Anticonflict Effect Research Articles

Characterization of the anticonflict effect of MK-801, a non-competitive NMDA antagonist.

Brain serotonergic, noradrenergic and GABAergic mechanisms are all involved in the regulation of conflict behaviour, and the GABAA/benzodiazepine receptor complex may play the most central role in this context. Since facilitation of GABAergic inhibitory transmission produces anticonflict effects, it has been suggested that antagonism of excitatory inputs may serve the same cause, and, indeed, blockade of excitatory neurotransmission mediated via N-methyl-D-aspartate (NMDA), receptors, produces anticonflict effects. In the present study, using a modified Vogel's rat conflict model, we have investigated whether the anticonflict effect of the non-competitive NMDA antagonist MK-801 can be linked to NMDA receptor blockade, and if stimulation of these receptors instead produces proconflict effects. The tentative involvement of noradrenergic, serotonergic or GABAergic effects in the MK-801-induced anticonflict effect was also studied. MK-801 produced a dose-dependent and specific anticonflict effect (maximal effect after 0.05 mg/kg, intraperitoneally, -90 min.). This anticonflict action was completely counteracted by NMDA in a dose (0.125 microgram, intracerebroventricularly) not affecting behaviour per se. The highest dose tested of NMDA alone (0.5 microgram) tended to produce a proconflict effect, but this action may be unspecific due to concomitant drug-induced motor-inhibition. Neither bicuculline and picrotoxin, antagonists at the GABAA/benzodiazepine receptor complex, nor the adrenoceptor antagonists propranolol and prazosin significantly altered the MK-801-induced anticonflict effect, whereas L-5-HTP (50 mg/kg, intraperitoneally, after inhibition of peripheral decarboxylation with benzerazide) completely abolished the anticonflict effect of MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of postsynaptic 5-HT 1A receptors in the anticonflict effect of ipsapirone

In the present paper we have studied the anticonflict effect (in the Vogel test) of ipsapirone, a partial agonist of 5-hydroxytryptamine A (5-HT 1A) receptors, administered to the hippocampus of rats. In addition, a comparison of the effect of ipsapirone with the effect of other 5-HT 1A receptor ligands (busipone, gepirone and 8-OH-DPAT) has been carried out. Finally, the interaction between ipsapirone and NAN-190 (an antagonist of 5-HT 1A receptors and α 1-adrenoceptors) has also been examined. It has been found that ipsapirone injected intrahippocampally (i.hp.) in doses of 0.3, 1 and 3 μg (bilaterally) shows an anticonflict effect by increasing the number of punished licks by about 36, 151 and 109%, respectively. A similar effect has also been found after i.hp. injections of buspirone (0.3–3 μg), gepirone (3–30 μg) and 8-OH-DPAT (0.3–3 μg). We have also demonstrated that the anticonflict effect of ipsapirone injected i.hp. is antagonized by NAN-190 administered i.hp. (0.3 or 1 μg) or intraperitoneally (i.p., 1 mg/kg). Futhermore, NAN-190 injected i.hp. (0.3 μg) antagonizes the anticonflict effect of ipsapirone administered i.p. (5 mg/kg). At the same time, the anticonflict effects of ipsapirone are not affected by prazosin (0.3–1 μg i.hp. or 0.5–1 mg/kg i.p.), a selective antagonist of α 1adrenoceptors. Our results seem to indicate that the anticonflict effect of ipsapirone stems from stimulation of postsynaptic 5-HT 1A receptors in the hippocampus.

Anti-conflict effect of 5-HT1A agonists in rats: a new model for evaluating anxiolytic-like activity

A new conflict procedure was developed to study the potential anti-punishment effects of 5-HT( 1A) agonists as compared to diazepam. In this paradigm, the opportunity existed for rats to choose during punished periods between immediate, punished reinforcement and delayed, non-punished reinforcement. The results confirm that, for non-sedative doses (1 mg/kg), diazepam increases the number of punished responses. Furthermore, the present paradigm seems sensitive for the detection of 5-HT(1A) activity. Buspirone, gepirone, ipsapirone, zalospirone and 8-OH-DPAT increased responding for immediate but punished reinforcement. 1-(2-pyrimidinyl)piperazine, the common metabolite of the azapirones, does not participate in their anti-conflict effect. NAN 190, a 5-HT(1A) antagonist, was shown to block the 5-HT(1A) agonists. The findings of the present study suggest that benzodiazepines and 5-HT( 1A) agonists reduce the capacity to tolerate delays in reward. Abnormality in serotonin systems may be associated with poor impulse control.

The role of 5-hydroxytryptamine 1A (5-HT 1A) receptors in the anticonflict activity of β-adrenoceptor antagonists

Using the conflict drinking test as a model, we studied in rats the effect of the nonselective β-adrenoceptor blockers pindolol and cyanopindolol which bind to 5-HT 1A and 5-HT 1B receptors, and of the selective β 1- and β 2-adrenoceptor antagonists betaxolol and ICI 118,551, respectively, which have a negligible affinity for 5-HT receptors. Both pindolol (2.0–8.0 mg/kg) and cyanopindolol (0.5–2.0 mg/kg) showed an anticonflict effect, having dose dependently increased the number of punished licks. On the other hand, neither betaxolol nor ICI 118,551-administered separately or in combination-affected the punished responding. The anticonflict effects of pindolol and cyanopindolol were completely abolished by the 5-HT 1A receptor and α 1-adrenoceptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phtalimmido)buty]piperazine (NAN-190), but were not modified by the selective α 1--adrenoceptor antagonist prazosin. The effects of pindolol and cyanopindolol were also not modified in animals with lesions of 5-HT neurons, produced by p-chloroamphetamine (PCA). Moreover, it was also found that the anticonflict effects of pindolol and cyanopindolol in PCA-pretreated rats were antagonized by NAN-190 but not prazosin. Our results indicate that the anticonflict effects of pindolol and cyanopindolol depend on their agonist action on postsynaptic 5-HT 1A receptors.

Effects of olanzapine and other antipsychotic agents on responding maintained by a conflict schedule.

The effects of the "atypical" antipsychotic olanzapine and several other antipsychotics were examined using a conflict schedule. Rats were trained to respond for food on a three-component schedule, comprising variable-interval 30s (food, VI30) and fixed-ratio 10s (food + shock, FR10) components separated by time-out (TO). Olanzapine (0.3125-1.25mg/kg), clozapine (1.25-5mg/kg) and chlordiazepoxide (2.5-5mg/kg) decreased or had no effect on VI30 responding, whereas responding in the FR10 component increased. Chlordiazepoxide (5mg/kg) also increased TO responding. The antipsychotic agents haloperidol (0.125 and 0.25mg/kg), trifluoperazine (0.0625-0.25mg/kg), remoxipride (1.25-5mg/kg) and risperidone (0.0625-0.5mg/kg) decreased V130 responding and either had no effect, or decreased TO and FR10 rates. The anticholinergic agent scopolamine (0.03125-0.25mg/kg) decreased VI30 responding. The 5-HT(2) antagonist ritanserin (2.5 and 5mg/kg) and the anticholinergic agent trihexyphenidyl (2.5 and 5mg/kg) had no effect on responding. Flumezanil (10mg/kg) reduced the anticonflict effect of chlordiazepoxide but not olanzapine. These results further emphasize the unusual profile of olanzapine.

Antagonism of diazepam's anticonflict effects in rats by nicotine, but not by arecoline

AbstractThe purpose of the present study was to determine the possible role of cholinergic mechanisms in the anticonflict effects of the anxiolytic diazepam. Male Sprague‐Dawley rats were tested with a modified Geller‐Seifter procedure using a multiple reinforcement schedule in which unpunished responding in one component was reinforced according to a fixed‐interval 60‐sec schedule, and punished responding in the other component resulted in both food and a brief electric shock presentation according to a fixed‐ratio 1 schedule. In Experiment 1 (−)‐nicotine antagonized the increase in punished responding that was produced by diazepam. In Experiment 2 diazepam produced selective increases in punished responding that again was antagonized by (−)‐nicotine, a nicotinic cholinergic agonist, whereas arecoline, a muscarinic cholinergic agonist, did not antagonize diazepam's increase in punished responding. Neither drug produced any significant changes in unpunished responding. In Experiment 3 it was shown that the centrally acting nicotinic antagonist, mecamylamine, was able to block nicotine's antagonism of diazepam. These results suggest that there is an interaction between central nicotinic cholinergic mechanisms and diazepam's anticonflict effects in this animal model for anxiolytics, and support clinical observations that smoking can reduce some effects of benzodiazepines. © 1994 Wiley‐Liss, Inc.

Anticonflict action of chlordiazepoxide in rats with combined lesions

Lesions of brain areas thought to promote anxiety do not diminish the anticonflict effects of benzodiazepines (BZDs). After initial training in the lick-suppression conflict test, eight rats received electrolytic lesions of the amygdala, dorsal raphe, locus coeruleus, and mammillary bodies. Ten others received sham lesions. Postoperative testing revealed a significant increase in punished licking at two stages after surgery in lesioned animals when compared with their own preoperative baseline levels and with the punished licking of control animals. Systemic administration of chlordiazepoxide (CDP, 2.5–10.0 mg/kg) resulted in a comparable dose-dependent increase in punished licking in both groups. These results suggest that the several structures lesioned need not be intact for CDP to have an antianxiety effect. It appears that sites of anxiolytic action are much more widely spread than currently believed and that other brain areas should be considered.

Perinatally protein-deprived rats and reactivity to anxiolytic drugs in the plus-maze test: An animal model for screening antipanic agents?

Adult rats submitted to a protein deprivation schedule at perinatal age (from 14th day of fetal life until 50 days of age) and then recovered on balanced chow (D rats) were assayed in the elevated plus-maze test for anticonflict effects of diazepam and drugs with therapeutic efficacy in panic disorders as compared with controls (C rats). Diazepam and alprazolam showed a similar anticonflict effect in D rats than in C rats. In contrast, buspirone, which was ineffective in C rats at a wide dosage range, showed a significant anticonflict effect on D rats at 0.3 mg/kg. Neither propranolol, desipramine, nor phenelzine treatment (10 mg/kg/day during 3–7 days) induced anticonflict effect in C rats. Conversely, these treatments fostered a significant and selective anxiolytic effect on D rats. Such results underscore long-lasting alterations caused by early undernutrition, namely, changes in reactivity to the drugs assayed. In addition, perinatally deprived rats may represent a useful animal model for studying potential antipanic agents.

Anticonflict effects of buspirone and chlordiazepoxide in pigeons under a concurrent schedule with punishment and a changeover response.

A procedure was developed with pigeons to extend the experimental analysis of punished behavior and the effects of anxiolytic drugs. Under this procedure the completion of a fixed-ratio requirement on a changeover key switched between two variable-interval schedules of reinforcement that were programmed on a second response key. Under one schedule, correlated with a green keylight, key pecks produced only food; under the second schedule, correlated with a red keylight, key pecks produced both food and electric shock. Pigeons were switched into the component with shock if they did not enter that component within 5 min. Parameter values of the variable-interval schedules were manipulated systematically and the effects of two clinically active anxiolytic drugs, buspirone and chlordiazepoxide, were examined. Responding was suppressed during the component with shock (punishment) and, under non-drug conditions, pigeons infrequently switched into the punishment component; changeover responses occurred rapidly when switched into the punishment component. Both buspirone (0.1-3.0 mg/kg) and chlordiazepoxide (3.0-30 mg/kg) increased punished responding at doses that had little effect on unpunished responding; d-amphetamine (0.3-5.6 mg/kg), which was studied only under one parameter of the variable-interval schedule, produced greater decreases in rates of punished responding than in unpunished responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Dihydroergosine: anticonflict effect in rats and enhancing effects on [ 3H]muscimol binding in the human brain post mortem

The anticonflict activity of the ergot alkaloid, dihydroergosine, a drug which binds to 5-hydroxytryptamine 1 (5-HT 1) receptors and to γ-aminobutyric acid A (GABA A) receptor-associated Cl − ionophore, was studied in water-deprived rats. In vitro effects of this drug on [ 3H]muscimol and [ 3H]flunitrazepam binding to the crude synaptosomal pellet of the human frontal cortex post-mortem were also investigated. Dihydroergosine, given 2 h prior to testing, enhanced drinking under punished (0.8 mA) conditions, and diminished it under unpunished conditions. The mechanism of this effect was (−)-propranolol- and pindolol-in-sensitive and picrotoxin-sensitive. Flumazenil either failed to affect, or at a higher dose (10 mg/kg), counteracted the dihydroergosine-induced enhancement of punished drinking. This dose of flumazenil was itself anxiogenic. Dihydroergosine had mild sedative and analgesic properties. Low concentrations of dihydroergosine (10 nM to 100 μM) enhanced the binding of [ 3H]muscimol but not of [ 3H]flunitrazepam. The results suggest that dihydroergosine may possess anxiolytic properties presumably mediated by its specific action at the GABA/benzodiazepine/chloride channel complex.

Effects of Menatetrenone on Bone Loss Induced by Ovariectomy in Rats

The anxiolytic effects of buspirone and its major metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP) have been investigated with a conflict (shock-induced suppression of drinking) paradigm in rats. Buspirone (10 mg/kg, p.o.) showed an anticonflict activity with a bell-shaped dose-response relationship without any effect on spontaneous water consumption. Higher doses of buspirone reduced the punished response. Diazepam (20 and 40 mg/kg, p.o.) also showed an anticonflict activity in a dose-dependent manner, but animals with diazepam showed an increase in spontaneous water consumption at these doses. On the other hand, 1-PP (6.25-200 mg/kg, p.o.) showed a weak anticonflict activity with a significant effect at 25 mg/kg without any effect on spontaneous water consumption. In the 7-day treatment test, buspirone (5 and 10 mg/kg, p.o.), 1-PP (5 and 25 mg/kg, p.o.) and diazepam (10 and 40 mg/kg, p.o.) did not develop the tolerance to the anticonflict activity. Conversely, the anticonflict activity of diazepam was increased by the repeated treatment. Diazepam (10 mg/kg, p.o.) showed an anticonflict activity without any effect on spontaneous water consumption in this test. These results demonstrated that buspirone clearly exhibited an anticonflict effect similar to that of diazepam in a Vogel-type conflict test, and its real anxiolytic effect may not be always based on 1-PP, the main metabolite of buspirone.

Comparison of alcohol-preferring (P) and nonpreferring (NP) rats on tests of anxiety and for the anxiolytic effects of ethanol

Rats of the selectively bred alcohol-preferring P and alcohol-nonpreferring NP lines were evaluated using three different behavioral measures of anxiety. Compared with NP rats, P rats (1) showed greater footshock-induced suppression of operant responding in an approach-avoidance conflict test; (2) spent less time in the open arms of an elevated plus maze; and (3) took longer in a passive avoidance test to step down from a platform to a grid floor where footshock was received 24 hours earlier. These findings indicate a greater degree of anxiety in the P than in the NP line of rats in these situations. Pretreatment with intraperitoneal (IP) ethanol (0.5–1.0 g/kg) injections produced anticonflict or anxiolytic effects in P but not in NP rats. However, the anticonflict effects of ethanol were small relative to those produced by chlordiazepoxide (CDP, 7.5 mg/kg) in both lines. The results demonstrate that selective breeding for divergent oral ethanol preference has produced associated differences between the P and NP lines of rats in behavioral tests of anxiety and in the anxiolytic effects of ethanol.

Neurochemical effects of 5-HT 1 receptor ligands in pigeons

Pigeon cerebrospinal fluid was assayed for 5-HT (5-hydroxytryptamine) and catecholamine metabolites after systemic drug injection. The 5-HT 1-like receptor agonist 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), and 1-(3-chlorephenyl)piperazine (mCPP) decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) without altering other metabolites. 5-HIAA decreases occured at doses of 8-OH-DPAT and RU 24969 that have anti-conflict effects in pigeons, whereas TFMPP and mCPP decreased 5-HIAA only at behaviorally disruptive doses. The novel compound 1-(2-methoxyphenyl)-1-(4-(2-phthalimido)butyl)piperazine (NAN-190), a putative 5-HT 1A receptor antagonist, did not affect 5-HIAA, but attenuated the decreases produced by the agonists. NAN-190 and the α 1-adrenoceptor antagonist prazosin increased levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol and had additive effects when co-administered. The rank order of potency in inhibiting [ 3H]8-OH-DPAT binding in pigeon cerebrum was 8-OH-DPAT = RU 24969 > NAN-190 ⪢mCPP>TFMPP. The results support suggestions that decreased 5-HT neurotransmission underlies the anxiolytic-like effects of 5-HT 1A receptor agonists in pigeons.

Anxiolytic-like effects of alpha-2-adrenoceptor agonists on conflict behavior in the rat: Pre- versus postsynaptic receptor mechanisms

The effects of acute pretest administration and chronic posttest administration of clonidine or the selective α 2-adrenoceptor agonist UK-14,304 on conflict behavior were investigated. In daily 10-min sessions, water-deprived rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. Prior to treatment, subjects accepted 25–30 shocks/session (punished responding) and consumed approximately 12–15 ml/session (unpublished responding). Acute pretest administration of clonide or UK-14,304 did not increase punished responding. In contrast, chronic posttest clonidine administration (40 μg/kg, IP, twice daily for 8 weeks) resulted in a robust and time-dependent increase in punished responding (60–70 shocks/session) relative to saline-treated controls. Moreover, the selective α 2-adrenoceptor agonist UK-14,304 also increased punished responding when administered chronically (1.0 mg/kg, BID). Administration of the noradrenergic neurotoxin N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine HCl (DSP4, 65 mg/kg, IP) significantly decreased punished responding in control conditioned suppression of drinking sessions. The anticonflict effect associated with chronic posttest clonidine treatment was not altered by DSP4 pretreatment. These findings suggest that chronic posttest α 2-adrenoceptor agonist treatment produces an anticonflict effect independent of its actions at presynaptic α 2-adrenoceptors.

Role of the central serotonergic system in the anticonflict effect of d-AP159

d-AP159 is a d-optical isomer, and in rats it has a high affinity for 5-hydroxytryptamine1A (5-HT1A) receptors and potent anticonflict activity, equal to that of buspirone. The anticonflict effects of d-AP159 and buspirone were investigated in animals in which lesions of the serotonergic neurons were caused by intradorsal raphe (d-RA) injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). The anticonflict effect of buspirone, but not that of d-AP159, was attenuated in 5-HT neuron-lesioned rats. The anticonflict effect of d-AP159 injected into various brain sites was also studied. d-AP159 and buspirone microinjected into the d-RA caused significant anticonflict activity in rats. There was a significant anticonflict effect of d-AP159 injected into the amygdala centralis (ACE), but not the dorsal hippocampus (d-HC). The anticonflict effect of d-AP159 injected into the d-RA was antagonized by systemic administration of (−)propranolol but not Ro 15-1788. This effect of d-AP159 injected into the ACE was antagonized by systematic administration of Ro 15-1788 but not (−)propranolol. These results suggest that the d-RA and the ACE play important roles in the anticonflict effects of d-AP159 but that the mechanisms by which this drug acts at these sites are different.

Perinatal Protein Deprivation Enhances the Anticonflict Effect Measured after Chronic Ethanol Administration in Adult Rats

The anticonflict effects of ethanol, diazepam and pentobarbital were evaluated in adult rats fed a low protein diet during the perinatal period in the plus-maze test, after single injections and following chronic ethanol administration (1 g·kg-1·d-1 for 30 d). Reactivity to the anticonflict effect of these drugs was similar in control and protein-deprived rats after acute treatment. After chronic ethanol administration, control rats showed tolerance to ethanol and cross-tolerance (i.e., lower reactivity) to the anxiolytic effect of diazepam and pentobarbital. Conversely, protein-deprived rats showed greater reactivity to ethanol and lack of cross-tolerance to diazepam and pentobarbital following chronic ethanol treatment. A significantly greater density of cortical γ-aminobutyric acid receptors subtype A (GABA-A) was detected in protein-deprived rats after chronic ethanol administration compared with the density after chronic saline treatment, whereas no differences were observed in nourished controls. This suggests that the greater anxiolytic activity detected in protein-deprived rats may correlate with higher GABA-A receptor density.

Direct evidence for mediation of an anticonflict effect of baclofen by GABAb receptors

The present article reports an experiment on the effects of baclofen (0, 0.5, 1.0, and 2.0 mg/kg) on punished drinking in rats and the modification of these by delta-amino- n-valeric acid (DANVA) (0 and 10.0 mg/kg). Baclofen significantly enhanced punished drinking and this increase was abolished by DANVA, which had no intrinsic anxiogenic activity. It is concluded that GABAb receptors probably mediate this effect of baclofen and that such receptors may be a potential site of anxiolytic drug action.

Schedule dependence of the interaction of naloxone and chlordiazepoxide

Reports that the opiate antagonist, naloxone, blocks the anticonflict effects of diazepam and chlordiazepoxide suggest endogenous opioid involvement in the anxiolytic actions of the benzodiazepines. However, naloxone's ability to antagonize the anticonflict effects of the benzodiazepines is not universal, but schedule specific. The present experiments investigated the importance of the timing of conflict periods and control of reinforcement on the naloxone-benzodiazepine interaction. We tested the effects of naloxone (3 mg/kg, IP) and chlordiazepoxide (5 mg/kg, IP) on acquisition of a successive discrimination schedule, with nonreward periods similar in length and frequency to those of signalled DRL, and on an FI60-s schedule, Chlordiazepoxide increased rewarded responding and, unexpectedly, decreased nonrewarded responding during acquisition of successive discrimination. This reduction in nonrewarded responding was reversed by naloxone. Under the FI60 schedule, chlordiazepoxide increased nonrewarded responding, an effect that was totally blocked by naloxone at the beginning of the FI. Naloxone's ability to reverse the response-releasing effect of chlordiazepoxide decreased later in the FI. These results suggest endogenous opioid systems are involved in the anxiolytic actions of the benzodiazepines when the animal is adapting to recently introduced conflict. Once adaptation occurs, other neurotransmitter systems mediate the actions of the benzodiazepines.

Effects of alprazolam on anxiety-related behavior of rats in a modified forced-swim test employing straw suspension

The present study was undertaken to examine how the triazolobenzodiazepine derivative, alprazolam, which processes anxiolytic activity in man and anticonflict effects in animals, could affect both the duration of immobility and the incidence of straw-climbing behavior of rats in a modified forced-swim (MFS) test. After a 5-min test of forced swimming, four straws were suspended just above the surface of the water and subsequently the straw-climbing trials were counted for 5 min as an index of escape behaviors induced by negative emotionality (anxiety and/or fear). Rats were injected IP with either alprazolam (0.1, 0.2, 1, and 2 mg/ kg) or its vehicle 30 min before testing. Alprazolam prolonged the duration of immobility and inhibited the straw-climbing counts in a dose-dependent manner. This effect is in the same direction as the effect shown by an anxiolytic benzodiazepine such as diazepam. The results suggest that alprazolam may possess anxiolytic effects at lower doses, whereas at a high dose of 2 mg/kg this compound might elicit sedation, concomitantly with its anxiolytic and/or antipanic effects. In addition, it appears that alprazolam is more potent than diazepam in the MFS test following a single-injection protocol.

The 5,7-DHT-induced anticonflict effect is dependent on intact adrenocortical function

We have recently reported that the anxiolytic-like effect observed in rats severely depleted of brain serotonin (5-HT) by means of 5,7-DHT is indirect and probably involves the GABA A/benzodiazepine chloride ionophore receptor complex (GABA A/BDZ-RC). One tentative explanation for this effect considered the involvement of corticosteroids. In the present series of experiments we have therefore investigated the effect of adrenalectomy (ADX) on the 5,7-DHT-induced anxiolytic-like effect displayed by rats in Vogel's conflict test. ADX totally abolished the anticonflict effect of the 5,7-DHT lesion. Replacement treatment with corticosterone, but not with dexamethasone, reinstated the anticonflict effect. These results indicate that an intact adrenocortical function, possibly via brain steroid type I receptors, is required for the expression of the 5,7-DHT-induced anxiolytic-like effect. It is postulated that ADX lowers the concentration of endogenous positive modulators at the GABA A/BDZ-RC to a level no longer sufficient to produce anxiolytic-like effects in 5,7-DHT-lesioned animals. The finding that 5,7-DHT-lesioned animals were more sensitive than sham-lesioned controls to the anticonflict effect of the barbiturate-like corticosteroid THDOC provides further support for the contention that an increased endogenous activity at the GABA A/BDZ-RCes is involved in the anxiolytic-like effect observed in rats with a severe depletion of brain 5-HT.