Review of 5-ht receptors in the hippocampus

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The effects of 5-HT on memory and the hippocampus: a model and data

Meeter, Talamini, Schmitt, Riedel

Review of 5-HT receptors in the hippocampus

Serotonergic receptors are heterogeneous, and the nomenclature has long been under debate. In recent years, however, consensus has grown around a division in seven families, which will be followed here. The following discussion deals mainly with data reported in hippocampal in vitro and in vivo studies. The effects of 5-HT in this region have been organized into three categories: effects on the membrane potential of principal cells, effects on plasticity, and interactions with acetylcholine (ACh).

Location and density of 5-HT receptors in the hippocampus

5-HT innervation of the hippocampus originates from the raphe nuclei in the midbrain (Wyss et al., 1979). 5-HT is released both via varicosities into the extracellular space, and via synapses (Umbriaco et al., 1995), the latter usually being situated on the dendrites or soma of selected classes of GABA-ergic interneurons (Gulyás et al., 1999). Direct effects of 5-HT on principal cells thus occur through its release in extracellular space.

Depolarizing / hyperpolarizing effects

5-HT has both depolarising and hyperpolarizing effects in the hippocampus, via its different receptors. Activation of receptors from the 5-HT2 family (5-HT2A and 5-HT2C, present in all areas of the hippocampus) has been suggested to induce depolarization in principal cells in the dentate gyrus (Piguet and Galvan, 1994) and other areas of the brain (Barnes and Sharp, 1999). These depolarizing effects of 5-HT are counteracted by a direct hyperpolarization of pyramidal and granular cells in the hippocampus through 5-HT1a receptors, which are present in high density on the membranes of these cell types (Burnet et al., 1995). Another receptor that is also relatively abundant in the hippocampus is the 5-HT3 receptor (Parker et al., 1996). This receptor is present primarily on interneurons (Morales et al., 1996), and stimulates the release of GABA in the hippocampus (Piguet and Galvan, 1994), which also leads to hyperpolarization of principal cells. A similar functional path has been ascribed to 5-HT6 receptors, which are also found on hippocampal interneurons (Woolley et al., 2004). Specific 5-HT6 antagonists have been found to increase glutamate release in the hippocampus (Dawson et al., 2001).

The hyperpolarizing effects of 5-HT appear to dominate the depolarizing effects of 5-HT, as bath application hyperpolarizes granule cells in slice preparations of the dentate gyrus (Piguet and Galvan, 1994). As 5-HT1A and 5-HT3 receptors are abundant in all hippocampal layers and subregions(Burnet et al., 1995, Parker et al., 1996), hyperpolarization may be the dominant influence of 5HT everywhere in the hippocampus.

Another effect of 5-HT is the reduction of afterhyperpolarizing (AHP) currents in CA1 pyramidal cells through activation of 5-HT4 receptors (Torres et al., 1996), and in CA1 and CA3 through 5-HT7 receptors (Bacon and Beck, 2000, Tokarski et al., 2003). Although 5-HT application may thus result mainly in hyperpolarization of hippocampal principal cells, the diminution of AHP currents may increase firing to sustained depolarizing inputs (Gulyás et al., 1999), as principal cells will adapt less strongly to current in the absence of AHP.

Effects on LTP and LTD

The data on the influence of 5-HT on long-term potentiation (LTP) is fragmentary. Specific agonists of the 5-HT2A receptor have been found to enhance LTP in the hippocampus (Wang and Arvanov, 1998), and it has been speculated that 5-HT4 receptor agonists also enhance LTP (Barnes and Sharp, 1999). Agonists of the 5-HT1A receptor have been reported to specifically impair LTD, thereby increasing on balance LTP (Normann et al., 2000). On the other hand, fluvoxamine, a selective serotonin reuptake inhibitor, blocks LTP in CA1, an effect that has been related to 5-HT1A receptors (Kojima et al., 2003). Moreover, 5-HT3 antagonists can facilitate LTP, which suggests that 5-HT3 receptors may inhibit induction of LTP (Staubli and Xu, 1995). Complete abolishment of 5-HT innervation in the hippocampus increases LTP in vivo (Ohashi et al., 2003) –which would suggest that, on balance, 5-HT exerts a negative influence on LTP. It is, however, not clear whether this effect is specific to LTP, or secondary to other changes.

Interactions with ACh

Neurotransmitters do not only have effects by themselves, they can also alter the impact of other neurotransmitters. In the case of 5-HT, much attention has been given to its interactions with the cholinergic system. 5-HT4 and 5-HT-1A agonists increase ACh release, as measured by in vivo microdialysis in the hippocampus and cortex (Koyama et al., 1999, Yamaguchi et al., 1997). The same is true for at least some receptors of the 5-HT2 family (Nair and Gudelsky, 2004). On the other hand, 5-HT3 receptors inhibit ACh release in the hippocampus (Diez-Ariza et al., 2002), and the same has been suggested for 5-HT6 receptors (Woolley et al., 2004). Perhaps because of these counteractive effects, 5-HT denervation of the hippocampus does not significantly alter ACh release in slice preparations of the hippocampus (Birthelmer et al., 2003). No clear conclusions are thus possible regarding the overall effect of 5-HT on ACh release in the hippocampus. Whether or not ACh increases 5-HT release is also not clear, as nicotinergic and muscarinergic ACh receptors have opposite effects on 5-HT release (Vizi and Kiss, 1998).


Partly because of the heterogeneity of the 5-HT receptor group, the effects of 5-HT on principal cells in the hippocampus are not yet clear. In some categories, effects of different receptors have opposite directions, and may even cancel each other out. There are two areas where a clear net effect has been documented:

  • 5-HT hyperpolarizes hippocampal principal cells directly, through 5- HT1A receptors, and indirectly, via 5-HT3 and 5-HT6 receptors on interneurons

  • 5-HT diminishes adaptation in principal cells through a reduction of afterhyperpolarizing currents.

It may be that 5-HT, on balance, impairs LTP, but we judged support for this conjecture too uncertain to include it in our model.


Bacon WL, Beck SG (2000). 5-Hydroxytryptamine(7) receptor activation decreases slow afterhyperpolarization amplitude in CA3 hippocampal pyramidal cells~. J Pharmacol Exp Ther 294: 672-679.

Barnes NM, Sharp T (1999). A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083-1152.

Birthelmer A, Ehret A, Amtage F, Forster S, Lehmann O, Jeltsch H, et al. (2003). Neurotransmitter release and its presynaptic modulation in the rat hippocampus after selective damage to cholinergic or/and serotonergic afferents. Brain Res Bull 59: 371-381.

Burnet PWJ, Eastwood SL, Lacey K, Harrison PJ (1995). The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain. Brain Res 676: 157-168.

Dawson LA, Nguyen HQ, Li P (2001). The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology 25: 662-668.

Diez-Ariza M, Garcia-Alloza M, Lasheras B, Del Rio J, Ramirez MJ (2002). GABA(A) receptor antagonists enhance cortical acetylcholine release induced by 5-HT(3) receptor blockade in freely moving rats. Brain Res 956: 81-85.

Gulyás AI, Acsády L, Freund TF (1999). Structural basis of the cholinergic and serotonergic modulation of GABAergic neurons in the hippocampus. Neurochemistry International 34: 359-372.

Kojima T, Matsumoto M, Togashi H, Tachibana K, Kemmotsu O, Yoshioka M (2003). Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors. Brain Res 959: 165-168.

Koyama T, Nakajima Y, Fujii T, Kawashima K (1999). Enhancement of cortical and hippocampal cholinergic neurotransmission through 5-HT1A receptor-mediated pathways by BAY x 3702 in freely moving rats. Neurosci Lett 265: 33-36.

Morales M, Battenberg E, de Lecea L, Bloom FE (1996). The type 3 serotonin receptor is expressed in a subpopulation of GABAergic neurons in the rat neocortex and hippocampus. Brain Res 731: 199-202.

Nair SG, Gudelsky GA (2004). Activation of 5-HT2 receptors enhances the release of acetylcholine in the prefrontal cortex and hippocampus of the rat. Synapse 15: 202-207.

Normann C, Peckys D, Schulze CH, Walden J, Jonas P, Bischofberger J (2000). Associative long-term depression in the hippocampus is dependent on postsynaptic N-type Ca2þ channels. J Neurosci 20: 8290–8297.

Ohashi S, Matsumoto M, Togashi H, Ueno K, Yoshioka M (2003). The serotonergic modulation of synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway. Neurosci Lett 342: 179-182.

Parker RM, Barnes JM, Ge J, Barber PC, Barnes NM (1996). Autoradiographic distribution of [3H]-(S)-zacopride-labelled 5-HT3 receptors in human brain. J Neurol Sci 144: 199-127.

Piguet P, Galvan M (1994). Transient and long-lasting actions of 5-HT on rat dentate gyrus neurones in vitro. J Physiol 481: 629-639.

Staubli U, Xu FB (1995). ffects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat. J Neurosci 15: 2445.

Tokarski K, Zahorodna A, Bobula B, Hess G (2003). 5-HT7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons. Brain Res 993: 230-234.

Torres GE, Arfken CL, Andrade R (1996). 5-Hydroxytryptamine4 receptors reduce afterhyperpolarization in hippocampus by inhibiting calcium-induced calcium release. Mol Pharmacol 50: 1316-1322.

Umbriaco D, Garcia S, Beaulieu C, Descarries L (1995). Relational features of acetylcholine, noradrenaline, serotonin and GABA axon terminals in the stratum radiatum of adult rat hippocampus (CA1). Hippocampus 5: 605-620.

Vizi ES, Kiss JP (1998). Neurochemistry and pharmacology of the major hippocampal transmitter systems: Synaptic and nonsynaptic interactions. Hippocampus 8: 566-607.

Wang RY, Arvanov VL (1998). M100907, a highly selective 5-HT2A receptor antagonist and a potential atypical antipsychotic drug, facilitates induction of long-term potentiation in area CA1 of the rat hippocampal slice. Brain Res 779: 309-313.

Woolley ML, Marsden CA, Fone KCF (2004). 5-HT6 receptors. Current Drug Targets - CNS & Neurological disorders 3: 59-79.

Wyss JM, Swanson LW, Cowan WM (1979). A study of subcortical afferents to the hippocampal formation in the rat. Neuroscience 4: 463-476.

Yamaguchi T, Suzuki M, Yamamoto M (1997). Evidence for 5-HT4 receptor involvement in the enhancement of acetylcholine release by p-chloroamphetamine in rat frontal cortex. Brain Res 772: 95-101.

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