Reconciling the role of central serotonin neurons in human and animal behavior

Abstract

Animal research suggests that central serotonergic neurons are involved in behavioral suppression, particularly anxiety-related inhibition. The hypothesis linking decreased serotonin transmission to reduced anxiety as the mechanism in the anxiolytic activity of benzodiazepines conflicts with most clinical observations. Serotonin antagonists show no marked capacity to alleviate anxiety. On the other hand, clinical signs of reduced serotonergic transmission (low 5-HIAA levels in the cerebrospinal fluid) are frequently associated with aggressiveness, suicide attempts, and increased anxiety. The target article attempts to reconcile such human and animal findings by investigating whether anxiety reduction or increased impulsivity is more Likely to account for animal behavioral changes associated with decreased serotonergic transmission. The effects of manipulating central serotonin in experimental anxiety paradigms in animals (punishment, extinction, novelty) are reviewed and compared with the effects of antianxiety drugs. Anxiety seems neither necessary nor sufficient to induce control by serotonergic neurons on behavior. Further evidence suggests that behavioral effects of anxiolytics thought to be mediated by decreases in anxiety are not caused by the ability of these drugs to reduce serotonin transmission. Blockade of serotonin transmission, especially at the level of the substantia nigra, results in a shift of behavior toward facilitation of responding. This behavioral shift is particularly marked when there is competition between acting and restraining response tendencies and when obstacles prevent the immediate attainment of an anticipated reward. It is proposed that serotonergic neurons are involved not only in behavioral arousal but also in enabling the organism to arrange or tolerate delay before acting. Decreases in serotonin transmission seem to be associated with the increased performance of behaviors that are usually suppressed, though not necessarily because of the alleviation of anxiety, which might contribute to the suppression.

Deficits in Impulse Control Associated with Tonically-elevated Serotonergic Function in Rat Prefrontal Cortex

“…The positive relationship between elevated 5-HT release and loss of impulse control was evident despite time of sampling, either before or during task performance, suggesting that this may be a deficit linked to the tonic regulation of 5-HT release. Previous studies have strongly implicated serotonergic influences on impulsivity (Soubrié 1986, Stein et al 1993Harrison et al 1997a;Puumala and Sirviö 1998;Evenden 1999b;Fairbanks et al 2001), particularly when associated with aggression (Brown et al 1982;Linnoila et al 1983;Van Erp and Miczek 2000). Many of these reports have linked impulsive tendencies with a deficiency in 5-HT function.…”

“…Recent studies provide support for the notion that impulsivity is a multifaceted disorder of response control (Soubrié 1986), timing (Ho et al 1998) and/or an intolerance to delayed reinforcement (Wogar et al 1993;Ho et al 1998;Evenden 1999b;Rogers et al 1999). The view that distinct neural and neurochemical systems underlie different aspects of impulsive behavior receives support from the mixed effects of 5-HT receptor ligands on different tests of impulsivity.…”

“…A critical element of the task is the capacity to inhibit premature responding during the inter-trial interval of 5 s prior to the presentation of the visual discriminanda. Following Soubrié (1986) we defined this form of behavior as impulsive, although it is recognized that this term potentially encompasses a much wider repertoire of behavioral control processes (see Evenden 1999b). In order to increase the sensitivity of the procedure to detect impulsive tendencies, subjects were challenged with sessions incorporating a longer inter-trial interval of 7 s. In view of the mutual antagonism between 5-HT and dopamine (DA) systems, particularly in the frontal cortex (Millan et al 1998) and the ameliorative effects of psychomotor stimulants in attention-deficit hyperactivity disorder (ADHD) (Morrow 1991) we also measured DA in the dialysate fluid.…”

Fractionating Impulsivity: Contrasting Effects of Central 5-HT Depletion on Different Measures of Impulsive Behavior

“…In support of the general hypothesis that decreased 5-HT function increases impulsive behavior (Linnoila et al, 1983;Soubrié, 1986), selective lesions of the 5-HT system in the rat have been reported to increase impulsivity on these measures (eg Fletcher, 1995;Harrison et al, 1997aHarrison et al, , b, 1999Mobini et al, 2000;Wogar et al, 1993). The finding that the same neurochemical manipulation increases all these aspects of impulsivity suggests that impulsivity is a unitary construct, at least in terms of its regulation by the serotonergic system.…”

Tryptophan Depletion Disrupts the Motivational Guidance of Goal-Directed Behavior as a Function of Trait Impulsivity

“…5-HT neurotransmission has been implicated not only in the processing of incentive-motivational signals but also in the inhibitory control of behavior (Soubrie, 1986;Evenden, 1999). Like depression, impulsive pathology has been associated with a deficiency of central 5-HT.…”