Locus ceruleus and panic/anxiety
The brain region that is frequently studied in relation to panic disorder is the locus ceruleus. This region is a metencephalic nucleus located in the caudal pontine central grey. It contains 50 % of all brain noradrenergic neurons and is composed almost exclusively of 12 000 noradrenergic neurons on each side of brain. It also produces a major portion of norepinephrine in the central nervous system. Collateral branches of axons of noradrenergic neurons project to most regions of the brain. Of those numerous projections, there are many that have been associated with panic disorder or panic attacks: with the limbic system, especially the amygdala, hippocampus, septum, and cingulate cortex, all cortices, brain stem, reticular formation, cerebellum and spinal cord (Cooper et al., 1991). Evidence from lesion, electrical and chemical stimulation, and single-unit recording studies suggests that locus ceruleus seems to be implicated in the sleep-wake cycle, arousal, anxiety and fear (Redmond & Huang, 1979; Redmond et al., 1976). The activation of locus ceruleus seems to be reflected in the central and peripheral concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), metabolite of norepinephrine (Elsworth et al., 1982). Many researchers have used the peripheral concentrations of MHPG as an index of central noradrenergic activity (reviewed by Cooper et al., 1991). Although MHPG is the main metabolite of central norepinephrine, a substantial part of it found in the urine and possibly in plasma may come from the metabolism of peripheral norepinephrine. Despite that, about 60 % of urinary MHPG in primates is still derived from the brain. Drugs that act on the primate central noradrenergic system also modify the MHPG found in the periphery. Stimulation of rat locus ceruleus results in an increase of peripheral MHPG. The plasma and urinary concentrations of MHPG are thus relatively helpful indices of the modifications of norepinephrine in the brain (Cooper et al., 1991). It has been shown that electrical and pharmacological stimulation of locus ceruleus produces anxiety or parallel behavior in animals. For instance, in Redmond & Huang's study (1979), the monkeys reacted to this stimulation as if faced with a real danger in their natural environment. In his study, arousal, anxiety and fear were associated with increased concentrations of norepinephrine and its metabolite MHPG in the brain, plasma and cerebral-spinal fluid. Other study has demonstrated that alpha2-adrenoreceptors antagonists, such as yohimbine or piperoxan, which are panicogenic in humans provoke fearful behavior in monkeys and also increase the firing rate of noradrenergic neurons of the locus ceruleus (Olpe et al., 1983). Modifications of the noradrenergic activity also occur in rats when exploratory behavior in the plus maze test is decreased by alpha2-antagonists (Handley & Methani, 1984). Also, stimulation of the locus ceruleus inhibits muricidal behavior and aggression and produces fear reactions in rats (Kozak et al., 1984). On the other hand, Kaitin et al. (1986) reported that in human subjects, electrical stimulation of locus ceruleus does not produce panic. Most agents that alleviate anxiety (benzodiazepines, alcohol, opiates) act also to lower the activity of locus ceruleus. Nybäck et al. (1975), Geyer & Lee (1984) and Huang (1979) demonstrated that anxiolytics morphine, barbiturates, clonidine and desipramine reduce fear-related behaviors in monkeys as well as they decrease the activity of locus ceruleus neurons. Muricidal behavior in rats is increased by anxiolytics that also reduce the firing rate of neurons in locus ceruleus (Kostowski et al., 1983). Locus ceruleus also contains benzodiazepine receptors, as well as receptors for endogenous opiates. During syndrome of withdrawal from benzodiazepines, opiates and alcohol, anxiety increases as does the activity of locus ceruleus, both lasting as long as the withdrawal symptoms persist. Benzodiazepines with anxiolytic qualities reduce the noradrenergic turnover (Gallager et al., 1980, Tanaka et al., 1983, Glavin, 1985). The effects of yohimbine, an agent that is able to induce panic attacks via blockage of alpha2-adrenergic autoreceptors, can be reduced or abolished by administration of benzodiazepines diazepam and alprazolam (Charney et al., 1983, Charney & Heninger, 1985). Charney & Heninger (1985) reported that a long-term treatment with alprazolam decreases baseline plasma MHPG levels, suggesting that the antipanic effect is most likely due to an interaction between the benzodiazepine and noradrenergic systems.