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Serotonin and anxiety

Frederico G. Graeff
Department of Neurology, Psychiatry and Medical Psychology, Faculty of Medicine of Ribeirão Preto , University of São Paulo , Brazil

Early pre-clinical evidence has shown that drugs that decrease serotonin (5-HT) activity release behaviour suppressed by punishment in conflict tests, and that benzodiazepine anxiolytics reduce 5-HT turnover in the brain. Because conflict tests are reliable animal models of anxiety, Wise et al. (1972) suggested that 5-HT enhanced anxiety by acting on limbic forebrain structures as well as on the midbrain periaqueductal grey matter (PAG). Further experimental evidence has supported the anxiogenic role of 5-HT in forebrain structures such as the amygdala and hippocampus. However, results with electrical or chemical stimulation of the DPAG have shown that 5-HT impairs escape behaviour elicited by DPAG stimulation, pointing to an anxiolytic role of 5-HT.

To solve this contradiction, it has been suggested that the emotional states determined by the two types of animal model are different. Conflict tests would generate conditioned (anticipatory) anxiety, whereas periaqueductal grey stimulation would produce unconditioned aversion, as evoked by cutaneous pain or proximal predatory threat. Anxiety would be enhanced by 5-HT in the forebrain, whereas aversion would be inhibited by 5-HT in the PAG (Graeff 1991). Within a clinical context, conditioned anxiety would be related to generalised anxiety disorder (GAD), while unconditioned aversion, to panic disorder (PD). Thus, an increase in 5-HT activity is supposed to aggravate GAD, but to improve PD (Deakin and Graeff 1991).

The above hypothesis has been tested in an animal model of anxiety and panic, the elevated T-maze (ETM). This apparatus consists of one arm enclosed by walls, transversal to two opposed open, aversive arms, all elevated from the floor. The same rat learns to avoid open arms exploration (inhibitory avoidance) and then performs one-way escape from one of the open arms. Pharmacological results support the view that the avoidance task models GAD, while the escape task models PD. Direct interventions in the dorsal raphe nucleus (DRN), which sends 5-HT-containing fibres to both the amygdala and the PAG have shown that the decrease of 5-HT output impairs avoidance (anxiolytic effect) and enhances escape (panicogenic effect) in the ETM; the increase of 5-HT output does the opposite. These results fulfil the predictions from the hypothesis under testing.

Results obtained with microinjection of drugs inside the amygdala and in the PAG also support the dual role of 5-HT in anxiety and panic (Graeff 2004). Nevertheless, they cast doubt on the suggested rostrocaudal organization of anxiety and panic in the brain, since some manipulations in the amygdala affected escape (besides avoidance) while some interventions in the PAG changed avoidance (besides escape) in the ETM. In this regard, McNaughton and Corr (2004) argued that the brain neurone systems underpinning defensive approach (anxiety) and defensive avoidance (fear/panic) comprise two parallel longitudinal sets of brain structures going from the neocortex to the midbrain; the amount of anxiety representation decreases from top to bottom, whereas fear/panic would be more integrated in the midbrain than in the forebrain.

Pharmacological results obtained in human beings with two procedures of experimental anxiety, one representing anticipatory anxiety (conditioning of skin conductance response to a tone by one-trial association with a loud noise) and the other representing unconditioned aversion (simulation of public speaking) are generally consistent with the hypothesis that 5-HT enhances anxiety, while decreasing aversion (Graeff 2004).


Deakin JFW, Graeff FG (1991) 5-HT and mechanisms of defence. J Psychopharmacol 5:305-15.

Graeff FG (1991) Neurotransmitters in the dorsal periaqueductal gray and animal models of panic anxiety. In: Briley M, File SE, editors. New concepts in anxiety. London : Macmillan Press, p. 288-312.

Graeff FG (2004) Serotonin, the periaqueductal gray and panic disorder. Neurosci Biobehav Rev 28:239-59.

McNaughton and Corr (2004) A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci Biobehav Rev 28:285-305.

Wise CD, Berger BD, Stein L (1972) Benzodiazepines: Anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177:180-3.


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