Long-Term Repetitive Transcranial Magnetic Stimulation Increases the Expression of Brain-Derived Neurotrophic Factor and Cholecystokinin mRNA, but not Neuropeptide Tyrosine mRNA in Specific Areas of Rat Brain

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a therapeutic tool in various neurological and psychiatric disorders, and we recently found that it has a neuroprotective effect both in vitro andTranscranial magnetic stimulation (TMS), a technique in which a time-varying strong electric current is applied through a coil held in direct contact with the subject's head, was originally developed for diagnostic use in neurology (for review see Rossini and Rossi 1998). A possible effect of TMS on mood was first reported in 1987 (Bickford et al. 1987) and, although discussed controversially, to date several lines of evidence resulting from both preclinical (Fleischmann et al. 1995;Zyss et al. 1997) and clinical (e.g., Pascual-Leone et al. 1996) studies support the notion that repetitive TMS (rTMS) may have antidepressant properties: rTMS induces transient enhancement of mood in healthy subjects, and daily application alleviates symptoms in patients suffering from treatment-resistant major depression (for review see George et al. 1999).Although rTMS is currently being evaluated as a possible alternative or add-on therapy in the treatment of refractory depression, knowledge concerning its effects at the molecular and cellular level is still very limited. Recently, Ji et al. (1998) reported a specific activation of brain regions in terms of immediate early gene expression in rats in response to rTMS. In addition, we provided a first evidence for a neuroprotective effect of long-term rTMS in vivo and in vitro (Post et al. 1999). The in vitro studies showed that magnetic stimulation analogous to TMS increased the overall viability of mouse monoclonal hippocampal HT22 cells and had a neuroprotective effect against oxidative stressors such as amyloid beta (A ␤ ) and glutamate. Moreover, the treatment increased the release of the potentially neuroprotective secreted amyloid precursor protein (sAPP) into the supernatant of HT22 cells and into cerebrospinal fluid from rats. Accordingly, HT22 cells preincubated with cerebrospinal fluid from long-term rTMStreated rats were found to be protected against A ␤ (Post et al. 1999). However, the neurochemical mechanisms underlying these neuroprotective properties as well as the putative therapeutic effects of rTMS in neurological and psychiatric disorders still remain to be elucidated.Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is abundantly expressed in the adult brain. The neurotrophic and also neuroprotective effects of BDNF have been characterized extensively both in vitro and in vivo. In addition, upregulation of BDNF has been implicated in neuronal responses to various kinds of injuries, such as epileptic seizures, cerebral ischemia, and hypoglycemia (for review see Connor and Dragunow 1998). Recent work raised the possibility that one of the many long-term effects of antidepressant treatment may be regulation of neurotrophins: antidepressant drug treatment and electroconvulsive seizures (ECS) were shown to marke...

Neuroendocrine and Behavioral Effects of Repetitive Transcranial Magnetic Stimulation in a Psychopathological Animal Model Are Suggestive of Antidepressant-like Effects

“…Therefore, the current data could be extrapolated to the clinical condition and provide new insights into the mechanisms underlying the antidepressant effects of rTMS. With respect to the changes in HPA system activity, the present findings further support the concept of a common final pathway for different types of antidepressant treatment strategies (e.g., Müller et al 2000).…”

“…Moreover, we recently demonstrated that long-term rTMS in rats has a neuroprotective effect both in vitro and in vivo (Post et al 1999). In addition, we observed rTMS-induced changes in the expression of brain-derived neurotrophic factor (BDNF) and cholecystokinin simi-lar to those reported after antidepressant drug treatment and electroconvulsive seizures (Müller et al 2000). These data suggest that a common molecular mechanism may underlie different antidepressant treatment strategies and that animal experiments might be helpful in understanding the neurobiological changes induced by rTMS, which still remain to be investigated.…”

“…In support of this hypothesis are a number of findings showing dopamine agonists to reduce floating time in rats tested in the forced swim paradigm (Borsini and Meli 1988). Furthermore, we recently reported that rTMS induced an increase in the expression of neuropeptide CCK mRNA after chronic treatment in rats (Müller et al 2000). CCK, acting as a neuromodulator, increases the firing rate of dopaminergic ventral tegmental and substantia nigra neurons, and the ability of CCK to directly affect local dopamine release has been demonstrated in numerous experiments (for review, see Crawley and Corwin 1994).…”

“…Therefore, the increase in CCK expression reported could possibly contribute to the behavioral effects of rTMS measured in the forced swim test. A further explanation for the increase in active stress coping comes from our recent finding of a significant increase in BDNF mRNA and protein in specific areas of the rat brain after chronic rTMS (Müller et al 2000). In line with this finding is the observation that local infusion of high concentrations of BDNF into the midbrain exerts antidepressant-like effects in the forced swim test.…”

“…Each HAB and LAB rat received 1,000 stimuli/day resulting from 20 trains with a maximum magnetic induction field modulus of 4 Tesla [120 A/ s; 130% of rats' motor threshold, determined as described previously (Müller et al 2000)] at a rate of 20 Hz for 2.5 s. These stimulation parameters were chosen according to the results of accurate computer reconstructions as described above. Between trains there was an interval of 2 min for cooling to prevent overheating of the stimulation coil.…”