The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases.

The development of neurologic disease is a complex and multi-faceted process. Several factors, such as physiology, environment and genetics may play key roles in the manifestation of the associated illnesses. During the past decades, it has become clear that, at the cellular level, mitochondria function as more than "just" an energy source for our cells and plays a significant role in such aspects as neuronal development, maintenance and degeneration. Malfunctions in mitochondrial respiration and ATP production may prove disastrous for our cells and neurons, ultimately resulting in apoptosis, neurodegeneration and consequently, neurodegenerative diseases.

Olfactory bulbectomy induces rapid and stable changes in basal and stress-induced locomotor activity, heart rate and body temperature responses in the home cage.

BACKGROUND: Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical changes. However, the extent and onset of physiological and behavioral changes induced after bulbectomy have been little examined. METHODS: Male Sprague-Dawley rats received telemetric implants. Before and immediately after OBX surgery, basal and stress-induced heart rate, body temperature, and locomotor activity were measured in the home cage in sham (n=9) and OBX animals (n=11). Stress was induced using novel cage stress or witness stress. RESULTS: Bulbectomized animals differed physiologically and behaviorally from shams. Nocturnally, OBX animals were significantly more active compared with shams, had a higher core body temperature and displayed a decreased heart rate variability. During the light period, OBX animals had a significantly lower basal heart rate and a reduced heart rate variability. These effects became apparent 2-3 days after OBX surgery, and were stable over time. After witness stress, OBX animals showed smaller autonomic (body temperature and heart rate) responses compared with shams, but showed no difference in locomotor responses. In contrast, novel cage stress led to increased locomotor responses in OBX rats compared with sham rats, while no differences were found in autonomic responses. CONCLUSION: Removal of the olfactory bulbs results in rapid, stable and persistent changes in basal locomotor activity, body temperature, heart rate and heart rate variability. Although the sleep-wake cycle of these parameters is not altered, increases in circadian amplitude are apparent within 3 days after surgery. This indicates that physiological changes in the OBX rat are the immediate result of olfactory bulb removal. Further, stress responsivity in OBX rats depends on stressor intensity. Bulbectomized rats display smaller temperature and heart rate responses to less intense witness stress compared with sham rats. Increased locomotor responses to more intense novel cage stress are present in the home cage as well as the open field. The present study shows that olfactory bulbectomy has rapid and persistent influence on basal and stress-induced physiological parameters.

SSR149415, a non-peptide vasopressin V1b receptor antagonist, has long-lasting antidepressant effects in the olfactory bulbectomy-induced hyperactivity depression model.

Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical CNS changes, reminiscent of symptoms of human depression. Such depression-like behavior after OBX can be reversed with antidepressants. Recently, a connection between the vasopressin 1b (V1b) receptor and the development of depression has been suggested; therefore, a vasopressin V1b receptor antagonist (SSR149415) was investigated in the OBX model. Male rats received olfactory bulbectomy or sham surgery. After recovery, animals received 14 consecutive daily doses of SSR149415 (10 or 30 mg/kg), imipramine (20 mg/kg), or vehicle (5% hydroxy-propyl methylcellulose). Animals were tested in an open field after acute treatment, on days 7 and 14 of treatment and 1 week after cessation of treatment. Similar to imipramine, repeated, but not acute, administration of SSR149415 completely reversed OBX-induced hyperactivity, leaving activity in shams unaffected. This reversal of OBX-induced hyperactivity in the SSR149415 treated rats was still present 7 days after cessation of treatment. Although the behavioral effects of treatment with SSR149415 were specific for the OBX animals, adrenal gland weights were reduced in both sham and OBX animals treated with 30 mg/kg SSR149415. Chronic but not acute administration of SSR149415 normalizes OBX-induced hyperactivity up to 1 week after cessation of treatment, suggesting that a V1b receptor antagonist may have long-lasting antidepressant activity.

The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects.

Current antidepressants have a delayed onset of action and disturbing side effects, including inhibition of sexual behavior. It is hypothesized that novel drugs, hitting multiple disease-relevant targets, may yield a new generation of superior antidepressants. One such approach is simultaneous inhibition of serotonin, norepinephrine and dopamine transporters. We tested the triple uptake inhibitor (TUI), DOV 216,303 (5, 10 and 20 mg/kg) after 1, 7 and 14 days administration in the olfactory bulbectomized (OBX) rat depression model, and in a model of rat sexual behavior to detect putative sexual side effects. Chronic, but not acute treatment of DOV 216,303 (20 mg/kg) normalized OBX-induced hyperactivity in the open field, similar to the effect of imipramine (20 mg/kg). None of the doses of DOV 216,303 had any effect on sexual behavior at any time point. The results indicate that DOV 216,303 displays antidepressant efficacy and is devoid of sexual side effects.

Aggression in male rats receiving anabolic androgenic steroids: effects of social and environmental provocation.

This study examined the effects of anabolic androgenic steroids (AAS) on aggression under different social and environmental conditions. Three AAS were tested in gonadally intact male rats: testosterone propionate (TP), nandrolone (ND), and stanozolol (ST). Doses of 5 mg/kg were given 5 times/week, with gonadally intact controls receiving vehicle only (propylene glycol). Animals received six weekly tests under each condition in a counterbalanced order. Results show that the three AAS differed in their ability to elicit aggression. Males receiving TP were more aggressive than controls, ND males were similar to controls, and ST males were less aggressive than controls. In the social and environmental provocation tests TP-treated males were more aggressive than other groups, but were able to discriminate between intact and castrated opponents and between their home cage and a neutral cage. In the environmental provocation test, TP males were also more aggressive against opponents when tested in the opponent's home cage. It is suggested that chronic exposure to high levels of TP does not eliminate the ability to discriminate between social or environmental cues, as might be expected if it induces a " 'roid rage." However, TP does increase the likelihood that the animal will respond with aggression/dominance in a provoking situation. All three AAS variably affected serum testosterone and LH levels, as well as testes, seminal vesicle, and prostate weights. No effect on body weight was observed.