Locomotor response to apomorphine (0.5 mg/kg s.c.) was tested in rats pre-treated with multiple rapid transcranial magnetic stimulation (rTMS) or electroconvulsive shock (ECS). rTMS (B = 1.6T, f = 20 Hz, t = 300 s) was delivered 9 times during 18 days (group rTMS1, total number of stimulations 54,000) or 18 times during 18 days (group rTMS2, total number of stimulations 108,000); ECS (I = 150 mA, f = 50 Hz, t = 500 ms) was delivered 9 times at 48 h intervals. Apomorphine given 24 h after the last treatment induced hyperactivity that was significantly more pronounced in rats receiving ECS and rTMS. The effect was most pronounced for electroconvulsive treatment, the least in the rTMS1 group. The results indicate that an increase in the total number of impulses during the rTMS may increase the responsiveness of rats to dopaminergic stimulation to the level comparable with that induced by ECS.
To assess the similarity of the behavioural effects of the rapid transcranial magnetic stimulation (rTMS) to those produced by other antidepressant treatments, in particular to repeated electroconvulsive shock (ECS), we carried out experiments on Wistar rats. The effects of a standard ECS procedure (9 daily treatments; the current parameters: 150 mA, 50 Hz, 0.5 s) were compared with 18 d treatment with rTMS of the same field intensity of 1.6 T but with different stimulation frequency (20 or 30 Hz) and a different number of sessions (9 or 18). Twenty-four hours after the last treatment the forced swimming test was carried out and the immobility time was recorded. The standard ECT reduced the immobility by 50%, the intensive rTMS (90 or 104 K impulses for the whole period of treatment) caused a significant effect, although smaller than that induced by ECT (reduction by 20-30%). The stimulation at 20 Hz required 18 treatment sessions to produce a significant effect, while only 9 sessions with stimulation at 30 Hz were sufficient to produce a comparable result. This suggests that the effectiveness of rTMS may be augmented by increasing the number or frequency of rTMS impulses.
Since the time of introducing ECT to the clinical practice, the method always raised questions regarding possibility that the current running through structures of a brain may evoke structural changes and, as a result, evoke convulsive attacks. Pathological changes (swelling, gliosis, atrophy, necrosis) were observed most often after "mega"--schemes including series of several to several hundred ECT treatments. Regime used nowadays including only 8-12 ECT sessions seems to be entirely safe. There are, however, only a few experimental works dealing with this problem. In 1992 research started on a new neurophysiological technique--transcranial magnetic stimulation (TMS) in depression. The advantage of this method is that is does not seem to evoke convulsive attacks. Prolonged rapid rate TMS (rTMS) seems to be particularly efficient in treatment of depression. Despite thousands of works describing various functional effects of TMS, there are obviously no researches on structural effects of the technique. In the case of experimental research on animals a few works were published and their results seem to be ambiguous. We have examined the influence of prolonged repetitive rTMS (B = 1.4 T, t = 5.5 min, f = 30 Hz), and standard ECT (I = 150 mA, t = 0.5 s, f = 50 Hz) on the structure of brain tissue in rats. Both groups of animals (n = 10) received 12 stimulation sessions. After the treatment the animals were routinely processed for electron microscopy (EM) and for light microscopy (LM). Our investigations suggest that the technique of ECT shows a considerable neurotoxic potential. In comparison to ECT--the rTMS method seems to be more safe.
Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular β-amyloid precursor protein, and secreted β-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower β-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.
Abstract Letrozole, an aromatase inhibitor (AI), is used as an adjuvant therapy in estrogen receptor-positive (ER+) breast cancer patients. Similar to other AIs, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here we studied effects of letrozole on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies. Mice were continuously treated with once-a-day subcutaneous (s.c.) injections of letrozole (0.1 or 0.3 mg/kg/day) or vehicle and subjected to behavioral testing starting on day 21 after treatment initiation. During the treatments, vaginal smears were taken from the mice to evaluate estrous cyclicity. Both doses of letrozole suspended cyclicity and the smears showed that the mice were in constant metestrus. Exposure to letrozole did not significantly affect response to novelty measured as a locomotor activity in open field. However, repeated testing in open field (4 days × 15 min) revealed that letrozole 0.3 mg/kg facilitated locomotor habituation (a form of non-associative learning), significantly reducing locomotor activity on 3rd and 4th day of testing. These findings suggest that certain doses of letrozole may have positive effects on cognitive behavior. Training to find a hidden platform in the Morris water maze (15 days x 4 trials), however, indicated that letrozole 0.1 mg/kg-treated mice had significant learning impairment, as, throughout the training, they swam longer times than vehicle-treated mice to reach the hidden platform. Similarly, in a probe test performed 72 h after the last day of the training, letrozole 0.1 mg/kg-treated mice did not show preference for the training platform zones. These results indicate that cognitive impairments reported by women treated with letrozole can be captured in BALB/c mice treated with clinically relevant doses of the drug. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation but rather delayed acquisition of spatial information. The current study shows that letrozole dose dependently modulates behavioral response and that its effects are task dependent.
