Forced Swim Immobility Research Articles

C1473G polymorphism in mouse tph2 gene is linked to tryptophan hydroxylase‐2 activity in the brain, intermale aggression, and depressive‐like behavior in the forced swim test

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of brain serotonin synthesis. The C1473G polymorphism in the mouse tryptophan hydroxylase-2 gene affects the enzyme's activity. In the present study, we investigated the linkage between the C1473G polymorphism, enzyme activity in the brain, and behavior in the forced swim, intermale aggression, and open field tests using mice of the C57BL/6 (C/C) and CC57BR/Mv (G/G) strains and the B6-1473C (C/C) and B6-1473G (G/G) lines created by three successive backcrossings on C57BL/6. Mice of the CC57BR/Mv strain had decreased brain enzyme activity, aggression intensity, and immobility in the forced swim test, but increased locomotor activity and time spent in the central part of the open field arena compared with animals of the C57BL/6 strain. Mice of the B6-1473G line homozygous for the 1473G allele had lower TPH2 activity in the brain, aggression intensity, and immobility time in the forced swim test compared with animals of the B6-1473C line homozygous for the 1473C allele. No differences were found between the B6-1473G and B6-1473C mice in locomotor activity and time spent in the central part of the arena in the open field test. Thus, the C1473G polymorphism is involved in the determination of TPH2 activity and is linked to aggression intensity and forced-swim immobility in mice. At the same time, the polymorphism does not affect locomotion and anxiety-related behavior in the open field test. The B6-1473C and B6-1473G mice represent a valuable experimental model for investigating molecular mechanisms of serotonin-related behavior.

Changes in brain orexin levels in a rat model of depression induced by neonatal administration of clomipramine

Depression is associated with a deficiency of serotonergic neurons that have been found to suppress orexinergic neurons, which in turn activate these neurons in a feedback loop. This evidence suggests that orexins may be involved in the pathology of depression. Long Evans rats were treated with clomipramine (CLI) and saline (SAL) from postnatal days 8 through 21. One set of rats from both groups was sacrificed at 35 days of age for quantification of orexins in multiple brain regions. At 3-4 months of age a second set of rats was tested for immobility in a forced swim procedure, a common test for depressive signs in rats, and a third set was sacrificed for the quantification of orexins. Compared with the control rats, adult rats with neonatal CLI treatment had (1) increased forced swim immobility and (2) increased orexins A and B in the hypothalamus. However, both orexins A and B levels were decreased in multiple brain regions in the juvenile CLI rats compared with same-age controls. We concluded that although orexin levels were decreased in juvenile CLI rats, adult CLI rats with features of depression had significantly higher levels of hypothalamic orexins compared with adult controls. These results imply that orexins are likely to be involved in the pathological regulation of depression.

Failure of neonatal clomipramine treatment to alter forced swim immobility: chronic treadmill or activity-wheel running and imipramine

We examined whether chronic running on a treadmill or activity wheel would attenuate the increased swim immobility that has been reported after neonatal clomipramine (CLI) treatment. Male Sprague–Dawley pups ( N = 60) were injected with the monoamine reuptake inhibitor clomipramine hydrochloride (40 mg/kg per day i.p.) from 8 to 21 days of age. Another group ( N = 12) received saline vehicle. At age 4 weeks, the CLI pups were randomly assigned to experimental conditions: (1) sedentary; (2) 24-h access to an activity wheel; (3) sedentary that received the antidepressant drug imipramine hydrochloride (10 mg/kg twice daily) during the last 10 days of the experiment; (4) activity wheel + imipramine; (5) treadmill running (30 m/min for 1 h at 0°incline, 6 days/week). At age 16 weeks, rats underwent the Porsolt swim test 48 h after the last imipramine injection and/or the last exercise session. The increase in swim immobility among CLI-treated rats was small (one quarter of SD) and not statistically significant ( p > 0.10). The results are not consistent with our previous finding of antidepressant-like effects of activity-wheel running based on brain noradrenergic adaptations and enhanced male copulatory performance after neonatal CLI treatment. The lack of change in swim performance after clomipramine questions the generalizability of the CLI model of depression and the validity of the forced swim test as a behavioral measure of depression when it is used after neonatal CLI injection or chronic activity-wheel running.

Antidepressant-like effect of lead in adult mice.

It has been reported that lead can cause behavioral impairment by inhibiting the N-methyl-D-aspartate (NMDA) receptor complex. MK-801, a noncompetitive NMDA receptor antagonist, exhibits an antidepressant-like action in the forced swimming test. The purpose of the present study was to determine whether subacute lead exposure in adult male Swiss mice weighing 30-35 g causes an antidepressant-like action in a forced swimming test. Mice were injected intraperitoneally (ip) with 10 mg/kg lead acetate or saline daily for 7 consecutive days. Twenty-four hours after the last treatment, the saline and lead-treated mice received an injection of MK-801 (0.01 mg/kg, ip) or saline and were tested in forced swimming and in open-field tests. Immobility time was similarly reduced in the saline-MK-801, Pb-saline and Pb-MK-801 groups compared to the saline-saline group (mean +/- SEM; 197.3 +/- 18.5, 193.5 +/- 15.8, 191.3 +/- 12.3 and 264.0 +/- 14.4 s, respectively; N = 9). These data indicate that lead may exert its effect on the forced swimming test by directly or indirectly inhibiting the NMDA receptor complex. Lead treatment caused no deficit in memory of habituation and did not affect locomotor activity in an open-field (N = 14). However, mice that received MK-801 after lead exhibited a deficit in habituation (22% reduction in rearing responses between session 3 and 1; N = 14) as compared to control (41% reduction in rearing responses; N = 15), further suggesting that lead may have affected the NMDA receptor activity. Forced-swim immobility in a basin in two daily consecutive sessions was also significantly decreased by lead exposure (mean +/- SEM; day 1 = 10.6 +/- 3.2, day 2 = 19.6 +/- 3.6; N = 16) as compared to control (day 1 = 18.4 +/- 3.8, day 2 = 34.0 +/- 3.7; N = 17), whereas the number of crossings was not affected by lead treatment, further indicating a specific antidepressant-like action of lead.

Different Behavioral Patterns Related to Alcohol Use in Rodents: A Factor Analysis

To estimate genetic correlations among behavioral measures from explorative crossmaze, inescapable slip funnel, as well as from drinking tests, the data from five pairs of high/low alcohol drinking rat (AA/ANA, P/NP, HAD1/LAD1, HAD2/LAD2, HIGH_IPH/LOW_IPH) and from three pairs of mouse (B10.AKM/B10.A(4R), HD/LD, Small_Brain/Large_Brain) lines were evaluated by the use of principal component analysis. The analysis yielded a two-factor solution explaining 71.8% of total variability. Both the factors had high positive loadings on alcohol drinking. The first factor had sufficient positive loadings on latency of crossmaze exploration and total time of slip funnel immobility, whereas, there was a negative loading on slip funnel avoidance. The second factor had positive loadings on efficacy of crossmaze exploration and slip funnel escape attempts, whereas there was a negative loading on slip funnel immobility. The number of defecations in the crossmaze, time in open arms of the elevated plus-maze, time immobile during the forced-swim test, as well as intake of a saccharin solution, additionally available for a lesser number of the lines, were studied for correlations with the factor scores. The first factor of “alcohol drive with timidity and meekness” exhibited positive relation to saccharin intake. Time in the open arms of the elevated plus-maze showed significant negative correlation with a latency of crossmaze exploration. The second factor of “alcohol drive with novelty seeking and persistence” showed a negative link to crossmaze defecations and forced-swim immobility.

Acute and longer term effects of meso-2,3 dimercaptosuccinic acid (DMSA) on the behavior of lead-exposed and control mice

We investigated the effect of chelating agent meso-2,3 dimercaptosuccinic acid (DMSA_ on spatial learning and forced-swim immobility in Binghamton Heterogeneous Stock (HET) mice. Forced-swim immobility (characterized by increasingly frequent bouts of complete motionlessness in a forced-swim test, i.e., behavioral despair) is reduced by exposure to lead. In Experiment 1, male and female HETs ( n = 81) were assigned to lead-exposed (0.5% lead acetate ad lib in drinking fluid), pair-fed (PF), or water control groups. Six weeks after the termination of lead exposure, half of each group was injected intraperitoneally (IP) with 50 mg/kg DMSA or vehicle once per day for 5 days. Following treatment, all animals were tested for acquisition and extinction in the Morris Water maze, followed by immobility testing in an inescapable forced-swim task. Neither Pb nor DMSA affected Morris maze performance. However, consistent with previously published work, Pb reduced immobility in the forced-water swim relative to both PF and water controls. Additionally, lead-exposed males, but not females, showed sustained improvement following DMSA treatment on immobility measures. Experiment 2 was designed to demonstrate the effect of the above DMSA protocol on blood-Pb, and also examined the immediate effects of DMSA on immobility during treatment. Thus, in Experiment 2, animals were exposed to an identical Pb and DMSA treatment protocol, but the effects of DMSA on immobility during the course of DMSA treatment were measured, and animals were sacrificed immediately after treatment so that blood-Pb measures could be taken. Under these circumstances, DMSA markedly reversed the lead-induced reduction in immobility immediately during the treatment phase. Although DMSA clearly reduced blood-lead in males, its influence on female blood levels was far less. Taken together, the data from these experiments suggest that DMSA ameliorates lead-induced immobility changes in mice, but that gender may modulate DMSA's effect on blood-lead and longer-term behavioral effects. However, further work is needed to clarify the role of gender in response to DMSA.