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Serotonin in the lateral septum (LS) has been implicated in the modulation of defensive behaviors and in anxiety. However, it is currently unknown whether changes in 5-HT mechanisms in this brain area may selectively affect defensive responses associated with specific subtypes of anxiety disorders recognized in clinical settings. To address this question, we evaluated the effect of the intra-LS injection of the 5-HT(1A/7) receptor agonist 8-OH-DPAT (0.6, 3.0, 15.0 nmol) in male Wistar rats exposed to the elevated T-maze animal model of anxiety. This test allows the measurement of two behavioral defensive responses in the same rat: inhibitory avoidance and escape behavior. In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. The effects of 8-OH-DPAT were compared to those caused by a standard anxiolytic compound, the benzodiazepine receptor agonist midazolam (MDZ, 20 nmol). We also investigated whether the intra-LS injection of the 5-HT(1A) receptor antagonist WAY-100635 (0.37 nmol) was able to block the effects of 8-OH-DPAT. All animals were also tested in an open field for locomotor activity assessments. Results showed that whereas intra-LS administration of MDZ decreased avoidance latencies, suggesting an anxiolytic action, 8-OH-DPAT caused the opposite effect. Neither drug affected the escape performance. Intra-LS administration of WAY-100635 blocked the anxiogenic effect caused by 8-OH-DPAT. No changes to locomotion were detected in the open field. The data suggests that LS 5-HT(1A) receptors are involved in the control of inhibitory avoidance behavior and that a failure in this regulatory mechanism may be of importance to the physiopathology of generalized anxiety disorder.

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.

Behavioral effects of the phenethylamine derivative (+/-)-1-(2,5-dimethoxy-4-ethylthiophenyl)-2-aminopropane (ALEPH-2) were studied in mice and rats. Murine locomotor activity, measured with a photocell actometer, was markedly depressed following IP injection of 2 and 6 mg/kg of the drug. The same doses of the drug also decreased frequency and duration of head dipping and the number of rearings in the hole board apparatus. In the murine elevated plus maze 2 and 6 mg/kg of ALEPH-2 increased the percentage of both open arm entries and time. The total number of entries into the enclosed arms was not significantly affected by the drug. In the rat, 2-12 mg/kg ALEPH-2, IP, decreased photobeam counts in the actometer in a dose-dependent fashion. Both 2 and 4 mg/kg of the drug increased the percentage of open arm entries, but only the highest dose significantly increased the percentage of time spent on the open arms. The dose of 4 mg/kg ALEPH-2 also significantly decreased the total number of enclosed arm entries. Finally, in a recently developed model of anxiety and memory, the elevated T-maze, the doses of 2 and 4 mg/kg ALEPH-2 did not change inhibitory avoidance of the open arms. Nevertheless, the highest dose had an amnestic effect on this task, repeated 72 h later in the absence of drug. In addition, this dose significantly increased the latency to escape from the open arms and had an amnestic effect measured 72 h later. Overall, these results indicate that ALEPH-2 possesses anxiolytic, amnestic as well as sedative and/or motor depressant actions.

In hippocampal and cortical slices taken from rats moved in their home cages to a novel environment for 5 min, there were decreases in basal and K(+)-evoked [14C]GABA release and an increased [14C]GABA uptake compared with slices taken from rats remaining undisturbed in the animal house. The changes in 5-hydroxytryptamine (5-HT) release and uptake in response to a novel environment were markedly time dependent. In rats killed immediately after the 5-min exposure, there was decreased hippocampal [3H]5-HT uptake and higher hippocampal basal release, whereas in rats killed 30 min later there was increased [3H]5-HT uptake and lower basal release in both hippocampal and cortical slices. Rats exposed to cat odor in the novel environment showed increased release and decreased uptake of GABA in both brain areas compared with the group exposed to a neutral odor in the same novel environment, and these differences between the two odor groups were found both immediately and 30 min after the odor exposure. In contrast, only one measure of 5-HT function differed between the neutral and cat odor groups, with the latter showing increased cortical [3H]5-HT uptake 30 min after odor exposure.

Rats were treated for 5 days with vehicle or chlordiazepoxide (CDP, 5, 10, or 20 mg/kg/day) and then exposed to a cloth impregnated with a neutral or cat odor. Those exposed to cat odor made significantly fewer contacts with the cloth and spent less time in contact with it and more time sheltering than those exposed to the neutral odor. CDP (5 mg/kg) significantly increased the time in contact with both odor cloths, but there were no other significant effects in the cat odor group. Rats previously exposed to cat odor showed significant anxiogenic responses in the social interaction and elevated plus-maze tests that were significantly reversed by CDP. There was no reduction in the responses to the cat odor on a second occasion as a result of the first exposure occurring after treatment with CDP (5 or 20 mg/kg). The anxiogenic effects of pentylenetetrazole (20 mg/kg) as detected in the social interaction and plus-maze tests were unaffected by prior odor experience. It is suggested that during exposure to the cat odor the responses of rats reflect avoidance components of a phobic anxiety state. Benzodiazepines are relatively ineffective against these responses in contrast to their efficacy against the generalised anxiety responses detected in the social interaction and plus-maze tests.