Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions, impairments frequently described in heavy MDMA users. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier. RESULTS: The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory' and 'cognition', 'dendrite development' and 'regulation of synaptic plasticity' gene sets in the hippocampus, parallel to the upregulation of the CB1 cannabinoid- and Epha4, Epha5, Epha6 ephrin receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development', 'regulation of synaptic plasticity' and 'positive regulation of synapse assembly' gene sets were upregulated. Changes in the dorsal raphe region were mild and in most cases not significant. CONCLUSION: The present data raise the possibility of new synapse formation/synaptic reorganization in the frontal cortex three weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is suggested by the data, which underlines the particular vulnerability of this brain region after the drug treatment. Finally, our results also suggest the substantial contribution of CB1 receptor and endocannabinoid mediated pathways in the hippocampal impairments. Taken together the present study provides evidence for the participation of new molecular candidates in the long-term effects of MDMA

Developmental consequences of perinatal cannabis exposure: behavioral and neuroendocrine effects in adult rodents

Cannabis is the most commonly used illicit drug among pregnant women. Since the endocannabinoid system plays a crucial role in brain development, maternal exposure to cannabis derivatives might result in long-lasting neurobehavioral abnormalities in the exposed offspring. It is difficult to detect these effects, and their underlying neurobiological mechanisms, in clinical cohorts, because of their intrinsic methodological and interpretative issues. The present paper reviews relevant rodent studies examining the long-term behavioral consequences of exposure to cannabinoid compounds during pregnancy and/or lactation. Maternal exposure to even low doses of cannabinoid compounds results in atypical locomotor activity, cognitive impairments, altered emotional behavior, and enhanced sensitivity to drugs of abuse in the adult rodent offspring. Some of the observed behavioral abnormalities might be related to alterations in stress hormone levels induced by maternal cannabis exposure. There is increasing evidence from animal studies showing that cannabinoid drugs are neuroteratogens which induce enduring neurobehavioral abnormalities in the exposed offspring. Several preclinical findings reviewed in this paper are in line with clinical studies reporting hyperactivity, cognitive impairments and altered emotionality in humans exposed in utero to cannabis. Conversely, genetic, environmental and social factors could also influence the neurobiological effects of early cannabis exposure in humans

5-HT modulation of pain perception in humans

© 2017, The Author(s). Introduction: Although there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain. Objectives: Here, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers. Methods: Fifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session. Results: Our investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood. Conclusion: As far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes

Rats exposed to cocaine during late gestation and early postnatal life show deficits in hippocampal pyramidal and granule cells in later life

In humans, the offspring of maternal cocaine misusers are known to have subtle cognitive and motor impairments in later life. It was therefore hypothesized that such exposure in animals would also affect the morphological structure of the brain. This possibility was investigated by exposing rats to cocaine between embryonic day 15 and postnatal day 6. Samples of the cocaine-exposed and control rats were killed for examination at 22 and 150 postnatal days of age. Stereological procedures (the Cavalieri principle together with the physical disector method) were utilized to estimate the total number of pyramidal and granule cells in defined regions of the hippocampal formation. At 22 days of age, the control offspring had about 373 000 pyramidal cells whereas the cocaine-treated animals only had about 310 000 cells in the CA1 + CA2 + CA3 region. By 150 days of age the values were about 396 000 and 348 000, respectively. The differences between age-matched groups were statistically significant. There were about 626 000 and 687 000 dentate gyrus granule cells in the 22-day-old control and cocaine-treated groups, respectively. By postnatal day 150 the control rats had about 832 000 granule cells whilst the cocaine-treated rats had about 693 000. There was a significant main effect of age as well as group–age interaction in this measure. These results show that even moderate exposure to cocaine during the late gestation and early postnatal period in rats is a potent teratogen and can markedly influence the development of neurons in the hippocampal formation