Anxiolytic-like Effects In Rats Research Articles

The novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats without producing the adverse effects associated with benzodiazepines

We previously reported that a δ opioid receptor agonist SNC80 produced potent anxiolytic-like effects in rodents. Recently, we succeeded in synthesizing a novel δ opioid receptor agonist KNT-127. In this study, we investigated the anxiolytic-like effects of KNT-127 using three different rat models of innate anxiety. In an elevated plus-maze test, KNT-127 (0.3, 1, and 3.0 mg/kg, s.c.) significantly and dose-dependently increased the time rats spent in the open arms 30 min after administration. The magnitude of the KNT-127 (3.0 mg/kg, s.c.)-induced anxiolytic-like effects was similar to that produced by diazepam (1.0 mg/kg, s.c.), a benzodiazepine anxiolytic. The anxiolytic-like effects of KNT-127 (3.0 mg/kg, s.c.) were abolished by pretreatment with naltrindole (0.1 mg/kg, s.c.), a selective δ opioid receptor antagonist, suggesting that KNT-127-induced anxiolytic-like effects are mediated by δ opioid receptors. These findings were supported by results obtained from light/dark and open-field tests. Interestingly, in contrast to diazepam (1.0 mg/kg, s.c.), KNT-127 (3.0 mg/kg, s.c.) caused no significant performance changes in the Y-maze test, the ethanol-induced sleeping test, and footprint test. This is the first study to demonstrate that the novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats, without producing the adverse effects associated with benzodiazepines.

Genistein induces non-rapid eye movement sleep in mice

It has long been thought that the treatment of core anxiety symptoms will produce a satisfactory resolution of insomnia. Genistein, the principal isoflavone constituent of soybean, has been reported to exert anxiolytic-like effects in rats. Whether genistein modulates sleep behavior, however, remains to be elucidated. In the present study, we examined the effect of genistein on sleep wake profiles in freely moving mice by EEG and EMG recording as well as immunohistochemical staining for c-Fos. Our results showed that genistein administered i.p. at doses of 80 and 160 mg/kg significantly increased the amount of non-rapid eye movement (non-REMNREM) sleep and as well as the number of NREM sleep episodes, with a concomitant reduction of wakefulness. It increased the state transitions from wakefulness to NREM sleep and subsequently from NREM to wakefulness. However, genistein neither had an effect on the amount of REM sleep nor on EEG power density of NREM or REM sleep. Immunostaining revealed a reduction of c-Fos expression in neurons of the locus coeruleus and the tuberomammillary nucleus after administration of genistein, as compared with the vehicle control. These results indicate that treatment with genistein leads to an inhibition of arousal-promoting neurons and thus promotes NREM sleep, suggesting its potential application for the treatment of insomnia.

Riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines

In this study, we investigated the anxiolytic-like effect of riluzole using three different innate anxiety models in rats. In the elevated plus-maze test, riluzole significantly increased the time spent in, and entries into, the open arm after 60 min administration. This finding was supported by results obtained from light/dark and open-field tests. The magnitude of the anxiolytic-like effects of riluzole in each of the behavioral models was similar to those produced by a benzodiazepine, diazepam, suggesting that riluzole has a robust anxiolytic-like activity in rats. To clarify the involvement of sodium channels in this anxiolytic activity, we examined the effect of a co-administered sodium channel activator, veratrine. The anxiolytic-like action of riluzole was diminished by veratrine in the elevated plus-maze, light/dark and open-field tests. Based on these results, it is suggested that the anxiolytic mechanism of riluzole is clearly distinct from that of diazepam. In addition, to examine whether riluzole directly and non-selectively affected the GABAA-benzodiazepine receptor complex, we performed three behavioral tests (footprint analysis, Y-maze test and the ethanol-induced sleeping time test) that are closely related to the GABAA-benzodiazepine pathways. In contrast to diazepam, riluzole produced no significant effects in these tests. Here, we provide the first report demonstrating that riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines.

Anxiolytic-like effects of compound zhi zhu xiang in rats.

The purpose of this study was to determine whether compound zhi zhu xiang (CZZX) exerts anxiolytic-like effects in rats. The animals were orally administered CZZX (0.75, 1.5, and 3 g/kg daily) for 10 days and tested in the elevated plus maze (EPM), Vogel conflict test (VCT), and open field. Repeated treatment with CZZX (3 g/kg/day, p.o.) significantly increased the percentage of both entries into and time spent on the open arms of the EPM compared with saline controls. In the VCT, repeated treatment with CZZX (1.5 and 3 g/kg/day, p.o.) significantly increased the number of punished licks. The drug did not change the total entries into the open arms of the EPM or interfere with water consumption or nociceptive threshold, discarding potential confounding factors in the two tests. In the open field, locomotion was not reduced, discarding the possible sedative effect of CZZX. In the binding assay, the binding of [3H] Ro 15-1788 (flumazenil) to the benzodiazepine binding site in washed crude synaptosomal membranes from rat cerebral cortex was affected by CZZX. These data indicate an anxiolytic-like profile of action for CZZX without sedative side effects, and this activity may be mediated by benzodiazepine binding site modulation at γ-aminobutyric acid-A receptors.

Involvement of Estrogen Receptors in the Anxiolytic-Like Effect of Phytoestrogen Genistein in Rats with 12-Weeks Postovariectomy

Phytoestrogens are natural compounds found in some vegetables, and they replicate many of the physiochemical and physiological properties of estrogens, including the regulation of mood. The phytoestrogen genistein exerts anxiolytic-like effects in rats with a chronic absence of ovarian hormones, but the mechanism involved in this effect remains to be explored. The present study explored the participation of estrogen receptor-β in the anxiolytic-like effect of genistein (1.0 mg/kg, i.p., for 4 days) in Wistar rats with 12-weeks postovariectomy, considered as experimental model of post-surgical menopause. In the light/dark test, a useful tool for anxiety study and for the screening of anxiolytic drugs, genistein reduced the latency to enter and increased the time spent in the light compartment and significantly increased the frequency and time spent exploring the light compartment compared with the control group, which is considered as an anxiolytic-like effect at experimental level. All behavioral effects produced by genistein in the light/dark test were blocked by previous tamoxifen administration (5.0 mg/kg, s.c., for 6 days), a non selective antagonist for estrogen receptor-β. The effects produced by genistein or tamoxifen in this test were not related to significant changes in general motor activity evaluated in the open field test. In conclusion, the specific contribution of present investigation was identify that estrogen receptor-β is involved in the anxiolytic-like effect produced by phytoestrogen genistein in rats with a long-term absence of ovarian hormones; supporting the hypothesis that estrogen receptor-β participates in the regulation of anxiety associated with low concentration of ovarian hormones and in the anxiolytic-like effects produced by natural estrogenic compounds such as phytoestrogens.

Synthesis and Influence of Two Quinoxalinone Derivatives on Anxiety- and Depressive-Like Responses in Wistar Rat

Two new quinoxalinone derivatives have been synthesized adopting the HONG method, and investigated for some neuropharmacological effects (anxiety- and depressive-like responses) in rats. The present experiment sought to determine whether treatment with these compounds produces changes in affective responses. We found that the chronic injection of 6-nitro-2(1H)-quinoxalinone (NQu) showed obvious anxiolytic- and antidepressant-like effects, respectively, measured in the behavioral tests of Elevated Plus Maze (EPM) and Forced Swim Test (FST). At the dose of 30 mg/kg, NQu showed a comparative anxiolytic-like effect in rats as diazepam (Dz) (1 mg/kg), and a comparative antidepressant effect as clomipramine (Clmp) (2 mg/kg; i.p). The 2(1H)-quinoxalinone (Qu) significantly reduced depressive-like responses as evaluated in FST, whereas no anxiolytic-like effect was found as measured by open field test (OF). Additionally, the locomotor activity levels were unaffected by treatment as measured by OF and EPM.

Anxiolytic-like effect of central administration of NOP receptor antagonist UFP-101 in rats submitted to the elevated T-maze

Depression and anxiety disorders present several genetic and neurobiological similarities. Drugs with antidepressant activity are effective in the treatment of a wide spectrum of anxiety disorders. Preclinical results showed that acute and chronic treatment with the NOP antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) produced antidepressant-like effects in rodents. Thus, the present study aimed to investigate the effect of central administration of UFP-101 on the anxiety-related behavior in rats as evaluated in the elevated T-maze (ETM) test. Our results showed that UFP-101 reduced the latency of inhibitory avoidance in the ETM, indicating an anxiolytic-like effect. The endogenous peptide N/OFQ prevented this anxiolytic-like action of UFP-101, demonstrating its modulation via central NOP receptors. However, UFP-101 failed to interfere with the latency to escape. No change was observed in locomotor activity after UFP-101 treatment, ruling out any nonspecific motor effect. In conclusion, our results showed that the central administration of UFP-101 presents an anxiolytic-like effect in rats evaluated in the ETM test, providing new insights for drug development to treat anxiety disorders targeting the N/OFQ-NOP receptor system.

Anxiolytic-like effect of Griffonia simplicifolia Baill. seed extract in rats

The seeds of Griffonia simplicifolia Baill., a tropical shrub native to West Africa, are rich in 5-hydroxy-l-tryptophan (5-HTP), a direct precursor in the synthesis of serotonin (5-HT). In spite of the modern therapeutic application of Griffonia simplicifolia seed extract in mood disorders, no scientific evidence has been provided till now. For this reason the aim of our study was to investigate the effect of Griffonia simplicifolia seed extract on anxiety behavior. Griffonia simplicifolia seed extract, dosed at 1, 5, 10 and 25 mg/kg, was orally administered in rats which were submitted to the dark-light test and open field test, 60 min after the treatment. In the dark-light test, the administration of the extract at the doses of 10 and 25 mg/kg was able to significantly increase the time spent in the light compartment (P<0.05). In the open field test, the extract dosed at 5, 10 and 25 mg/kg induced an anti-tigmotactic effect, as indicated by a significant increase of time spent in the central area of the open field (P<0.01). In conclusion these findings indicate that Griffonia simplicifolia seed extract exerts anxiolytic-like effect in rats and suggest its potential usefulness for the treatment of anxiety in humans.

Diazepam-Induced Increases of Synaptic Efficacy in the Hippocampal – Medial Prefrontal Cortex Pathway Are Associated With Its Anxiolytic-like Effect in Rats

The medial prefrontal cortex (mPFC) has recently been shown to be an important brain region for emotional function as well as cognitive ability. In previous experiments, we studied the population spike amplitude (PSA) in the mPFC induced by stimulation of the CA1/subicular region as an index of synaptic efficacy in the hippocampal-mPFC pathway. In the present study, we investigated the relationship between the anxiolytic effect of diazepam and the changes of synaptic efficacy in this pathway. In contextual fear conditioning tests, diazepam (0.1 mg/kg) was not effective for fear-related freezing behavior. At a dose of 0.5 mg/kg, diazepam decreased freezing behavior 20 min after administration, with no discernible effect 30 min after administration. In electrophysiological experiments, 0.1 mg/kg diazepam had no effect on the PSA in the mPFC. In contrast, 0.5 mg/kg diazepam increased the PSA in the mPFC within 30 min of administration; however, this PSA increase was attenuated over the 30-min period. Based on these results, we propose that the diazepam-induced PSA increase in the mPFC is associated with its anxiolytic-like effect.

Inhibition of the NMDA receptor/Nitric Oxide pathway in the dorsolateral periaqueductal gray causes anxiolytic-like effects in rats submitted to the Vogel conflict test

BackgroundSeveral studies had demonstrated the involvement of the dorsolateral portion of periaqueductal grey matter (dlPAG) in defensive responses. This region contains a significant number of neurons containing the enzyme nitric oxide synthase (NOS) and previous studies showed that non-selective NOS inhibition or glutamate NMDA-receptor antagonism in the dlPAG caused anxiolytic-like effects in the elevated plus maze.MethodsIn the present study we verified if the NMDA/NO pathway in the dlPAG would also involve in the behavioral suppression observed in rats submitted to the Vogel conflict test. In addition, the involvement of this pathway was investigated by using a selective nNOS inhibitor, Nω-propyl-L-arginine (N-Propyl, 0.08 nmol/200 nL), a NO scavenger, carboxy-PTIO (c-PTIO, 2 nmol/200 nL) and a specific NMDA receptor antagonist, LY235959 (4 nmol/200 nL).ResultsIntra-dlPAG microinjection of these drugs increased the number of punished licks without changing the number of unpunished licks or nociceptive threshold, as measure by the tail flick test.ConclusionThe results indicate that activation of NMDA receptors and increased production of NO in the dlPAG are involved in the anxiety behavior displayed by rats in the VCT.

The Aqueous Extracts ofPassiflora alataandPassiflora edulisReduce Anxiety-Related Behaviors Without Affecting Memory Process in Rats

Several species of Passiflora have been employed widely as a folk medicine because of sedative and tranquillizer activities. In this study, we evaluate the effects on anxiety and memory process of two popularly used Passiflora species. To this aim, male Wistar rats (weighing 250-300 g) were intraperitoneally injected with the aqueous extract of Passiflora alata or Passiflora edulis (25, 50, 100, or 150 mg/kg; single injection) 30 minutes prior to the elevated plus-maze test, inhibitory avoidance test, or habituation to an open-field apparatus. The effects of both species of Passiflora were compared with that of diazepam (1 mg/kg), a standard anxiolytic drug. Our findings revealed that, similar to diazepam, the treatment with P. alata (100 and 150 mg/kg) and P. edulis (50, 100, and 150 mg/kg) induced anxiolytic-like effects in rats. Memory was not affected by the treatment with any dose of P. alata or P. edulis, but diazepam disrupted memory process in rats. Phytochemical analysis showed that the content of flavonoids of the aqueous extract of P. edulis is almost twice that of P. alata. These differences in contents of flavonoids could explain the lower active doses of the aqueous extract of P. edulis in inducing anxiolytic-like effects compared to P. alata. In conclusion, our findings suggest that, distinct from diazepam, the aqueous extract of both species of Passiflora induced anxiolytic-like effects in rats without disrupting memory process.

Genome Scan for Loci Predisposing to Anxiety Disorders Using a Novel Multivariate Approach: Strong Evidence for a Chromosome 4 Risk Locus

We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders--including social phobia, agoraphobia, and simple phobia--in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P<.05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.

Anxiolytic-like effects induced by nitric oxide synthase inhibitors microinjected into the medial amygdala of rats

The amygdaloid complex plays a central role in the neuroanatomical circuits that coordinate defensive responses. Nitric oxide (NO) has been involved in the neurochemical, hormonal, and behavioral changes related to stress and anxiety. A high density of NO-producing neurons is observed in the medial amygdala (MeA). These neurons are activated after exposure to threatening stimuli such as a live predator. To test the hypothesis that microinjection into the MeA of two NO synthase inhibitors, NG-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole (7-NI), would produce anxiolytic effects. Male Wistar rats (n=8-10/group) were submitted to stereotaxic surgery to implant bilateral stainless steel guide cannulae aimed at the MeA. Six days after the surgery, the animals received intra-MeA microinjections of the drugs or vehicle and, 10 min later, were submitted to the elevated plus-maze (EPM) or the light-dark transition procedures. Both L-NAME (50-200 nmol) and 7-NI (5 and 10 nmol) increased open-arm exploration in the EPM without changing the number of enclosed arm entries, indicating an anxiolytic-like effect. The anxiolytic-like effect of L-NAME (200 nmol) was prevented by pretreatment with L-arginine (100 nmol). Injections of 7-NI or L-NAME outside the MeA did not produce any significant change in EPM exploration. When tested in the light-dark test, L-NAME (200 nmol) or 7-NI (10 nmol) increased the time when the animal remained in the light compartment of the light-dark box. The present results suggest that inhibition of NO formation in the MeA produces anxiolytic-like effect in rats.

The NK 1 receptor antagonist NKP608 lacks anxiolytic-like activity in Swiss-Webster mice exposed to the elevated plus-maze

The selective non-peptide NK 1 receptor antagonist NKP608 has been shown to exert potent anxiolytic-like effects in the rat and gerbil social interaction tests. In vitro binding of NKP608 in cortical, striatal and rest-of-brain tissue samples from mice, rats and gerbils indicated comparable pIC 50 values for rats and mice (in all three tissues) and only slightly higher values for gerbils. It would therefore be expected that doses previously found to produce anxiolytic-like effects in rats and gerbils would also be active in mice. The present study evaluated NKP608 in one of the most widely-used animal models of anxiety, the mouse elevated plus-maze. Two consecutive experiments were conducted in which the effects of NKP608 (0.0003–10.0 mg/kg, p.o.) were compared to those produced by the prototypical benzodiazepine anxiolytic, chlordiazepoxide (CDP, 15 mg/kg, p.o.). Ethological scoring methods were used to provide comprehensive behavioural profiles for each compound. In both experiments, acute CDP treatment resulted in significant anxioselective effects, i.e., reductions in measures of open arm avoidance without any alteration in general activity levels (closed arm entries and rearing). Although the results of Experiment 1 (0.001–10.0 mg/kg NKP608) suggested a weak anxiolytic-like action of NKP608 at 0.001 mg/kg (significant increase in percent open arm entries), Experiment 2 failed both to replicate this effect or to find any behavioural activity at lower (0.0003 mg/kg) or higher (0.03 mg/kg) doses. Present findings suggest that the anxiolytic efficacy of this NK 1 receptor antagonist may be test-specific and thus limited to particular subtypes of anxiety. These new data are also discussed in relation to the general difficulty of relating the behavioural profiles of NK 1 receptor antagonists to their potency at NK 1 receptors.

Anandamide hydrolysis: a new target for anti-anxiety drugs?

The major psychoactive constituent of cannabis, Δ 9-tetrahydrocannabinol, affects emotional states in humans and laboratory animals by activating brain cannabinoid receptors. A primary endogenous ligand of these receptors is anandamide, the amide of arachidonic acid with ethanolamine. Anandamide is released in selected regions of the brain and is deactivated through a two-step process consisting of transport into cells followed by intracellular hydrolysis. Pharmacological blockade of the enzyme fatty acid amide hydrolase (FAAH), which is responsible for intracellular anandamide degradation, produces anxiolytic-like effects in rats without causing the wide spectrum of behavioral responses typical of direct-acting cannabinoid agonists. These findings suggest that anandamide contributes to the regulation of emotion and anxiety, and that FAAH might be the target for a novel class of anxiolytic drugs.

Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors.

Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the deactivation of fatty acid ethanolamides such as the endogenous cannabinoid anandamide, the intestinal satiety factor oleoylethanolamide, and the peripheral analgesic and anti-inflammatory factor palmitoylethanolamide. In the present study, we report on the design, synthesis, and structure-activity relationships (SAR) of a novel class of potent, selective, and systemically active inhibitors of FAAH activity, which we have recently shown to exert potent anxiolytic-like effects in rats. These compounds are characterized by a carbamic template substituted with alkyl or aryl groups at their O- and N-termini. Most compounds inhibit FAAH, but not several other serine hydrolases, with potencies that depend on the size and shape of the substituents. Initial SAR investigations suggested that the requirements for optimal potency are a lipophilic N-alkyl substituent (such as n-butyl or cyclohexyl) and a bent O-aryl substituent. Furthermore, the carbamic group is essential for activity. A 3D-QSAR analysis on the alkylcarbamic acid aryl esters showed that the size and shape of the O-aryl moiety are correlated with FAAH inhibitory potency. A CoMSIA model was constructed, indicating that whereas the steric occupation of an area corresponding to the meta position of an O-phenyl ring improves potency, a region of low steric tolerance on the enzyme active site exists corresponding to the para position of the same ring. The bent shape of the O-aryl moieties that best fit the enzyme surface closely resembles the folded conformations observed in the complexes of unsaturated fatty acids with different proteins. URB524 (N-cyclohexylcarbamic acid biphenyl-3-yl ester, 9g) is the most potent compound of the series (IC(50) = 63 nM) and was therefore selected for further optimization.

Melatonin alters behavior and cAMP levels in nucleus accumbens induced by cocaine treatment

This study describes the effects of melatonin on cocaine-induced anxiety-like behavior and nucleus accumbens (NAc) cAMP levels in rats. Animals drinking a solution of melatonin (200 ng/ml) at night, either during repeated cocaine administration (15 mg/kg i.p., twice a day for 9 days) or during its withdrawal, showed less anxiety-like behavior in a defensive withdrawal paradigm 48 h after the last injection of cocaine. Melatonin did not alter behavior in control rats treated with saline. Animals exposed for 1 week to unrestricted free-choice oral melatonin self-administration (200 ng/ml) did not show preference for the drinking solution containing melatonin. Pretreatment with melatonin (200 ng/kg i.p. or 200 ng/ml orally) significantly attenuated the augmentation of cAMP levels in NAc following acute cocaine administration (15 mg/kg i.p.). Taken together, these results suggest that a low-dose night-time melatonin treatment results in anxiolytic-like effects in rats withdrawn from repeated cocaine administration, can antagonize cocaine-induced activation of NAc cAMP levels and has low dependence liability.

Anticonflict effect of the glycineB receptor partial agonist, D-cycloserine, in rats. Pharmacological analysis.

Several studies have provided evidence that antagonists and partial agonists of glycine(B) receptors exhibit an anxiolytic-like activity in different animal models. Using the conflict-drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of D-cycloserine (DCS), a partial agonist of the glycine(B) site of the N-methyl-D-aspartate (NMDA) receptor complex. Diazepam was used as a reference drug. DCS (200 and 300 mg/kg) and diazepam (5 mg/kg) produced an anxiolytic-like effect in rats by increasing the number of shocks accepted. We also demonstrated that NMDA (15 mg/kg) reduced the anxiolytic-like activity of DCS (200 mg/kg), whereas glycine (800 mg/kg) and flumazenil (10 mg/kg) did not affect the anticonflict effect of DCS (200 mg/kg). The anticonflict effect of diazepam (5 mg/kg) was totally blocked by flumazenil (10 mg/kg). The obtained results have shown that DCS exhibits an anxiolytic-like activity which depends on NMDA receptors rather than on glycine(B) or benzodiazepine sites.

Stimulation of group II metabotropic glutamate receptors or inhibition of group I ones exerts anxiolytic-like effects in rats.

Using the conflict drinking Vogel test in rats as a model we examined the anxiolytic-like activity of (S)-4-carboxyphenylglycine (S-4CPG), an antagonist of group I metabotropic glutamate receptors (mGlu receptors), of (RS)-a-methylserine-O-phosphate-monophenyl ester (MSOPPE), an antagonist of group II mGlu receptors, and of (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), an agonist of group II mGlu receptors. The obtained results indicate that intrahippocampal administration of S-4CPG and L-CCG-I, but not MSOPPE to rats produces a dose-dependent anticonflict effect, which is unrelated to the reduced perception of the stimulus or to an increased thirst drive. The hippocampus may be one of the neuroanatomical sites of the anxiolytic-like effects of either agent.

The effects of compounds varying in selectivity as 5-HT 1A receptor antagonists in three rat models of anxiety

Compounds varying in selectivity as 5-HT 1A receptor antagonists have recently been reported to produce benzodiazepine-like antianxiety effects in mice. To assess the cross-species generality of these findings, the present experiments compared the effects of diazepam (0.625–5 mg/kg) with those of several non-selective (MM-77, 0.03–1 mg/kg and pindobind-5-HT 1A, 0.1–5 mg/kg) and selective (WAY100635, 0.01–10 mg/kg, p-MPPI, 0.01–3 mg/kg and SL88.0338, 0.3–10 mg/kg) 5-HT 1A receptor antagonists in three well-validated anxiolytic screening tests in rats: punished lever-pressing, punished drinking, and the elevated plus-maze. In the punished lever-pressing conflict test, none of the 5-HT 1A receptor antagonists modified rates of punished responding, whereas in the punished drinking test, WAY100635 (0.3–1 mg/kg), SL88.0338 (3–10 mg/kg), p-MPPI (1 mg/kg), MM-77 (0.03–0.3 mg/kg), but not pindobind-5-HT 1A, produced clear anticonflict activity. However, the increase in punished responding with the 5-HT 1A compounds was smaller than that produced by diazepam, indicating weaker anxiolytic-like activity. In the elevated plus-maze test, WAY100635 (0.1–0.3 mg/kg), SL88.0338 (0.3–10 mg/kg), MM-77 (0.01–3 mg/kg), pindobind-5-HT 1A (0.1–3 mg/kg), but not p-MPPI, showed anxiolytic-like activity on traditional behavioral indices, increasing the percentage of time spent in open arms and the percentage of open arm entries. As was the case in the punished drinking test, the magnitude of the positive effects of the 5-HT 1A compounds was generally smaller than that of diazepam. Of the ethological measures recorded in the plus-maze, all compounds markedly decreased risk assessment (i.e. attempts) over the entire dose-range, but only diazepam clearly increased directed exploration (i.e. head-dipping). Although the present results demonstrate that 5-HT 1A receptor antagonists elicit anxiolytic-like effects in rats, this action appears to be test-specific and, unlike previous findings in mice, smaller than that observed with benzodiazepines. The data are discussed in relation to the possible relevance of species differences in 5-HT 1A receptor function and the nature of the anxiety response studied.