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.     

Inverse agonist properties of the THBC discriminative stimulus: asymmetrical generalization with FG 7142.

Male rats were trained to discriminate the stimulus properties of the beta-carbolines 1,2,3,4-tetrahydro-beta-carboline (THBC) (15.0 mg/kg) or FG 7142 (5.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. Consistent with the serotonergic properties of THBC, administration of the 5HT1B agonists TFMPP and mCPP to THBC-trained rats resulted in THBC-appropriate responding. Norharmane, a beta-carboline metabolite of THBC, also mimicked the THBC discriminative stimulus. In contrast, the benzodiazepine receptor partial inverse agonist FG 7142, the anxiogenic/convulsant pentylenetetrazole (PTZ), two physiological stressors and the alpha 2 adrenergic antagonists yohimbine and idazoxan failed to produce THBC-appropriate responding. In the FG 7142-trained rats, THBC and norharmane dose-dependently mimicked the FG 7142 discriminative stimulus. This generalization was not based upon the serotonergic properties of THBC and norharmane since administration of the serotonin agonist mCPP to FG 7142-trained rats failed to produce FG 7142-appropriate responding. The ability of THBC to substitute for the FG 7142 discriminative stimulus was antagonized by the benzodiazepine receptor mixed agonist/antagonist CGS 9896 and the benzodiazepine receptor antagonist RO 15-1788, indicating that THBC produces an inverse agonist stimulus in FG 7142-trained rats. These results suggest that THBC produces a discriminative stimulus which consists of both serotonergic and inverse agonist components.     

Evidence for noradrenergic involvement in mediating the FG 7142 discriminative stimulus.

Rats were trained to discriminate the stimulus properties of the benzodiazepine receptor partial inverse agonist beta-carboline-3-carboxylate acid methyl amide (FG 7142) (5.0 mg/kg) or the alpha 2-adrenergic receptor antagonist 17 alpha-hydroxyyohimban-16 alpha-carboxylic acid methyl ester (yohimbine) (3.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. These compounds have in common a beta-carboline structure and anxiogenic behavioral profiles. The yohimbine discriminative stimulus was mimicked by the alpha 2-adrenergic receptor antagonist idazoxan and antagonized by the alpha 2-adrenergic receptor agonist clonidine, indicating that the yohimbine stimulus was mediated through the alpha 2-adrenergic receptor. The anxiogenic beta-carbolines FG 7142, 1,2,3,4-tetrahydro-beta-carboline (THBC), and norharmane, the anxiogenic/convulsant agent pentylenetetrazole (PTZ), and two physiological stressors failed to mimic the yohimbine discriminative stimulus. In contrast, both yohimbine and idazoxan dose responsively mimicked the anxiogenic FG 7142 stimulus. The present results demonstrate that an asymmetrical generalization exists between the discriminative stimuli produced by yohimbine and FG 7142. Furthermore, these data suggest that yohimbine can produce a multicomponent discriminative stimulus, part of which may be anxiogenic in nature. The ability of alpha 2-adrenergic receptor antagonists to mimic the FG 7142 cue suggests that activation of the noradrenergic system may underlie cues produced by benzodiazepine receptor inverse agonists.     

FG 7142 specifically reduces meal size and the rate and regularity of sustained feeding in female rats: evidence that benzodiazepine inverse agonists reduce food palatability.

Benzodiazepine receptor inverse agonists reduce food intake in males, but their actions in females, in whom stress-related eating disorders are more common, as well as their behavioral mode of action remain unclear. The consummatory effects of benzodiazepine receptor ligands have alternately been hypothesized to reflect changes in the hedonic evaluation of food or secondary effects of anxiety-related or cognitive properties. To test the anorectic mode of action of benzodiazepine inverse agonists, the effects of FG 7142 on feeding microstructure were studied in nondeprived female Wistar rats (n=32). Microstructure analysis used a novel meal definition that recognizes prandial drinking. On pharmacologically synchronized diestrus I, rats were pretreated (-30 min dark onset) with the benzodiazepine partial inverse agonist FG 7142 (i.p. 0, 3.75, 7.5, 15 mg/kg) in a between-subjects design. FG 7142 delayed the onset of (16-541%), decreased the amount eaten (36-52%) and drunk (63-87%), and reduced the time spent drinking (59-87%) within the first nocturnal meal. Dose-dependent incremental anorexia continued 6 h into the dark cycle, whereas FG 7142 did not suppress the quantity, duration or rate of drinking past the first meal. Treated rats ate smaller meals (17-42%) of normal duration. This reflected that FG 7142 slowed feeding within meals (9-38%) by decreasing the regularity and maintenance of feeding from pellet-to-pellet. FG 7142 did not influence postprandial satiety; meal frequency and inter-meal intervals were unaffected. FG 7142 anorexia was blocked by the benzodiazepine receptor antagonist flumazenil in a 2:1 molar ratio (n=17 rats). The very early, nonspecific (+10 min), but not subsequent (2.5, 4.5 h) feeding-specific phase, of FG 7142 anorexia was mirrored by anxiogenic-like behavior in FG 7142-treated (7.5 mg/kg) female rats (n=48) in the elevated plus-maze. Thus, benzodiazepine receptor inverse agonists preferentially lessen the maintenance of feeding in female rats, effects opposite to those of palatable food.     

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.     

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.     

Effects of diazepam,FG 7142, and RO 15-1788 on schedule-induced polydipsia and the temporal control of behavior

Although benzodiazepine agonists and inverse agonists have opposite effects on drinking elicited by water deprivation, there is much less information about the effects of these drugs on nonhomeostatic drinking. In this experiment the effects of diazepam (0.3–5.0 mg/kg), a benzodiazepine receptor agonist, and FG 7142 (1.0–9.0 mg/kg), an inverse agonist, were determined on drinking elicited by a FT-60 schedule of food delivery (SIP). Both diazepam and FG 7142 dose-dependently reduced SIP, measured as either licking or volume consumed. In addition, diazepam reduced panel pressing for food, decreased locomotor activity, and changed the time course of each behavior. In contrast, FG 7142 reduced schedule-induced drinking without significantly altering other behaviors. The antagonist RO 15-1788, when given in combination with these drugs, only partially restored the reductions in licking produced by diazepam, but was much more effective in reversing the effects of FG 7142 at doses of the antagonist that failed by themselves to affect responding. The opposite pattern of effects was seen on the volume of water consumed. These effects are discussed in terms of the behavioral and pharmacological specificity of these drugs.     

Differential pharmacological reactivity of aversion induced by stimulation of periaqueductal gray or mesencephalic locomotor region

Rats were trained to switch-off aversive electrical brain stimulations applied to the periaqueductal gray (PAG) or mesencephalic locomotor region (MLR) by pressing a bar (switch-off behavior). We investigated the effects of IP injections of the benzodiazepine (BZ) receptor inverse agonist FG 7142 (2.5, 5, 10 mg/kg) or BZ receptor agonist chlordiazepoxide (CDP: 5 mg/kg) on the switch-off latency, i.e., the time elapsed between the onset of the stimulation and its offset by a press of the bar. It was found that FG 7142 decreased, whereas CDP increased the mean switch-off latency for electrical stimulation of the PAG, which is interpreted as a potentiating effect of FG 7142 and a reducing effect of CDP on the electrically induced aversive state. By contrast, neither FG 7142 nor CDP were found to affect the mean switch-off latency for MLR stimulations. These results suggest a difference in the pharmacological sensitivity to BZ receptor ligands between aversive states elicited by electrical stimulation of the PAG or MLR.     

Continuous exposure to FG 7142: behavioural sensitisation is not accompanied by changes in benzodiazepine/GABA receptor coupling

Chronic intermittent high-dose treatment with N-methyl-β-carboline-3-carboxamide (FG 7142) leads to kindling accompanied by reduction in γ-aminobutyric acid (GABA) receptor function, whereas chronic continuous administration may result in behavioural effects in the opposite direction from those of acute FG 7142. In the present study, we have investigated the effects of continuous administration of low doses of FG 7142 on the response to an acute challenge dose of FG 7142 in an ethologically based model of anxiety. Rats treated continuously for 14 days with FG 7142 delivered by osmotic minipump at a rate of 1.2-1.5 mg/kg/day showed sensitisation to the anxiogenic effects of a challenge dose of FG 7142 (6 mg/kg), as measured in the elevated plus-maze. This was not accompanied by any change in benzodiazepine/GABA receptor coupling, as assessed by the 'GABA shift'. These results indicate that continuous low-dose treatment with FG 7142 can elicit sensitisation to the behavioural effects of FG 7142, but that this is unlikely to be mediated by changes in benzodiazepine/GABA receptor coupling.     

A benzodiazepine receptor inverse agonist inhibits stress-induced ulcer formation

The effects of a benzodiazepine receptor inverse agonist (FG 7142) on gastric ulcer formation were studied in restrained rats. FG 7142 (10-50 mg/kg) reduced in a dose-dependent fashion both the number and cumulative length of gastric ulcers elicited by restraint for 2 hr at 4 degrees C, but did not affect ulcer formation in unrestrained animals maintained in this environment. FG 7142 also reduced gastric ulcer formation in restrained rats maintained at 22 degrees C for 5 hr. The ability of FG 7142 to reduce restraint-stress induced gastric ulcer formation was blocked by the benzodiazepine receptor antagonist ZK 93426 and the beta-adrenoceptor antagonist propranolol. These findings suggest that FG 7142 produces a benzodiazepine-receptor mediated reduction in gastric ulcer formation, which may result from its ability to increase activity of the sympathetic nervous system.     

Effects of the beta-carboline FG 7142 on saccharin preference and quinine aversion in water-deprived rats

Three groups of water-deprived male rats were given the choice of 0.05% sodium saccharin solution and water; 0.0005% quinine solution and water; water in both containers. N'-Methyl-beta-carboline-3-carboxamide (FG 7142), a benzodiazepine receptor inverse agonist, dose-dependently (2.5-10 mg X kg-1 i.p.) reduced intake of fluid in each group. The saccharin-choice group were most sensitive, showing a significant reduction at 2.5 mg X kg-1. Preference for the saccharin solution was reduced by FG 7142 but it did not increase aversion to the quinine solution. Hence, FG 7142 did not generally increase the rejection of flavoured solutions in a two-bottle test. A previously proposed "proconflict" effect of FG 7142 is discussed, in the light of these results.     

Benzodiazepine receptor agonists and inverse agonists yield concordant rather than opposing effects on startle responses

Benzodiazepine receptor agonists and inverse agonists exert generally opposite actions at both the cellular and behavioural levels. The present study, however, reveals that both the benzodiazepine receptor agonist, chlordiazepoxide and the partial inverse agonist, FG7142, yield a dose-dependent (2-16 mg/kg, i.p) reduction in the amplitude of the acoustic startle response in the rat. The similarity in drug effects on startle was not attributable to congruent effects on basal somatic activity, as chlordiazepoxide resulted in a dose-dependent decrease in activity whereas FG7142 was associated with a small but non-significant increase in activity. As these results contrast with the bidirectional actions of benzodiazepine receptor agonists and inverse agonists in behavioural tests of fear or anxiety, the neuronal mechanisms mediating the effects of benzodiazepine receptor ligands on the acoustic startle response may be distinct from those that underlie the specific fear- attenuating and potentiating actions, respectively, of benzodiazepine receptor agonists and inverse agonists.     

The effects of FG 7142 and RO 15-1788 on the release of punished responding produced by chlordiazepoxide and ethanol in the rat

Previous results in our laboratory have shown that both chlordiazepoxide and ethanol will release punished responding in a rat operant conflict test using incremental shock. In the present study, a benzodiazepine antagonist and a benzodiazepine inverse agonist were used to explore the neurochemical basis for this behavioral action. N-methyl--carboline-3-carboxamide (FG 7142) at high doses (20 and 40 mg/kg) produced suppression of both punished and unpunished responding, and reversed the release of punished responding produced by both chlordiazepoxide and ethanol, but only at doses that produced an effect on its own. FG 7142 thus acted to oppose the actions of both ethanol and benzodiazepines but in an additive, not interactive, manner. In contrast, RO 15-1788 produced no changes when injected by itself in doses as high as 12 mg/kg and reversed chlordiazepoxide-induced but not ethanol-induced release of punished responding. RO 15-1788 also reversed the decrease in punished responding produced by FG 7142. Results suggest that ethanol does not interact directly with the benzodiazepine binding sites on the GABA/benzodiazepine ionophore complex to produce its anxiolytic action.     

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.     

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.     

Discriminative stimulus properties of the benzodiazepine receptor antagonist flumazenil

Rats were trained to discriminate the stimulus properties of the benzodiazepine (BZ) receptor antagonist flumazenil using a conditioned taste aversion procedure. On drug trials, fluid-restricted rats were injected with flumazenil (32 mg/kg), given access to a 0.25% saccharin solution for 30 min, and injected with LiCl (1.8 mEq/kg IP). On saline trials, injections of saline bracketed the period of saccharin consumption. Acquisition of the discriminated taste aversion, as measured by differential effects of drinking between saline and drug trials, developed after only five pairings of flumazenil with the LiCl injections. Flumazenil did not alter saccharin consumption in unconditioned controls (N=9) that never received LiCl. The discrimination was also measured by flumazenil's ability to reduce the preference for saccharin over tap water using two-bottle choice tests. Flumazenil demonstrated dose-dependent generalization upon decreasing the training dose as low as 1 mg/kg. Two other BZ receptor antagonists of different chemical structure, CGS 8216 and ZK 93426, substituted completely for the flumazenil stimulus. Partial generalization was exhibited to the partial inverse agonists FG 7142 and beta-CCE, while the full inverse agonists DMCM and PTZ failed to substitute for the flumazenil stimulus. The BZ receptor agonists diazepam and alprazolam failed to substitute for the flumazenil stimulus, although partial generalization was shown with CDP. The results suggest that the BZ receptor antagonist flumazenil may produce intrinsic discriminative stimulus effects that are independent from those of BZ receptor agonists or inverse agonists.     

Ro 15-4513, like anxiogenic beta-carbolines, increases dopamine metabolism in the prefrontal cortex of the rat

The effects of Ro 15-4513, FG 7142 and beta-CCM on the activity of the mesocortical dopaminergic system were examined by measuring the changes in the content of the principal dopamine (DA) metabolite, dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex of the rat. Ro 15-4513 increased the DOPAC content in the prefrontal cortex in a dose-dependent manner (5-40 mg/kg i.p.) but had no effect on DA concentrations. A similar increase in DOPAC content was induced by FG 7142 (40 mg/kg i.p.) and beta-CCM (8 mg/kg s.c.), two beta-carboline derivatives that interact with benzodiazepine recognition sites as partial inverse agonists. These effects of Ro 15-4513, FG 7142 and beta-CCM on DA metabolism in the prefrontal cortex are mediated via benzodiazepine recognition sites, since they were prevented by the administration of the benzodiazepine antagonists Ro 15-1788 and ZK 93426. These data indicate that Ro 15-4513 is an inverse agonist at benzodiazepine recognition sites.     

Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference

This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP) + ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.     

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.