Pingfu Feng

Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine.

Depression is associated with deficiencies in monoaminergic transmitters and possibly neurotrophins. A common cellular response to these molecules is the activation of extracellular signal-regulated kinase (ERK). A deficiency of ERK signal transduction in depression was therefore hypothesized and was tested in a rat model of depression, produced by neonatal treatment with clomipramine (CLI). We measured sexual behaviors and brain levels of ERK, phosphorylated ERK (pERK), protein phosphatase 1 (PP1), and MAPK phosphatase-2 (MKP-2) during adulthood in control and neonatally CLI-treated rats (CLI rats). As expected, the CLI rats exhibited significantly lower sexual activities and also exhibited (1). significant decreases of pERK1/2 in the frontal cortex and pERK1 in the hippocampus, (2). slight but significant reduction of ERK2 in the frontal cortex and hippocampus, (3). no change of pERK1/2 levels in the temporal cortex, occipital cortex, parietal cortex, midbrain, and medulla, (4). significantly higher levels of PP1 in both the frontal cortex and hippocampus, (5). no change in MKP-2 in any examined region, and (6). all five measures of sexual function were significantly correlated with ERK2 and pERK2 in the frontal cortex. These findings suggest that a deficiency in the ERK signaling pathway is involved in the display of depressive behaviors.

Brainstem carbachol injections in the urethane anesthetized rat produce hippocampal theta rhythm and cortical desynchronization: A comparison of pedunculopontine tegmental versus nucleus pontis oralis injections

Previous research has demonstrated that brainstem injections of acetylcholine agonists (e.g., carbachol) produced electrophysiological indicators of rapid-eye-movement (REM) sleep in the cat. Recent reports now indicate that this phenomenon may hold true for rats as well. Relatively few reports, however, have examined the effect of these injections on REM indicators in the anesthetized rat, a preparation useful for elucidating underlying neurobiological mechanisms controlling REM sleep processes. The present study compared the effect of injections of carbachol (5 micrograms in 250 nl) into the pedunculopontine tegmental nucleus (PPTg) or the nucleus pontis oralis (NPO) on two tonic indicators of REM sleep in the urethane-anesthetized rat. Namely, changes in the hippocampal EEG and in the cortical EEG. Carbachol injections into either site produced a change in both the hippocampal EEG and cortical EEG to a REM-like state at short latencies. The length of these changes (duration of effect), however, was site-dependent. Thus, PPTg carbachol injections induced significantly longer lasting effects in both the hippocampal and cortical EEG than did NPO injections. The results that brainstem carbachol injections in rats, as in cats, may provide a useful model for investigating tonic REM sleep processes.

The critical window of brain development from susceptive to insusceptive. Effects of clomipramine neonatal treatment on sexual behavior.

The immature brain is much more sensitive to abnormal experience, particularly sleep deprivation, drug exposure, and maternal separation. The critical time period during which features in the brains susceptibility to such experience change, however, has not yet been determined. In previous studies on rats, we found that neonatal treatment with clomipramine (CLI) during postnatal days 8--21 (P8-21) produced behavioral and physiological abnormalities in adult rats that resembled the abnormalities found in human endogenous depression. The objective of the present study is to determine (1) the critical (more specifically, the latest) time frame in which CLI treatment will produce adult depression and (2) the shortest treatment window during which CLI can induce adult depression. Male rats were neonatally treated with CLI (20 mg/kg, sc) twice daily or with an equivolume of saline. The treatment windows were P12--17, P14--20, P16--22, and P12--15. Six variables, including number of mounts, intromission, ejaculation, mount latency, ejaculation latency, and post-ejaculation interval, were measured visually between the ages of 4 and 5 months. Rats treated with CLI showed significant sexual impairment in treatment windows P12--17 and P14--20 and slight sexual deficiency in the short window P12--15. No significant sexual impairment was found in window P16--22. We concluded that P14--20 was the latest window during which CLI treatment produces adult sexual deficiency and that 6 days might be the shortest treatment window to produce significant behavior abnormalities.