Behavioral effects of acute and chronic imipramine in the elevated T-maze model of anxiety

The elevated T-maze is an animal model of anxiety, consisting of three elevated arms: one enclosed and two open. Inhibitory avoidance of the open arms-representing learned fear-has been related to generalized anxiety and the unconditioned escape from one of the open arms to panic. In the present study, we investigated the effects of acute and chronic (21 days) administration of imipramine (5, 10, and 15 mg/kg; IP) in male Wistar rats that have been previously exposed for 30 min to one of the open arms of the T-maze, 24 h before the test. The results show that this preexposure shortens the first escape latency, without changing open-arm avoidance. Under these experimental conditions, chronic imipramine exerted anxiolytic-like effects in the two elevated T-maze tasks; impaired the acquisition of inhibitory avoidance and prolonged escape latency from the open arms. Acute imipramine enhanced both avoidance and escape latencies. Both acute and chronic imipramine decreased locomotor activity measured in a square arena. The obtained results are compatible with the view that inhibitory avoidance and one-way escape in the elevated T-maze reflect different types of fear/anxiety, that may be related to generalized anxiety and panic disorder, respectively.     

Picrotoxin blocks the anxiolytic- and panicolytic-like effects of sodium valproate in the rat elevated T-maze

The effect of acute sodium valproate administration, an anxiolytic and putative panicolytic drug, was evaluated in rats tested in the elevated T-maze, an animal model that measures two defensive reactions: avoidance (inhibitory avoidance), related to generalized anxiety, and escape (escape from open arms), related to panic. Additionally, the involvement of gamma-aminobutyric acid (GABA) neurotransmission in sodium valproate effects was studied by picrotoxin co-administration. Sodium valproate (300 mg/kg, intraperitoneally, 30 min before the test) impaired both avoidance latency (time to leave the closed arm) and one-way escape (latency to enter the closed arm) indicating anxiolytic and panicolytic effects, respectively. Pre-treatment with picrotoxin (0.5 mg/kg, intraperitoneally, 5 min before sodium valproate administration) blocked the effects of sodium valproate on inhibitory avoidance and one-way escape. No locomotor effect was seen in the open-field. These data suggest that sodium valproate exerts anxiolytic-like and panicolytic-like effects in the elevated T-maze and that these effects were mediated by picrotoxin-sensitive GABA type A receptors.     

Effects of sibutramine on anxiety-related behaviours in rats.

Sibutramine is an anorexiant drug that inhibits the reuptake of noradrenaline and serotonin, a pharmacological property shared with drugs clinically effective in treating anxiety pathologies. However, the effects of this compound on experimental and clinical anxiety have not been assessed yet. In this study, we evaluated the effects of sibutramine on anxiety-related behaviours which have been related to specific anxiety disorders. Acute injection of sibutramine (5, 10 or 20 mg kg(-1); intraperitoneally) in male Wistar rats impaired inhibitory avoidance in the elevated T-maze (ETM) and in the light/dark transition test, indicative of an anxiolytic effect. The drug also inhibited one-way escape in the ETM. Sibutramine, however, was ineffective in changing rat performance in the elevated plus-maze. Therefore, sibutramine decreased the expression of defensive behaviours that have been associated with generalized anxiety disorder (inhibitory avoidance) and with panic disorder (one-way escape). Yet, in contrast to what has been reported with drugs such as the tricyclic anti-depressants that also inhibit monoamine reuptake, the anxiolytic effects of sibutramine were revealed after a single administration.     

Anxiolytic effect of intra-amygdala injection of midazolam and 8-hydroxy-2-(di-n-propylamino)tetralin in the elevated T-maze

The effects of intra-amygdala injection of midazolam (20 nmol) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 8 and 16 nmol) were investigated in rats submitted to the elevated T-maze, a new animal model of anxiety. This test allows the measurement, in the same rat, of conditioned and unconditioned fear/anxiety responses. Both drugs impaired inhibitory avoidance of the open arms of the T-maze (task representing conditioned fear), indicating an anxiolytic effect, but did not change escape performance from one of the open arms (representing unconditioned fear). The results further implicate gamma-aminobutyric acid (GABA)/benzodiazepine and serotonergic systems within the basolateral/lateral amygdala in the modulation of conditioned anxiety responses.     

Response to electric shock in rats: Effects of selective midbrain raphe lesions

The forebrain serotonin (5-HT) concentrations of rats with lesions in the median (M; n = 5), dorsal (D; n = 5), and both (DM; n = 6) midbrain raphe nuclei were, respectively, 22, 48 and 70% lower than in control animals (n = 10). The lesion and control groups, However, did not evidence differences in pain sensitivity as measured by the flinch-jump technique. On the other hand, of the animals tested, those with M (n = 3) and DM (n = 4) lesions required more trials than controls (n = 6) to acquire a one-way avoidance response. D lesion rats (n = 2) did not differ from controls in one-way avoidance learning, except in terms of prolonged escape latencies during the first three trials. The previously reported increased sensitivity to painful stimuli subsequent to medial forebrain bundle lesions or para-chlorophenylalanine administration, therefore, does not appear to be due exclusively to disruption of ascending 5-HT fibers originating in the dorsal and median raphe nuclei. The effects of midbrain raphe lesions on avoidance learning, furthermore, depend on lesion locus, and are not due to either hypo- or hyperalgesia.     

Open field activity and avoidance behavior following serotonin depletion: a comparison of the effects of parachlorophenylalanine and electrolytic midbrain raphe lesions.

Three experiments were performed in order to compare the behavioral effects of electrolytic destruction of the dorsal and median mesencephalic raphe nuclei (MR lesion) and parachlorophenylalanine (pCPA; 300 mg/kg, IP) administration. Forebrain 5-hydroxytryptamine (5-HT) was measured in all animals following completion of behavioral testing. In the first experiment open field behavior (one 50 min session) and two-way (shuttle) conditioned avoidance acquisition (50 massed trials) were examined 68-72 hr after vehicle or pCPA administration in rats which had received control operations or MR lesions two weeks earlier. Only the MR lesion and the MR lesion + pCPA groups evidenced increased open field activity and facilitated two-way avoidance learning. Although the reduction in forebrain 5-HT of the pCPA group (85%) was greater than in the MR lesion group (55%), the pCPA treated animals did not differ from the control group. In the second experiment animals were tested in the open field 24, 48 or 72 hr after pCPA treatment to determine its effects on activity level as a function of the time after injections. No differences between the vehicle and pCPA groups, however, were found. In the third experiment, the effects of pCPA (72 hr postinjection) on the acquisition of an unsignalled one-way avoidance response was examined. MR lesion rats tested in the same apparatus and with the same procedure repeatedly have been shown to be impaired in this task. The pCPA and vehicle animals, however, did not differ. Reduction in 5-HT following electrolytic MR lesions and pCPA administration, thus, produce different behavioral effects. MR lesions, but not pCPA treatment, result in (1) increased activity in a novel environment, (2) facilitated two-way conditioned avoidance learning, and (3) impaired acquisition of an unsignalled one-way avoidance response. These data support earlier studies suggesting that the behavioral effects of electrolytic MR lesions are not due primarily to their disruption of ascending 5-HT pathways. The role of 5-HT in avoidance conditioning and the regulation of activity level, furthermore, remains to be elucidated.     

Lesion of serotonergic neurons antagonizes clonidine-induced suppression of avoidance behavior and locomotor activity in rats

The effects of clonidine on avoidance acquisition and locomotor activity were studied in male Wistar rats with 5,6-dihydroxytryptamine (5,6-DHT) lesions of the median raphe nucleus. Lesioned animals showed marked depletion in forebrain serotonin and 5-hydroxyindole acetic acid concentrations. Clonidine (0.2 mg/kg IP in a single daily dose for 6 consecutive days) inhibited avoidance acquisition and reduced locomotor activity in unlesioned rats. In 5,6-DHT rats clonidine failed to produce depressive effects. The resistance of raphe-lesioned rats to clonidine is discussed on the basis of possible interaction between noradrenergic and serotonergic brain systems.     

Effects of Hypericum perforatum and paroxetine on rat performance in the elevated T-maze.

Hypericum perforatum extract exhibits an antidepressant effect and since several antidepressant drugs are also effective on generalised anxiety disorder (GAD) and panic disorders (PD), H. perforatum may possess some anxiolytic/antipanic effect. Thus, the aim of the present study was to evaluate the putative antipanic/anxiolytic effect of standardised H. perforatum extract (LI 160) on rats tested in the elevated T-maze, an animal model of innate (panic) and learned (generalised) anxiety, at doses that exhibit antidepressant-like activity. H. perforatum (150, 300 and 500 mg/kg, administered orally 24, 18 and 1h before the test) decreased the immobility time in the forced swim test. Rats were treated orally with H. perforatum (150 or 300 mg/kg) or paroxetine (5mg/kg) 24, 18, and 1h before being tested in the elevated T-maze (subacute treatment). Immediately after this test, the animals were submitted to the open field to evaluate locomotor activity. Paroxetine was used as a positive control, since it was clinically effective in GAD and PD. Other groups of animals were submitted to the same drug treatment for 7 days (subchronic treatment). Paroxetine (5mg/kg) impaired inhibitory avoidance after subacute treatment, while subchronic administration increased one-way escape latency. Subacute treatment with H. perforatum (300 mg/kg) exerts a partial anxiolytic-like effect in the inhibitory avoidance task. Repeated administration of H. perforatum (300 mg/kg) induced an anxiolytic effect (decreased inhibitory avoidance) and an antipanic effect (increased one-way escape). No effect on locomotor activity was found with any treatment. Thus, the results suggest that H. perforatum extract could exert an anxiolytic and antipanic effect.     

FOREBRAIN PATHWAYS MEDIATING STRESS-INDUCED RENIN SECRETION

1. All stressors tested so far increase plasma renin levels; among these are exposure to foot-shock, immobilization, forced swimming, head-up tilt, exercise, hypotension haemorrhage and conditioned fear. 2. In old rats (22 months old), conditioned fear stress fails to increase plasma renin concentrations to the same level as in young rats (7 months old). 3. Destruction of cells in the paraventricular hypothalamic nucleus (PVH), either electrolytically or with the cell-selective neurotoxin ibotenic acid, prevents the effect of conditioned fear stress, but not of immobilization, on plasma renin concentration. 4. Ibotenic acid-induced lesions in the central amygdaloid nucleus inhibit conditioned fear stress-induced increases in plasma renin concentrations, but do not reduce the renin response to immobilization. Lesions in lateral amygdaloid nuclei do not reduce the renin response to stressors. 5. Although lesions in the bed nucleus of the stria terminalis (BNST) reduce the adrenocortical response to conditioned fear stress, they do not reduce the effect of stress on plasma renin concentration. 6. Destruction of catecholaminergic terminals in the PVH prevents the effect of conditioned fear stress on plasma renin concentration. 7. Electrolytic lesions in the dorsal raphe nucleus, which is a major site of origin of ascending serotonergic pathways, also inhibit the effect of conditioned fear stress on plasma renin concentration. 8. Activation of serotonin_1A (5HT_1A) receptors with the anti-anxiety drugs buspirone and ipsapirone reduces the firing rate of serotonergic neurons in the dorsal raphe nucleus in the midbrain and decreases the effect of stress on plasma renin concentrations. In contrast, the benzodiazepine anxiolytic drugs, chlordiazepoxide and midazolam, are ineffective in inhibiting the renin response to stress. 9. Chemical sympathectomy combined with adrenal medullectomy does not prevent the effect of conditioned fear stress on plasma renin concentration, suggesting that the sympathetic system is not the sole mediator of the message from the brain to the kidneys. 10. Combined, these observations suggest that aversive information from the cortex is transmitted via the amygdala to catecholaminergic cells in the medulla and to serotonergic cells in the dorsal raphe that stimulate the PVH to increase the release of renin.     

The neurobehavioural toxicity of endosulfan in rats: a serotonergic involvement in learning impairment

Oral administration of the insecticide endosulfan (2 mg/kg per day) for 90 days in immature male rats resulted in an inhibition of pole-climbing escape response to electric shock (unconditioned) and avoidance response to buzzer (conditioned). These responses reflect respectively their learning and memory processes. The escape response but not the avoidance response was reinstated significantly by the 5-hydroxytryptamine (5-HT) depletor, p-chlorophenylalanine (PCPA, 100 mg/kg per day for 3 days). Endosulfan increased 5-HT concentrations in the cerebrum and midbrain regions. Protein conten and acetylcholinesterase activity were unaltered in the brain. The spontaneous motor activity of these animals was stimulated. Their muscle coordination on rota-rod apparatus was unaffected. These findings were interpreted as an indication that a motivation deficit and not motor impairment was responsible for the inhibitory action of endosulfan on pole-climbing escape and avoidance responses. Thus, endosulfan was suggested to produce learning and memory deficit. A serotonergic involvement was significant in endosulfan-induced learning impairment and it appeared to be negligible in its memory disrupting action.     

Benzodiazepine (ω) receptor partial agonists and the acquisition of conditioned fear in mice

It is well established that benzodiazepines can produce anterograde amnesia in humans and interfere with the acquisition of passive avoidance and spatial responses in rodents. However, the extent to which the disruption of learning is a secondary effect of the sedation produced by these drugs has not been clearly established. In order to investigate this question, the effects of several BZ () receptor partial agonists were studied on the acquisition of conditioned fear (passive avoidance learning) in mice. As these drugs have been shown to produce anticonvulsant and anxiolytic-like effects without sedation or depression of motor activity, it was of interest to see whether they could disrupt learning. Clear effects on the acquisition of conditioned fear were produced by imidazenil (0.01–1.0 mg/kg), divaplon (1–60 mg/kg), ZK 91296 (3–60 mg/kg), and Ro 17-1812 (0.1–10 mg/kg). However, bretazenil (0.1–10 mg/kg) did not produce statistically significant effects. Only the high dose of imidazenil (1.0 mg/kg) decreased levels of exploratory behaviour. These results show that BZ () receptor partial agonists without apparent sedative actions can disrupt fear learning, indicating that the effects of this class of drugs on passive avoidance learning can be dissociated from sedation. The reasons for the observed differences between the different compounds studied are unclear at present and may be related to differences in intrinsic activity or receptor subtype selectivity.     

Interactions of verapamil and diltiazem with ketamine: effects on memory and sleeping time in mice

The effects of ketamine (3, 10 and 30 mg/kg) alone and in combination with verapamil (10 mg/kg) or diltiazem (30 mg/kg) on the acquisition, consolidation and retrieval of memory using a passive avoidance task in mice were studied. Ketamine significantly inhibited the acquisition and consolidation of memory at 10 and 30 mg/kg dose levels and these effects were antagonized by diltiazem 30 mg/kg but not by verapamil 10 mg/kg. Studies of sleeping time demonstrated that pretreatment with verapamil 10 mg/kg increased the duration of sleeping time. Diltiazem, however, did not potentiate the effects of ketamine on sleeping time. The present findings indicate that diltiazem can counter the effects of ketamine on memory. The data also indicates that pretreatment of surgical patients with verapamil may reduce the dose of ketamine required for anesthesia.     

The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats

The effects of acute administration of 10 different antidepressant drugs were examined on the performance of a two-way conditioned avoidance response in rats. The antidepressant drugs impaired avoidance behavior by decreasing avoidance responding and increasing the number of escape failures. The order of effectiveness for increasing overall response latency at a common dose of 10 mg/kg was: desipramine, maprotiline, protriptyline, (+) oxaprotiline, nortriptyline, imipramine, amitriptyline, (-) oxaprotiline, fluoxetine, and chlorimipramine. Avoidance behavior was impaired most by those antidepressant drugs that are also potent inhibitors of norepinephrine uptake.     

Effects of acute and chronic treatment with Hypericum perforatum L. (LI 160) on different anxiety-related responses in rats.

The study investigates the effects of acute and chronic oral treatment with Hypericum perforatum L. (HP LI 160, 62.5-500 mg/kg) in rats submitted to different anxiety models: the elevated T-maze (for inhibitory avoidance and escape measurements), the light/dark transition, and the cat odor test. These models were selected for their presumed capacity of evidencing specific subtypes of anxiety disorders as recognized in clinical practice. The results showed that acute HP (125 mg/kg) impaired elevated T-maze inhibitory avoidance, an anxiolytic effect, without altering escape performance. Chronic HP (250 mg/kg) enhanced avoidance latencies only in animals that were preexposed to the open arms of the maze. Preexposure shortens escape latency, improving it as an escape index. Differently from the reference drug imipramine (IMP, 15 mg/kg), chronic HP did not impair escape from the open arms of the maze. On the other hand, similarly to IMP, the extract increased the number of transitions between the two compartments in the light/dark transition model. Treatment regimens with HP and IMP did not alter behavioral responses of rats to a cloth impregnated with cat odor. These observations suggest that HP LI 160 exerts anxiolytic-like effects in a specific subset of defensive behaviors, particularly those related to generalized anxiety.     

Raphe lesions modify ethanol's effects on plasma corticosterone and NEFA

Male rats received dorsal or median raphe electrolytic lesions or sham operations. Ten days later subjects received 3.0 g/kg ethanol or saline and were decapitated 30 minutes later. Both dorsal and median raphe lesions significantly increased corticosterone and non-esterified fatty acid levels. Ethanol significantly increased corticosterone and non-esterified fatty acid levels in rats with dorsal or median raphe lesions. Dorsal raphe lesions significantly attenuated the elevating effect of ethanol on corticosterone. These results confirm, in part, previous pharmacological studies and suggest the effects of ethanol on corticosterone, but not non-esterified fatty acid, involve serotonergic neurons.     

Systemic administration of a delta opioid receptor agonist,KNT-127, facilitates extinction learning of fear memory in rats

Strategies to facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy for anxiety disorders. Previously, we demonstrated that systemic administration of a delta opioid receptor agonist, KNT-127, has clear anxiolytic-like effects in rats, without impairing memory. These observations led us to hypothesize that KNT-127 might be an appropriate therapeutic agent for anxiety disorders when combined with exposure therapy. In the present study, we demonstrate that KNT-127 (3 mg/kg) facilitates extinction learning of fear memory using the contextual fear conditioning test. As expected, a partial agonist at the glycine-binding site on the glutamatergic N-methyl-d-aspartate receptor, d-cycloserine (15 mg/kg), facilitated extinction learning of contextual fear in rats. In contrast, a benzodiazepine anxiolytic, diazepam (1 mg/kg), impaired the fear extinction learning. Interestingly, the facilitatory effect of KNT-127 on extinction learning was observed not only after a 10-min re-exposure, but also after a much shorter (2-min) re-exposure to the context, while d-cycloserine was ineffective at facilitating extinction when a short-duration exposure was given. Our findings may suggest that administration of a delta opioid receptor agonist might have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders.     

Anxiolytic-like property of risperidone and olanzapine as examined in multiple measures of fear in rats

Atypical antipsychotics are also used in the treatment of anxiety-related disorders. Clinical and preclinical evidence regarding their intrinsic anxiolytic efficacy has been mixed. In this study, we examined the potential anxiolytic-like effects of risperidone and olanzapine, and compared them with haloperidol, chlordiazepoxide (a prototype of sedative-anxiolytic drug) or citalopram (a selective serotonin reuptake inhibitor). We used a composite of two-way avoidance conditioning and acoustic startle reflex model and examined the effects of drug treatments during the acquisition phase (Experiment 1) or extinction phase (Experiments 2 and 3) on multiple measures of conditioned and unconditioned fear/anxiety-like responses. In Experiment 4, we further compared risperidone, olanzapine, haloperidol, citalopram and chlordiazepoxide in a standard elevated plus maze test. Results revealed three distinct anxiolytic-like profiles associated with risperidone, olanzapine and chlordiazepoxide. Risperidone, especially at 1.0 mg/kg, significantly decreased the number of avoidance responses, 22 kHz ultrasonic vocalization, avoidance conditioning-induced hyperthermia and startle reactivity, but did not affect defecations or time spent on the open arms. Olanzapine (2.0 mg/kg, sc) significantly decreased the number of avoidance responses, 22 kHz vocalization and amount of defecations, but it did not inhibit startle reactivity and time spent on the open arms. Chlordiazepoxide (10 mg/kg, ip) significantly decreased the number of 22 kHz vocalization, avoidance conditioning-induced hyperthermia and amount of defecations, and increased time spent on the open arms, but did not decrease avoidance responses or startle reactivity. Haloperidol and citalopram did not display any anxiolytic-like property in these tests. The results highlight the importance of using multiple measures of fear-related responses to delineate behavioral profiles of psychotherapeutic drugs.     

Chlorpheniramine exerts anxiolytic-like effects and activates prefrontal 5-HT systems in mice

Rationale

The traditional antihistamine chlorpheniramine ameliorates panic attacks, phobias, and lowered mood, and this therapeutic effect is independent of the blockade of histamine H₁ receptors. Since chlorpheniramine inhibits the reuptake of serotonin (5-HT), the anxiolytic-like effect of chlorpheniramine may be produced by an increase in serotonergic function.

Objective

To elucidate the mechanisms underlying the anxiolytic-like effects of chlorpheniramine in mice, we examined the involvement of 5-HT systems in the prefrontal cortex that is a crucial region in the regulation of emotional function.

Results

Chlorpheniramine (0.05?C5?mg/kg, i.p.) dose-dependently and significantly decreased the duration of freezing behavior in both the elevated open-platform and conditioned fear tests. The anti-freezing effects of chlorpheniramine (5?mg/kg, i.p.) in these tests were inhibited by pretreatment with the non-selective antagonist at 5-HT receptors, methiothepin (0.01?mg/kg, s.c.). In addition, the local injection of chlorpheniramine (10?C100?ng/mouse) and 5-HT (1?C10???g/mouse) into the medial part of the prefrontal cortex (mPFC) dose-dependently and significantly decreased the duration of freezing behavior in the elevated open-platform test. In a microdialysis study, chlorpheniramine (0.5 and 5?mg/kg, i.p.) dose-dependently and significantly increased the extracellular 5-HT level in the mPFC. In addition, the local perfusion of chlorpheniramine (10 and 30???M), but not of the selective H1 receptor antagonist, cetirizine, into the mPFC markedly increased the extracellular 5-HT level in the mPFC.

Conclusion

The anxiolytic-like effect of chlorpheniramine is produced, at least in part, by the facilitation of serotonergic neurotransmission in the PFC.     

Morphine analgesia, two-way avoidance, and consummatory behavior following lesions in the midbrain raphe nuclei of the rat

Rats with lesions in the median raphe nucleus (MR group) or in both the dorsal and median raphe nuclei (R group) were compared with operated control animals on the following measures: telencephalic serotonin (5-HT) concentration; daily water consumption; acquisition of a two-way conditioned avoidance response; and morphine analgesia. Both lesions produced significant reductions in telencephalic 5-HT, reaching 33% in the MR group and 57% in the R group. Transient increases in water intake were observed in both groups, being more prolonged and of greater magnitude in the R group. On the other hand, facilitated shuttlebox avoidance learning was observed only in the R group. Neither lesion affected pain sensitivity or morphine (3–9 mg/kg) analgesia as measured by the hot-plate technique. Therefore, while the midbrain raphe appears to be involved in the regulation of water intake and some behavioral responses to painful stimuli, lesions in these nuclei and reduction of telencephalic 5-HT are not sufficient to block morphine analgesia.     

Serotonergic neurons in the median raphe nucleus regulate inhibitory avoidance but not escape behavior in the rat elevated T-maze test of anxiety

Rationale A wealth of evidence supports the involvement of the serotonergic neurons of the median raphe nucleus (MRN) in anxiety. However, it is presently unclear whether serotonergic pathways arising from this nucleus play distinguishing regulatory roles in defensive behaviors that have been associated with specific subtypes of anxiety disorders.Objectives To evaluate the role of the MRN serotonergic neurons in the regulation of two defensive behaviors, inhibitory avoidance and escape, which have been related, respectively, to generalized anxiety and panic disorders.Methods Male Wistar rats were submitted to the elevated T-maze test of anxiety after intra-MRN administration of drugs that either non-selectively or selectively change the activity of the serotonergic neurons.Results Intra-MRN injection of FG 7142 (0.04 and 0.08 nmol) and kainic acid (0.03 and 0.06 nmol), drugs that non-selectively stimulate the MRN serotonergic neurons, facilitated inhibitory avoidance acquisition, but impaired escape performance. Microinjection of muscimol (0.11 and 0.22 nmol), a compound that non-selectively inhibits the activity of the MRN serotonergic neurons, impaired inhibitory avoidance and facilitated escape performance. Both kainic acid and muscimol also changed rat locomotion in the open-field test. Intra-MRN injection of 8-OH-DPAT (0.6–15 nmol) and WAY-100635 (0.18–0.74 nmol), respectively an agonist and an antagonist of somatodendritic 5-HT_1A receptors located on serotonergic neurons of the MRN, only affected inhibitory avoidance—while the former inhibited the acquisition of this behavior, the latter facilitated it.Conclusion MRN serotonergic neurons seem to be selectively involved in the regulation of inhibitory avoidance in the elevated T-maze. This result supports the proposal that 5-HT pathways departing from this nucleus play an important role in anxiety processing, with implications for pathologies such as generalized anxiety disorder.