Long-term cognitive deficits induced by a single, extremely low dose of tetrahydrocannabinol (THC): behavioral, pharmacological and biochemical studies in mice.

We have previously reported that an injection of a single, extremely low dose (0.001 mg/kg) of delta 9-tetrahydrocannabinal (THC, the major psychoactive ingredient of marijuana) to mice deteriorated their performance in the Morris water maze test 3 weeks later. In the present study we verify our original findings and show that the long-term cognitive deficits that are induced in mice by a low dose of THC are even more pronounced in another behavioral test-the water T-maze. This effect was abolished by the CB1 receptor antagonist SR141716A, indicating the involvement of CB1 receptors. In an attempt to find a biochemical correlate to these deleterious consequences of such a low dose of THC, we investigated its effect on the activation of extracellular signal-regulated kinase (ERK1/2) in the cerebellum and hippocampus of the mice, two brain regions that were shown to participate in spatial learning. A significant increase in ERK1/2 phosphorylation was found in the cerebellum of mice 24 h following the injection of 0.001 mg/kg THC. These findings lead to further studies into the neuronal mechanisms underlying the long-term deleterious effects of THC and should be taken into consideration when evaluating the therapeutic benefits of cannabinoid drugs.

A single low dose of tetrahydrocannabinol induces long-term cognitive deficits.

Delta(9)-Tetrahydrocannabinol (THC) was shown to exert either neuroprotective or neurotoxic effects. Based on our in vitro studies and on pharmacokinetic considerations, we have recently presented a hypothesis that explains this dual activity of THC. This explanation is based on the assumption that extremely low doses of cannabinoids are neurotoxic. The present study verifies this assumption and shows that a single injection of 0.001 mg/kg THC (3-4 orders of magnitude lower than conventional doses) significantly affected the performance of mice in the Morris water maze test 3 weeks later. The THC-injected mice showed both longer escape latencies and lower scores in the probe tests compared to their matched controls, indicating the induction of cognitive deficits.

Plasma levels of nitric oxide and L-arginine in sleep apnea patients: effects of nCPAP treatment.

Sleep apnea syndrome has been shown to be associated with decreased levels of circulating nitric oxide (NO) after waking up from sleep. In this study we investigated overnight plasma concentrations of NO in sleep apnea patients before and after nasal continuous positive airway pressure (nCPAP) treatment and the effects of nCPAP on morning levels of L-arginine. In experiment 1, NO concentrations measured hourly during sleep were found to be significantly lower in a group of eight sleep apnea patients in comparison with six age-similar snorers and six normal young adults. In experiment 2, overnight NO concentrations were compared in 5 sleep apnea patients before and 9.3 +/- 3.9 mo after treatment with nCPAP. A significant increase in NO concentrations was found in four out of five patients, and a significant increase in L-arginine was found in all five patients after treatment. In experiment 3, removal of nCPAP for a single night in seven sleep apnea patients caused a significant decrease in morning levels of NO and L-arginine. These results demonstrate that sleep apnea is associated with a chronic state of diminished circulating NO concentrations that can be ameliorated by nCPAP treatment.

Decreased pituitary-gonadal secretion in men with obstructive sleep apnea.

Decreased libido is frequently reported in male patients with obstructive sleep apnea (OSA). The decline in morning serum testosterone levels previously reported in these patients was within the normal adult male range and does not explain the frequent association of OSA and sexual dysfunction. We determined serum LH and testosterone levels every 20 min between 2200-0700 h with simultaneous sleep recordings in 10 men with sleep apnea and in 5 normal men free of any breathing disorder in sleep. The mean levels and area under the curve of LH and testosterone were significantly lower in OSA patients compared with controls [LH, 24.9 +/- 10.2 IU/liter.h vs. 43.4 +/- 9.5 (P < 0.005); testosterone, 67.2 +/- 11.5 nmol/liter.h vs. 113.3 +/- 26.8 (P < 0.003)]. Four of 10 patients had hypogonadal morning (0700 h) serum testosterone levels. Analysis of covariance (ANCOVA) revealed that the 2 groups differed significantly in the amount of LH and testosterone secreted at night independent of age or degree of obesity. After partialing out body mass index, there was a significant negative correlation between the amounts of LH and testosterone secreted at night and the respiratory distress index, but not with degree of hypoxia. Our findings suggest that OSA in men is associated with dysfunction of the pituitary-gonadal axis. The relation between LH-testosterone profiles and the severity of OSA suggests that sleep fragmentation and, to a lesser extent, hypoxia in addition to the degree of obesity and aging may be responsible for the central suppression of testosterone in these patients.

Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment.

Sleep apnea syndrome is associated with recurrent episodic hypoxia during sleep, which has been implicated in the development of cardiovascular morbidity. Hypoxia is the major stimulus of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine. In the present article we describe the results of three experiments in which plasma concentrations of VEGF were measured in patients with sleep apnea. In Experiment 1, apnea-hypopnea index was found to be a significant independent predictor of morning VEGF concentrations in 85 male subjects investigated in the sleep laboratory, of whom 47 had an apnea-hypopnea index greater than 20. In Experiment 2, VEGF concentrations measured hourly during the sleep period were found to be significantly higher in a group of five sleep apnea patients compared with six age-similar snorers and six normal young adults (129.1 +/- 43.4 versus 74.6 +/- 11.5 and 32.5 +/- 12.8 pg/ml, respectively [p < 0.007]). In Experiment 3, VEGF concentrations were compared in patients with sleep apnea before and 1 year after nasal continuous positive airway pressure treatment. A significant decrease in VEGF concentrations was found only in patients in whom nocturnal hypoxia improved after treatment (57.1 +/- 62.5 versus 39.6 +/- 46.9 pg/ml, p < 0.01). There was no comparable improvement in patients who did not accept treatment (53.9 +/- 23.6 versus 54.0 +/- 21.5 pg/ml, ns). These results raise the possibility that VEGF may contribute to the long-term adaptation of sleep apnea syndrome to recurrent nocturnal hypoxia.