[Household chaos and borderline personality features in adolescents and young adults]. / Chaos in de thuissituatie en borderlinekenmerken bij adolescenten en jong­volwassenen.

BACKGROUND: A complex pattern of individual and environmental factors is involved in the etiology of borderline personality disorder (BPD). Household chaos might be a factor of importance in this interaction. Studies report a relationship between household chaos and various problem areas, some of which are also related to BPD features. It is unclear if and how these factors are correlated. AIM: To investigate a possible association between household chaos and BPD features in adolescents and young adults. In addition, we investigated the effect of age within this association. METHOD: A clinical sample of 452 adolescents and young adults, aged 12-26 completed questionnaires on household chaos and BPD features. RESULTS: Adolescents and young adults who experienced a higher level of household chaos, reported more BPD features. No evidence was found for an effect of age on the association between household chaos and BPD features. CONCLUSION: Adolescents and young adults in a clinical population who experience a higher level of household chaos seem to report more BPD features. Age doesn’t seem to have an effect on this association. This research is a first step in understanding associations between household chaos and BPD features. In order to gain more insight in the transactions between household chaos and BPD features in adolescents and young adults, more longitudinal research is needed.

Discriminative stimulus properties of eltoprazine in the pigeon.

Twelve pigeons were successfully (ED50 = 2.4 mg/kg p.o.) trained to discriminate the 5-HT(1A/B) receptor agonist eltoprazine (5.0 mg/kg p.o.) from its vehicle in a fixed-ratio (FR)30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that 5-HT1A receptor agonists, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) (66.7%), flesinoxan (72.7%), buspirone (58.3%), and ipsapirone (36.4%) only partially substituted for the eltoprazine cue. Compounds with mixed agonistic action at 5-HT1 receptors, completely (> or = 80%) [(eltoprazine; TFMPP (1-(3-trifluoromethylphenyl) piperazine (ED50 = 7.68 mg/kg) and RU 24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole) (ED50 = 15.8 mg/kg)] substituted for eltoprazine; whereas m-CPP (1-(3-chlorophenyl)piperazine) did not. The selective 5-HT reuptake inhibitor fluvoxamine partially (44%) substituted for the eltoprazine cue. The 5-HT1A receptor antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)butyl]piperazine) fully blocked the eltoprazine cue. Both (+/-)-pindolol and (+/-)-propranolol showed partial antagonism of the eltoprazine cue (66.7 and 50.0%, respectively). (+/-)-Pindolol also showed partial substitution (50%) for the eltoprazine cue, but NAN-190 and (+/-)propranolol did not. It is concluded that the discriminatory stimulus properties of eltoprazine in the pigeon are mediated by 5-HT1A and 5-HT1B receptors.

A comparison of the effects of different serotonin reuptake blockers on sexual behaviour of the male rat.

In human males, SSRIs differentially affect (premature) ejaculation; paroxetine and fluoxetine markedly and sertraline, moderately inhibited ejaculation latency, whereas fluvoxamine did not inhibit this parameter (Waldinger, M.D., Hengeveld, M.W., Zwinderman, A.H., Olivier, B., The effect of SSRI antidepressants on ejaculation: a double-blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline. J. Clin. Psychopharmacol. (in press)). The present studies tried to investigate, using sexual behaviour in male rats, whether such differences could also be found in animal paradigms of sexual behaviour. In a series of three experiments we compared various specific serotonin reuptake inhibitors (SSRIs) for their ability to suppress sexual behaviour in male rats. In the first experiment sexually experienced rats were tested 60 min after oral administration of clomipramine, fluvoxamine, fluoxetine (all in a range of 0, 3, 10 and 30 mg/kg p.o.), sertraline or paroxetine (both in a range of 0, 1, 3 and 10 mg/kg p.o.). Clomipramine, paroxetine and fluvoxamine did not significantly inhibit male sexual behaviour, although some trends were observed. Sertraline inhibited sexual behaviour at 3 and 10 mg/kg p.o., the effects being stronger at 3 mg/kg p.o. Fluoxetine (3 mg/kg p.o.) facilitated sexual behaviour, while at 30 mg/kg p.o. a modest increase in the postejaculatory interval was noted. In the second experiment, sexual behaviour of sexually naive male rats was slightly inhibited by paroxetine 10 mg/kg p.o., but sertraline (range 1-10 mg/kg p.o.), fluvoxamine and fluoxetine (both in a range of 3-30 mg/kg p.o.) were ineffective. In the last experiment the effects of paroxetine (0-10 mg/kg p.o.), fluvoxamine and fluoxetine (both 0-30 mg/kg p.o.) were studied during an exhaustion design in sexually experienced male rats. As rats get more 'sluggish' when they have had multiple ejaculations, we hoped to see stronger inhibitory effects in the last cycle prior to exhaustion. None of the drugs dose-dependently inhibited the pattern of sexual behaviour during the first sexual cycle. In the last cycle the patterning of sexual behaviour differed, but only paroxetine (10 mg/kg p.o.) inhibited sexual behaviour significantly. The total number' of ejaculations during the test was not reduced by any of the SSRIs tested. Contrary to human findings, we did not find major inhibitory effects of SSRIs on male rat sexual behaviour at non-sedative doses. The only differentiation that could be made is that paroxetine and sertraline had slightly stronger effects than the other 5-HT reuptake inhibitors. Masculine sexual behaviour in rats does not constitute a suitable model to investigate the differential mechanism of sexual inhibition of SSRIs that have been described in human males.

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 degrees C and 18 degrees 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 degrees C and 18 degrees C conditions, although more efficaciously at 37 degrees C. The partial, non-selective benzodiazepine receptor agonist bretazenil and the partial benzodiazepine, selective receptor agonist alpidem significantly reduced ultrasonic vocalisations at 37 degrees C, but not at 18 degrees C. The full benzodiazepine, 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, 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-beta-carboline-3-carboxamide) and the full, non-selective benzodiazepine receptor inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-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 degrees 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 degrees C and 37 degrees 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 degrees C and 18 degrees C, (2) differentiate partial from full receptor agonists by absence of effects at the 18 degrees C condition, (3) suggest a key role for benzodiazepine, receptors in the modulation of ultrasonic vocalisations. These data contribute to the predictive validity of pup vocalizations as an animal model of anxiety.

Patterns of c-fos expression induced by fluvoxamine are different after acute vs. chronic oral administration.

Fluvoxamine is a selective serotonin (5-HT) reuptake inhibitor (SSRI) with a broad spectrum of behavioral and therapeutic effects, e.g. in depressive illness. We used the expression of c-fos, after both acute and chronic oral administration of fluvoxamine in the rat, to study its immediate and long-term effects, in relation to the distribution of Galanin (GAL) and Vasoactive Intestinal Polypeptide (VIP). After acute oral administration, most consistent increases were apparent in (parts of); the nucleus of the solitary tract, medial part; the lateral parabrachial nucleus, external part; the bed nucleus of the stria terminalis, dorsolateral part; and the central nucleus of the amygdala, lateral part. After chronic administration, distribution of Fos-IR was similar to acute administration, although numbers of Fos-IR neurons were no longer significantly different from control values. It is concluded that activation of 5-HT3-receptors in the caudal brainstem or gastro-intestinal afferents of the vagal nerve may play a role in the observed pattern of Fos-IR after fluvoxamine administration. The relationship with the antidepressant effects of fluvoxamine needs further investigations.

Ultrasonic vocalizations in rat pups: effects of serotonergic ligands.

Ligands with varying intrinsic activity and selectivity for the various subtypes of the serotonin receptor were tested in the rat pup ultrasonic vocalization (USV) model, a putative animal model reflecting anxiety. USV were elicited by isolating rat pups from their mother and littermates by placing them on a warm (37 degrees C) or a cold (18 degrees C) plate. Concurrently, the negative geotaxic (NG) response and rectal temperature were determined to assess the potentially sedative and hypothermic effects of putative anxiolytics. USV were reduced at low doses and in both temperature conditions by the full 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin.HBr) and the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378 (2-[4-[4-[2-pyrimidinyl]-1,2-piperazinyl]butyl]-1,2-benzi-isoth iozol-3-(2H)one-1,1-dioxide. 2HCl). The 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)-butyl]piperazide.2H Cl), (+/-)-WAY 100,135 (+/-)-(N-tert-butyl-3(4-(2-methoxy phenyl)piperazin-1 -yl)-2-phenyl propionamine.2HCl), and ((S)-UH-301 (S)-5-fluoro-8-hydroxy-2-(di-n-propyl-amino)tetralin.HBr) reduced USV at higher doses and only in one of both test conditions. The selective 5-HT1A receptor antagonist DU 125530 (2-[4-[4[(7-chloro-2,3dihydro-4-benzodioxin-5-yl)-1-piperazi nyl]butyl]-1,2-benzisothiazol-3(2H)-one-1,1, dioxide, monomesylate), did not influence USV at the cold plate up to high doses, although concomitantly the negative geotaxis was disturbed. The negative geotaxis was impaired after all 5-HT1A receptor ligands, except BMY 7378 and (+/-)-WAY 100,135. Hypothermia coincided with USV-suppression, except for NAN-190 and (S)-UH-301. The USV-suppressing action of flesinoxan (3 mg/kg) could be antagonized by DU 125530, but not its NG effect. However, the hypothermia induced by flesinoxan was antagonized by DU 125530. USV were also suppressed by the 5-HT uptake inhibitors fluvoxamine (both warm and cold plate) and clomipramine (only warm plate). The tricyclic antidepressant imipramine only decreased USV on the cold plate, however, in a U-shaped dose-response curve. At the highest dose tested, no decrease was present. The 5-HT uptake stimulant tianeptine reduced USV under both conditions. Fluvoxamine had no side effects, clomipramine induced hypothermia and tianeptine clearly had sedative properties. The 5-HT1B/2C receptor agonist TFMPP (trifluorometaphenylpiperazine) stimulated USV at a low dose at the cold plate and suppressed USV at a high dose under both conditions. The 5-HT2A/2C receptor antagonist ketanserine enhanced USV at low doses under both conditions and had no effect at a higher dose. Concurrently heavy sedation and hypothermia occurred. The 5-HT3 receptor agonist phenylbiguanide and the 5-HT3 receptor antagonist ondansetron had no effect in this paradigm. Clearly, subtypes of the 5-HT receptor affect rat pup USV differentially.

The putative 5-HT1A receptor antagonist DU125530 blocks the discriminative stimulus of the 5-HT1A receptor agonist flesinoxan in pigeons.

Twelve homing pigeons were trained to discriminate the 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT(1A/1B) receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT(1B/2C) receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-he xane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ), (+/-)-pindolol and (S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (+/-)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, (S)-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT1A receptor and that DU125530 acts as a full antagonist on the 5-HT1A receptor.

Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs.

Guinea pigs possess central 5-HT1D receptors similar to humans but different from rats and mice. In order to study the role of this receptor on animal behaviour, it may be of interest to develop a paradigm measuring affective states in the guinea pig. Therefore we assessed the effects of a variety of psychotropic drugs on guinea pig pup isolation calls. Anxiolytic compounds such as the benzodiazepine receptor agonists diazepam and alprazolam, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, and alcohol reduced isolation calling by the guinea pig pup. Moreover, mixed antidepressant/anxiolytic compounds like the 5-HT uptake inhibitors fluvoxamine and clomipramine or the MAO-inhibitor clorgyline as well as the antidepressant NA uptake inhibitors desipramine and maprotiline suppressed vocalizations. The 5-HT1D/1A receptor agonist 5-CT was also very effective in reducing separation calls. Remarkably, the partial 5-HT1A receptor agonists buspirone and BMY 7378 did not affect calling. The neuroleptic haloperidol, the psychostimulant d-amphetamine, the putative anxiogenics DMCM and m-CPP and the putative anxiolytics ondansetron and CI-988 had no effect on isolation calls of guinea pig pups. We propose this paradigm could be helpful to assess behavioural effects of anxiolytic and antidepressant drugs in a species different from rat or mouse, and in which the effects of 5-HT1D receptor ligands may possibly be established.

The 5-HT1A receptor is not involved in emotional stress-induced rises in stress hormones.

To determine whether emotional stress-induced rises in stress hormone levels are mediated by activation of 5-HT1A receptors, we studied the effects of the selective 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) on plasma ACTH, corticosterone, prolactin, and glucose levels in the conditioned ultrasonic vocalisation (USV) model in adult rats. The effects of WAY-100635 on USVs were also investigated in this paradigm. WAY-100635 (0.3, 1, and 3 mg/kg SC) had no clear effects on basal plasma ACTH, corticosterone, and glucose levels, but the 3 mg/kg dose significantly increased the plasma prolactin levels. The increases in plasma ACTH, corticosterone, and prolactin levels induced by the USV procedure were not affected by WAY-100635. This indicates that the 5-HT1A receptor does not play a major role in the distress-induced activation of the hypothalamic-pituitary-adrenal axis and prolactin secretion. The USVs were significantly enhanced by low doses of WAY-100635 (0.03 and 0.3 mg/kg SC), whereas higher doses (1.0 and 3.0 mg/kg SC) had no effect. These findings suggest that blockade of 5-HT1A receptors during stress may enhance the behavioural stress-response.

Chronic treatment with eltoprazine does not lead to tolerance in its anti-aggressive action, in contrast to haloperidol.

The behavioral effects of eltoprazine and haloperidol during a 4 week treatment period were studied in the resident-intruder model of aggression in male rats. Eltoprazine, a serotonergic (5-HT1A/1B) agonist with specific anti-aggressive actions in animals, was compared to haloperidol, a neuroleptic often used to control behavioral disorders. Eltoprazine (1 or 3 mg/kg p.o.) and haloperidol (2 mg/kg p.o.) were given 60 min before a 10 min aggression test. Acutely, eltoprazine reduced aggression, without adversely affecting other behaviors. Eltoprazine (1 or 3 mg/kg p.o.) was subsequently given daily for 4 weeks and aggression tests were performed each week. The anti-aggressive effects of eltoprazine remained stable over the period of 4 weeks whereas exploration was increased. After a wash-out period of 1 week aggression had returned to baseline levels. Acutely given, haloperidol (2 mg/kg p.o.) completely reduced aggression concomitant with massive sedation. Significant tolerance developed to the sedatory actions of haloperidol over the 4 week treatment period. Aggression returned slowly, but remained below baseline values. One week after wash-out a new challenge with haloperidol (2 mg/kg p.o.) revealed significant tolerance. After 2 weeks wash-out aggression had returned to baseline. The data demonstrate persistent and specific anti-aggressive effects after eltoprazine showing no tolerance. In contrast, haloperidol showed tolerance and rebound effects for aggression. The development of tolerance after haloperidol has a different course for sedation than for the anti-aggressive action.

Serotonin receptors and animal models of aggressive behavior.

Various models of rodent agonistic behavior are described, which differentiate between offensive and defensive/flight models. Particular attention is given to one male and one female paradigm for offensive aggression, i.e. resident/intruder or territorial aggression (RI) and maternal aggression (MA). After an overview of the serotonin (5-HT) system in the CNS, a description is given of the ligands available. Subsequently, the effects of various drugs affecting serotonergic transmission in the RI- and MA-paradigms are described. The 5-HT1A receptor agonists busipirone, ipsapirone, and 8-OH-DPAT decreased aggression in RI and MA, but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific antiaggressive profile. Nonselective 5-HT1 receptor agonists, such as RU24969, eltoprazine, and TFMPP reduced aggression quite specifically, did not decrease social interest or exploration, and sometimes even increased these behaviors. In RI and MA, the behavioral effects of these drugs were roughly similar. In contrast, MA was more sensitive to treatment with the 5-HT reuptake blocker fluvoxamine, which blocked RI aggression nonspecifically at the highest dose only. DOI, a 5-HT2A/2C# receptor agonist, decreased aggressive behavior and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by "wet dog shaking" characteristic of 5-HT2 receptor stimulation. The nonspecific 5-HT receptor agonist (and 5-HT2 receptor antagonist) quipazine also induced "wet dog shaking" at doses which suppressed aggression, social interest, and exploration but increased inactive behaviors (sitting and lying). The discussion delineates a specific role for 5-HT1B receptor-subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs, and this fact underlines the consistent role of 5-HT in different forms of aggression.

Discriminative stimulus properties of flesinoxan: effects of enantiomers, (S)-UH301 and WAY-100635.

Rats were trained to discriminate the specific 5-HT1A receptor agonist (+)-flesinoxan (R(+)-N(-)[2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4- benzodioxin-5-yl)-1-piperazinyl]ethyl]-4-fluorobenzoamide) (1.5 mg/kg p.o.) from water in a two-lever operant procedure. Generalization tests were conducted with the enantiomers and racemate of flesinoxan and the 5-HT1A receptor antagonists (S)-UH301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) and WAY-100635 ((N(-)[2(-)[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). (S)-UH301, WAY-100635 and fentanyl were investigated for their antagonistic properties. The (+)-flesinoxan stimulus generalized to (-)-flesinoxan and the racemate. The ED50 values for generalization corresponded well with the affinities of the enantiomers and the racemate for the 5-HT1A receptor. The flesinoxan cue could not be mimicked by (S)-UH301 or WAY-100635, but (S)-UH301 reduced response rates. Antagonism tests showed that both (S)-UH301 and WAY-100635 dose dependently antagonized the flesinoxan cue, with ID50 values of 0.52 and 0.03 mg/kg s.c., respectively. Fentanyl had no significant antagonistic properties. It is concluded that rats can learn to discriminate orally administered (+)-flesinoxan from water. The generalization of flesinoxan to the (-)-enantiomer and the antagonism of flesinoxan's cue by specific 5-HT1A receptor antagonists are further evidence for the involvement of flesinoxan's 5-HT1A receptor agonistic properties in its discriminative stimulus effects.

Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs.

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.

The corticosterone-enhancing effects of the 5-HT1A receptor antagonist, (S)-UH301, are not mediated by the 5-HT1A receptor.

We tried to antagonize the endocrine and behavioural changes induced by the selective 5-HT1A receptor agonist, flesinoxan, with the putative 5-HT1A receptor antagonist, (S)-UH301 ((S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin). The interaction of (S)-UH301 (3 and 10 mg/kg s.c.) with flesinoxan (3 mg/kg s.c.) showed no antagonistic effects of (S)-UH301 on flesinoxan-induced corticosterone secretion. In fact, like flesinoxan (1 and 3 mg/kg s.c.), (S)-UH301 (3 and 10 mg/kg s.c.) itself dose dependently increased plasma corticosterone levels. Unlike flesinoxan, (S)-UH301 did not induce hyperglycemia, lower lip retraction and flat body posture. Moreover, flesinoxan-induced hyperglycemia and behavioural changes were effectively antagonized by (S)-UH301, showing potent 5-HT1A receptor antagonistic effects of (S)-UH301. Therefore we conclude that (S)-UH301 is a potent 5-HT1A receptor antagonist and that the (S)-UH301-induced corticosterone secretion is mediated by a non-5-HT1A receptor mechanism.

New animal models of anxiety.

In an attempt to develop new animal models of anxiety with face and predictive validity for the spectrum of human anxiety disorders, two new animal paradigms have been described, stress-induced hyperthermia (SIH) in mice and ultrasonic pup vocalizations (UV) in rats. In SIH mice develop enhanced body temperature in anticipation of an aversive event. This SIH can be antagonized by benzodiazepines, alcohol and 5-HT1A receptor agonists, but not by specific 5-HT reuptake inhibitors (SSRIs) or 5-HT3 receptor antagonists. When rat pups are separated from their mother and littermates they produce ultrasonic sounds, indicative of a separation distress. Benzodiazepines, 5-HT1A receptor agonists and SSRIs decrease this calling, whereas 5-HT3 receptor antagonists have no effect. Antidepressants in general do not decrease pup calling because in contrast to the SSRIs, noradrenergic uptake blockers enhance calling. These two animal models of anxiety can be added to the range of anxiety models and will be of help in predicting new putative anxiolytic drugs.

Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan.

Using a two-lever operant drug discrimination procedure, rats were trained to discriminate the 5-HT1A receptor agonist, flesinoxan (0.5 mg/kg i.p.), from saline. Hereafter, several non-serotonergic drugs were tested in generalization and antagonism tests. The flesinoxan stimulus did not generalize to the stimuli of either the alpha 1-adrenoceptor antagonist, prazosin, the alpha 2-adrenoceptor agonist, clonidine, the dopamine receptor agonist, apomorphine, the dopamine receptor antagonists, haloperidol and pimozide, the benzodiazepine receptor agonist, chlordiazepoxide, nor to the peripherally acting vasodilator, hydralazine. In antagonism studies, prazosin, haloperidol, pimozide and the alpha 2-adrenoceptor antagonist, idazoxan, failed to block the flesinoxan stimulus. In substitution tests, however, flesinoxan partially generalized to idazoxan and completely to the alpha 2-adrenoceptor antagonist, yohimbine. The affinities of yohimbine and idazoxan for the 5-HT1A receptor may explain the latter result. The present findings suggest that the central mechanism through which flesinoxan exerts its discriminative stimulus effects does not involve alpha 1- and alpha 2-adrenoceptors, dopamine and benzodiazepine receptors. Finally, the results with the blood pressure lowering agents, hydralazine, clonidine and prazosin do not support the suggestion that the centrally mediated blood pressure lowering effects of flesinoxan contribute to its internal stimulus effect.

(S)-UH301, a silent 5-HT1A receptor antagonist, enhances plasma corticosterone levels in the rat.

The putative silent 5-HT1A receptor antagonist (S)-UH301 (S-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin) dose-dependently enhanced (3 to 10 mg/kg, sc) plasma corticosterone levels in undisturbed rats, an effect shared with 5-HT1A receptor agonists. (S)-UH301 did not influence plasma glucose levels. This unexpected finding may be indicative of a partial 5-HT1A-receptor agonistic effect of (S)-UH301, or reveals a hitherto unknown mechanism of action in (S)-UH301.

Dose-dependent discriminative stimulus properties of 8-OH-DPAT.

Separate groups of rats were trained to discriminate either 0.1mg/kg (low dose; L) or 2.5mg/kg (high dose; H) of 8-OH-DPAT from saline, in a standard operant task. Both cues were found to be dose, time and route dependent and generalized completely to the 5-HT(1A) agonists ipsapirone and flesinoxan. Buspirone substituted completely for 8-OH-DPAT in L and partially in H, whereas the 5-HT(1A/1B) receptor agonist eltoprazine substituted completely for 8-OH-DPAT in H but only partially in L. The 5-HT(1A/1B) receptor agonist RU24969, the 5-HT(1B/2C/1A) receptor agonist TFMPP and the 5-HT reuptake blocker fluvoxamine did not completely mimic the effect of 8-OH-DPAT in either L or H and the 5-HT(1A) mixed agonists/antagonists BMY 7378 and NAN-190 produced partial generalization in L, but no generalization in H. In antagonism tests, NAN-190 and BMY 7378 only partially blocked the 8-OH-DPAT cue in both groups. The non-selective 5-HT receptor antagonist methysergide did not completely block the 8-OH-DPAT cue in in L or H. However, in generalization studies, it completely mimicked the 8-OH-DPAT cue in L and produced partial generalization in H. The beta-adrenergic/5-HT(1A/1B) receptor antagonist pindolol completely blocked the 8-OH-DPAT cue in L and H and did not mimic the 8-OH-DPAT cue in either condition. The alpha(2)-adrenoceptor blocker yohimbine substituted fully for the 8-OH-DPAT cue in L and partially in H. Idazoxan did not substitute for the cue of 8-OH-DPAT in H, but produced nearly 80% generalization in L. The dopamine receptor antagonist pimozide neither blocked nor mimicked the cue of 8-OH-DPAT in either group. A number of other drugs (i.e. m-CPP, S(-)-propranolol, DOI, ketanserin, clonidine and apomorphine) were only tested in H. S(-)-Propranolol blocked the 8-OH-DPAT cue but the other compounds produced neither stimulus generalization nor antagonism. The present study demonstrates that the cues produced by the low and the high training dose of 8-OH-DPAT are quantitatively different and mediated by the agonistic activity of 8-OH-DPAT at 5-HT(1A) receptors. Although the results suggest that the 8-OH-DPAT cue (both L and H) is mediated via postsynaptic 5-HT(1A) receptors, the involvement of presynaptic 5-HT(1A) receptors cannot yet be ruled out.

Short inescapable stress produces long-lasting changes in the brain-pituitary-adrenal axis of adult male rats.

Recently, we reported that rats exposed to a single and short session of inescapable footshocks showed alterations in behavioural response to environmental stimuli which developed progressively over a week and remained present for at least 28 days. The aim of the present study was to investigate whether these behavioural changes were accompanied by alterations in the brain-pituitary-adrenal axis. Male Wistar rats were subjected to 10 inescapable footshocks (S) of 6 s duration and 1 mA intensity during a period of 15 min. Control rats (C) were placed in the shock apparatus for 15 min without receiving shocks. The effects of these experimental procedures were studied 14 days later. Exposure to shocks did not affect basal plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). However, the novelty-induced ACTH response was increased in S rats as compared to C rats whereas the CORT response did not differ between C and S rats. The ACTH content of the anterior pituitary gland and adrenal weight were not affected by exposure to inescapable footshocks 14 days earlier. Quantitative immunocytochemistry of vasopressin (AVP) and corticotropin-releasing factor (CRF) in the external zone of the median eminence showed that prior footshock exposure increased the AVPi stores to 167% as compared to C rats, whereas CRFi content was not changed. In addition, S rats showed increased mineralocorticoid (MR) and glucocorticoid (GR) receptor binding capacity in the hippocampus as compared to C rats, whereas affinities were not affected. We conclude that a single and short session of inescapable footshocks has long-lasting effects on brain-pituitary-adrenal functioning concomitant with behavioural alterations.