Reduction of the intoxicating effects of ethanol by drugs acting at the benzodiazepine-GABA receptor complex

The ability of the benzodiazepine receptor partial inverse agonists Ro 15-4513, Ro 15-3505 and FG 7142, and the picrotoxin site ligands pentylenetetrazole and Ro 5-3663 to reduce ethanol-induced intoxication were investigated. Ro 15-4513 (0.3-3 mg/kg), Ro 15-3505 (3 mg/kg), pentylenetetrazole (20 and 25 mg/kg) and Ro 5-3663 (4 mg/kg) all significantly attenuated the intoxicating effects of ethanol. In contrast, FG 7142 (20 and 40 mg/kg) failed to reduce ethanol intoxication, but reversed the effect of Ro 15-4513. This pattern of results differs from that obtained using other behavioral paradigms. Since drugs which reduce the effects of GABA generally reduce the intoxicating effects of ethanol, it is suggested that the beta-carbolines may be unusual in their interaction with ethanol.     

Reversal of alcohol-induced amnesia by the benzodiazepine inverse agonist Ro 15-4513

We investigated the effects of benzodiazepine inverse agonists on ethanol-induced amnesia using a passive avoidance task. Pretraining treatment of mice with ethanol significantly impaired the passive avoidance response: there was a significant reduction in the % retention and step-down latency. The benzodiazepine inverse agonists, Ro 15-4513 and beta-CCM, significantly increased the % retention and prolonged the step-down latencies in mice treated with ethanol, but FG 7142 did not. The anti-amnesic effects of Ro 15-4513 were completely antagonized by co-administration of Ro 15-1788, a benzodiazepine antagonist. These results suggest that the anti-amnesic effect of Ro 15-4513 on alcohol-induced amnesia is mediated by benzodiazepine receptors.     

Strain differences in sensitivity to the hypothermic effects of benzodiazepine receptor ligands in mice

The hypothermic effects of intraperitoneal (IP) administration of the full benzodiazepine agonist lop razolam (1, 10 mg/kg); the partial agonist Ro 17-1812 (1, 10 mg/kg); the benzodiazepine receptor antagonist flumazenil (10, 20 mg/kg); the benzodiazepine inverse agonists Ro 15-4513 (1, 3, 10 mg/kg) and Ro 19-4603 (0.03, 0.1, 0.3 mg/kg) and the-carboline inverse agonists FG 7142 (10, 30 mg/kg) and DMCM (1, 3, 10 mg/kg) were investigated in three strains of mice. TO mice were less sensitive than CBA/cA and DBA/2 mice, since only loprazolam and the partial and full-carboline inverse agonists FG 7142 and DMCM lowered body temperature in these animals. CBA/cA mice were particularly sensitive to the hypothermic effects of loprazolam and Ro 17-1812, and also responded to the-carboline but not the benzo diazepine inverse agonists. In contrast, DBA/2 mice responded with moderate hypothermia to loprazolam, Ro 17-1812, and to the partial inverse agonist Ro 15-4513, and exhibited marked hypothermia in response to the more efficacious benzodiazepine inverse agonist Ro 19-4603 and to FG 7142 and DMCM. Flumazenil did not alter body temperature. DBA/2 mice were also more sensitive to the convulsant activity of inverse agonists than TO mice. CBA/cA mice exhibited enhanced sensitivity to the convulsant, but not the hypothermic, effects of Ro 19-4603, showing dissociation of these responses. The mechanisms underlying the genetic differences in sensitivity of mice to the hypothermic and convulsant action of the different ligands are unknown and warrant further investigation.     

Preferential decrease in dopamine utilization in prefrontal cortex by zopiclone, diazepam and zolpidem in unstressed rats

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg-1 p.o.) and diazepam (10 and 40 mg kg-1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg-1 p.o.). Diazepam (10 and 40 mg kg-1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg-1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15-1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor GABA receptor chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.     

The activation of mesoprefrontal dopamine neurons by FG 7142 is absent in rats treated chronically with diazepam

Administration of methyl-beta-carboline-3-carboxamide (FG 7142, 15 mg/kg i.p.) to rats has previously been shown to cause a selective increase in the levels of 3,4-dihydroxy-phenylacetic acid (DOPAC) in the prefrontal cortex and ventral tegmental area (VTA) via an interaction with benzodiazepine receptors. On withdrawal 3 days following chronic treatment with diazepam for 21 days, FG 7142 no longer increased DOPAC levels in either the prefrontal cortex or the VTA. Chronic diazepam treatment alone was ineffective in altering dopamine metabolism in the eight brain regions examined. The present findings indicate that chronic diazepam treatment may cause changes at the level of GABA/benzodiazepine receptor macromolecular complex, which is normally functionally integrated with the mesoprefrontal dopaminergic neurons, so that FG 7142 can no longer exert its intrinsic actions.     

Behavioral studies with the beta-carboline FG 7142 combined with related drugs in monkeys

The beta-carboline FG 7142 was studied alone and in combination with Ro 15-1788, CGS 8216 and lorazepam in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of food presentation. FG 7142 (0.3-5.6 mg/kg i.v.) produced dose-related decreases in the rate of FI responding, effects opposite to those of moderate doses of lorazepam (0.03-0.3 mg/kg i.v.). Pretreatment with low doses of Ro 15-1788 (0.1 and 0.3 mg/kg i.v.) shifted the dose-response curve of FG 7142 progressively to the right indicating pharmacological antagonism at benzodiazepine recognition sites. In comparison, pretreatment with the pyrazoloquinoline CGS 8216 (0.1-1.0 mg/kg i.v.), which alone decreased responding, did not alter the effects of FG 7142 in a systematic manner. Combinations of behaviorally active doses of FG 7142 and lorazepam had primarily additive effects: the opposing actions of one drug tended to cancel the other's effect on responding. These results show that the reduction in behavior by FG 7142 is modified predictably by Ro 15-1788 but not by CGS 8216, and behaviorally active doses of both FG 7142 and lorazepam may be needed for their mutual antagonism.     

Effects of benzodiazepine receptor ligands on the performance of an operant delayed matching to position task in rats: opposite effects of FG 7142 and lorazepam

The effects of a series of benzodiazepine (BZ) receptor ligands, ranging from a full agonist through to partial inverse agonists, were examined on short term working memory in the rat. The behavioural paradigm used was a discrete trial, operant delayed matching to position task, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. The benzodiazepine receptor (BZR) full agonist lorazepam (0.25, 0.375 and 0.5 mg/kg) dose and delay dependently impaired matching accuracy. Lorazepam also increased the latency to respond and decreased the number of nose pokes made into the food tray during the delays. In contrast, the BZR partial agonist ZK 95 962 (1, 3, 10 mg/kg) did not affect matching accuracy, but did increase the speed of responding. The BZR antagonist ZK 93 426 (1.25, 5, 25 mg/kg) had no effects in this paradigm. The BZR weak partial inverse agonists Ro 15-4513 (0.1, 1 and 10 mg/kg) and ZK 90 886 (1, 3 and 10 mg/kg) did not affect accuracy of performance. However, both of these drugs increased the latency to respond and decreased nose poke responses. These motoric effects were particularly strong following 10 mg/kg Ro 15-4513. This shows that the effects of drugs on the accuracy of responding and on the speed of responding can be dissociated. The BZR partial inverse agonist FG 7142 had effects on matching accuracy that were dependent upon dose. The lowest dose of FG 7142 (1 mg/kg) significantly improved accuracy, whereas the highest dose (10 mg/kg) impaired accuracy. This impairment induced by FG 7142 (10 mg/kg) was accompanied by an increase in the latency to respond and a decrease in the number of nose pokes. Taken together, these results show that the accuracy of delayed matching performance can be modulated in opposite ways by the BZR full agonist lorazepam and a low dose of the BZR partial inverse agonist, FG 7142.     

EEG effects of Ro 15-4513 and FG 7142 alone and in combination with ethanol

The electrophysiological effects of Ro 15-4513 and FG 7142 alone and in combination with ethanol were investigated. Intraperitoneal administration of Ro 15-4513 (3, 6 mg/kg) was found to significantly increase power in the 6-16 Hz frequency range, an effect which was antagonized by ethanol (1 g/kg). FG 7142 administration (2, 5 mg/kg IP) was found to enhance spectral power in the 6-8 Hz range, an effect which was also blocked by coadministration of ethanol. Both drugs also produced dose-related abnormal EEG activity in the form of episodic bursts of EEG spiking. These ictal episodes, which lasted 5-40 seconds, were associated with an arrest of behavior but no overt behavioral convulsions. Coadministration of ethanol caused an elimination or significant reduction in these episodes. These studies suggest that Ro 15-4513 and FG 7142 have potent electrophysiological actions of their own which are partially antagonized by ethanol.     

Loss of Inositol Phospholipids in Epididymal Sperm Following Exposure of Mice to Long-Term Feeding of Organophosphates

Abstract: The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5-4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed-type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5-25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5-4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central-type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA-benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2-5 mg/kg) and diazepam (5-25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5-4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5-4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral-type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists.     

Effects of central and peripheral type benzodiazepine ligands on growth hormone and gonadotropin secretion in male rats.

The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5-4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed-type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5-25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5-4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central-type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA-benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2-5 mg/kg) and diazepam (5-25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5-4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5-4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral-type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists.     

Benzodiazepine receptor ligands and the consumption of a highly palatable diet in non-deprived male rats

Non-deprived rats were familiarised with a highly palatable diet until baseline consumption in a 60-min daily access period had stabilised. The benzodiazepine receptor agonist midazolam (1.25–10.0 mg/kg, IP) produced a large, dose-related increase in food consumption during the first 30 min of access. It also produced significant, short-term hyperphagia in animals which had been partially pre-satiated on the diet before drug administration, an effect which was reversible by the benzodiazepine receptor antagonist Ro15-1788. Administered alone, Ro15-1788 (1.25–10.0 mg/kg, IP) had no intrinsic activity in the food consumption test. In contrast, CGS 8216 (2.5–40.0 mg/kg, IP) produced a marked dose-related suppression of food intake. This anorectic effect was shared by two benzodiazepine receptor inverse agonists, FG 7142 and DMCM, which also produced dose-dependent reductions in consumption. The effects on feeding produced by FG 7142 (20 mg/kg, IP) and DMCM (1.25 mg/kg, IP) were reversed by either Ro15-1788 (2.5 and 5.0 mg/kg) or midazolam (5.0 and 10.0 mg/kg). A matched anorectic effect produced by CGS 8216 (40 mg/kg) was not, however, reversed by either Ro15-1788 or midazolam. This suggests that at a high dose CGS 8216 may act by a mechanism different from that of the two inverse agonists. The feeding test described in the report proved sensitive to both hyperphagic and anorectic effects of drugs active at benzodiazepine receptors, pointing to a possible bi-directional control of palatable food consumption.     

beta-Carboline FG 7142-reduced aggression in male rats: reversed by the benzodiazepine receptor antagonist, Ro15-1788

The beta-carboline FG 7142 decreases conspecific aggression in male hooded rats. The purpose of this study was to examine the effects of pretreatment with Ro15-1788 or chlordiazepoxide (CDP) in this paradigm. The six groups (n = 8) were saline, FG 7142 (5 mg/kg, immediate, IP), CDP (5 mg/kg, -10 min, IP), CDP (5 mg/kg, -10 min) plus FG 7142 (5 mg/kg, immediate), Ro15-1788 (10 mg/kg, -10 min, IP), and Ro15-1788 (10 mg/kg, -10 min) plus FG 7142 (5 mg/kg, immediate). Following injection of the more aggressive member of a pair of isolation-housed rats, the pair was observed in a living cage over four 6-min trials interpolated over a 40 min session. In the first 20 min after the injection FG 7142 decreased aggression, decreased the pinning of the other animal, and increased avoiding behavior. These effects were the opposite of those seen in the Ro15-1788-injected rats and Ro15-1788 pretreatment reversed the effects of FG 7142. CDP alone caused prolonged aggressive behavior but as a pretreatment only partially reversed the effects of FG 7142.     

Effects of two benzodiazepine inverse agonists, RO 15-4513 and FG 7142, on recovery from pentobarbital and halothane anesthesia in the rat

A new class of drugs, the benzodiazepine inverse agonists, have recently been shown to antagonize some of the behavioral and sedative effects of benzodiazepines, barbiturates, and alcohol. Preliminary studies suggested that at least one of these drugs, RO 15-4513, may also be able to reverse the general anesthetic properties of volatile halogenated agents. Another inverse agonist, FG 7142, exhibits a similar ability to antagonize alcohol or benzodiazepines. However, FG 7142 is less potent than RO 15-4513 and has less affinity for the benzodiazepine receptor (BZR). The present studies were therefore undertaken to compare the analeptic effects and relative potencies of RO 15-4513 and FG 7142 on the anesthetic properties of pentobarbital compared with the general anesthetic agent halothane as measured by the time for recovery of the righting reflex in the rat. Three basic experimental paradigms were employed. Drug (FG or RO) or carrier was administered 5 minutes prior to the induction of pentobarbital anesthesia. Drug or carrier was administered to anesthetized animals 60 minutes after pentobarbital injection. Lastly, drug or carrier was administered 5 minutes prior to 15 minutes of halothane anesthesia. In addition, the selective benzodiazepine antagonist, flumazenil (RO 15-1788), was used to determine if the effects of the benzodiazepine inverse agonists on recovery from barbiturate or halothane anesthesia were due to activity at the BZR. The results revealed that RO was both more potent and more effective than FG at speeding recovery from barbiturate anesthesia in the rat. RO's effects appeared to be primarily due to BZR inverse agonist activity since it could be reversed by the BZR antagonist, flumazenil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic treatment with lorazepam and FG 7142 may change the effects of benzodiazepine receptor agonists, antagonists and inverse agonists by different mechanisms

Treatment of mice with lorazepam 10 mg/kg p.o. or FG 7142 40 mg/kg i.p. once a day for 14 days changed the effects of benzodiazepine (BZ) receptor ligands injected acutely on the threshold of pentylenetetrazol (PTZ)-induced seizures. The effects of the two pretreatments differed qualitatively as well as quantitatively. Lorazepam elicited a shift in the effects of all BZ receptor ligands tested, whereby the agonists lorazepam and ZK 93423 now acted like partial agonists given acutely, the partial agonist ZK 91296 acted like an antagonist and the antagonists Ro 15-1788 and ZK 93426 like partial inverse agonists. The proconvulsant effects of the partial inverse agonist FG 7142 and the full inverse agonist DMCM on the PTZ-induced seizures did not change. However, FG 7142 became a full inverse agonist i.e. became convulsant, and DMCM may have increased in potency as a convulsant. After FG 7142 pretreatment lorazepam and ZK 93423 behaved like partial agonists given acutely whereas there was no change in effect for ZK 91296, Ro 15-1788 and ZK 93426. FG 7142 became convulsant (i.e. kindling occurred) and the potency of DMCM as a convulsant was non-significantly increased, while their proconvulsant effects with respect to PTZ-induced seizures were not altered. The fact that the effects of the two very different pretreatments on the BZ receptor ligand continuum were in the same direction may be explainable by assuming two different mechanisms, both of which may involve the GABA receptors.     

Inverse agonist properties of the FG 7142 discriminative stimulus.

A two-lever, food-motivated discrimination was established between the benzodiazepine receptor partial inverse agonist FG 7142 (5.0 mg/kg) and its vehicle. The FG 7142 discriminative stimulus was pharmacologically characterized by testing trained rats with a variety of benzodiazepine receptor ligands. Administration of the inverse agonist DMCM (0.15-0.30 mg/kg) dose-dependently mimicked the FG 7142 stimulus. In contrast, the benzodiazepine receptor agonist chlordiazepoxide, partial agonist ZK 91 296, mixed agonist/antagonist CGS 9896 and antagonist RO 15-1788 blocked the FG 7142 cue. These results indicate that the FG 7142 discriminative stimulus is based on its inverse agonist activity. The generalization of FG 7142 to the anxiogenic/convulsant compound pentylenetetrazole (PTZ), but not to the anorectic agent norfenfluramine, indicates that the anxiogenic properties of FG 7142, rather than its anorectic actions, may underlie the FG 7142 discriminative stimulus.     

Anxiogenic properties of an inverse agonist selective for alpha3 subunit-containing GABA A receptors

Alpha3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA(A) receptors containing an alpha3 rather than an alpha1, alpha2 or alpha5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of alpha3IA are most probably mediated by the alpha3 subtype. Alpha3IA has good CNS penetration in rats and mice as measured using a [(3)H]Ro 15-1788 in vivo binding assay. At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. alpha1-containing receptors), alpha3IA (30 mg kg(-1) i.p.), like the nonselective partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain-pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil). Neurochemically, alpha3IA (30 mg kg(-1) i.p.) as well as FG 7142 (15 mg kg(-1) i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress. Taken together, these data demonstrate that an inverse agonist selective for GABA(A) receptors containing an alpha3 subunit is anxiogenic, and suggest that since alpha3-containing GABA(A) receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.     

Suppression of cytotoxic T lymphocyte (CTL) activity by FG 7142, a benzodiazepine receptor 'inverse agonist'.

A dose-dependent (12.5-100 mg/kg) suppression of cytotoxic T lymphocyte (CTL) activity was observed in mice after administration of the benzodiazepine receptor 'inverse agonist' FG 7142 (N-methyl-beta-carboline-3-carboxamide). This compound produces a syndrome resembling stress or anxiety in both animals and man. Addition of FG 7142 (1-1000 nM) to either a 4-hour 51Chromium-release assay or 5-day in vitro CTL generation system did not affect CTL activity. Pretreatment with the benzodiazepine receptor antagonist Ro 15-1788 (10 mg/kg) attenuated FG 7142-induced suppression of CTL activity, but had no effect when administered alone. Time-course studies indicated that FG 7142-induced suppression of CTL activity was long-lasting. The suppression of CTL activity by FG 7142 provides further evidence that the central nervous system pathways subserved by the benzodiazepine/GABA receptor chloride channel complex may play an important role in the modulation of immune function.     

The anxiolytic beta-carboline ZK 93423 prevents the stress-induced increase in dopamine turnover in the prefrontal cortex

The effects of electric foot-shock on the activity of the mesocortical dopaminergic (DAergic) neurons were estimated by measuring the changes in dihydrophenylacetic acid (DOPAC) and DA content in the prefrontal cortex of the rat. A marked rise in DOPAC content (+80%) and a significant decrease in DA levels (-23%) were observed after a 20 min foot-shock session. These effects were completely prevented by pretreatment with diazepam (5 mg/kg i.p.). ZK 93423, a recently synthesized beta-carboline with benzodiazepine-like properties, prevented the decrease in DA content induced by foot-shock at the dose of 20 mg/kg. Moreover, the stress-induced increase in DOPAC levels was partly or completely blocked by pretreatment with 20 or 40 mg/kg of ZK 93423, respectively. These results provide further support for the view that the mesocortical DAergic system can be modulated by drugs that selectively interact with the benzodiazepine recognition site.     

Interactions of Ro 15-4513 with diazepam, sodium pentobarbital and ethanol in a holeboard test

Ro 15-4513 (1.5 mg/kg) decreased the exploratory activity of mice in a holeboard test. This effect was reversed by diazepam (1 mg/kg), ethanol (1 g/kg) and sodium pentobarbital (15 mg/kg). Higher doses of these three agents reduced the number of exploratory head-dips, and Ro 15-4513 antagonised these effects. These observations are consistent with the suggestion that Ro 15-4513 is a partial inverse agonist at benzodiazepine receptors and acts by reducing the efficacy of GABA. Ro 15-4513's interaction with ethanol in the holeboard closely resembled its interaction with the barbiturate.     

Anxiogenic beta-carboline FG 7142 produces activation of noradrenergic neurons in specific brain regions of rats.

By measuring the levels of two major metabolites of rat brain noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), we investigated the effects of anxiogenic beta-carboline FG 7142, an inverse agonist of benzodiazepine (BZD) receptors, on brain noradrenergic activity of rats. Thirty min after treatment with FG 7142 (15 mg/kg IP), levels of both MHPG and DHPG in the hypothalamus, amygdala and thalamus, but not in the hippocampus and cerebral cortex, significantly increased. These increases were significantly antagonized by pretreatment with BZD receptor antagonist Ro 15-1788 (15 mg/kg, IP). Sixty min after treatment with FG 7142 at the same dose, significant increases in both metabolite levels occurred in the hypothalamus, amygdala, thalamus and cerebral cortex, and increases in MHPG levels only were observed in the hippocampus. These increases were significantly blocked by pretreatment with alpha 2-adrenoreceptor agonist clonidine (100 microgram/kg, IP). The present findings suggest that FG 7142 can produce increases in brain noradrenergic activity in specific brain regions by interacting with BZD receptors, and may support the hypothesis that hyperactivity of brain noradrenergic systems may be one neural mechanism in provocation of aversive emotional changes (anxiety, fear or panic).