The prefrontal cortex plays a key role in the control of higher brain functions and is involved in the pathophysiology and treatment of schizophrenia. Here we report that approximately 60% of the neurons in rat and mouse prefrontal cortex express 5-HT(1A) and/or 5-HT2A receptor mRNAs, which are highly co-localized (approximately 80%). The electrical stimulation of the dorsal and median raphe nuclei elicited 5-HT1A-mediated inhibitions and 5-HT2A-mediated excitations in identified pyramidal neurons recorded extracellularly in rat medial prefrontal cortex (mPFC). Opposite responses in the same pyramidal neuron could be evoked by stimulating the raphe nuclei at different coordinates, suggesting a precise connectivity between 5-HT neuronal subgroups and 5-HT1A and 5-HT2A receptors in pyramidal neurons. Microdialysis experiments showed that the increase in local 5-HT release evoked by the activation of 5-HT2A receptors in mPFC by DOI (5-HT2A/2C receptor agonist) was reversed by co-perfusion of 5-HT1A agonists. This inhibitory effect was antagonized by WAY-100635 and the prior inactivation of 5-HT1A receptors in rats and was absent in mice lacking 5-HT1A receptors. These observations help to clarify the interactions between the mPFC and the raphe nuclei, two key areas in psychiatric illnesses and improve our understanding of the action of atypical antipsychotics, acting through these 5-HT receptors.

Cytokines produced during infection/inflammation activate adaptive CNS responses, including acute stress responses mediated by the hypothalamo-pituitary-adrenal (HPA) axis. The mechanisms by which cytokines engage HPA control circuitry remain unclear, though stimulated release of prostanoids from neighboring vascular cells has been implicated in this regard. How specific vascular cell types, endothelial cells (ECs) vs. perivascular cells (PVCs; a subset of brain-resident macrophages), participate in this response remains unsettled. We exploited the phagocytic activity of PVCs to deplete them in rats by central injection of a liposome-encapsulated pro-apoptotic drug. This manipulation abrogated CNS and hormonal indices of HPA activation under immune challenge conditions (interleukin-1; IL-1) that activated prostanoid synthesis only in PVCs, while enhancing these responses to stimuli (lipopolysaccaride; LPS) that engaged prostanoid production by ECs as well. Thus, PVCs provide both prostanoid-mediated drive to the HPA axis, and an anti-inflammatory action that constrains endothelial, and overall CNS, responses to inflammatory insults.

All phases of lipopolysaccharide (LPS)-induced fever are mediated by prostaglandin (PG) E2. It is known that the second febrile phase (which starts at ~1.5 h post-LPS) and subsequent phases are mediated by PGE2 that originated in endotheliocytes and perivascular cells of the brain. However, the location and phenotypes of the cells that produce PGE2 triggering the first febrile phase (which starts at ~0.5 h) remain unknown. By studying PGE2 synthesis at the enzymatic level, we found that it was activated in the lung and liver, but not in the brain, at the onset of the first phase of LPS fever in rats. This activation involved phosphorylation of cytosolic phospholipase A2 (cPLA2) and transcriptional up-regulation of cyclooxygenase (COX)-2. The number of cells displaying COX-2 immunoreactivity surged in the lung and liver (but not in the brain) at the onset of fever, and the majority of these cells were identified as macrophages. When PGE2 synthesis in the periphery was activated, the concentration of PGE2 increased both in the venous blood (which collects PGE2 from tissues) and arterial blood (which delivers PGE2 to the brain). Most importantly, neutralization of circulating PGE2 with an anti-PGE2 antibody both delayed and attenuated LPS fever. It is concluded that fever is initiated by circulating PGE2 synthesized by macrophages of the LPS-processing organs (lung and liver) via phosphorylation of cPLA2 and transcriptional up-regulation of COX-2. Whether PGE2 produced at the level of the blood–brain barrier also contributes to the development of the first phase remains to be clarified.

Abstract-Inflammation is associated with increased sympathetic drive in cardiovascular diseases. Blood-borne proinflammatory cytokines, markers of inflammation, induce cyclooxygenase 2 (COX-2) activity in perivascular macrophages of the blood-brain barrier. COX-2 generates prostaglandin E 2 , which may enter the brain and increase sympathetic nerve activity. We examined the contribution of this mechanism to augmented sympathetic drive in rats after myocardial infarction (MI). Approximately 24 hours after acute MI, rats received an intracerebroventricular injection (1 L/min over 40 minutes) of clodronate liposomes (MIϩCLOD) to eliminate brain perivascular macrophages, liposomes alone, or artificial cerebrospinal fluid. A week later, COX-2 immunoreactivity in perivascular macrophages and COX-2 mRNA and protein had increased in hypothalamic paraventricular nucleus of MI rats treated with artificial cerebrospinal fluid or liposomes alone compared with sham-operated rats. In MIϩCLOD rats, neither perivascular macrophages nor COX-2 immunoreactivity was seen in the paraventricular nucleus, and COX-2 mRNA and protein levels were similar to those in sham-operated rats. Prostaglandin E 2 in cerebrospinal fluid, paraventricular nucleus neuronal excitation, and plasma norepinephrine were less in MIϩCLOD rats than in MI rats treated with artificial cerebrospinal fluid or liposomes alone but more than in sham-operated rats. Intracerebroventricular CLOD had no effect on interleukin 1␤ and tumor necrosis factor-␣ mRNA and protein in the paraventricular nucleus or plasma interleukin-1␤ and tumor necrosis factor-␣, which were increased in MI compared with sham-operated rats. In normal rats, pretreatment with intracerebroventricular CLOD reduced (PϽ0.05) the renal sympathetic, blood pressure, and heart rate responses to intracarotid artery injection of tumor necrosis factor-␣ (0.5 g/kg); intracerebroventricular liposomes had no effect. The results suggest that proinflammatory cytokines stimulate sympathetic excitation after MI by inducing COX-2 activity and prostaglandin E 2 production in perivascular macrophages of the blood-brain barrier. (Hypertension. 2010;55:652-659.)Key Words: cytokines Ⅲ cyclooxygenase 2 Ⅲ perivascular macrophages Ⅲ clodronate liposomes Ⅲ myocardial infarction Ⅲ heart failure Ⅲ inflammation T here is increasing appreciation for the role of inflammation in cardiovascular and cardiovascular-related diseases, including myocardial infarction (MI), heart failure (HF), hypertension, obesity, and diabetes mellitus. [1][2][3][4][5] Recent studies have established a causal relationship between inflammation and activation of the sympathetic nervous system, 6,7 but exactly how inflammatory mediators trigger an increase in sympathetic activity remains unknown. The present study examined one putative mechanism.The proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin 1␤ (IL-1␤), well-recognized markers of inflammation, are too large to cross the blood-brain barrier. In normal animals, they can affect...