Effects of reversible inactivation of the dorsomedial hypothalamus on panic- and anxiety-related responses in rats

The medial hypothalamus is part of a neurobiological substrate controlling defensive behavior. It has been shown that a hypothalamic nucleus, the dorsomedial hypothalamus (DMH), is involved in the regulation of escape, a defensive behavior related to panic attacks. The role played by the DMH in the organization of conditioned fear responses, however, is less clear. In the present study, we investigated the effects of reversible inactivation of the DMH with the GABA A agonist muscimol on inhibitory avoidance acquisition and escape expression by male Wistar rats (approximately 280 g in weight) tested in the elevated T-maze (ETM). In the ETM, inhibitory avoidance, a conditioned defensive response, has been associated with generalized anxiety disorder. Results showed that intra-DMH administration of the GABA A receptor agonist muscimol inhibited escape performance, suggesting an antipanic-like effect (P < 0.05), without changing inhibitory avoidance acquisition. Although a higher dose of muscimol (1.0 nmol/0.2 µL; N = 7) also altered locomotor activity in an open field when compared to control animals (0.2 µL saline; N = 13) (P < 0.05), the lower dose (0.5 nmol/0.2 µL; N = 12) of muscimol did not cause any motor impairment. These data corroborate previous evidence suggesting that the DMH is specifically involved in the modulation of escape. Dysfunction of this regulatory mechanism may be relevant in the genesis/maintenance of panic disorder.

The inactivation of the basolateral nucleus of the rat amygdala has an anxiolytic effect in the elevated T-maze and light/dark transition tests

Pharmacological evidence indicates that the basolateral nucleus of the amygdala (BLA) is involved in the mediation of inhibitory avoidance but not of escape behavior in the elevated T-maze test. These defensive responses have been associated with generalized anxiety disorder (GAD) and panic disorder, respectively. In the present study, we determined whether the BLA plays a differential role in the control of inhibitory avoidance and escape responses in the elevated T-maze. Male Wistar rats (250-280 g, N = 9-10 in each treatment group) were pre-exposed to one of the open arms of the maze for 30 min and 24 h later tested in the model after inactivation of the BLA by a local injection of the GABA A receptor agonist muscimol (8 nmol in 0.2 æL). It has been shown that a prior forced exposure to one of the open arms of the maze, by shortening latencies to withdrawal from the open arm during the test, improves the escape task as a behavioral index of panic. The effects of muscimol in the elevated T-maze were compared to those caused by this GABA agonist in the avoidance reaction generated in the light/dark transition test. This defensive behavior has also been associated with GAD. In the elevated T-maze, intra-BLA injection of muscimol impaired inhibitory avoidance (control: 187.70 ± 14.90 s, muscimol: 37.10 ± 2.63 s), indicating an anxiolytic effect, without interfering with escape performance. The drug also showed an anxiolytic effect in the light/dark transition test as indicated by the increase in the time spent in the lighted compartment (control: 23.50 ± 2.45 s, muscimol: 47.30 ± 4.48 s). The present findings point to involvement of the BLA in the modulation of defensive responses that have been associated with GAD.

Behavioral effects of intra-amygdala injections of GABA and 5-HT acting drugs in the elevated plus-maze

The effect of drugs bilaterally injected into the basolateral/medial nuclei of the amygdala on the behavior of male Wistar rats (300-330 g) in the elevated plus-maze was measured. The benzodiazepine agonist midazolam (MDZ, 20 and 40 nmol, 0.2 µl; N = 8-14) significantly increased open-arm exploration (percent open-arm entries; control = 20.27 + or - 3.71; 40 nmol MDZ = 42.63 + or - 7.16), having thus an anxiolytic effect. On the contrary, the non-selective 5-HT2 antagonist ketanserin (KET, 1 and 10 nmol, 0.2 µl; N = 8-11) had an anxiogenic effect (percent open-arm entries: control = 35.61 + or - 6.41; 10 nmol KET = 18.65 + or - 3.89). The 5-HT1A full agonist 8-OH-DPAT (2, 4 and 8 nmol, 0.2 µl; N = 9.12) did not significantly achange rat behavior in the plus-maze. While the present anxiolytic effect of midazolam agrees with results reported by others using punished behavior, the effect of the serotonergic drugs does not. Therefore, the effect of 5-HT acting drugs injected into the amygdala may be determined by the type of experimental model of anxiety used

Anxiolytic effect of carbamazepine measured in the elevated plu-maze

the anxiolytic effect of carba,zepine was measured in rats placed in an elevated plus-maze. Doses from 5 to 40 mg/Kg, ip, of carbamazepine increased the percentage of open arm entries as well as the percentage of time spent in the two opwn arms of the maze. Both of these measures ar interpreted as indexes of anxiety. The total number of entries in either the open or the two enclosed arms, considered as an index of general activity, was not changed by the drug. Therefore, carbamzepine, carba,azepine caused a selective anxiolytic effect as measured in the elevated plus-maze, which is predictive of clinical efficacy