Treatment with tetrahydrocannabinol (THC) prevents infertility in male cystic fibrosis mice.

BACKGROUND: Cystic fibrosis (CF) is a hereditary disease caused by mutations of the gene encoding a channel protein CFTR, conducting Cl- and HCO3 - ions. The disease is characterized by disturbances in most physiological systems, and more than 95% of men are infertile. The mechanism underlying the etiology of CF is associated with an imbalance of fatty acids. It has been suggested that the function of the endocannabinoid system is also disturbed in CF, because endocannabinoids are derivatives of fatty acids. We assumed, therefore, that endocannabinoid activity, which plays an important role in fertility, is disrupted in CF and could be one of the causes of infertility. The aim of the present study was to test the hypothesis that stimulation of endocannabinoid receptors in infancy would normalize their function and prevent infertility in adulthood. METHODS: Knockout male mice (cftr-/-) were treated with tetrahydrocannabinol (THC), endocannabinoid receptors agonist, in infancy from days 7 until 28, daily. RESULTS: CF males treated with THC were fully fertile, producing offspring comparable by the number of litters and the number of pups with wild-type mice. CF males that were not treated with THC were completely infertile. CONCLUSIONS: The present study shows that (i) endocannabinoid function is impaired in CF mice, as evidenced by the regenerating effect of its stimulation on the fertility of otherwise infertile males, (ii) endocannabinoid system dysfunction is apparently the determining factor causing infertility in CF, and (iii) mild stimulation of the endocannabinoid system in infancy and adolescence appears to normalize many reproductive processes and thereby prevent infertility in CF males.

Behavioral alterations in cystic fibrosis mice are prevented by cannabinoid treatment in infancy.

Substantial data have been accumulated regarding the molecular basis of cystic fibrosis (CF) pathogenesis, whereas the influence of biochemical impairments on brain processes has been the focus of much less attention. We have studied some behavioral parameters, such as motor activity and anxiety level, in a mice model of CF. We have assumed that functioning of the endocannabinoid system could be impaired in CF (endocannabinoids are fatty acid derivatives, and fatty acid deficiency is considered a major factor in CF etiology). We have suggested that chronic treatment with cannabinoid receptors agonist during infancy would balance cannabinoid levels and prevent CF-related behavioral alterations. Motor activity and anxiety level were studied in naïve adult CF mice (cftr-deficient mice) and compared with wild-type mice and to CF mice treated chronically with Δ9-tetrahydrocannabinol (Δ9-THC; endocannabinoid receptor agonist) during infancy (from days 7 to 28). Motor activity was tested in the tetrad, and level of anxiety in the plus maze, a month after cessation of treatment. Motor activity decrease and elevated anxiety level were found in adult naïve CF mice compared with wild-type mice. CF mice treated with THC in infancy showed normal motor activity and anxiety levels in adulthood. Motor function alteration and elevated anxiety levels in CF can result from lack of CFTR-channel in neurons and disturbed activity of various brain areas, as well as being secondary and mediated by fatty acids deficiency, altered levels of endocannabinoids and their receptors. It can be suggested that chronic treatment during infancy restores endocannabinoid function and thus prevents behavioral alterations.

Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain.

Burning of Boswellia resin as incense has been part of religious and cultural ceremonies for millennia and is believed to contribute to the spiritual exaltation associated with such events. Transient receptor potential vanilloid (TRPV) 3 is an ion channel implicated in the perception of warmth in the skin. TRPV3 mRNA has also been found in neurons throughout the brain; however, the role of TRPV3 channels there remains unknown. Here we show that incensole acetate (IA), a Boswellia resin constituent, is a potent TRPV3 agonist that causes anxiolytic-like and antidepressive-like behavioral effects in wild-type (WT) mice with concomitant changes in c-Fos activation in the brain. These behavioral effects were not noted in TRPV3(-/-) mice, suggesting that they are mediated via TRPV3 channels. IA activated TRPV3 channels stably expressed in HEK293 cells and in keratinocytes from TRPV3(+/+) mice. It had no effect on keratinocytes from TRPV3(-/-) mice and showed modest or no effect on TRPV1, TRPV2, and TRPV4, as well as on 24 other receptors, ion channels, and transport proteins. Our results imply that TRPV3 channels in the brain may play a role in emotional regulation. Furthermore, the biochemical and pharmacological effects of IA may provide a biological basis for deeply rooted cultural and religious traditions.

Deep brain stimulation and fluoxetine exert different long-term changes in the serotonergic system.

Both selective serotonin reuptake inhibitors (SSRIs) and ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) modulate serotonergic activity. We compared the acute (1 day) and long-term (12 days) effects of vmPFC stimulation and fluoxetine on serotonin (5-HT) release and receptor expression in rats. Samples to measure serotonin levels were collected from the hippocampus using microdialysis. Serotonin transporter (SERT), 5-HT1A and 5-HT1B mRNA were measured using in situ hybridization. [3H]8-OH-DPAT and [125I]cyanopindolol autoradiography were used to measure 5-HT1A and 5-HT1B binding. Our results show that after fluoxetine injections serotonin levels were approximately 150% higher than at baseline. Twelve days later, pre-injection 5-HT extracellular concentration was substantially higher than on day 1. In contrast, serotonin levels following DBS were only 50% higher than at baseline. While pre-stimulation 5-HT on day 12 was significantly higher than on treatment day 1, no stimulation-induced 5-HT peak was recorded. SERT expression in the dorsal raphe was increased after acute fluoxetine and decreased following a single day of DBS. Neither fluoxetine nor DBS administered acutely substantially changed 5-HT1A or 5-HT1B binding. Chronic fluoxetine treatment, however, was associated with a decrease in [3H]8-OH-DPAT prefrontal cortex and hippocampus expression. In contrast, chronic DBS induced a significant increase in [125I]cyanopindolol binding in the prefrontal cortex, globus pallidus, substantia nigra and raphe nuclei. mRNA expression of 5-HT1A and 5-HT1B in raphe nuclei was not altered by either treatment. These results suggest that fluoxetine and DBS modulate activity of the serotonergic system but likely exert their effects through different mechanisms.

Deep brain stimulation induces antidepressant-like effects in serotonin transporter knockout mice.

BACKGROUND: Some of the antidepressant-like effects of ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) in rodents have been attributed to the modulation of prefrontal-raphe pathways. This is largely different from selective serotonin reuptake inhibitors (SSRIs), which increase serotonin (5-HT) levels by inhibiting the serotonin transporter (SERT). SSRIs have limited efficacy when given to SERT knockout (KO) mice, or patients with mutations in the serotonin transporter promoter gene (5-HTTLPR). HYPOTHESIS: vmPFC DBS will induce antidepressant-like effects and serotonin release in SERT KOs. RESULTS: DBS-treated wild-type and SERT KO mice had a significant 22-26% decrease in immobility in the forced swim test. DBS delivered to either group was associated with 33-55% increase in 5-HT levels. CONCLUSIONS: DBS induced a significant antidepressant-like effect in KO mice. This suggests that it may be reasonable to consider DBS in states where SERT is not fully operational.

Rodent Hypoxia-Ischemia Models for Cerebral Palsy Research: A Systematic Review.

Cerebral palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5-3/1000 live term births, and up to 22/1000 prematurely born babies. CP results from injury to the developing brain incurred before, during, or after birth. The most common form of this condition, spastic CP, is primarily associated with injury to the cerebral cortex and subcortical white matter as well as the deep gray matter. The major etiological factors of spastic CP are hypoxia/ischemia (HI), occurring during the last third of pregnancy and around birth age. In addition, inflammation has been found to be an important factor contributing to brain injury, especially in term infants. Other factors, including genetics, are gaining importance. The classic Rice-Vannucci HI model (in which 7-day-old rat pups undergo unilateral ligation of the common carotid artery followed by exposure to 8% oxygen hypoxic air) is a model of neonatal stroke that has greatly contributed to CP research. In this model, brain damage resembles that observed in severe CP cases. This model, and its numerous adaptations, allows one to finely tune the injury parameters to mimic, and therefore study, many of the pathophysiological processes and conditions observed in human patients. Investigators can recreate the HI and inflammation, which cause brain damage and subsequent motor and cognitive deficits. This model further enables the examination of potential approaches to achieve neural repair and regeneration. In the present review, we compare and discuss the advantages, limitations, and the translational value for CP research of HI models of perinatal brain injury.

Acute high frequency stimulation of the prefrontal cortex or nucleus accumbens does not increase hippocampal neurogenesis in rats.

To date, the effects of deep brain stimulation (DBS) on hippocampal neurogenesis have been mainly characterized in the context of memory. Acute stimulation (i.e. for 1 h) of either the entorhinal cortex or the anterior thalamus increases both cell proliferation and survival. We investigate whether stimulation applied to targets being considered for the treatment of depression, namely the ventromedial prefrontal cortex (vmPFC) or nucleus accumbens (Acb), also increases hippocampal neurogenesis in rodents. Rats were treated with vmPFC or Acb DBS for 1 h at different settings. 5'-bromo-2'deoxyuridine (BrdU) was injected three days following stimulation onset and animals were sacrificed 24 h or 28 days later. Overall, we found that neither vmPFC nor Acb DBS increased hippocampal neurogenesis. In summary, the delivery of acute stimulation into targets homologous to those used in human depression trials does not increase hippocampal neurogenesis.

Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release.

BACKGROUND: Medial forebrain bundle (MFB) deep brain stimulation (DBS) is currently being investigated in patients with treatment-resistant depression. Striking features of this therapy are the large number of patients who respond to treatment and the rapid nature of the antidepressant response. OBJECTIVE: To study antidepressant-like behavioral responses, changes in regional brain activity, and monoamine release in rats receiving MFB DBS. METHODS: Antidepressant-like effects of MFB stimulation at 100 µA, 90 µs and either 130 Hz or 20 Hz were characterized in the forced swim test (FST). Changes in the expression of the immediate early gene (IEG) zif268 were measured with in situ hybridization and used as an index of regional brain activity. Microdialysis was used to measure DBS-induced dopamine and serotonin release in the nucleus accumbens. RESULTS: Stimulation at parameters that approximated those used in clinical practice, but not at lower frequencies, induced a significant antidepressant-like response in the FST. In animals receiving MFB DBS at high frequency, increases in zif268 expression were observed in the piriform cortex, prelimbic cortex, nucleus accumbens shell, anterior regions of the caudate/putamen and the ventral tegmental area. These structures are involved in the neurocircuitry of reward and are also connected to other brain areas via the MFB. At settings used during behavioral tests, stimulation did not induce either dopamine or serotonin release in the nucleus accumbens. CONCLUSIONS: These results suggest that MFB DBS induces an antidepressant-like effect in rats and recruits structures involved in the neurocircuitry of reward without affecting dopamine release in the nucleus accumbens.

Supraorbital stimulation does not induce an antidepressant-like response in rats.

BACKGROUND: Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve. OBJECTIVE: To show that supraorbital stimulation is effective in preclinical models. METHODS: Rats were given supraorbital stimulation at different settings in the forced swim test (FST) and open field. RESULTS: Supraorbital stimulation did not induce an antidepressant-like response in rats undergoing the FST. This is in contrast to other neuromodulation treatments, such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy, which are all effective in this paradigm. CONCLUSIONS: Supraorbital stimulation was ineffective in rats undergoing the FST. Such findings do not invalidate results of recent clinical trials.