Search

We analyzed the frequency of single-nucleotide polymorphisms (SNPs) at positions −1053 (rs 2981572), 1380 (rs 2981573), 1462 (rs 2232360), and 3978 (rs 1518108) of the human interleukin-20 (IL-20) gene by tetraprimer ARMS-PCR method. A significant association between patients with psoriasis and the G allele at position −1053 (P<0.05) was established. The pairwise linkage disequilibrium (LD) matrix showed that the nearly complete LD was present within the polymorphisms at positions −1053, 1380, and 1462 of the IL-20 gene. We found that patients with plaque psoriasis had a higher frequency of the HT3 GAA haplotype (P<0.01, OR 2.341, 95% CI: 1.346–4.074) compared to the control group. Likewise, the HT3 GAA haplotype was associated with an increased risk of early-onset psoriasis (P<0.01, OR 2.305, 95% CI: 1.285–4.132), late onset of disease (P<0.01, OR 2.542, 95% CI: 1.266–5.102), familial psoriasis (P<0.02, OR 2.220, 95% CI: 1.249–3.945), and sporadic disease (P<0.01, OR 2.523, 95% CI: 1.390–4.580). Our data indicate that IL-20 gene polymorphisms should have a role in determining susceptibility to plaque-type psoriasis. The possible role of the studied SNPs in the regulation of the expression of IL-20 is unknown yet and needs further studies.

15th International Symposium on Regulatory Peptides

The effects of morphine, μ-opioid receptor agonist, and naloxone, a non-selective opioid receptor antagonist, in the locomotor activity and place conditioning tests were studied in the CCK2 receptor-deficient male mice. The exposure of mice to the motility boxes for 3 consecutive days induced a significant inhibition of locomotor activity in the wild-type (+/+) mice compared to homozygous (−/−) animals. The administration of naloxone (10 mg/kg i.p.) to animals, adapted to the motility boxes, induced a significant reduction of locomotor activity in the homozygous (−/−), but not in the wild-type (+/+) mice. Treatment of habituated mice with morphine (10 mg/kg i.p.) caused a stronger increase of locomotor activity in the wild-type (+/+) mice compared to the homozygous (−/−) littermates. In the place preference test the pairing of the preferred side with naloxone (1 and 10 mg/kg i.p.) induced a dose-dependent place aversion in the wild-type (+/+) mice. The treatment with naloxone was less effective in the homozygous (−/−) mice, because the high dose of naloxone (10 mg/kg) tended to shift the preference. The pairing of morphine (3 mg/kg i.p.) injections with the non-preferred side induced a significant place preference both in the wild-type (+/+) and homozygous (−/−) mice. The increased density of opioid receptors was established in the striatum of homozygous (−/−) mice, but not in the other forebrain structures. In conclusion, the targeted invalidation of CCK2 receptors induces a dissociation of behavioural effects of morphine and naloxone. Morphine-induced place preference remained unchanged, whereas hyper-locomotion was less pronounced in the mutant mice compared to the wild-type (+/+) littermates. By contrast, naloxone-induced place aversion was weaker, but naloxone caused a stronger inhibition of locomotor activity in the homozygous (−/−) mice than in the wild-type (+/+) animals. These behavioural alterations can be explained in the light of data that the targeted m

Behavior Genetics Association 33rd Annual Meeting Abstracts

Rationale Evidence suggests that GABA and CCK have opposite roles in the regulation of anxiety. Objective The aim of the present work was to study diazepam-induced anxiolytic-like action and impairment of motor co-ordination, and the parameters of benzodiazepine receptors in mice lacking CCK2 receptors. Methods The action of diazepam (0.5–3 mg/kg IP) was studied in the elevated plus-maze model of anxiety and rotarod test using mice lacking CCK2 receptors. The parameters of benzodiazepine receptors were analysed using [3H]-flunitrazepam binding. Results In the plus-maze test, the exploratory activity of the homozygous (−/−) mice was significantly higher compared to their wild-type (+/+) littermates. However, the wild-type (+/+) mice displayed higher sensitivity to the anxiolytic-like action of diazepam. Even the lowest dose of diazepam (0.5 mg/kg) induced a significant increase of open arm entries in the wild-type (+/+) mice. A similar effect in the homozygous (−/−) mice was established after the administration of diazepam 1 mg/kg. The highest dose of diazepam (3 mg/kg) caused a prominent anxiolytic-like effect in the wild-type (+/+) mice, whereas in the homozygous (−/−) animals suppression of locomotor activity was evident. The performance of the homozygous (−/−) mice in the rotarod test did not differ from that of the wild-type (+/+) littermates. However, a difference between the wild-type (+/+) and homozygous (−/−) animals became evident after treatment with diazepam. Diazepam (0.5 and 3 mg/kg) induced significantly stronger impairment of motor co-ordination in the homozygous (−/−) mice compared to their wild-type (+/+) littermates. The density of benzodiazepine binding sites was increased in the cerebellum, but not in the cerebral cortex and hippocampus, of the homozygous (−/−) mice. Conclusions Female mice lacking CCK2 receptors are less anxious than their wild-type (+/+) littermates. The reduced anxiety in homozygous (−/−) mice probably explains why the adminis

Behavior Genetics Association 33rd Annual Meeting Abstracts

Poster session P.3. Anxiety disorder and anxiolytic

The Na,K‐ATPase (Na pump) is a membrane protein complex that maintains the internal high K+ and low Na+ by using the energy of ATP.1 Because the Na pump is important in many basic and specialized cellular functions, its regulation has to be highly precise and flexible...

The present study supports a role of CCK2 receptors in the regulation of dopamine neurones. In pharmacological studies conducted on male CCK2 receptor-deficient mice the changes in the activity of dopamine system were established. A low dose of dopamine agonist apomorphine (0.1 mg/kg), stimulating the pre-synaptic dopamine receptors, induced significantly stronger suppression of locomotor activity in mutant mice (−/−) compared to their wild-type littermates (+/+). The administration of amphetamine (3–6 mg/kg), a drug increasing dopamine release, caused a dose-dependent stimulation of locomotor activity in wild-type mice. In mice lacking CCK2 receptors, a lower dose of amphetamine (3 mg/kg) tended to suppress the motor activity, whereas the higher dose (6 mg/kg) induced the significantly stronger motor stimulation in mutant mice. Moreover, in the CCK2 receptor-deficient mice the affinity of dopamine D2 receptors, but not 5-HT2 receptors, was increased. Altogether, the targeted genetic suppression of CCK2 receptors increased the sensitivity of pre- and post-synaptic dopamine D2 receptors.

Rationale Cholecystokinin (CCK) interacts with the endopioid system in the regulation of various physiological functions, including the control of pain sensitivity, motor activity and emotional behaviour. Objective The aim of the present work was to study the pain sensitivity, morphine-induced antinociception and density of opioid receptors in mice lacking CCK2 receptors. Methods Plantar analgesia and hotplate tests were used to evaluate pain sensitivity and morphine-induced antinociception. The parameters of opioid receptors were analysed by using [3H]-diprenorphine binding. Results In the plantar analgesia test the latency of hind paw withdrawal was significantly increased in CCK2 receptor deficient mice compared to wild-type (+/+) littermates. The treatment with saline reversed the reduced pain sensitivity in heterozygous (+/−) and homozygous (−/−) mice. The administration of morphine (1 mg/kg) induced a significantly stronger antinociceptive effect in homozygous (−/−) mice compared with wild-type (+/+) animals. In the hotplate test, only homozygous (−/−) mutant mice displayed the delayed latency of hind paw licking/shaking in comparison with wild-type (+/+) mice. The injection of saline and isolation of mice for 30 min reversed the delayed response in homozygous (−/−) mice. However, in this test, the anti-nociceptive action of morphine (5–10 mg/kg) in mutant mice did not differ from that in wild-type (+/+) littermates. By contrast, the jump latency was decreased in both homozygous (−/−) and heterozygous (+/−) mice in the hotplate test. The increased density of opioid receptors was established in the striatum of homozygous (−/−) mice. Conclusion It is apparent that the targeted mutagenesis of the CCK2 receptor gene has different effects on the sensitivity of opioid receptors in various brain structures. This is a probable reason for the altered pain sensitivity and morphine-induced antinociception in mutant mice compared to wild-type (+/+) littermates.

We analyzed three single-nucleotide polymorphisms (SNPs) at the interleukin-10 (IL-10) 5′ flanking region (positions −1082 A/G, −819 C/T and −592 C/A) in an association case–control study involving 248 patients with plaque type of psoriasis and 148 unrelated healthy volunteers using ARMS (amplification refractory mutation system)-PCR (Polymerase Chain Reaction) method. No difference was found in the frequencies of haplotype distribution between healthy controls and patients with psoriasis. There were no significant differences in the IL-10 haplotype distribution depending on the age of onset and family history of psoriasis. However, the results of our study demonstrate that the IL-10 haplotype has a role in determining severity and course of plaque type of psoriasis. IL-10 ACC haplotype (P<0.05) is likely to be defining lower activity of disease (PASI≤20; extent≤10%) and ATA haplotype is likely to be associated with persistent eruption (P<0.01). As ACC haplotype is suggested to be associated with high IL-10 secretion and ATA is related to low IL-10 secretion, potential differences in the IL-10 secretion levels might contribute the differences in the clinical course of psoriasis.

The aim of a present study was to analyse the gene expression profiles in the periaqueductal grey (PAG) of rats related to their exploratory activity in the elevated plus-maze model of anxiety. Animals were divided into the groups according to their exploratory activity in the plus-maze as follows: rats with low activity (‘anxious’), moderate activity (‘intermediate’) and high activity (‘non-anxious’). Control animals were not exposed to the elevated plus-maze. The differential expression of genes was analysed using the cDNA representational difference analysis (RDA) in combination with the sequencing and database search. Reverse transcription-polymerase chain reaction with specific primers was applied to confirm the differences found by the RDA. We established that animals displaying the different exploratory activity have also the different gene expression profiles in the PAG. Among the identified genes, we were able to confirm the increased expression of limbic system-associated membrane protein (LSAMP) in animals having the reduced exploratory activity in the elevated plus-maze. ‘Anxious’ group of rats had 1.6-fold higher expression of LSAMP gene compared to ‘non-anxious’ animals. By contrast, ‘home-cage’ control rats and ‘intermediate’ group did not differ significantly by their LSAMP gene expression level. In conclusion, it is likely that LSAMP plays a role in the regulation of exploratory behaviour of rats in the novel aversive environment.

Egis, in collaboration with Orion Pharma and Pharmacia, is developing deramciclane, a 5-HT(2A) antagonist and a 5-HT(2C) inverse agonist, as a potential treatment for anxiety disorders [300642]. The compound was also in development for epilepsy but no recent development has been reported for this indication. As of May 2001, comprehensive phase III studies with deramciclane in ten European countries were progressing according to plan [399853], [408534]. By August 2001, phase III studies were also underway in South Africa [420313]. In November 2001, Pharmacia indicated that NDA filing is expected to take place in 2004 [431903]. In February 2001, Orion announced its intention to commercialize deramciclane globally [399853]. In August 2001, Orion and Pharmacia signed an agreement under which the two companies were to collaborate in the development and commercialization of deramciclane in the US [420313]. Analysts at Morgan Stanley predicted in November 2001, that deramciclane would make sales of $25 million in 2004, rising to $150 million in 2005 [435320]. Analysts at Lehman Brothers predicted in December 2001, that deramciclane had a 75% chance of being marketed by 2004, with peak sales potential of $450 million [434768].

IL-10 is an important regulatory cytokine that is involved in many aspects of the immune response and is dysregulated in human autoimmune disease. The IL-10 gene is highly polymorphic and certain haplotypes result in differential IL-10 expression. Psoriasis is a chronic inflammatory skin disease that is associated with relative under expression of the anti-inflammatory cytokine IL-10. The aim of our study was to observe association of single nucleotide polymorphism in the IL-10 gene at position –592 (C to A, SNP ID rs1800872) with psoriasis. We searched for associations between the different forms of psoriasis (early and late-onset psoriasis) and IL-10 gene polymorphism at position –592 depending on the sex of patients and the family history of psoriasis. One-hundred 82 patients with psoriasis and 77 control subjects were included in this study. To detect the nucleotides at position –592 (C or A), we applied ARMS (Amplification Refractory Mutation System)-PCR. The A/ C genotype was found in 81 patients with psoriasis (44.5%) compared with 36 (46.8%) of the controls, the C/C genotype was found in 101 patients with psoriasis (55.5%) compared with 41 (53.2%) of the controls. We did not find any patient with A/A genotype. According to the literature the frequency of A/A genotype is very low. The background for that peculiar finding needs further studies, but dysfunctional immune response in A/A patients might be the cause. We also found no statistically significant differences between the allelic frequencies in patients with early onset psoriasis (A/C 43.5%, C/ C 56.5%) and late-onset psoriasis (A/C 47.1%, C/C 52.9%) compared to healthy individuals. Genotype of psoriasis patients was not dependent neither from the sex nor family history of psoriasis. Our results show that genetic polymorphism at position –592 of the IL-10 promoter is probably not associated with psoriasis.

The aim of the present study was to find the genes expressed in the amygdaloid area after exposure to cat odour. Cat odour exposure was used to induce the ethologically relevant fear response in male rats. The differential expression of genes was analyzed using the cDNA Representational Difference Analysis (RDA). The differentially expressed clones were identified by sequencing and database search. Reverse transcription-polymerase chain reaction (RT-PCR) was applied to confirm the differences found by the RDA. Exposure of rats to cat odour induced avoidance of odour stimulus and suppressed the exploratory activity of animals. We found that during the cat odour exposure, several genes with various functions were activated in the amygdaloid area. Among the identified genes, we found the activation of the wolframin gene. RT-PCR confirmed quantitative elevation in the levels of wolframin transcripts in the amygdaloid area. This study supports the role of wolframin in the regulation of emotional behaviour.

No abstract available

No abstract available

Rationale: Cholecystokinin (CCK) has been shown to coexist and interact with dopamine in the regulation of behaviour. Two different CCK receptors (CCK1 and CCK2) have an opposite influence on the activity of dopamine neurons. Stimulation of CCK2 receptors decreases the release of dopamine and that receptor could mediate the neuroleptic-like effect of CCK. Objective: To investigate the activity of the dopaminergic system in pharmacological experiments on CCK2 receptor (CCK2R)-deficient mice. Methods: We used age- and sex-matched littermates in all our experiments. To evaluate the behavioural differences, we performed the rotarod test and measured the locomotor activity of animals using computer-connected photoelectric motility boxes. Amphetamine and apomorphine, two dopaminergic drugs with different pharmacodynamic properties, were used to influence the activity of the dopaminergic system in the brain. Neurochemical differences related to the different genotype were analysed by means of high-performance liquid chromatography and radioligand binding studies. Results: Motor co-ordination was significantly impaired in the rotarod test of CCK2R receptor-deficient mice. Moreover, the locomotor activity of heterozygous (+/–) and homozygous (–/–) CCK2R receptor-deficient mice was somewhat reduced. A low dose of apomorphine (0.1 mg/kg), an unselective agonist of dopamine receptors, suppressed locomotor activity significantly more in homozygous (–/–) and heterozygous (+/–) mutant mice than in their wild-type (+/+) littermates. Amphetamine (3–6 mg/kg), increasing release of dopamine from the presynaptic terminals, caused a dose-dependent motor stimulation in wild-type (+/+) mice. In heterozygous (+/–) and homozygous (–/–) mice, a lower dose of amphetamine (3 mg/kg) did not alter the locomotor activity, whereas the higher dose of (6 mg/kg) induced a significantly stronger increase in locomotor activity in homozygous (–/–) mice than in their heterozygous (+/–) and wild-type (+/+

The present study was aimed at establishing behavioral differences between three inbred mouse strains (129S2/SvHsd, C57BL/6JOlaHsd, FVB/NHsd) and two F1 hybrid lines derived from them (129×C57BL/6 and 129×FVB). The choice of the given strains was based on the frequent use of these mice in transgenic research. For the behavioral phenotyping, we employed a test battery consisting of the following models: elevated plus-maze (EPM), open field (OF), light–dark exploration, spontaneous locomotor activity, rota-rod (RR), Porsolt's forced-swimming test (FST), and Morris water task. Significant variations between the strains were established in all tests. Anxiety-like behavior was more pronounced in the 129S2/Sv and 129×C57BL/6 mice, the FVB/N mice were spontaneously hyperactive, the best coordination ability was demonstrated by the C57BL/6 and 129×C57BL/6 groups. A good performance in the learning test was established in both hybrid lines and the 129S2/Sv mice, whereas the well-known visual impairment of the FVB strain was confirmed by low performance in spatial and non-spatial tasks. Differences related to the gender were revealed occasionally; most importantly, 129×C57BL/6 males had a higher anxiety level than their female counterparts in the EPM. Several other gender dissociations suggest the strain and task specificity. In conclusion, we would like to highlight the importance of the genetic background and gender of mice for the molecular biological and pharmacological studies and also the need for well-established testing protocols to obtain wide information at the first stage of behavioral screening of genetically modified mice.

Objective: To investigate whether a 5-hydroxytryptamine (5-HT) reuptake inhibitor (paroxetine) has an anxiogenic-like effect and what possible pharmacological mechanism underlies that action. Methods: We used the rat elevated plus-maze paradigm followed by measurement of locomotor activity. Some of the rats were subjected to handling and adaptation to the experimental situation, while the rest were naive to the test situation. Paroxetine was administered as a single treatment and in combination with the 5-HT1A receptor agonist (8-OH-DPAT) or 5-HT2A/2C receptor antagonist (deramciclane). Results: The administration of paroxetine induced an anxiogenic-like action in rats adapted to handling, but not in handling naive animals. Treatment with paroxetine (0.1–2 mg/kg) reduced the number of open arm visits and time spent in open arms, and the ratio between open and total arm entries in the elevated plus-maze. Paroxetine also decreased the number of line crossings and head-dips. Paroxetine caused the strongest anti-exploratory action at a dose of 0.5 mg/kg. Paroxetine did not suppress the locomotor activity of rats, showing that the described anti-exploratory effect was behaviourally specific to the plus-maze. Pretreatment with 8-OH-DPAT (0.05 mg/kg) completely reversed the anxiogenic-like action of paroxetine, whereas treatment with deramciclane (2 mg/kg) affected only the number of closed arm visits. Deramciclane (0.5–2 mg/kg) and 8-OH-DPAT (0.01–0.1 mg/kg) changed neither exploratory behaviour nor locomotor activity if given as single treatments to the habituated rats. Conclusion: The 5-HT reuptake inhibitor, paroxetine, at a low dose (0.5 mg/kg) induces an anxiogenic-like action in handling adapted rats. The effectiveness of 8-OH-DPAT against paroxetine probably supports a role of both pre- and postsynaptic 5-HT-ergic mechanisms in the anxiogenic-like action of paroxetine. Handling adaptation 5-Hydroxytryptamine Paroxetine 8-OH-DPAT Deramciclane Elevated plus-maze Anxi

OBJECTIVE: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. DESIGN: Prospective animal study. INTERVENTIONS: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). OUTCOME MEASURES: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. RESULTS: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. CONCLUSIONS: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rat

This study investigated a role of cholecystokinin (CCK) in the anxiolytic-like action of morphine, an agonist of μ-opioid receptors, in the rat plus-maze model of anxiety. The acute administration of morphine (1 mg/kg) induced a significant increase of exploratory activity in the plus-maze, but did not affect the locomotor activity in the motility test. The higher dose of morphine (2.5 mg/kg) tended to decrease the locomotor activity and, therefore, did not cause the anxiolytic-like action in the plus-maze. The other drugs (naloxone, BOC-CCK-4, L-365,260) and their combinations with morphine (0.5–1 mg/kg) did not affect the locomotor activity of rats. The opioid antagonist naloxone itself (0.5 mg/kg) did not change the exploratory activity in the plus-maze, but potently antagonized the anxiolytic-like action of morphine (1 mg/kg). An agonist of CCKBreceptors BOC-CCK-4 (1–50 μg/kg) induced a dose-dependent anxiogenic-like action in the plus-maze. Nevertheless, only one dose of BOC-CCK-4 (10 μg/kg) completely reversed the action of morphine. Also, one dose of CCKBreceptor antagonist L-365,260 (10 μg/kg) was effective to modify the behaviour of rats in the elevated plus-maze. Namely, this dose of L-365,260 increased the ratio between open and total arm entries, a behavioural measure believed to reflect the anxiolytic-like action in the elevated plus-maze. The combination of L-365,260 (100 μg/kg) with the sub-effective dose of morphine (0.5 mg/kg) caused the anxiolytic-like action in the plus-maze not seen if the drugs were given alone. In conclusion, morphine induces a potent anxiolytic-like action in the elevated plus-maze and CCK is acting as an endogenous antagonist of this effect of morphine.

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED50 values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D2 antagonist), 0.023 mg/kg for SCH 23390 (dopamine D1 antagonist), 6.42 mg/kg for clozapine (dopamine D4 antagonist). This supports the involvement of D1 and D2 receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural

Poster abstract

The administration of paroxetine (0.5–8 mg/kg), a selective 5-HT reuptake inhibitor, induced a dose-dependent reduction of exploratory activity of rats in the motility test. In the elevated plus-maze paroxetine was less effective, only 8 mg/kg of paroxetine decreased the exploratory behaviour of rats. The doses of paroxetine (2–8 mg/kg) reducing the exploratory activity in the motility test increased the density of CCK receptors in the frontal cortex, but not in the hippocampus. The treatment of rats with the CCKB receptor antagonist LY288,513 (0.01–1 mg/kg) did not change the exploratory activity. However, the reduction of exploratory activity induced by the low dose of paroxetine (2 mg/kg), but not by the higher dose (8 mg/kg), was dose-dependently reversed by the administration of LY288,513. Moreover, LY288,513 did not affect the anti-exploratory action of paroxetine (8 mg/kg) in the elevated plus-maze. Diazepam at doses (0.5–1.0 mg/kg) not suppressing the locomotor activity did not change the anti-exploratory action of paroxetine in the motility test. It is likely that the anti-exploratory action of a low dose of paroxetine (2 mg/kg) is not related to the increase in anxiety, but rather to the reduction of exploratory drive. Evidence exists that this effect of paroxetine is mediated via the activation of CCK-ergic transmission.