In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

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From inflammation to sickness and depression: when the immune system subjugates the brain

In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Stress and the brain: from adaptation to disease

Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

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The molecular neurobiology of depression

The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.

The corticosteroid receptor hypothesis of depression.

Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) administration induce hypophagia in rodents. Both IL-1 and LPS are known to activate cerebral norepinephrine and serotonin metabolism, and IL-1 affects that of acetylcholine and histamine. Each of these neurotransmitters has been implicated in feeding behavior. Therefore, the ability of specific antagonists of the above neurotransmitter systems to counteract feeding responses to peripherally injected mIL-1β and LPS was studied. Feeding was assessed in nondeprived mice by measuring the intake of sweetened milk in a 30-min period, as well as daily food pellet intake. LPS and mIL-1β reliably reduced milk intake, and often reduced food pellet intake and body weight. Treatment of the mice with peripherally administered α-adrenergic (phentolamine or prazosin) or β-adrenergic antagonists (propranolol), either alone or in combination, did not significantly alter the hypophagic responses to mIL-1β or LPS. Mice in which cerebral norepinephrine was depleted with DSP-4 or 6-hydroxydopamine also displayed the usual hypophagia in response to mIL-1β and LPS. The hypophagic responses to mIL-1β and LPS were not affected by the histaminergic antagonists, pyrilamine (H1), cimetidine (H2), thioperamide (H3), or the histamine-depleting agent, α-fluoromethylhistidine, nor by the muscarinic cholinergic antagonist, scopolamine. The responses to mIL-1β were also unaffected by the dopamine receptor antagonist, haloperidol, the opioid receptor antagonist, naloxone, and the NO synthase inhibitor, l-NAME. These results suggest that adrenergic, dopaminergic, histaminergic, cholinergic, opioid or nitric oxide systems are not essential for the hypophagia induced by IL-1, and that multiple redundant pathways may be involved in illness-related hypophagia.

Endotoxin- and interleukin-1-induced hypophagia are not affected by adrenergic, dopaminergic, histaminergic, or muscarinic antagonists.

Hippocampal noradrenergic responses to CRF injected into the locus coeruleus of unanesthetized rats.

Numerous studies have shown that the effects of interleukin-1 (IL-1) and endotoxin (LPS) on behavior are sensitive to cyclooxygenase (COX) inhibitors. However, neither the location of the COX involved nor the specific isoform, COX1 or COX2, is known. A previous study using selective COX1 and COX2 inhibitors did not provide an unequivocal answer. Therefore, we tested the response of sweetened milk ingestion to IL-1 and LPS in mice in which the COX1 or the COX2 gene was deleted (COX1ko and COX2ko). When IL-1beta was administered 90 min before the milk, COX1ko mice showed responses similar to those of normal mice. In contrast, COX2ko mice exhibited responses considerably less than normal, with some mice showing no response. Indomethacin pretreatment almost prevented the feeding responses to IL-1 in normal and COX1ko mice. The milk intake response to LPS in COX1ko mice was like that of normal mice. The results from COX1ko mice suggest that COX1 is not necessary for the decreased milk intake following IL-1 and LPS. The results from COX2ko mice are consistent with the involvement of COX2 in the IL-1-induced depression of milk intake, but other mechanisms may effect decreases in sweetened milk intake.

Cyclooxygenase 1 is not essential for hypophagic responses to interleukin-1 and endotoxin in mice

A new design of carbon fiber microelectrode for in vivo voltammetry using fused silica

Recently, there are important changes in recreational drug use. The aim of the present study was to analyse reports published on a recreational web site by drug users who ingested seeds of plants belonging to the Convolvulaceae family and to compare them with available medical case reports. We have also included reports describing the effects induced by “druids fantasy,” which is a new drug allegedly containing the same alkaloid as the seeds of A. nervosa. Our search reveals the reoccurrence of recreational use of I. tricolor and violacea (morning glory), which had not been reported in medical literature since 1968. We have also found that drug users are experimenting with other species, such as I. purpurea, whose psychoactive properties are unknown. Symptoms and doses reported by drug users were comparable with the few available medical case reports. The most worrying symptom was suicidal ideation reported by two subjects who ingested A. nervosa and Ipomoea seeds. Effects induced by druids fanta...

Artur H. Swiergiel

Papers

Endotoxin- and interleukin-1-induced hypophagia are not affected by adrenergic, dopaminergic, histaminergic, or muscarinic antagonists.

Hippocampal noradrenergic responses to CRF injected into the locus coeruleus of unanesthetized rats.

Cyclooxygenase 1 is not essential for hypophagic responses to interleukin-1 and endotoxin in mice

A new design of carbon fiber microelectrode for in vivo voltammetry using fused silica

Recreational use of D-lysergamide from the seeds of Argyreia nervosa, Ipomoea tricolor, Ipomoea violacea, and Ipomoea purpurea in Poland.