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Biomedical subjects

K W Gee

Publications and source records attributed to K W Gee.

At least 73 records · Page 4Linked to original sources
PubMed1984

Regional distribution of putative vasopressin receptors in rat brain and pituitary by quantitative autoradiography.

Quantitative light microscopic autoradiography was used to map and characterize the distribution of [3H]arginine vasopressin [( 3H]AVP) binding sites in the rat brain. HPLC analysis for possible degradation of AVP during binding indicated that addition of specific peptidase inhibitors prevented metabolism of AVP. Binding sites for [3H]AVP were observed in the hypothalamus and pituitary as well as in brain regions where AVP may act as a neuroregulator. Within the hypothalamus, dense AVP binding sites were seen in the suprachiasmatic, supraoptic, and paraventricular nuclei. High specific binding was also apparent in the median eminence tubero-infundibular region and in the posterior lobe of the pituitary. [3H]AVP labeling at possible neuroregulatory sites was observed in the hippocampus, lateral septum, superficial cortex, cerebellum, nucleus tractus solitarious, adenohypophysis, and spinal cord.

Animals↗
PubMed1984

Benzodiazepine receptor heterogeneity: possible molecular basis and functional significance.

The pharmacological actions of the benzodiazepines (BZs) are thought to be mediated through specific receptor sites in the mammalian central nervous system. Characterization of these receptor sites in the brain has yielded evidence for heterogeneity of BZ receptor sites. Current theories on the molecular basis of the apparent BZ receptor heterogeneity and the possible functional significance of BZ receptor subtypes are presented. Studies of BZ receptor heterogeneity have provided insights into the molecular events that may be responsible for BZ modulation of gamma-aminobutyric-ergic function.

Benzodiazepinones↗
PubMed1983

Comparison of the distribution of convulsant/barbiturate and benzodiazepine receptors using light microscopic autoradiography.

Some convulsant drugs elicit CNS excitation by blocking neuronal activity at GABAergic synapses whereas depressant compounds may result in the enhancement of GABAergic transmission. These effects are thought to involve drug actions at a multireceptor complex involving a benzodiazepine receptor, GABA receptor, picrotoxin receptor and a chloride ionophore. A radiolabeled convulsant, [35S]t-butylbicyclophosphorothionate [( 35S]-TBT) has been developed and used to characterize the binding to the "picrotoxin" or convulsant/barbiturate site. The microscopic distribution of the convulsant/barbiturate sites are reported in this communication, as demonstrated by receptor autoradiography after labeling tissue sections with [35S]-TBT. Comparison of the distribution of these sites with those of the benzodiazepine receptors show a close regional correlation in many areas. The convulsant/barbiturate sites and the benzodiazepine receptors, however, are unevenly distributed in the rat cerebellum and exist in separate lamina.

Animals↗
PubMed1983

Light microscopic autoradiographic visualization of [3H]-arginine vasopressin binding sites in rat brain.

Specific [3H]-arginine vasopressin ([3H]-AVP) binding sites were identified in the rat brain by light microscopic autoradiography. Discrete intrahypothalamic nuclei were densely labelled by [3H]-AVP. High specific binding was observed in the paraventricular and supraoptic nuclei. These binding sites may represent specific receptors for AVP, postulated to exist in the mammalian central nervous system.

Animals↗
PubMed1983

CL 218872 antagonism of diazepam induced loss of righting reflex: evidence for partial agonistic activity at the benzodiazepine receptor.

A recent hypothesis suggests that the "selective anxiolytic" activity of the triazolopyridazine, CL 218872, is a reflection of this compounds high affinity for a benzodiazepine (BZD) receptor subtype. Subsequent to this proposal, the observation was made that CL 218872 does not effectively discriminate BZD receptor subtypes in vitro at physiological temperatures (37 degrees C). Based upon this observation, a selective effect in vivo related to the high affinity of CL 218872 for a BZD receptor subtype appears unlikely. The present study provides evidence for an alternative hypothesis to explain the unique pharmacological properties of CL 218872. The ability of CL 218872 to antagonize diazepam induced loss of righting reflex and enhance the anticonvulsant effect of diazepam in mice suggests that this triazolopyridazine may act as a partial agonist at the BZD receptor. Compared to the pharmacologically active BZDs, the unique actions of CL 218872 may be related to the lower intrinsic activity of this compound.

Animals↗
PubMed1983

Photoaffinity labeling of benzodiazepine receptors in rat brain with flunitrazepam alters the affinity of benzodiazepine receptor agonist but not antagonist binding.

Recently, it was proposed that beta-carbolines interact with a subset of benzodiazepine (BZD) binding sites in mouse brain. This postulate was based upon evidence showing changes in binding properties of the BZD receptor following photoaffinity labeling of membranes with flunitrazepam (FLU). Under conditions in which 80% of specific [3H]diazepam binding was lost in photolabeled membranes, specific [3H]propyl beta-carboline-3-carboxylate [( 3H]PCC) binding was spared. In this study, the binding of the BZD antagonists [3H]PCC, [3H]Ro15 1788 and [3H]CGS 8216 was examined in rat brain membranes following photoaffinity labeling with FLU. No significant changes in the apparent KD and small reductions in the Bmax of 3H antagonist binding were observed. However, in the same membranes, up to 89% of specific [3H]FLU binding was lost. When [3H]PCC (0.05 nM) was used to label the receptors in control and photolabeled membranes, the ability of BZD receptor agonists to inhibit [3H]PCC binding was greatly diminished in the photolabeled membranes. In contrast, the potency of BZD antagonists remained the same in both control and treated membranes. Based upon PCC/[3H]Ro15 1788 competition experiments, the ability of PCC to discriminate between BZD receptor subtypes was unaffected by photoaffinity labeling of cortical membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed1983

Selective anxiolytics: are the actions related to partial "agonist" activity or a preferential affinity for benzodiazepine receptor subtypes?

Both pharmacological and biochemical evidence support the existence of BZ receptor subtypes. Determination of the molecular basis of BZ receptor heterogeneity requires additional research. The physiological significance of BZ receptor subtypes is not currently understood. One hypothesis presented to explain the unique pharmacological effects of CL 218872 suggests that CL 218872 has preferential affinity for a BZ receptor subtype (i.e., type I sites) that mediates the anxiolytic effects of the clinically active BZs. An alternative hypothesis has been proposed to account for these observations and is based upon the possibility that CL 218872 may act as a partial agonist at the BZ receptor. The partial agonist theory is supported by behavioral evidence and the relatively small differences in affinity of the BZ receptor subtypes discriminated by CL 218872 at physiological temperatures. In addition, in vivo binding studies suggest that occupancy of type II BZ receptor subtypes (i.e., those with low affinity for CL 218872) is necessary for CL 218872 to produce minimal anticonflict activity (4). Unlike certain other neurotransmitter systems, it is difficult to correlate the heterogeneous binding properties of BZ receptor ligands with their agonist/antagonist potential at BZ receptor. For example, CL 218872 discriminates BZ receptor subtypes and acts as an agonist at the BZ receptor. Beta-carbolines such as PCC also discriminate receptor subtypes, yet they act as antagonists at the BZ receptor. Compounding the complexity, neither the nature nor the existence of an endogenous ligand is known. So, the designation of agonist or antagonist effects is made on a purely functional basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Effects of haloperidol-induced dopamine receptor supersensitivity on kindled seizure development.

By using kindling by repetitive amygdala stimulation as a model of generalized seizure development in the rat, we have shown that dopamine receptor subsensitivity has been shown to occur in selected brain areas after the development of seizures. In the present study, the influence of initially altered dopamine receptor sensitivity on the development of seizures was examined by inducing receptor supersensitivity through chronic haloperidol injection before amygdaloid kindling stimulation. Rats injected with haloperidol (5 mg/kg i.p.) for 18 or 30 days were stimulated in the amygdala daily until full seizures were elicited. Starting 2 days after the last injection, rats treated with 5 mg/kg of haloperidol i.p. required significantly more stimulations than their respective control groups. The slowed rate of seizure development was not significant if the kindling stimuli were initiated 6 days posthaloperidol treatment nor if 10-mg doses of haloperidol were used for 30 days. [3H]Spiroperidol binding assays were performed on tissue from striatum and amygdala-pyriform cortex at various times after drug treatment. Increased receptor binding was observed in striatum and amygdala-pyriform cortex of all haloperidol treatment groups. These observations lend support to the hypothesis that dopamine plays a role in seizure suppression as an increased receptor sensitivity to dopamine delayed kindled seizure development.

Amygdala↗
PubMed1982

Regional heterogeneity of benzodiazepine receptors at 37 degrees C: an in vitro study in various regions of the rat brain.

The most compelling pharmacological evidence in support of benzo-diazepine (BZD) receptor heterogeneity is derived from the study of the complex interactions of CL 218872 and propyl beta-carboline-3-carboxylate (PCC) with brain BZD receptors. In the present study, we provide evidence to support the hypothesis that intraregional BZD receptor heterogeneity in rat brain is a result of the different conformational states of a single receptor. This hypothesis is based upon the observation that CL 218872 and PCC lose the ability to effectively discriminate BZD receptor subtypes in rat cerebral cortex, hippocampus and pons-medulla at physiological temperature (37 degrees C). Interestingly, both PCC and CL 218872 show higher affinity for BZD receptors in the cerebellum when compared to other brain regions at 37 degrees C. This observation suggests that interregional BZD receptor heterogeneity occurs under physiologically relevant temperatures. We propose that distinct cerebellar and non-cerebellar type BZD receptors exist in vivo while marked differences in the affinity of the type I and type II BZD receptor subtypes postulated by Klepner et al. 1979 may only occur in vitro at 0 degree--4 degree C.

Animals↗
PubMed1982

The effect of GABA on in vitro binding of two novel non-benzodiazepines, PK 8165 and CGS 8216, to benzodiazepine receptors in the rat brain.

The effect of gamma-aminobutyric acid (GABA) on the binding of PK 8165, a quinoline derivative, and CGS 8216, a pyrazoloquinoline, was assessed in two different regions of the rat brain. PK 8165, a compound with reported anxiolytic properties, inhibited [3H]-propyl beta-carboline-3-carboxylate labeled receptors in the cerebellum with an IC50 of 844 nM and 370 nM in the absence and presence of micro M GABA, respectively. GABA (100 micro M) was less effective in the cerebral cortex, decreasing the IC50 value from 280 to 197 nM. In saturation isotherm studies with [3H]-CGS 8216, a benzodiazepine receptor antagonist, GABA (100 micro M) induced a small but significant reduction in the apparent affinity of [3H]-CGS 8216 for benzodiazepine receptors in the cerebral cortex but the Bmax was unchanged.

Animals↗
PubMed1982

A novel pyrazoloquinoline that interacts with brain benzodiazepine receptors: characterization of some in vitro and in vivo properties of CGS 9896.

The novel pyrazoloquinoline, CGS, 9896, was a potent inhibitor of specific [3H]-flunitrazepam binding in several brain regions with subnanomolar KI values. The inhibition of [3H] propyl beta-carboline-3-carboxylate ([3H]-PCC-) binding by CGS 9896 was enhanced by gamma-aminobutyric acid (GABA) but not by chloride ion. GABA enhancement of CGS 9896 inhibition of [3H]-PCC binding predicts this compound has benzodiazepine (BZD) agonist-type activity. Behavioral studies support this prediction. CGS 9896 was found to protect mice against bicuculline and metrazol induced seizure at doses that did not induce ataxia or sedation. CGS 9896 may represent a class of compounds with potential therapeutic value. The high affinity of this non-BZD compound suggests that CGS 9896 may also be of value as a high affinity ligand for the continued study of BZD receptors.

Animals↗