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In the present study, we examined the in vitro and in vivo modulation of IL-1 receptors by stress and endotoxin treatment. The treatment of AtT-20 mouse pituitary adenoma cells for 24 h with neuroendocrine mediators of stress such as CRF and catecholamines produced dose-dependent increases in cAMP production and [125I]IL-1 alpha binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF-stimulated cAMP production and decreased both basal and CRF-mediated increases in [125I]IL-1 alpha binding. Furthermore, in keeping with the effects of stress mediators to up-regulate IL-1 receptors in AtT-20 cells, ether-laparotomy stress in mice resulted in a significant increase in [125I]IL-1 alpha binding in the pituitary with no significant alterations observed in the brain; in contrast, [125I]oCRF binding in the pituitary was significantly decreased after the ether-laparotomy stress. Next, we investigated the modulation of IL-1 beta levels and [125I]IL-1 alpha binding following endotoxin treatment. IL-1 beta levels were dramatically increased in the peripheral tissues (pituitary, testis, and spleen) at 2-6 h after a single LPS injection (30 micrograms LPS/mouse); however, no significant changes were observed in brain (hippocampus and hypothalamus). [125I]IL-1 alpha binding in the pituitary gland, liver, spleen, and testis was significantly decreased at 2 h following a single administration of both low (30 micrograms LPS/mouse) and high (300 micrograms LPS/mouse) doses of endotoxin. [125I]IL-1 alpha binding in the hippocampus was not significantly altered at 2 h by low dose of LPS and was significantly decreased by high-dose administration of LPS (300 micrograms/mouse). Following two LPS injections (at 0 and 12 h), dramatic increases in IL-1 beta concentrations in the hypothalamus, hippocampus, spleen, and testis were observed at 2 h after the second LPS injection; a small but statistically nonsignificant change was evident in the pituitary. Moreover, dramatic decreases in [125I]IL-1 alpha binding were seen after two injections of 30 micrograms LPS/mouse in both central and peripheral tissues. These data provide further support for a role for IL-1 in coordinating brain-endocrine-immune responses to stress and infection.

CRF and IL-1 receptors were identified, characterized, and localized in brain, endocrine, and immune tissues. CRF receptors with comparable kinetic and pharmacological characteristics were localized in the anterior and intermediate lobes of the pituitary, in brain areas involved in mediating stress responses, and in the macrophage-enriched marginal zones of the spleen. The discrete localization of IL-1 receptors in neurons of the hippocampus provides further support for the role of IL-1 as a neurotransmitter/neuromodulator/growth factor in the CNS. The neuroendocrine effects of IL-1 may be mediated through actions of the cytokine in brain. However, given the high densities of IL-1 receptors in the anterior pituitary and testis, direct effects of the cytokine at the pituitary or gonadal levels seem highly likely. Overall, these data support a role for IL-1 and CRF in coordinating and integrating the brain-endocrine-immune responses to physiological, pharmacological, and pathological stimuli.

In summary, the data from both neurochemical and neuroanatomical studies demonstrate widespread and long-lasting degeneration of serotonin neurons in brain without any major or consistent effects on catecholamine neurons following in vivo administration of MDMA in both rats and rhesus monkeys. A detailed examination of the parameters involved in the neurotoxic and neurodegenerative effects of MDMA on brain serotonin neurons indicate that the severity of the lesion is dependent on the dose of drug administered with the drug being more potent in rhesus monkeys than in rats. Furthermore, the neurodegenerative effects of the drug are long-lasting (up to one year) with respect to neuronal regeneration (i.e. recovery of serotonin uptake sites) while functional recovery may be permanently impaired since serotonin content remains markedly (40-50%) below levels in age-matched controls for as long as one year after drug administration. The neurochemical and autoradiographic data suggest that there are some regional differences and morphological specificity to the neurodegenerative effects of MDMA as demonstrated by greater reductions in serotonin uptake sites in brain regions containing primarily terminals while regions containing axons of passage and cell bodies are relatively unaffected.

The data presented herein appear to strongly implicate the brain 5HT2 receptor as the site-of-action of the hallucinogenic PIAs and LSD. If so, this discovery represents a major step in understanding the molecular pharmacology of hallucinogenic drugs. Using radioactive hallucinogenic drugs, detailed properties of brain 5HT2 receptors indicating the interaction of 5HT2 receptors with GTP-binding proteins have been revealed. Autoradiographic studies have revealed an extensive cortical distribution of brain 5HT2 receptors; these studies have also suggested that the PIAs may be 5HT1C agonists. Radiolabeling studies in conjunction with drug discrimination studies indicate that MDMA is apparently "amphetamine-like" and not "LSD-like" while MDA is apparently both "LSD-like" and "amphetamine-like." However, MDMA does appear to possess the potential to act as a 5HT2 agonist at high dosages.

CRH-IR is significantly reduced in the cerebral cortex of individuals with AD, PD and PSP. Furthermore, we report that the decreases in CRH-IR in AD are accompanied by reciprocal increases in CRH receptors in affected cortical areas. The changes in pre- and postsynaptic markers for CRH are significantly correlated with decrements in ChAT activity. The demonstration of an up regulation of CRH receptors following a decrease in CRH-IR indicates a physiological relevance of the receptor site and is consistent with the concept that CRH acts as a neurotransmitter in normal cortical functions and that disease of this peptidergic systems may be important in certain clinical manifestations of dementia. While the clinical consequences of the changes in CRH in these various disorders are unclear, future therapies directed at increasing CRH levels in brain may prove useful for treatment.