A theoretical study of H2 O2 as the surrogate of dose in minibeam radiotherapy, with a diffusion model considering radical removal process.

BACKGROUND: Minibeam radiation therapy (MBRT) is an innovative dose delivery method with the potential to spare normal tissue while achieving similar tumor control as conventional radiotherapy. However, it is difficult to use a single dose parameter, such as mean dose, to compare different patterns of MBRT due to the spatially fractionated radiation. Also, the mechanism leading to the biological effects is still unknown. PURPOSE: This study aims to demonstrate that the hydrogen peroxide (H2 O2 ) distribution could serve as a surrogate of dose distribution when comparing different patterns of MBRT. METHODS: A free diffusion model (FDM) for H2 O2 developed with Fick's second law was compared with a previously published model based on Monte Carlo & convolution method. Since cells form separate compartments that can eliminate H2 O2 radicals diffusing inside the cell, a term describing the elimination was introduced into the equation. The FDM and the diffusion model considering removal (DMCR) were compared by simulating various dose rate irradiation schemes and uniform irradiation. Finally, the DMCR was compared with previous microbeam and minibeam animal experiments. RESULTS: Compared with a previous Monte Carlo & Convolution method, this analytical method provides more accurate results. Furthermore, the new model shows H2 O2 concentration distribution instead of the time to achieve a certain H2 O2 uniformity. The comparison between FDM and DMCR showed that H2 O2 distribution from FDM varied with dose rate irradiation, while DMCR had consistent results. For uniform irradiation, FDM resulted in a Gaussian distribution, while the H2 O2 distribution from DMCR was close to the dose distribution. The animal studies' evaluation showed a correlation between the H2 O2 concentration in the valley region and treatment outcomes. CONCLUSION: DMCR is a more realistic model for H2 O2 simulation than the FDM. In addition, the H2 O2 distribution can be a good surrogate of dose distribution when the minibeam effect could be observed.

The antidepressant-like effects of topiramate alone or combined with 17ß-estradiol in ovariectomized Wistar rats submitted to the forced swimming test.

RATIONALE: There is a significant delay in the clinical response of antidepressant drugs, and antidepressant treatments produce side effects. OBJECTIVE: We examined the relationship between 17ß-estradiol and topiramate in ovariectomized Wistar rats submitted to the forced swimming test (FST). METHODS: Topiramate was administered alone or combined with 17ß-estradiol to ovariectomized rats submitted to the FST. RESULTS: Topiramate (20 mg/kg, P < 0.05; 30 mg/kg, P < 0.05) reduced immobility by increasing swimming; these effects were antagonized by finasteride (50 mg/kg). In interaction experiments, topiramate (10 mg/kg) plus 17ß-estradiol (5 micrograms per rat; P < 0.05) reduced immobility by increasing swimming behavior. Besides, 17ß-estradiol (2.5 micrograms per rat) shortened the onset of the antidepressant-like effects of topiramate (P < 0.05). In the open field test, topiramate alone or combined with 17ß-estradiol (P < 0.05) reduced locomotion. CONCLUSIONS: Topiramate alone or combined with 17ß-estradiol produced antidepressant-like actions; and 17ß-estradiol shortened the onset of the antidepressant-like effects of topiramate.

Estrous cycle variation in anxiolytic-like effects of topiramate in Wistar rats in two animal models of anxiety-like behavior.

The anxiolytic-like effects of topiramate were assessed during several estrous cycle phases in Wistar rats tested in two animal models of anxiety-like behavior. In a conflict operant test, during proestrus, diazepam (1.3, 2.0mg/kg; P<0.05) or topiramate (20.0, 30.0mg/kg; P<0.05) increased the number of immediately punished responses. During metestrus-diestrus only the highest doses of diazepam (2.0mg/kg, P<0.05) or topiramate (30.0mg/kg, P<0.05) increased the number of immediately punished reinforcers. Similar results were obtained in the elevated plus-maze test: during proestrus, diazepam (1.3, 2.0mg/kg; P<0.05) or topiramate (20.0, 30.0mg/kg; P<0.05) produced anxiolytic-like actions. During metestrus-diestrus only the highest doses of diazepam (2.0mg/kg, P<0.05) or topiramate (30.0mg/kg, P<0.05) produced anxiolytic-like actions. Neither diazepam nor topiramate nor estrous cycle phases significantly modified the number of closed arm entries in the elevated plus-maze test. It is concluded that the response to neuromodulatory drugs for anxiety-like behavior varied according to the estrous cycle phases.

Intra-lateral septal infusions of folic acid alone or combined with various antidepressant drugs produce antidepressant-like actions in male Wistar rats forced to swim.

Intra-cerebral administrations of folic acid produce antidepressant-like effects; either alone or combined with several antidepressant drugs. However, the specific limbic structures implied in the antidepressant-like actions of folic acid are un-known. Thus, intra-lateral septal infusions of folic acid (5.0 nmol, P<0.05; 10.0 nmol, P<0.05) or oral administrations of folic acid (50 mg/kg, P<0.05, p.o.; 75.0; mg/kg, P<0.05, p.o.) or systemic administrations of fluoxetine (20.0 mg/kg, P<0.05; 25.0 mg/kg, P<0.05) reduced immobility by increasing swimming behavior in the forced swimming test (FST) of male Wistar rats. Conversely, desipramine (10.0 mg/kg, P<0.05; 15.0 mg/kg, P<0.05) reduced immobility by increasing climbing behavior. Subthreshold doses of folic acid (2.5 nmol/intra-LSN) combined with subthreshold doses of folic acid (25.0 mg/kg, p.o., P<0.05) or with subthreshold doses of fluoxetine (15.0 mg/kg, P<0.05) and they produced antidepressant-like effects which were canceled by ketanserin. In conclusion, intra-lateral septal infusions of folic acid alone or combined with systemic doses of folic acid or fluoxetine reduced immobility in the FST. These antidepressant-like actions, probably, were due to modifications of the serotonergic system since swimming behavior was increased and these effects were canceled by ketanserin.

Fluoxetine, 17-ß estradiol or folic acid combined with intra-lateral septal infusions of neuropeptide Y produced antidepressant-like actions in ovariectomized rats forced to swim.

Folic acid is antidepressant, either alone or combined with several antidepressant drugs. However, the antidepressant-like actions of folic acid combined with intra-lateral septal (LSN) infusions of neuropeptide Y (NPY) in the forced swimming test (FST) have not been tested before. Thus, systemic injections of fluoxetine (20.0mg/kg, P<0.05; s.c.) or 17-ß estradiol (10.0 µg/rat, P<0.05; s.c.) or oral administrations of folic acid (50.0 mg/kg, P<0.05; 75.0 mg/kg, P<0.05) or NPY intra-LSN (3.0 µg, P<0.05; 3.5 µg, P<0.05) reduced immobility of ovariectomized Wistar rats. Subthreshold doses of: folic acid (25.0 mg/kg) or 17-ß estradiol (5.0 µg/rat, P<0.05) or fluoxetine (15.0 mg/kg, P<0.05; s.c.) combined with subthreshold doses of NPY (2.5 µg/rat, P<0.05; intra-LSN) and these combinations produced antidepressant-like actions; which were canceled by BIBP 3226 (a NPY-Y1 receptor antagonist). It is concluded that folic acid produced antidepressant-like effects probably through the participation of the NPY Y1 receptors found in the lateral septal nuclei.

The folic acid combined with 17-ß estradiol produces antidepressant-like actions in ovariectomized rats forced to swim.

Folic acid or 17-ß estradiol produces antidepressant effects, either alone or combined with several antidepressants. However, the antidepressant-like actions of folic acid combined with 17-ß estradiol in the forced swimming test (FST) have not been tested before. Thus, in the present study, ovariectomized female rats received folic acid (5.0 nmol/i.c.v., P<0.05; 10.0 nmol/ i.c.v., P<0.05; or 50mg/kg, P<0.05, p.o.; 75.0; mg/kg, P<0.05, p.o.), or fluoxetine (20.0mg/kg, P<0.05; 25.0mg/kg, P<0.05) or 17-ß estradiol (10.0 µg/rat, P<0.05; 20.0 µg/rat, P<0.05) and they displayed reduced immobility by increasing swimming behavior when they were tested in the FST. Combination of subthreshold doses of folic acid (2.5 nmol/i.c.v.; or 25.0mg/kg, p.o.) with subthreshold doses of 17-ß estradiol (5.0 µg/rat, P<0.05) or with subthreshold doses of fluoxetine (15.0mg/kg, P<0.05) produced antidepressant-like actions. Ketanserin was used to evaluate the participation of the drugs used in the serotonergic pathway; ketanserin cancelled the antidepressant-like actions of the several combinations used. In conclusion, folic acid alone or combined with estradiol or fluoxetine in the FST reduced immobility in the FST. These antidepressant-like actions probably were due to modifications of the serotonergic system since swimming behavior was increased and these effects were cancelled by ketanserin.

Antidepressant-like or anxiolytic-like actions of topiramate alone or co-administered with intra-lateral septal infusions of neuropeptide Y in male Wistar rats.

We tested the effects of intra-lateral septal infusions of neuropeptide Y (NPY) combined with systemic injections of topiramate in the DRL-72s paradigm and the elevated plus-maze test in male Wistar rats. Intra-lateral septal infusions of desipramine (5.0 microg/microl; P<0.05) or intra-lateral septal infusions of NPY (3.0 microg/microl, P<0.05; 3.5 microg/microl, P<0.05) or systemic injections of topiramate (20.0mg/kg, P<0.05; 30.0mg/kg, P<0.05) or subthreshold doses of topiramate (10.0mg/kg) combined with intra-lateral septal infusions of subthreshold doses of NPY (2.5 microg/microl; P<0.05) induced a dose-dependent increase in reinforced lever presses and a cohesive rightward shift of the inter-response time distribution in the DRL 72s task. In the elevated plus-maze test, intra-lateral septal infusions of NPY (3.0 microg/microl, P<0.05; 3.5 microg/microl, P<0.05) or midazolam (10.0 microg/microl; P<0.05) or systemic injections of topiramate (20.0mg/kg, P<0.05; 30.0mg/kg, P<0.05) or subthreshold doses of systemic injections of topiramate (10.0mg/kg) combined with intra-lateral septal infusions of subthreshold doses of NPY (2.5 microg/microl; P<0.05) increased the exploration of the open arms without affecting locomotion. In conclusion, intra-septal NPY has anxiolytic effects in the EPM, and antidepressant effects in the DRL 72s test. Similarly, systemic topiramate has anxiolytic effects in the EPM, and antidepressant effects in the DRL 72s test. Finally, a combination of subthreshold doses of NPY and topiramate together also have anxiolytic and antidepressant effects, suggesting a synergistic effect.

Olanzapine plus 17-beta estradiol produce antidepressant-like actions in rats forced to swim.

Several combinations of effective treatments have been used in the search for higher response rates or more rapid responses than monotherapy to diminish treatment-resistant depression. One strategy is to combine olanzapine plus antidepressant drugs. In preclinical studies in male rats, olanzapine combined with fluoxetine produce antidepressant-like actions and increase the allopregnanolone levels in the brain. 17-beta estradiol also produces antidepressant-like actions by increasing allopregnanolone levels. However, the effects of combining olanzapine with 17-beta estradiol in the forced swimming test have not been tested before. Thus, systemic injections of vehicle plus olanzapine, or fluoxetine (20.0 mg/kg; 25.0 mg/kg) or 17-beta estradiol (10.0 microg/rat; 20.0 microg/rat) reduced immobility by increasing active behaviors, which were cancelled by finasteride (finasteride was used to block the endogenous production of allopregnanolone by the brain) in ovariectomized rats forced to swim. Subthreshold doses of olanzapine (2.5 mg/kg) combined with subthreshold doses of 17-beta estradiol (5.0 microg/rat) produced antidepressant-like actions, as did the combination subthreshold dose of olanzapine (2.5 mg/kg) plus the subthreshold dose of fluoxetine (15.0 mg/kg). Finasteride cancelled the antidepressant-like actions of the several combinations used. It is concluded that olanzapine alone or combined with fluoxetine or estradiol reduced immobility by increasing swimming. In conclusion, olanzapine produces antidepressant-like actions alone or in combination with estradiol. These antidepressant-like actions of this combination were cancelled by finasteride.

Desipramine or glutamate antagonists synergized the antidepressant-like actions of intra-nucleus accumbens infusions of minocycline in male Wistar rats.

Minocycline produces antidepressant-like actions in male rats tested in the forced swimming test (FST) and synergizes with several glutamate receptor antagonists. However, the limbic regions implicated in the antidepressant-like actions of minocycline are unknown. The objective of the present study was to test the potential antidepressant activity of nucleus accumbens infusions of minocycline alone or combined with antidepressant drugs or with several glutamate receptor antagonists, using the time-sampling method in the FST. The results show that intra-NAcc infusions of minocycline reduced immobility (1.0 microg, P<0.05; 1.5 microg, P<0.05) by increasing climbing (1.0 microg, P<0.05; 1.5 microg, P<0.05) in the FST. Likewise, systemic injections of desipramine (P<0.05), fluoxetine (P<0.05) or several glutamate receptor antagonists: EMQMCM (P<0.05), MTEP (P<0.05) or dizocilpine (P<0.05) combined with intra-nucleus accumbens infusions of vehicle produced antidepressant-like actions. The subthreshold dose of intra-nucleus accumbens infusions of minocycline combined with systemic injections of subthreshold doses of desipramine (P<0.05) or EMQMCM (P<0.05) or MTEP (P<0.05) or dizocilpine (P<0.05) produced antidepressant-like actions. It is concluded that intra-NAcc infusions of minocycline alone or combined with systemic injections of desipramine or with systemic injections of several glutamate receptor antagonists produced antidepressant-like actions in the FST.

Estradiol and neuropeptide Y (intra-lateral septal) reduce anxiety-like behavior in two animal models of anxiety.

Anxiolytic-like effects of intra-lateral septal nuclei (LSN) infusions of the neuropeptide Y (NPY) alone or combined with estradiol benzoate were assessed in ovariectomized Wistar rats in two animal models of anxiety-like behavior. In a conflict test, immediately punished responses were assessed: 17-beta-estradiol (50.0microg/rat, P<0.05) plus vehicle (intra-LSN) or intra-LSN infusions of NPY (2.5microg/microl, P<0.05; 3.0microg/mul, P<0.05) plus vehicle (systemic route) or the combination of subthreshold doses of 17-beta-estradiol (25.0microg/kg) plus intra-LSN infusions of NPY (2.0microg/mul, P<0.05) increased the amount of immediately punished reinforcers. In the elevated plus-maze test several spatial-temporal variables were evaluated: 17-beta-estradiol (50.0microg/kg, P<0.05) plus vehicle (intra-LSN) or intra-LSN infusions of NPY (2.5microg/mul, P<0.05; 3.0microg/mul, P<0.05) plus vehicle (systemic route) or the combination of subthreshold doses of 17-beta-estradiol (25.0microg/kg) plus intra-LSN infusions of NPY (2.0microg/mul, P<0.05) produced anxiolytic-like actions without affecting locomotion. It is concluded that estradiol or NPY may produce anxiolytic-like actions and that subthreshold doses of estradiol and subthreshold doses of NPY when combined produced anxiolytic-like actions.

Antidepressant-like actions of minocycline combined with several glutamate antagonists.

This study tested the potential antidepressant activity of minocycline alone or combined with two traditional antidepressant drugs or several glutamate receptor antagonists, using the time sampling method in the forced swimming test. Results showed that: desipramine (10.0 mg/kg, P<0.05; 15.0 mg/kg, P<0.05), minocycline (60.0 mg/kg, P<0.05; 80.0 mg/kg, P<0.05) and EMQMCM (1.5 mg/kg, P<0.05; 2.0 mg/kg, P<0.05), reduced immobility by increasing climbing. Fluoxetine (20.0 mg/kg, P<0.05; 25.0 mg/kg, P<0.05) reduced immobility by increasing swimming. MTEP (5.0 mg/kg, P<0.05; 10.0 mg/kg, P<0.05) and dizolcipine (1.0 mg/kg, P<0.05; 1.5 mg/kg, P<0.05) reduced immobility by increasing swimming and climbing. Combination experiments showed that a subthreshold dose of minocycline (50.0 mg/kg) synergized the antidepressant-like actions of subthreshold doses of: desipramine (5.0 mg/kg; P<0.05), EMQMCM (0.6 mg/kg; P<0.05), MTEP (2.5 mg/kg; P<0.05) and dizolcipine (0.5 mg/kg; P<0.05). In conclusion, minocycline produced antidepressant-like actions in the FST and subthreshold dose of minocycline combined with subthreshold dose of desipramine and several glutamate receptor antagonists and produced antidepressant-like actions.

Estrus variation in anxiolytic-like effects of intra-lateral septal infusions of the neuropeptide Y in Wistar rats in two animal models of anxiety-like behavior.

Anxiolytic-like effects of intra-lateral septal infusions of the neuropeptide Y (NPY) were assessed during several estrus phases in Wistar rats tested in two animal models of anxiety-like behavior. In a conflict operant test, results showed that during late proestrus, intra-lateral septal nuclei infusions of NPY (1.0 microg/microl, P<0.05; 2.0 microg/microl, P<0.05; 2.5 microg/microl, P<0.05) increased the number of immediately punished responses. During metestrus-diestrus only the highest doses of NPY (2.5 microg/microl, P<0.05) increased the number of immediately punished reinforcers. In the elevated plus-maze test, results showed that during late proestrus, intra-lateral septal nuclei infusions of NPY (1.0 microg/microl, P<0.05; 2.0 microg/microl, P<0.05) produced anxiolytic-like actions. During metestrus-diestrus only the highest doses of NPY (2.0 microg/microl, P<0.05) produced anxiolytic-like actions. Neither NPY nor estrus phases significantly modified the number of closed arms entries in the elevated plus-maze test. It is concluded that anxiolytic-like effects of NPY vary within the estrus cycle in Wistar rats.

Antidepressant-like and anxiolytic-like actions of the mGlu5 receptor antagonist MTEP, microinjected into lateral septal nuclei of male Wistar rats.

This study describes the effects of intra-lateral septal infusions of different doses of the mGluR5 antagonist MTEP in the DRL-72 s paradigm and the elevated plus-maze test in rats, two behavioral models known to be sensitive to antidepressant-like and anxiolytic-like drug effects, respectively. Intra-lateral septal infusions of MTEP induced a dose-dependent (5.0 microg/microl, P<0.05; 10.0 microg/microl, P<0.05) increase in reinforced lever presses and a cohesive rightward shift of the inter-response time distribution (5.0 microg/microl, P<0.05; 10.0 microg/microl, P<0.05). These effects are indicative of antidepressant-like actions of the compound. Desipramine, a prototypical antidepressant drug, induced (5.0 microg/microl; P<0.05) similar effects. In the elevated plus-maze test, intra-lateral septal infusions of MTEP (5.0 microg/microl, P<0.05; 10.0 microg/microl, P<0.05) increased the exploration of the open arms without affecting locomotion. This anxiolytic-like effect was similar to that observed with the infusion of the benzodiazepine midazolam (10.0 microg/microl; P<0.05) in the same brain area. It is concluded that intra-lateral septal infusions of the mGlu5 receptor antagonist MTEP produced antidepressant-like actions or anxiolytic-like effects in male rats.

Synergistic interaction between ketoconazole and several antidepressant drugs with allopregnanolone treatments in ovariectomized Wistar rats forced to swim.

This article was aimed to investigate the interest of the combination allopregnanolone plus ketoconazole in depression with the time-sampling method in the forced swimming task. Dose-response curves for fluoxetine (0.5, 1.0 or 2.0 mg/kg, twice day, during 2 weeks; i.p.), desipramine (0.5, 1.0 or 2.14 mg/kg, twice a day, during 2 weeks; i.p.), ketoconazole (6.25, 12.5, 25.0 and 37.5 mg/kg, once a day, during 2 weeks; i.p.) and allopregnanolone (0.5, 1.5, 2.0 mg/kg; once a day, during 2 weeks; s.c.) were established. Fluoxetine (1.0 mg/kg, p < 0.05; 2.0 mg/kg, p < 0.05) or ketoconazole (25.0 mg/kg, p < 0.05; 37.5 mg/kg, p < 0.05) produced antidepressant-like behavioral changes in swimming, highlighting a serotonergic mechanism while desipramine (1.0 mg/kg, p < 0.05; 2.14 mg/kg, p < 0.05) or allopregnanolone (1.5 mg/kg, p < 0.05; 2.0 mg/kg, p < 0.05) increased climbing behavior highlighting noradrenergic or dopaminergic effects. Subthreshold doses of fluoxetine (p < 0.05), desipramine (p < 0.05) or ketoconazole (p < 0.05) synergized with subthreshold doses of allopregnanolone and reduced immobility by increasing climbing. In conclusion, fluoxetine, desipramine, ketoconazole and allopregnanolone produced differential antidepressant-like actions in ovariectomized rats forced to swim. Ketoconazole, fluoxetine or desipramine synergized with allopregnanolone.

Rats socially-reared and full fed learned an autoshaping task, showing less levels of fear-like behaviour than fasted or singly-reared rats.

During the learning of instrumental tasks, rats are usually fasted to increase reinforced learning. However, fasting produces several undesirable side effects. The aim of this study was to test the hypothesis that control rats, i.e. full-fed and group-reared rats, will learn an autoshaping task to the same level as fasted or singly-reared rats. The interaction between fasting and single-rearing of rats was also tested. Results showed that control rats and fasted rats acquired the autoshaping task similarly, independently of rearing condition or gender. However, fasted or singly-reared rats produced fear-like behaviour, since male rats group-reared and fasted (85% body/wt, P <0.05), male rats singly-reared (full fed, P <0.05; 12 h fasted, P <0.05; 85% body/wt, P <0.05), female rats group-reared (12 h fasted, P <0.05; 85% body/wt, P <0.05) and female rats singly reared (full fed, P <0.05; 12 h fasted, P <0.05; 85% body/wt, P <0.05) displayed reduced amounts of time exploring the open arms of the elevated plus-maze. In conclusion, control rats learned the autoshaping task to the same level as fasted or singly-reared rats. However, fasting or single-rearing produced fear-like behaviour. Thus, the training of control rats in autoshaping tasks may be an option that improves animal welfare.

Female Wistar rats tested during late proestrus or during pregnancy and ovariectomized rats tested after receiving progesterone or allopregnanolone displayed reduced conflict behavior.

In a conflict test based on the rat's choice between an immediate punished reinforcer or a delayed nonpunished reinforcer, anxiolytic drugs increase the number of immediate punished reinforcers. In this study, two hypotheses were tested: first, during late proestrus or during midpregnancy, female rats will display an elevated amount of immediate punished reinforcers; second, ovariectomized rats will display an elevated amount of immediate punished reinforcers when they receive anxiolytic doses of neurosteroids. Thus, female rats (n = 15) were tested repeatedly during late proestrus, diestrus, and pregnancy in the aforementioned conflict task. They displayed an elevated amount of immediate punished reinforcers during late proestrus (P < .05) and during the 14th (P < .05) and 17th (P < .05) days of pregnancy compared to diestrus or 3rd, 7th, or 20th days of pregnancy. Likewise, ovariectomized rats (n = 90) displayed an elevated amount of immediate punished reinforcers compared to control rats only when they received anxiolytic doses of progesterone (1.0-2.0 mg/kg, P < .05) or allopregnanolone (1.0-2.0 mg/kg, P < .05). In conclusion, female rats displayed reduced conflict behavior during late proestrus and pregnancy, or after received anxiolytic doses of neurosteroids.