Innovations In Clinical Neuroscience

JAN-FEB 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Page 47 of 63

Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 1 – 2 , J A N U A R Y – F E B R U A R Y 2 0 1 7 ] 48 and hormonal release. For example, a C R diet has been shown to increase neuropeptide orexin levels, which mediate locomotor activity and have anti- depressive effects. Additionally, food restriction has been shown to c ause a significant increase in prepro- orexin gene expression in obese mice in comparison to AL-fed animals. 32,68,69 It is well known that corticotropin-releasing factor (CRF) is also involved in the expression of stress and anxiety-like behavior via multiple neurotransmitter systems. The IF diet appears to down- regulate CRF receptors in several areas of brain, resulting in a decrease of anxiety-like behavior in rats. 47 Mice lacking CRF receptor subtype 1 displayed reduction in anxiety-like behavior compared to the wild type animals. 63 However, the exact neurochemical mechanisms related to the anxiolytic-like properties of IF have yet to be determined and require further investigation. Effect of IF on locomotor activity and explorative behavior in the OFT model. In our study, total traveled distance in OFT was used to measure locomotor activity, and rearing frequency was used to measure explorative behavior of the animals during OFT. 10,47,64,65 In comparison with control groups, MDMA induced hyperactivity in AL groups, and, additionally, in OFT the rearing activity was almost absent during 60 minutes of observation. This finding suggests that the dosages of MDMA used in this study produced a significant increase in locomotor activity and a decrease in exploratory activity, in concordance with the anxiogenic-like profile of the drug that confirms the findings of previous studies. 65–75 Several studies have established that the alteration in MDMA-induced locomotor behavior is due to its interaction with 5-HT 1B receptor. In knockout mice lacking this receptor, locomotor response was abolished after MDMA administration. 3,75 Release of serotonin is known to produce hyperactivity in rodents, and studies have shown that this effect is produced through catecholaminergic mechanisms. MDMA also binds with low affinity to dopaminergic receptors and releases dopamine. 65 Moreover, it has b een suggested that hyperactivity following psychostimulant administration is a result of activation of dopamine-releasing neurons placed mainly in structures known communally a s the motive circuit. However, hyperactivity induced by MDMA is different from that induced by other psychostimulants, such as amphetamine. MDMA is thought to act on 5-HT pathways and specifically co- activate dopaminergic pathways in mice. 13 Increases in extracellular dopamine have been reported following the first few hours of MDMA administration in mice. 9,11 In our study, MDMA administration caused a decrease of exploratory behaviors (especially rearing) during the OFT without reducing locomotion. This behavioral profile is an indicator of anxiogenic-like activity of the drug in mice and is completely independent of the 5-HT 1B receptor. 7 3 Additionally, after the administration of MDMA, the IF test groups showed more hyperactivity in the OFT compared to the IF control group and both AL groups; however, the IF test group had lower rearing frequency compared to the IF control. There was an increase in exploratory behaviors and locomotor activity in the IF animals compared to the AL animals after MDMA administration. Also, when OFT was carried out on ninth day after MDMA gavage, the experimental animals that were under the IF protocol subgroups still showed more hyperactivity than the AL subgroups. Therefore, in this study, IF caused persistent increase in hyperactivity and exploratory responses to MDMA administration. This could be due to behavioral and neurobiological relationship between ingestive and drug seeking behaviors, as it has been previously shown that chronic food restriction enhances the rewarding locomotor- and cellular-activating effects of abused drugs. 76 Increased behavioral activity by MDMA and IF could be due to elevated serum corticosterone, which is a classic indicator of stress in rodents and leads to an increase of locomotor activity. 77,78 MDMA also increases serum corticosterone levels, and it has been reported that elevated corticostrone l evels increase psychostimulants- induced locomotor activity. 4,10,79 Additionally, high serum corticosterone levels in IF mice and rats have been observed in several studies. 32,47,80–83 C hronic food restriction (FR) generally acts as a stressor and has been shown to increase the locomotor and neurochemical effects of psychostimulants in mice and rats. 84–87 Effect of IF on neuronal density of hippocampus. Our data showed that numerical densities of CA1 neurons in the hippocampus of AL-AL subgroups were less than other groups. The data also showed that in the AL-IF group and the other subgroups that were maintained on IF diet before or after of administration of MDMA, numerical densities of CA1 hippocampal neurons were higher compared to the AL-AL subgroups. These results are supported by previous studies. 3,16,75 In animal models of neurodegenerative disorders, an IF diet is known to enhance resistance of neurons to age-related and disease-specific stresses, as well have protective effects after toxic insults. 2 4,49–51,88 Thickness of pyramidal cell layer of CA1 region has been previously used as a marker to evaluate the alteration of gross brain structures caused by IF. Mice on an IF diet have thicker CA1 pyramidal cell layers than their control counterparts. 33 Additionally, an IF diet is known to promote neurogenesis and has been shown to have a neuroprotective effect in different models. One mechanism of these effects is the expression of neurotrophic factors. 37 More specifically, there is increase in BDNF levels in hippocampus in IF animals, and BDNF signaling is known to regulate adult hippocampal neurogenesis during an IF diet. 37,89 During food restriction, less glucose is available in the mitochondria, leading to less ROS production and to less damage to proteins; DNA and membrane lipids are lessened as well, leading to neuroprotection. 41,90 MDMA-induced damage to neurons involves ROS generation caused by massive release of 5-HT and other catecholamine transmitters and their metabolic

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