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PubMed1999

Influence of plasma dialysate from normal and renal dysfunction rats on the electroencephalogram and gamma-aminobutyric acid A receptor complex modulation of thiopental.

We have previously reported that brain sensitivity to thiopental with respect to electroencephalogram (EEG) is enhanced in uranyl acetate pretreated renal dysfunction rats. The results were attributed to pharmacodynamic factors. In this study, in vivo EEG and in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex were performed to investigate the mechanism of the enhanced effect of thiopental. The receptor binding properties in the brain membrane from normal and renal dysfunction rats were examined using [3H]tertbutylbicycloorthobenzoate (TBOB), [3H]flunitrazepam and [3H]muscimol. The effect of plasma dialysate from normal (ND) and renal dysfunction rats (RDD) on the thiopental induced EEG and receptor binding were also examined to confirm the role of endogenous compounds. The intrinsic receptor binding characteristics of various sites and their allosteric interaction with thiopental was similar in membrane preparations from normal and renal dysfunction rats. However, RDD, when compared to ND, enhanced the EEG induced by thiopental. At the receptor level, RDD significantly enhanced the thiopental induced inhibition of TBOB. No difference was found between the influence of ND and RDD on the interaction between thiopental and flunitrazepam or muscimol binding. These results showed that the thiopental induced allosteric inhibition of TBOB binding was potentiated by some endogenous compounds in RDD and suggests that this action might be the mechanism, at least in part, for the increased sensitivity of thiopental in renal dysfunction rats.

Animals↗
PubMedDate not supplied

Regulation of intracellular [Ca2+] and GABA release by presynaptic GABAB receptors in rat cerebrocortical synaptosomes.

In this study we determined the changes in the intracellular free Ca2+ concentration, associated with the inhibitory modulation of the exocytotic release of GABA by GABAB receptor activation in rat cerebrocortical synaptosomes. We observed that SK&F 97541 and (-)baclofen both act as agonists of the presynaptic GABAB receptors in modulating GABA release and Ca2+ influx due to KCl (10 mM) depolarization, but SK&F 97541 is more potent than (-)baclofen in modulating both Ca2+ influx and GABA release. Thus, activation of GABAB receptors by either SK&F97541 (10 microM) or by (-)baclofen (100 microM) caused about 18% inhibition of the increase in [Ca2+]i, due to KCl depolarization, and inhibited the [3H]GABA release by about 30%. The pharmacological similarities of the GABAB receptor activation in producing inhibition of both calcium channel mediated influx of Ca2+ and transmitter release suggest that presynaptic inhibition of GABA release by GABAB receptor activation may result, at least in part, from inhibition of Ca2+ influx through P-type (or possibly Q-type) Ca2+ channels, sensitive to omega-Agatoxin IVA (200 nM). Furthermore, modulation of GABA release of GABAB receptors was abolished by preincubation with pertussis toxin, suggesting that a pertussis toxin sensitive G protein may be the coupling factor between GABAB receptors and the voltage-dependent Ca2+ channels associated with the exocytotic release of GABA in rat cerebrocortical nerve terminals.

Animals↗
PubMed2000

Benzodiazepine modulation of GABAergic responses is intact in the cerebellum of aged F344 rats.

During the aging process there is a decline in the function of many central nervous system receptor systems. In this report we examine the ability of midazolam to potentiate gamma-aminobutyric acid (GABA) mediated inhibition recorded from cerebellar Purkinje neurons using extracellular recording methods. We report that when midazolam is applied concurrently with GABA from glass multibarrel electrodes that midazolam potentiates GABA mediated inhibition in 46% of Purkinje neurons in 3-month-old F344 rats, 63% of neurons in 18-month-old F344 rats and 54% of cells in 24-month-old F344 rats. Thus, there is no age related decline in function of this response. In fact, the response to midazolam is significantly increased in 18-month-old rats.

Action Potentials↗
PubMed2005

Compartmental localization of gamma-aminobutyric acid type B receptors in the cholinergic circuitry of the rabbit retina.

Although many effects of gamma-aminobutyric acid (GABA) on retinal function have been attributed to GABA(A) and GABA(C) receptors, specific retinal functions have also been shown to be mediated by GABA(B) receptors, including facilitation of light-evoked acetylcholine release from the rabbit retina (Neal and Cunningham [1995] J. Physiol. 482:363-372). To explain the results of a rich set of experiments, Neal and Cunningham proposed a model for this facilitation. In this model, GABA(B) receptor-mediated inhibition of glycinergic cells would reduce their own inhibition of cholinergic cells. In turn, muscarinic input from the latter to the glycinergic cells would complete a negative-feedback circuitry. In this study, we have used immunohistochemical techniques to test elements of this model. We report that glycinergic amacrine cells are GABA(B) receptor negative. In contrast, our data reveal the localization of GABA(B) receptors on cholinergic/GABAergic starburst amacrine cells. High-resolution localization of GABA(B) receptors on starburst amacrine cells shows that they are discretely localized to a limited population of its varicosities, the majority of likely synaptic-release sites being devoid of detectable levels of GABA(B) receptors. Finally, we identify a glycinergic cell that is a potential muscarinic receptor-bearing target of GABA(B)-modulated acetylcholine release. This target is the DAPI-3 cell. We propose, based on these data, a modification of the Neal and Cunningham model in which GABA(B) receptors are on starburst, not glycinergic amacrine cells.

Amacrine Cells↗
PubMed2000

Wavelet analysis of dynamic PET data: application to the parametric imaging of benzodiazepine receptor concentration.

Receptor density and ligand affinity can be assessed using positron emission tomography (PET). Biological parameters (B(max)('), k(1), k(2), k(on)/V(R), k(off)) are estimated using a compartmental model and a multi-injection protocol. Parametric imaging of the ligand-receptor model has been shown to be of special interest to study certain brain disorders. However, the low signal-to-noise ratio in kinetic curves at the pixel level hampers an adequate estimation of model parameters during the optimization procedure. For this reason, mapping requires a spatial filter, resulting in a loss of resolution. Filtering the kinetic curves in the frequency domain using the Fourier transform is not appropriate, because of difficulties in choosing a correct and efficient cutoff frequency. A wavelet-based filter is more appropriate to such tracer kinetics. The purpose of this study is to build up parametric images at the pixel level while conserving the original spatial resolution, using wavelet-based filtering. Data from [(11)C]flumazenil studies, mapping the benzodiazepine receptor density, were used. An invertible discrete wavelet transform was used to calculate the time-frequency signals of the time-concentration PET curves on a pixel-by-pixel basis. Kinetic curves observed from large regions of interest in high and low receptor-density regions were used to calibrate the threshold of wavelet coefficients. The shrunken wavelet coefficients were then transformed back to the original domain in order to obtain the filtered PET signal. Maps of all binding parameters were obtained at the pixel level with acceptable coefficients of variation of less than 30% for the B(max)(') parameter in most of the gray matter. A strong correlation between model parameter estimates using the usual regions of interest and parametric imaging was observed for all model parameters (r = 0.949 for the parameter B(max)(')). We conclude that wavelet-based filters are useful for building binding parameter maps without loss of the original spatial resolution of the PET scanner. The use of the wavelet-based filtering method can be extended far beyond the multi-injection protocol. It is likely to be also effective for other dynamic PET studies.

Brain↗
PubMed2000

The neurosteroid pregnanolone prevents the anxiogenic-like effect of inescapable shock in the rat.

RATIONALE AND OBJECTIVES: The ability of progesterone (P4) and its neurosteroid metabolite, 3alpha-OH-5beta-pregnan-20-one (pregnanolone) in protecting against the anxiogenic-like effect of inescapable shock (IS) in male rats was examined, as these steroids exert anxiolytic, anticonvulsant, and ataxic effects similar to the benzodiazepines (BZ), drugs shown to prevent IS-induced anxiogenesis. METHODS: Adult male rats were injected with pregnanolone (8 mg/kg, SC), P4 (4 mg/rat) or its appropriate vehicle before exposure to IS. Twenty-four hours later, animals were injected with the steroid or its vehicle and then tested in the elevated plus-maze. In a control experiment, animals were injected with chlordiazepoxide (CDP, 15 mg/kg, IP) or vehicle before IS, and tested in the plus-maze 24 h later. RESULTS: Whereas CDP or pregnanolone before IS resulted in the loss of the anxiogenic-like response seen 24 h after IS, P4 before IS did not protect against the anxiogenic-like effect of IS. The acute anxiolytic-like effect of pregnanolone and P4 was lost in animals that were injected with vehicle before the IS, but was observed in animals that were injected with the steroids before IS. Moreover, P4 injection in non-shocked animals was associated with an anxiogenic-like response observed 24 h after steroid administration. CONCLUSION: The protection against the effect of IS afforded by a GABAergic neurosteroid is comparable to that observed with BZs, and thus provides further evidence of an allosteric relationship between the neurosteroid and BZ binding site on the GABA(A) receptor complex.

Animals↗
PubMed2006

Hyperthermia-induced seizures modify the GABA(A) and benzodiazepine receptor binding in immature rat brain.

Effects of hyperthermia-induced seizures (HS) on GABA(A) and benzodiazepine (BDZ) receptor binding in immature rat brain were evaluated using in vitro autoradiography. HS were induced in 10-days-old rats by a regulated stream of moderately heated air directed 50 cm above the animals. Rats were killed 30 min, 24 h or 20 days after HS and their brains were used for in vitro autoradiography experiments to determine GABA(A) and BDZ receptor binding. GABA(A) binding was significantly enhanced in all brain areas evaluated 30 min after HS, an effect that endures 24 h and 20 days after seizures. Concerning BDZ receptor binding, a significant increase was detected in entorhinal and perirhinal cortices and decreased in basolateral amygdala 30 min following HS. One day after HS, animals demonstrated enhanced BDZ binding in the cingulate, frontal, posterior parietal, entorhinal, temporal and perirhinal cortices; striatum, accumbens, substantia nigra pars compacta and amygdala nuclei. Twenty days after HS enhanced BDZ binding was restricted in the cingulated, frontal, anterior and posterior parietal cortices, as well as in substantia nigra pars reticulata, whereas decreased values were found in accumbens nucleus and substantia nigra pars compacta. Our data indicate differential effects of HS in GABA(A) and BDZ binding in immature brain. HS-induced GABA(A) and BDZ changes are different from those previously described in experimental models of temporal lobe epilepsy in adult animals.

Age Factors↗
PubMed1983

Potentiating action of midazolam on GABA-mediated responses and its antagonism by Ro 14-7437 in the frog spinal cord.

The effect of midazolam, a new water-soluble benzodiazepine, on an in vitro slice preparation of the frog spinal cord was investigated using electrophysiological recordings. Midazolam potently (ED50 = 1 nM) enhanced the depolarizing action of GABA on primary afferent fibres while leaving the depolarizing effect of glutamate, glycine or high K+ solutions unchanged. Concentrations of midazolam higher than 100 nM had an antagonistic effect on GABA responses. Ro 14-7437 was a powerful and selective antagonist of the midazolam potentiation without affecting control responses to GABA, glutamate or high K+. The antagonism of GABA responses induced by high doses of midazolam was not sensitive to Ro 14-7437. Our data suggest that midazolam is a very potent and selective modulator of GABA responses: this finding illustrates that electrophysiological techniques can detect specific effects of very low concentrations of benzodiazepines on a CNS slice preparation with well preserved architectural organization.

Animals↗
PubMed1996

Solubilized benzodiazepine receptors for use in receptor assays.

In the development of non-radioactive receptor assays for benzodiazepines, employing fluorescent ligands, it was observed that the fluorescence measurements were hampered by the background fluorescence of the receptor preparation. This receptor preparation is a brain tissue homogenate in which the benzodiazepine receptors are membrane-bound. To minimize the influence of the receptor material on the fluorescence detection, the benzodiazepine receptors were solubilized with 0.5% sodium deoxycholate. The binding characteristics of the receptors were examined after solubilization and compared with membrane-bound receptors. The Kd and Bmax values for membrane-bound receptors were 1.20 nM and 1.01 pM mg-1 protein and for solubilized receptors they were 4.1 nM and 0.54 pM mg-1 protein respectively. Inhibition curves with the benzodiazepine antagonist flumazenil and the agonist lorazepam revealed that their affinities for the solubilized receptor as compared to the membrane-bound receptor were also reduced from 0.67 nM to 3.2 nM and from 1.49 nM to 8.4 nM respectively. The detection limits for the two benzodiazepines, however, were not affected by the solubilization. Furthermore, three different methods to separate the fraction of free labelled ligand and the fraction bound to the solubilized receptor were compared, namely polyethylene glycol precipitation/filtration, ion exchange filtration and charcoal adsorption. Polyethylene glycol precipitation/filtration gave the highest yield for the bound fraction and the best reproducibility.

Adsorption↗
PubMed2006

Comparison of in vivo and ex vivo [3H]flumazenil binding assays to determine occupancy at the benzodiazepine binding site of rat brain GABAA receptors.

In the present study, the occupancy of flumazenil (Ro 15-1788; 1-30mg/kg p.o.) at the benzodiazepine site of rat brain GABA(A) receptors was compared using in vivo and ex vivo binding methodologies with [(3)H]flumazenil as the radioligand. Animals either received tracer quantities of [(3)H]flumazenil 3min before being killed for the in vivo binding, or were killed and brain homogenates incubated with 1.8nM [(3)H]flumazenil. The flumazenil dose required to inhibit in vivo binding of [(3)H]flumazenil by 50% (ID(50)) was 2.0mg/kg, which represents the most accurate measure of benzodiazepine site occupancy by flumazenil in vivo. Occupancy measured in crude brain homogenates using the ex vivo method was time dependent with a 3mg/kg dose giving occupancies of 77% and 12% using 0.5 or 60min ex vivo incubations times, respectively, presumably due to dissociation from the binding site during the ex vivo incubation. When incubation time was minimised (0.5min), and despite being under non-equilibrium conditions, the ex vivo method gave an ID(50) of 1.5mg/kg which was not too dissimilar from that observed using in vivo binding (2.0mg/kg). As expected, ex vivo binding can give an underestimation of receptor occupancy but this can be minimised by careful attention to the kinetics of unlabelled drug and radioligand.

Animals↗
PubMed2005

Anxiolytic-like actions of testosterone in the burying behavior test: role of androgen and GABA-benzodiazepine receptors.

The first objective of the present study was to explore if several androgens, including testosterone propionate (TP) and its reduced metabolites, 5alpha-androstan-3alpha, 17beta-diol (3alpha-androstanediol) and 5alpha-androstan-3alpha-ol-17-one (androsterone), produce an anxiolytic-like effect in the burying behavior paradigm. Additionally, the possible participation of androgen or GABA(A)-benzodiazepine receptors in the anxiolytic-like effect of TP was analyzed. Orchidectomized male rats were treated with four injections of TP (0.25, 0.50, 1.0 mg/rat), 3alpha-androstanediol or androsterone (0.5 and 1.0 mg/rat), and the cumulative burying (denoting anxiety levels) and burying behavior latency (reflecting reactivity) evaluated. Besides, a single injection (0.5 mg/rat, -30 m) of each androgen was also tested in castrated rats. Repeated treatment with TP (0.5 and 1.0 mg/rat), but not a single injection of this androgen, produced an anxiolytic-like effect without changes on reactivity. Neither repeated- nor single-treatment with 3alpha-androstanediol nor androsterone produced a reduction of anxiety-like behavior. For the experiment studying the TP mechanism of action, this androgen (0.5 mg/rat, four injections) was combined with an antagonist for androgen receptors, flutamide (50 mg/kg, SC, 7 injections), or with a benzodiazepine antagonist, flumazenil (15 mg/kg, IP, -30 m). Flutamide, but not flumazenil, blocked the anxiolytic-like effects produced by TP. Results are discussed on the basis of interaction of these steroids with androgen receptors or GABA(A)-benzodiazepine receptors.

Androgen Antagonists↗
PubMed2001

Sleep inducing effects of propofol microinjection into the medial preoptic area are blocked by flumazenil.

The intravenous anesthetic, propofol, has been shown to increase sleep when microinjected into the medial preoptic area (MPA) of the rat. Similar increases in sleep have also been observed with triazolam, pentobarbital and ethanol microinjection. Together, these findings implicate the MPA as an important anatomic site mediating the effects of sedatives on naturally occurring sleep. Although the molecular mechanism by which propofol in the MPA acts to induce sleep is unclear, potentiating effects on the GABA(A) receptor complex may play a role. To assess this possibility, we microinjected propofol alone, and in combination with the benzodiazepine receptor antagonist flumazenil, into the MPA. At a dose of 0.76 microg, flumazenil had no effect on sleep when given alone, and completely blocked the increase in sleep caused by a 40-ng dose of propofol although it did not affect the increase in sleep caused by an 80-ng dose of propofol. These data suggest that the sleep inducing property of propofol is in part mediated by direct or indirect actions on the GABA(A)-benzodiazepine receptor complex.

Anesthetics, Intravenous↗
PubMed1997

The antidopaminergic action of S-20098 is mediated by benzodiazepine/GABA(A) receptors in the striatum.

The naphthalenic compound S-20098, which is a melatonergic agonist, inhibits [3H]diazepam binding in striatal membranes. S-20098 also inhibits apomorphine-induced turning in 6-hydroxydopamine lesioned rats. This antidopaminergic effect is blocked by either intraperitoneal injection of the central-type benzodiazepine (BZ) antagonist, flumazenil, or intrastriatal injection of the GABA(A) antagonist, bicuculline. These findings indicate that S-20098 can activate central-type BZ receptors, and its antidopaminergic action, like that of melatonin, involves a GABAergic mechanism in the striatum.

Acetamides↗
PubMed2001

Functional pharmacology of GABA(A) receptors containing the chicken brain gamma 4 subunit.

The functional pharmacology of receptors composed of the chicken brain GABA(A) receptor gamma 4 subunit and the mammalian GABA(A) receptor alpha 3 and beta2 subunits was studied by heterologous expression in Xenopus laevis oocytes using the two electrode voltage-clamp technique. GABA-evoked currents had an EC(50) of 180+/-30 microM. Responses were blocked by the competitive and non-competitive GABA(A) receptor antagonists, bicuculline methochloride and picrotoxin. Sodium pentobarbital reversibly potentiated the current several-fold, and Zn(2+) ions blocked the current with high potency (IC50=20 microM). GABA-evoked currents were potentiated by the benzodiazepine site full agonists flunitrazepam and triazolam and less by the partial agonists abecarnil and bretazenil. The inverse agonists methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) reduced the current. However, the imidazobenzodiazepine Ro 15-4513, which acts as an inverse agonist at mammalian alphaxbetaygamma2 GABA(A) receptors (where x=1, 2, 3 or 5, and y=1, 2 or 3), acted as a positive agonist at the gamma 4 subunit-containing receptors.

Animals↗
PubMed2002

The relative amount of cRNA coding for gamma2 subunits affects stimulation by benzodiazepines in GABA(A) receptors expressed in Xenopus oocytes.

Benzodiazepine (BZD) potentiation of GABA-activated Cl(-)-current (I(GABA)) in recombinant GABA(A) receptors requires the presence of the gamma subunit. When alpha1, beta2 and gamma2S cRNA are expressed in a 1:1:1 ratio in Xenopus oocytes, BZD potentiation of I(GABA) is submaximal, variable and diminishes over time. Potentiation by BZDs is increased, more reproducible and is stabilized over time by increasing the relative amount of cRNA coding for the gamma2S subunit. In addition, GABA EC(50) values for alpha1beta2gamma2 (1:1:1) receptors are intermediate to values measured for alpha1beta2 (1:1) and alpha1beta2gamma2 (1:1:10) receptors. We conclude that co-expression of equal ratios of alpha1, beta2 and gamma2 subunits in Xenopus oocytes produces a mixed population of alpha1beta2 and alpha1beta2gamma2 receptors. Therefore, for accurate measurements of BZD potentiation it is necessary to inject a higher ratio of gamma2 subunit cRNA relative to alpha1 and beta2 cRNA. This results in a purer population of alpha1beta2gamma2 receptors.

Animals↗
PubMed1997

Anticonvulsant activity of azirino[1,2-d][1,4]benzodiazepines and related 1,4-benzodiazepines in mice.

The anticonvulsant properties of several 1,4-benzodiazepine and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal (IP) administration in DBA/2 mice (a strain genetically susceptible to sound-induced seizures) and in Swiss mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome or on seizures induced by administration of pentylenetetrazole. The 1,4-benzodiazepines were generally more potent than the related ABDZ derivatives. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of these derivatives was also evaluated by means of the rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. The potency of various 1,4-benzodiazepines and ABDZs as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as anticonvulsants and inhibited [3H]flumazenil binding in the micromolar range. Radioligand binding studies carried out in stable cell lines demonstrated that none of the ABDZs tested showed a particular subtype specificity. The pharmacological actions of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as anticonvulsants, were significantly reduced by treatment with flumazenil (8.24 mumol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced in DBA/2 mice by two beta-carbolines: methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,6-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). Both ABDZ4 and ABDZ5 give better protection against seizures induced by beta-CCM than DMCM, suggesting a preferential action on the benzodiazepine receptor subtype BDZ1.

Animals↗
PubMed1999

Sex and estrous cycle-dependent changes in neurosteroid and benzodiazepine effects on food consumption and plus-maze learning behaviors in rats.

Experiments were designed to investigate the influence of estrous cycle and gender of the rat on the effects of a gamma-aminobutyric acid type A (GABA(A)) receptor active neurosteroid, 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), the benzodiazepine, triazolam, and a GABA(A) receptor antagonistic neurosteroid, delta5-androsten-3beta-ol-17-one sulfate (dehydroepiandrosterone sulfate), on food intake and elevated plus-maze learning behaviors. Allopregnanolone (0.25 mg/kg, s.c.) and triazolam (0.25 mg/kg, i.p.) produced a hyperphagic effect, while dehydroepiandrosterone sulfate (5 mg/kg, s.c.) elicited an anorectic effect. However, allopregnanolone was more potent in diestrous females, whereas triazolam exhibited significantly higher hyperphagic potency in estrus females. The extent of anorexia following dehydroepiandrosterone sulfate was alike in male and female rats. The triazolam- and allopregnanolone-induced hyperphagic effect was blocked by bicuculline (1 mg/kg, i.p.), a selective GABA(A) receptor antagonist. In contrast to triazolam, the hyperphagic effect of allopregnanolone was insensitive to flumazenil (5 mg/kg, i.p.), a benzodiazepine antagonist. Vehicle-treated diestrous rats displayed moderately higher latencies in the elevated plus-maze learning task than estrus or proestrus females. Although allopregnanolone and triazolam elicited equipotent learning deficits in plus-maze learning in male and female rats, the magnitude of impairment-induced by triazolam was significantly higher in diestrous females than proestrus females. Dehydroepiandrosterone sulfate enhanced memory performance only in male rats. Although the use of the elevated plus-maze as a learning paradigm with benzodiazepines and neurosteroids may be sensitive to changes in anxiety, the differential data suggest that neurosteroid-induced effects are at least partly specific to learning behavior. These results confirm the role of estrous cycle and sex of rats in modifying the potency of neurosteroids and benzodiazepines on food consumption and learning and memory processes.

Analysis of Variance↗
PubMed1999

Evaluation of [methyl-3H]L655,708 and [ethyl-3H]RY80 as putative PET ligands for central GABA(A) receptors containing alpha5 subunit.

Two selective radioligands of gamma aminobutyric acid (GABA)A receptors containing the alpha5 subunit, [3H]L655,708 and [3H]RY80, were evaluated in rats as potential in vivo tracers for positron emission tomography (PET). Brain uptake index (BUI), a measure of first pass extraction, was moderate for [3H]L655,708 (BUI of 59%) and good for [3H]RY80 (BUI of 96%). This finding was consistent with their in vitro binding to plasma proteins of approximately 76% and 50%, respectively. Following intravenous injection of either radioligand, radioactivity in plasma was measured and uptake characteristics were assessed in brain within a time period relevant to PET scanning (up to 90 min). Discrete brain regions, such as frontal cortex, striatum, hypothalamus, thalamus, hippocampus, colliculi, medulla, and cerebellum, were sampled and the temporal distribution of radioactivity analysed. Despite the reasonable delivery to the brain, neither of the radioligands had sufficient retention in the tissues rich in alpha5-containing GABA(A) receptors to achieve a good selective signal. For both radioligands, a maximal tissue:cerebellum ratio of 1.5 was seen in hippocampus at 10 min after injection. Thus, neither of the compounds studied shows potential for further development as an in vivo PET ligand.

Alkynes↗