Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.

Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.

Administration of fenfluramine at different ambient temperatures produces different core temperature and 5-HT neurotoxicity profiles.

This study investigated the effect of two different ambient temperatures on fenfluramine-induced 5-HT neurotoxicity. Fenfluramine (FEN) (12.5 mg/kg x 4; injections made hourly) or saline (SAL) was administered to rats in either a normal laboratory temperature of 24 degrees C or a warm environment of 30 degrees C. Animals were kept at that ambient temperature for 20 h after FEN administration. Ambient temperature was controlled to +/-0.5 degrees C and rat core temperature was continually measured using a non-invasive apparatus. FEN-treated rats at 24 degrees C displayed a core temperature hypothermia with a peak low of 33.8 degrees C, and this core temperature hypothermia lasted for 20 h after FEN administration. Rats treated with FEN at 30 degrees C displayed a significant core temperature hyperthermia for 4 h after the first drug injection compared to SAL-treated groups, with a peak core temperature of 38.6 degrees C. 2 weeks after FEN injections, brain regions were analyzed by HPLC. Both groups of FEN-treated rats showed decreases in 5-HT and 5-HIAA in the hippocampus, frontal cortex, somatosensory cortex, striatum, hypothalamus and septum. However, FEN rats treated at 30 degrees C had significantly greater decreases (26-35%) in 5-HT compared to FEN-treated rats at 24 degrees C in the frontal cortex, hippocampus, striatum and somatosensory cortex and significantly greater decreases (26-50%) in 5-HIAA in the frontal cortex, hippocampus and somatosensory cortex. This study indicates fenfluramine can produce neurotoxicity in rats that display either a core temperature hypothermia or hyperthermia, although hyperthermic rats have greater 5-HT and 5-HIAA depletions than the hypothermic rats.

Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat.

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) is a drug of abuse and has been shown to be neurotoxic to 5-HT terminals in many species. MDMA-engendered neurotoxicity has been shown to be affected by both ambient temperature and core body temperature. We now report that small (2 degreesC) changes in ambient temperature produce changes in core temperature in MDMA-treated rats, but the same changes in ambient temperature do not affect core temperature of saline-treated animals. Furthermore, increases in core temperature of MDMA-treated animals increase neurotoxicity. Rats were given MDMA (20 or 40 mg/kg) or saline and placed in an ambient temperature of 20, 22, 24, 26, 28, or 30 degreesC using a novel temperature measurement apparatus that controls ambient temperature +/-0.5 degrees C. Two weeks after MDMA treatment, the rats were killed, and regional 5-HT and 5-hydroxyindole acetic acid levels were analyzed as a measure of neurotoxicity. Rats treated with MDMA at 20 and 22 degrees C showed a hypothermic core temperature response. Treatment with MDMA at 28 and 30 degreesC produced a hyperthermic response. At ambient temperatures of 20-24 degrees C, neurotoxicity was not observed in the frontal cortex, somatosensory cortex, hippocampus, or striatum. At ambient temperatures of 26-30 degrees C, neurotoxicity was seen and correlated with core temperature in all regions examined. These data indicate that ambient temperature has a significant affect on MDMA neurotoxicity, core temperature, and thermoregulation in rats. This finding has implications on both the temperature dependence of the mechanism of MDMA neurotoxicity and human use because fatal hyperthermia is associated with MDMA use in humans.

Co-administration of MDMA with drugs that protect against MDMA neurotoxicity produces different effects on body temperature in the rat.

The substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) has been shown to be neurotoxic to serotonin (5HT) terminals in the rat, and rat body temperature (TEMP) has been shown to affect this neurotoxicity. This study looked at the effect on CORE TEMP of three drugs that protect against MDMA neurotoxicity in the rat. Male Holtzmann rats were injected with a control saline (SAL) injection or with ketanserin (KET; 6 mg/kg), alpha-methyl-p-tyrosine (AMPT; 75 mg/kg) or fluoxetine (FLUOX; 10 mg/kg) before a 40-mg/kg MDMA or SAL injection. CORE TEMP was recorded throughout the study using a noninvasive peritoneally implanted temperature probe. Rats pretreated with KET had no change in CORE TEMP until MDMA was injected, at which time an immediate hypothermia was seen that continued for 180 minutes, with a peak low of 34.7 degrees C. Rats treated with AMPT had no change in CORE TEMP until the MDMA was injected, at which time an immediate hypothermia was seen that continued for 240 min., with a peak low of 34.3 degrees C. Two weeks later, brain regions were analyzed for 5-HT and 5-hydroxindole acetic acid levels. MDMA produced significant (P < .05) decreases in 5-HT and 5-hydroxindole acetic acid levels in the frontal cortex, somatosensory cortex, striatum and hippocampus, and pretreatment with KET or AMPT prevented these depletions. When rats were given the KET/MDMA or AMPT/MDMA drug injections and warmed to prevent hypothermia, the protection against neurotoxicity was removed, which indicated that the hypothermia mediated the protective effects of KET and AMPT. In comparison with the hypothermia seen with AMPT or KET pretreatment, pretreatment with FLUOX had no effect on CORE TEMP. The rats given the FLUOX/MDMA treatment did not have different CORE TEMPs than rats given SAL/MDMA. The FLUOX pretreatment protected against MDMA-induced 5-HT and 5-hydroxindole acetic acid depletions in the frontal cortex, somatosensory cortex, striatum and hippocampus. This study suggests that a decrease in CORE TEMP may be a mechanism of protection against MDMA neurotoxicity by some drugs but that there is also a mechanism of protection that is independent of a change in body temperature.