Introduction
The tail suspension test (TST) models "behavioral despair" and is a well-validated screening test for the behavioral effects of antidepressants in rodents. Remarkably, this paradigm detects the anti-immobility effects of a wide array of antidepressants, including tricyclic antidepressants (TCA), selective serotonin reuptake inhibitor (SSRI), monoamine oxidase inhibitor (MAOI), electro-convulsive shock (ECS), and even buproprion and atypical antidepressants.

Aims
This experiment was designed to test for genetic differences in "behavioral despair" and in imipramine responsivity among inbred mice strains. A second aim was to examine TST responses as a "stress reactivity" paradigm. We investigated the relationship between measures of immobility responses in the TST and the body temperature response following TST (a stress response).

Methods
Eleven inbred strains (129S6/SvEvTac, A/J, AKR/J, Balb/cJ, C3H/HeJ, C57BL/6J, DBA/2J, FVB/NJ, NMRI, SencarA/PtJ and SWR/J) were judiciously selected to represent the genetic diversity of inbred mouse populations. All mice underwent two trials of TST: (1) spontaneous, basal TST and (2) imipramine (30 mg/kg, i.p.) or saline TST. Duration of immobility was recorded during TST in 11 strains, and core temperature was measured in 4 strains (129S6, A/J, C57BL/6J and NMRI) following both basal and imipramine/saline TST.

Results
For the 11 strains tested on TST, significant strain differences in immobility duration were found for both basal TST and imipramine response TST, with heritability estimates of 0.31 and 0.60 respectively. Immobility duration for the DBA/2J, FVB/NJ and NMRI strains were significantly reduced for the imipramine groups compared to their corresponding saline groups. Surprisingly, the reduction of immobility was independent of the basal immobility (r=-0.06). Using an imipramine responder (NMRI) and imipramine non-responder (129S6) on TST, blood and brain leves of imipramine did not significantly differ betweestrains. Significant strain differences were also found for basal TST-induced hyperthermia, with NMRI strain showing the highest (38.5 °C) and A/J the lowest (36.5 °C). Imipramine (30 mg/kg, i.p.) demonstrated significant pharmacological activity in reducing body temperature in the 129S6 and NMRI strains. Remarkably, imipramine (30 mg/kg, i.p.) differentially exhibited an anti-immobility effect on TST in only the NMRI strain, but not the 129S6 strain. Furthermore, in the 129S6 strain, the TST-induced hyperthermia was selectively blocked with propranolol (10 mg/kg, i.p.), while this agent had no effect on immobility.

Conclusions

1. Strain differences in the basal TST immobility demonstrate genetic variability and suggest that "behavioral despair" may be a "stress reactivity" trait.
2. Strain differences between imipramine responders (NMRI) and non-responders (129S6) represent pharmacodynamic differences and not pharmacokinetic differences.
3. The non-significant correlation between basal TST immobility and anti-immobility effect of imipramine in the TST indicates distinct genetic architecture for mediating these responses.
4. The differential imipramine responses in the 129S6 strain for the TST-induced hyper thermia and duration of immobility suggest that these phenomena are regulated by separate pathways.

Supported by the UT Southwestern Medical Foundation and the NARSAD Young Investigator's Award (HG).

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