZK 93423 was prevented and reversed by two benzodiazepine receptor antagonists: Ro15-1788 and ZK 93426. However, the dosage of Ro15-1788 required for these actions was at least five times higher than that for the blockade of the diazepam effect. The results indicate that the β-carboline agonist ZK 93423 decreases the activity of reticulata neurons more effectively than diazepam.

View all citing articles on Scopus

View full text

Short communicationIncrease in nigral type II benzodiazepine recognition sites following striatonigral denervation

Abstract

Brain Res.

Pharmacol. Biochem. Behav.

J. Biol. Chem.

Pharmacol. Biochem. Behav.

3H-propyl-β-carboline-3-carboxylate as a selective radioligand for the BZI benzodiazepine receptor subclass

J. Neurochem.

Short communication
Increase in nigral type II benzodiazepine recognition sites following striatonigral denervation

³H-propyl-β-carboline-3-carboxylate as a selective radioligand for the BZI benzodiazepine receptor subclass