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Serotonin Receptor Knockouts: a Moody Subject David Julius* Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450

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Serotonin Receptor Knockouts: a Moody Subject David Julius* Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450 Proc. Natl. Acad. Sci. USA Vol. 95, pp. 15153–15154, December 1998 Commentary Serotonin receptor knockouts: A moody subject David Julius* Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450 The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) receptors are expressed in a number of brain regions to which is believed to play a significant role in determining one’s serotonergic neurons project, including the hippocampus, ce- emotional state. Indeed, serotonergic synapses are sites of rebral cortex, and amygdala (11, 12). As in the case of action for a number of mood-altering drugs, including the presynaptic autoreceptors, activation of postsynaptic 5-HT1A now-legendary antidepressant Prozac (fluoxetine) (1). As a receptors leads to hyperpolarization of the neuron and the result, there has been tremendous interest in identifying consequent inhibition of neurotransmitter release. This effect molecular components of the serotonergic system, including appears to be mediated through a biochemical signaling path- cell surface receptors and transporters, and understanding way in which 5-HT1A receptors activate a G protein (Gi)- whether and how these proteins contribute to the regulation of coupled inwardly rectifying potassium channel (13, 14). mood and emotion. This quest is driven, in part, by the In light of the pharmacological evidence that 5-HT1A re- possibility that behavioral disorders, such as depression or ceptors exert negative ‘‘feedback’’ control on serotonergic anxiety, may be linked to deficits in one or more components neurons, one would predict that mice lacking this receptor of this signaling system. Such information could, in turn, focus should show elevated levels of extraneuronal serotonin, or an attention on specific targets for the development of novel increase in the amount of serotonin released after nerve drugs with which to treat psychiatric disorders. In the case of stimulation. However, neither group observed a significant serotonin, this is a particularly challenging goal because the change in the serotonin content of brains from mutant animals system is quite complex, consisting of at least 14 distinct compared with wild-type controls. Furthermore, Ramboz et al. receptor subtypes (2). Nevertheless, pharmacological and (3) measured the amounts of serotonin released after electrical physiological studies have highlighted a subset of 5-HT recep- stimulation of slices taken from mesencephalic and hippocam- tor subtypes worthy of more immediate genetic analysis. One pal regions of the brain. In slices from wild-type animals, the of these, the 5-HT1A receptor, is the focus of two studies by 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8- Ramboz et al. (3) and Heisler et al. (4) in recent issues of the OH-DPAT) reduced serotonin release by 30–40%, suggesting Proceedings. These groups used gene ‘‘knockout’’ methods to that at least some component of autoregulation via the 5-HT1A generate mouse lines lacking 5-HT1A receptors so that they receptor is reconstituted in this assay. Interestingly, knockout could assess the effects of receptor ablation on behavior, using animals showed no significant difference from wild-type con- models of anxiety and depression. trols in the amount of electrically evoked serotonin release Why is the 5-HT1A subtype considered to be a particularly from these slices. Moreover, in contrast to wild types, the important and interesting member of the serotonin receptor evoked release observed in mutants was unaffected by pre- family? One reason is that the 5-HT1A receptor has for years treatment with 8-OH-DPAT, as one would expect in the been synonymous with the classical ‘‘autoreceptor’’ on sero- absence of functional 5-HT1A receptors. If one assumes that tonergic neurons in raphe´nuclei of the brain stem (5). These the in vitro slice preparation recapitulates regulation by pre- cells synthesize the majority of serotonin in the brain, sending synaptic autoreceptors in vivo (perhaps a large assumption their axonal projections throughout the central nervous sys- because somatodendritic receptors are lost in this prepara- tem. Activation of 5-HT receptors on cell bodies of these 1A tion), then these findings suggest either that the 5-HT1A neurons inhibits release of serotonin, thereby attenuating receptor does not play a significant part in modulating sero- serotonergic signaling at large. As such, this receptor repre- tonin release or that its role has been subsumed by another sents a potentially important regulatory site for modulating the subtype. actions of serotonin in the brain and spinal cord. Interest in this Perhaps the most obvious candidate for such a functional receptor also stems from clinical success with drugs that substitution is the 5-HT1B receptor. Like the 5-HT1A receptor, interact with this site. Most notably, partial agonists of the the 5-HT1B subtype is coupled negatively to adenylate cyclase 5-HT1A receptor, such as buspirone and gepirone, are effective and can be found on serotonergic cells of the raphe´nucleus, as anxiolytic (antianxiety) agents (6, 7), suggesting that alter- where it is located at the axon terminal (2, 5). 5-HT1B agonists, ations in 5-HT1A receptor activity may be linked to serotonin- such as the antimigraine drug sumatriptan, can inhibit neuro- mediated changes in mood. In addition, antagonists of the transmitter release from these cells, as Ramboz et al. demon- 5-HT1A receptor appear to accelerate and enhance the anti- strate, using slices from wild-type or mutant brains. The depressant action of so-called selective serotonin reuptake authors suggest that 5-HT1B receptors may be up-regulated in inhibitors (SSRIs) such as Prozac (8, 9), which increase levels the brains of knockout mice to compensate for the loss of of serotonin in the synaptic cleft by blocking transporters on somatodendritic 5-HT1A autoreceptors, thereby modulating the presynaptic membrane. In other words, blockade of inhib- the release of serotonin (and possibly other transmitters) itory autoreceptors may augment the ability of SSRIs to through increased inhibition at the axon terminal. If so, then elevate synaptic serotonin levels. Related speculation suggests the serotonergic feedback circuit shows impressive plasticity in that desensitization of 5-HT1A autoreceptors represents a the face of a genetic mutation that might otherwise perturb significant component of the antidepressant action of chron- homeostatic mechanisms controlling transmitter release. ically administered SSRIs (10). Finally, it must be mentioned These findings also remind us that the effects of any given that not all 5-HT1A receptors are presynaptic; postsynaptic The companions to this Commentary begin on page 14476 in issue 24 © 1998 by The National Academy of Sciences 0027-8424y98y9515153-2$2.00y0 and on page 15049 in issue 25 of volume 95. PNAS is available online at www.pnas.org. *e-mail: [email protected]. 15153 Downloaded by guest on September 26, 2021 15154 Commentary: Julius Proc. Natl. Acad. Sci. USA 95 (1998) mutation or chronic drug treatment on behavior may involve based models, as it is possible that the activity of serotonergic changes at the cellular or molecular level that are several steps neurons differs in knockout versus wild-type mice under some removed from their initial point of action. In any case, the behavioral circumstances. Thus, to address questions of mech- model of 5-HT1B receptor compensation put forth by Ramboz anism it will be necessary, as Heisler et al. suggest, to carry out et al. is still quite hypothetical and must be put to more electrophysiological and microdialysis studies in attempts to stringent tests. Rene´ Hen’s group has generated 5-HT1B correlate levels of serotonergic activity with behavior. Also, as receptor knockout mice (15), and crosses with the 5-HT1A Ramboz et al. suggest, issues regarding pre- versus postsynaptic receptor knockout line could produce some interesting ani- functions for 5-HT1A receptors might be clarified by tissue- mals with which to carry out double-mutant analysis of feed- specific knockouts (16) in which the receptor gene is inacti- back control mechanisms within the serotonergic pathway. vated solely in cells of the raphe´ nucleus. Similarly, the On the behavioral level, the thrust of these two papers is to interpretation of a standard gene knockout experiment is examine the connection between the 5-HT1A receptor and often complicated by possibilities of long-term developmental anxiety, and to validate the use of these mutant mice as a model changes, a sticking point that can be addressed only by system for studying anxiety-related mood disorders. As men- inducible knockout strategies (17) that enable one to eliminate tioned above, at least part of the motivation for this work protein expression acutely. For now, Ramboz et al. show nicely comes from the fact that 5-HT1A agonists are prescribed as that administration of a 5-HT1A receptor antagonist ‘‘pheno- anxiolytics, and antagonists may facilitate the antidepressant copies’’ the knockout in the open field anxiety test, lending actions of SSRIs. To examine the effects of 5-HT1A receptor some weight to the idea that the anxiolytic phenotype does not ablation on anxiety states, both groups compare the behaviors reflect some long-term developmental change that is several of wild-type, heterozygous, and mutant mice in various para- steps removed from receptor inactivation. Nonetheless, these digms that measure
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