Effects Of Benzodiazepine Receptor Ligands Research Articles

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.

Social approach–avoidance behavior of a high-anxiety strain of rats: effects of benzodiazepine receptor ligands

To better understand anxiety disorders with social impairments as well as to identify new treatments, it is important to develop preclinical procedures involving social components of anxiety. Recently, a novel procedure was reported: the rat Social Approach-Avoidance (SAA) test. In this test, the time spent by a test rat in a large social compartment containing an unfamiliar stimulus rat reflects the anxiety state of the animal. It was shown that pre-stressing the test rat increased the avoidance of the social compartment as characterized by an increase in the time spent in the nonsocial compartment. (1) To use a high-anxiety strain, F-344 rats, instead of pre-stressed animals, (2) to automate the test by using video tracking to measure time spent in both compartments and their subdivisions, and (3) to validate this modified test with known benzodiazepine receptor ligands. F-344 rats were treated with either chlordiazepoxide or diazepam (benzodiazepine receptor agonists), or RO 19-4603 or FG 7142 (benzodiazepine receptor inverse agonists). The agonists produced anxiolytic-like effects, whereas the inverse agonists produced anxiogenic-like effects. These effects were most marked in the two extreme zones in terms of distance to the stimulus rat. F-344 rats display spontaneous avoidance behavior in the modified SAA procedure, and approach-avoidance behavior in these rats is sensitive to benzodiazepine agonists and inverse agonists in a bidirectional manner. The finding that the assessment of time spent into two virtual zones in each of the compartments markedly increased the sensitivity to both anxiolytics and anxiogenics will be discussed using the concept of physical defensive distance.

Effects of benzodiazepine receptor ligands and ethanol in rats trained to discriminate pregnanolone

Although GABA A receptor positive modulators share many behavioral effects, subtle differences have been detected among their discriminative stimulus effects. The purpose of the present study was to determine the extent of shared discriminative stimulus effects of pregnanolone with various benzodiazepine receptor ligands and with ethanol. Naive male Sprague–Dawley rats were trained to discriminate the endogenous neuroactive steroid pregnanolone (5.6 or 8.0 mg/kg) from vehicle. The benzodiazepine receptor agonists, triazolam and lorazepam, the benzodiazepine receptor partial agonist, bretazenil, the benzodiazepine1 (BZ1) receptor subtype selective agonists, zolpidem and zaleplon and ethanol were tested. Triazolam, lorazepam and bretazenil substituted for pregnanolone. Lorazepam, but not triazolam or bretazenil, decreased response rates at the highest dose tested. Zaleplon completely substituted for pregnanolone with no effect on response rates. Zolpidem substituted for pregnanolone only at a dose that severely disrupted response rates. Ethanol partially substituted for pregnanolone and decreased response rates. The results are consistent with GABA A receptor mediation of the discriminative stimulus effects of pregnanolone. The effects on response rates suggest subtle differentiation among the GABA A receptor-mediated cues.

Benzodiazepines in perspective (II): The GABAA-Benzodiazepine Receptor Ligands.

A huge number of natural and synthetic compounds modulate the function of the γ-aminobutyric acid type A receptor (GABAA-R) by interacting with several allosteric binding sites which may differ in the various GABAA-R subtypes. The benzodiazepine receptor (BDZ-R) is the most intensively studied allosteric site. It is the first allosteric modulatory site on a neurotransmitter receptor that has been found to mediate two opposite functions: facilitation and depression of GABAA-R function. The effects of BDZ-R ligands on behavior range from agonistic (anxiolytic, anticonvulsant, myore-laxant/ataxic and hypno-sedative effects) to inverse-agonistic (anxiety and panic, hypervigilance and convulsions). Of particular interest for the future are BDZ-R partial agonists, as they lack several of the undesired properties of classic full agonists. Furthermore the GABAA-R system shows a high plasticity. This polymorphism raises the possibility that ligands selective for distinct subtypes of BDZ-R may emerge as useful drugs. In both cases the possibility exists of achieving very subtle manipulations of GABAA-R function by using allosteric modulators.

New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes.

It has been suggested that different BZ (omega) receptor subtypes may mediate distinct behavioural effects of BZ receptor ligands. The present study examined this hypothesis further. The antagonism exerted by the selective BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor agonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed. beta-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (omega) receptor full agonist diazepam and the selective BZ(1) (omega(1)) receptor full agonist zolpidem against seizures produced by isoniazid, but beta-CCT failed to affect their action on seizures produced by pentylenetetrazole (PTZ), suggesting that BZ(2) (omega(2)) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, beta-CCT abolished the anxiolytic-like action of diazepam. In tests designed to investigate the central depressant activity of drugs, beta-CCT antagonized the sedative effects of diazepam and zolpidem, but failed to modify clearly the myorelaxant effects of diazepam. These differences may be related to the selectivity of beta-CCT for BZ(1) (omega(1)) sites as indicated by the preferential displacement of [(3)H]flumazenil in BZ(1) (omega(1))-enriched structures as compared to BZ(2) (omega(2))-enriched structures in the mouse. In in vitro experiments, beta-CCT antagonized the potentiation of the GABA-induced Cl(-) current produced by zolpidem in HEK cells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purkinje neurones, while it failed to modify the diazepam potentiation at either alpha(3)beta(2)gamma(2) or alpha(5)beta(3)gamma(2) receptor subtypes. These results are consistent with the hypothesis that BZ(1) (omega(1)) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.

The role of the hippocampus and 5-HT/GABA interaction in the central effects of benzodiazepine receptor ligands.

The effects of an intrahippocampal administering of a nonselective full (midazolam), a partial benzodiazepine (BDZ) receptor agonist (bretazenil), and a BDZ1 selective (zolpidem) receptor ligand were examined in the open field test (OFT) of neophobia and Vogel's test (VT) of conflict behavior in rats. Moreover, the influence of local injections of a noncompetitive GABA(A) receptor antagonist, picrotoxin, on the anxiolytic-like effect of serotonin (5-HT) depletion (p-chlorophenylalanine, p-CPA) in the Vogel test was studied. It was found that in the OFT only midazolam (0.1 microg/site) given to the hippocampus (HP) disinhibited rat exploratory behavior, whereas all the examined compounds inhibited animal motor activity when injected locally at 10.0 microg/site, the highest dose used in the tests. In the VT, again, only midazolam disinhibited rat conflict behavior on a dose-dependent basis. Picrotoxin administered to the HP produced a tendency to increase locomotor activity in rats, and significantly attenuated the anti-conflict action of serotonin depletion without changing the pain threshold and spontaneous drinking of the animals. p-CPA induced potent, dose-dependent and selective 5-HT and 5-hydroxyindoleacetic acid decrease in the HP after administering the dose used in the behavioral experiment. Thus, the present data provide evidence for the lack of selective anxiolytic activity of a partial non-selective agonist and a full selective agonist at the BDZ1 receptor after their administration to the HP. The model of intra-HP drug injections appeared effective in discriminating the anxiolytic spectrum of activity of new psychotropic compounds. Moreover, the obtained results indicate that the dorsal HP is one of the central sites important for GABA/5-HT interaction that modulates rat emotional behavior.

A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: Comparison of quazepam and triazolam.

A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: Comparison of quazepam and triazolam.

Antiproliferative and differentiating effects of benzodiazepine receptor ligands on B16 melanoma cells

In this study, we evaluated the effect of several ligands active at the central-type and peripheral-type benzodiazepine receptor (BzR) (clonazepam, diazepam, PK11195 and Ro5-4864) on the growth and differentiation of B16 melanoma cells. All tested BzR ligands were able to suppress proliferation of the cells at the micromolar range and in a concentration-dependent manner. However, agents selectively active at the peripheral-type BzR (PK11195 and Ro5-4864) exhibited more potent antiproliferative activity. In addition, the BzR ligands were demonstrated to affect the cell cycle by reducing the percent of cells in the S phase and increasing the percent in the G2/M phase. BzR ligands induced cellular phenotypic alterations, which have been previously shown to be associated with melanoma cell differentiation. These alterations included: marked morphological changes, enhancement of melanogenesis, lipid accumulation and increase in the activity of γ glutamyl transpeptidase. All BzR ligands induced a marked reduction in the concentration of UTP and most of them did the same in GTP and CTP, while ATP levels were not significantly altered. In summary, BzR ligands (clonazepam, diazepam, PK11195 and Ro5-4864) were found to exert antitumor effects in B16 melanoma cells. These findings encourage further studies of a possible therapeutic potential of BzR ligands in treatment of melanoma.

Rat pup ultrasonic vocalization: effects of benzodiazepine receptor ligands

The involvement of the GABA A-benzodiazepine receptor complex in rat pup ultrasonic vocalisations was studied by testing benzodiazepine receptor ligands with varying intrinsic activity and selectivity for benzodiazepine subtype receptors. Ultrasonic vocalisations were recorded under two temperature conditions (37°C and 18°C), presumably reflecting a low and high stress state. The latency to the negative geotaxis response, a measure of motor coordination and the rectal temperature were determined to assess putative side effects of drugs. The full, non-selective benzodiazepine receptor agonists diazepam, chlordiazepoxide, alprazolam and oxazepam suppressed ultrasonic vocalisations both at 37°C and 18°C conditions, although more efficaciously at 37°C. The partial, non-selective benzodiazepine receptor agonist bretazenil and the partial benzodiazepine 1 selective receptor agonist alpidem significantly reduced ultrasonic vocalisations at 37°C, but not at 18°C. The full benzodiazepine 1 selective receptor agonist zolpidem behaved like other full, non-selective benzodiazepine receptor agonists by reducing ultrasonic vocalisations under both high and low temperature. The effects of zolpidem indicate that activation of benzodiazepine 1 receptors alone already suffices to suppress ultrasonic vocalisations. The non-selective, benzodiazepine receptor antagonist flumazenil and the partial, non-selective benzodiazepine receptor inverse agonist FG 7142 ( N′-methyl-β-carboline-3-carboxamide) and the full, non-selective benzodiazepine receptor inverse agonist DMCM (6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) had no significant effect on ultrasonic vocalisations under both temperature conditions. The involvement of benzodiazepine receptors in rat pup ultrasonic vocalisations (37°C-condition) was confirmed by antagonism of the ultrasonic vocalisations reducing effects of chlordiazepoxide by flumazenil (1 or 3 mg/kg). Using the rat pup ultrasonic vocalisations paradigm under 18°C and 37°C conditions combined with measurements of negative geotaxis-latencies and rectal temperatures it is possible to (1) distinguish benzodiazepine receptor agonists from other anxiolytics because of dissimilar dose response curves at 37°C and 18°C, (2) differentiate partial from full receptor agonists by absence of effects at the 18°C condition, (3) suggest a key role for benzodiazepine 1 receptors in the modulation of ultrasonic vocalisations. These data contribute to the predictive validity of pup vocalizations as an animal model of anxiety.

Comparison of responses of spontaneously active cells in the cerebellar purkinje layer to parallel fibre stimulation in slice preparations and urethane-anaesthetised rats: Effects of benzodiazepine receptor ligands

1. 1. GABA-mediated inhibitory responses were induced in spontaneously active Purkinje cells by parallel fibre stimulation in cerebellar slices or in urethane-anaesthetised rats. Effects of agonist and inverse agonist benzodiazepine (BDZ) receptor ligands were compared in the preparations. 2. 2. Purkinje cells fired simple spikes at higher rates in slice preparations while complex spikes were seldom ( in vivo) or never observed (slice). Cells fired more regularly in vivo resulting in the occurrence of rhythmic postinhibitory responses in the PSTH analysis in some preparations. 3. 3. Single pulse stimulation of parallel fibres at just suprathreshold intensity induced inhibition of Purkinje cell activity in both preparations. At lower firing rates there was a marked increase in the duration of this response, which was more evident in vivo where more slowly firing cells were encountered. 4. 4. BDZ receptor ligands modified inhibitory responses in slice preparations with only weak effects on the firing rates of the cells. These compounds predominately induced changes in firing rate in the anaesthetised rat with little evidence of direct modification of GABA-mediated synaptic transmission. 5. 5. In a few experiments, following injection of the partial inverse agonists β-CCE and β-CCM, block of the inhibitory response was observed independent of changes in firing rate. Bidirectional efficacy of BDZ receptor ligand (agonists decrease firing and increase inhibitory response, inverse agonists increase firing and decrease inhibitory response) was demonstrated for modulation of inhibitory responses in slices and for changes in firing rate in vivo. The increased firing rate response in vivo was biphasic the magnitude of the later phase being correlated with efficacy of inverse agonists. 6. 6. It is concluded that cerebellar slice preparations are more appropriate for studying direct effects of BDZ receptor ligands on GABA-mediated synaptic inhibition than in vivo preparations.

Effects of benzodiazepine receptor ligands on the ingestion of sucrose, intralipid, and maltodextrin: An investigation using a microstructural analysis of licking behavior in a brief contact test.

Effects of benzodiazepine receptor ligands on the ingestion of sucrose, intralipid, and maltodextrin: An investigation using a microstructural analysis of licking behavior in a brief contact test.

Effects of benzodiazepine receptor ligands on the ingestion of sucrose, intralipid, and maltodextrin: an investigation using a microstructural analysis of licking behavior in a brief contact test.

Microstructural analysis of licking behavior in the rat was conducted (a) to describe in detail the characteristics of benzodiazepine-induced changes in ingestion and (b) to determine if the changes are consistent with an alteration in palatability. The effects of the benzodiazepine receptor (BZR) agonist midazolam (0.3-3 mg/kg), and the partial inverse agonist Ro 15-4513 (0.3-3 mg/kg), on licking for several concentrations of sucrose, Intralipid, and maltodextrin in a brief contact test were investigated. Midazolam increased the total number of licks for all 3 fluids; conversely, Ro 15-4513 decreased the total number of licks. Midazolam increased mean bout duration for sucrose and maltodextrin drinking and there was a trend toward a similar effect with Intralipid drinking. Ro 15-4513 reduced mean bout duration for all 3 test fluids. These data are discussed in terms of bidirectional changes in fluid palatability by drug actions at BZRs.

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.

P-483 - Effects of benzodiazepine receptor ligands on changes in rat cerebral cortex electroencephalogram induced by psychological stress.

P-483 - Effects of benzodiazepine receptor ligands on changes in rat cerebral cortex electroencephalogram induced by psychological stress.

Primate displacement activities as an ethopharmacological model of anxiety.

Using a within-subject cross-over, vehicle-controlled design, we investigated the acute effects of benzodiazepine receptor ligands with different mechanisms of action on the displacement activities (scratching, self-grooming, and body shake) of seven male macaques living in social groups. Our aim was to test the discriminative validity of displacement activities as an ethopharmacological model of anxiety. Subjects were given i.m. lorazepam (0.10, 0.20, 0.25 mg/ kg) and FG 7142 (0.1, 0.3, 1.0 mg/kg). The frequency of displacement activities was decreased by the anxiolytic lorazepam and increased by the anxiogenic FG 7142 in a dose-dependent manner. Displacement activities were apparently more sensitive to anxiolytic treatment than other behavior patterns indicative of an anxiety state (i.e., visual scanning of the social environment and fear responses directed to dominant males). These results suggest that primate displacement activities are a valid ethopharmacological model of anxiety.

Effects of benzodiazepine receptor ligands on isolated rat superior cervical ganglia neurons.

We studied the effects of diazepam, CL 218,872, Ro 15-1788, beta-CCM and Ro 15-4513 on the gamma-aminobutyric acid-activated current in adult and newborn rat superior cervical ganglion neurons. Diazepam (10-1,000 nmol/l) potentiated the current in a concentration-dependent manner. CL 218,872 was less effective and weaker than diazepam. The other ligands reduced the amplitude of the current. These peripheral receptors might be involved in some of the side effects of benzodiazepines.

Biological function of GABA A/benzodiazepine receptor heterogeneity

γ-Aminobutyric acid (GABA) is the most prominent of the inhibiting neurotransmitters in the brain. It exerts its main action through GABA A receptors. The receptors respond to the presence of GABA by the opening of an intrinsic anion channel. Hence, they belong to the molecular superfamily of ligand-gated ion channels. There exist in the brain multiple GABA A receptors that show differential distribution and developmental patterns. The receptors presumably form by the assembly of five proteins from at least three different subunits (α1–6, β1–3 and γ1–3). The regulation of functional properties by benzodiazepine (BZ) receptor ligands, neurosteroids, GABA and its analogs differs dramatically with the α variant present in the complex. Additional variation of the GABA A receptors comes with the exchange of the γ subunits. No clear picture exists for the role of the β subunits, though they may play an important part in the sensitivity of the channel-receptor complex. The effects of BZ receptor ligands on animal behavior range from agonist effects, e.g. anxiolysis, sedation, and hypnosis, to inverse agonist effects, e.g. anxiety, alertness, and convulsions. The diversity of effects reflects the ubiquity of the GABA A/BZ receptors in the brain. Recent data provide some insight into the mechanism of action of BZ ligands, but no clear delineation can be drawn from a single ligand to a single behavioral effect. This may be due to the fact that intrinsic efficacies of the ligands differ between receptor subtypes, so that the diversity of native receptors is further complicated by the diversity of the mode the ligands act on GABA A receptor subtypes. The behavioral actions of alcohol (ethanol) are similar to those produced by GABA A receptor agonists. In agreement, alcohol-induced potentiation of GABAergic responses has often been observed at behavioral, electrophysiological and biochemical levels. Thus, there is clearly a GABA A-dependent component in the actions of alcohol. However, the site and mode of action of ethanol on GABA A/BZ receptors remain controversial.

Benzodiazepine receptor ligands modulate ethanol drinking in alcohol-preferring rats

The effects of benzodiazepine receptor ligands with different intrinsic activity profiles were studied on voluntary ethanol consumption in the selectively bred alcohol-preferring AA (Alko, Alcohol) rat line, and compared to those of an opiate antagonist, naloxone, and a serotonin uptake inhibitor, citalopram. The rats were first allowed to develop a strong preference for 10% (v/v) ethanol solution in tap water over plain water until their ethanol consumption stabilized. Thereafter, the period when ethanol solution was available for the rats was gradually reduced to 4 h, 3 times a week, every second working day. The acute effects of positive allosteric modulators (agonists) of the γ-aminobutyric acid type A (GABA A)/benzodiazepine receptor [midazolam, abecarnil, ethyl 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylate (ZK 91296), bretazenil, and 2 2,5-dihydro-2-(4-methylphenyl)-3 H-pyrazolo[4,3-C]quinolin-3(5 H)-one (CGS 9895)] and of negative allosteric modulators [inverse agonists, ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4 H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (Ro 15-4513) and t-butyl 5,6-dihydro-5-methyl-6-oxo-4 H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate (Ro 19-4603)] were tested after i.p. injections of three different drug doses using saline injections as a control treatment. The benzodiazepine agonists had rather modest effects on ethanol intake, measured 1 and 4 h after the injections, whereas the inverse agonists and naloxone strongly decreased ethanol consumption. Acute citalopram had no clear effect on ethanol drinking, but it slightly decreased the consumption of novel food during the 4-h session, as did all other benzodiazepine agonists except bretazenil. Neither the inverse agonists nor naloxone had any significant effect on food intake. Three additional groups of rats were repeatedly administered fixed doses of either abecarnil, naloxone (both at 5 mg/kg, i.p.), or saline (1 ml/kg) before five consecutive sessions. Naloxone significantly decreased ethanol consumption at 1-h and 4-h measuring points, whereas abecarnil tended to increase the drinking at 4 h. Food consumption at 4 h was slightly decreased by both compounds. The results suggest that the GABA A receptor may be involved in the regulation of voluntary ethanol drinking in alcohol-preferring AA rats, but do not indicate that these rats would consume ethanol because of its anxiolytic effects in a way that benzodiazepine agonists (full or partial) could substitute for it.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of benzodiazepine receptor ligands on simultaneous visual discriminations of variable difficulty

Benzodiazepine receptor (BZR) ligands have been demonstrated to affect the performance in tasks measuring attentional abilities. In such tasks, subjects typically are required to discriminate visual and/or auditory stimuli. The possibility that the effects of BZR ligands on the performance in tasks measuring attention are primarily due to effects on discriminative processes has not been tested systematically. Rats were trained to discriminate between simultaneously presented pairs of visual stimuli flashing either at 5 Hz versus 4.17, 3.75, 2.5, 1.67 or 1.25 Hz (group 1; FAST), or at 1.25, 1.46, 1.67, 2.5 or 3.33 Hz versus 5 Hz (group 2; SLOW) for 4.8 s (20 trials per discrimination type; sequence of pairs was randomized). In both groups, response accuracy depended significantly on the discriminability of the stimuli, with near perfect accuracy in response to most different pairs of stimuli and near chance-level accuracy in response to least different pairs of stimuli. Administration of the BZR full agonist chlordiazepoxide (1.56, 6.25, 9.38 mg/kg; i.p.) potently increased the number of errors of omission which, following the higher doses, confounded the effects on absolute numbers of correct and incorrect responses. However, the available data do not suggest that the agonist affected the animals' abilities to discriminate between the stimuli. Similarly, administration of the BZR ligands ZK 93 426 and MDL 26,479 (which negatively modulate GABAergic transmission) produced no systematic effects. These data suggest that the effects of BZR ligands on the performance in tasks measuring attentional abilities are not primarily due to effects on the animals' ability to discriminate sensory stimuli.