5-HT receptors discussed in this review, their cellular signaling pathways, ligands, and selected functional and therapeutic implications For an overview over the involvement in 5-HT heteroreceptor-mediated modulation of neurotransmitter release, see Table 11.
| 5-HT Receptor | Signal Transduction | Agonists | Antagonists | Function, Occurrence, Therapeutic Implications |
|---|---|---|---|---|
| 5-HT1A | Gi/o AC ↓ | 8-OH-DPATa, ipsapirone | Spiroxatrine, cyanopindolol, WAY 100635a | Inhibition of cellular function; somadendritic “autoreceptor” in raphe nuclei; also highly expressed in cingulate and entorhinal cortex, hippocampus, and lateral septum; involved in learning, memory, in anxiety and depression, and in ACTH release |
| 5-HT1B | Gi/o AC ↓ | Sumatriptan, CP-94253, L-694,247, 5-nonyloxytryptamine, CGS 12066B | SB 224289a, cyanopindolol, NAS-181a, GR 127935 | Inhibition of cellular function; presynaptic autoreceptor; highly expressed in basal ganglia, hippocampus, and striatum; involved in anxiety and depression, drug abuse, and migraine therapy |
| 5-HT1D | Gi/o AC ↓ | Sumatriptan, L-694,247, CGS 12066B | BRL 15572a, GR 127935 | Inhibition of cellular function; present in basal ganglia, periaqueductal grey, and spinal cord; involved in migraine therapy |
| 5-HT2A | Gq/11 PLC ↑ | α-Methyl-5-HT, DOI, DOB | Ketanserin,a R-96544,a AMI-193 | Facilitation/stimulation of cellular function and neuronal depolarization; highly expressed in neocortex, pyriform and entorhinal cortex, caudatum, claustrum, nucleus accumbens, olfactory tubercle, and hippocampus; involved in learning and therapy of schizophrenia with atypical antipsychotics |
| 5-HT2C | Gq/11 PLC ↑ | α-Methyl-5-HT, RO 60–0175,a WAY 161503 | RS 102221,a N-desmethylclozapine, SB 242084a | Facilitation/stimulation of cellular function; strongly expressed in choroid plexus, less in pyriform cortex, cingulate, nucleus accumbens, hippocampus, amygdala, caudatum, and substantia nigra; involved in cerebrospinal fluid secretion; therapy of schizophrenia with atypical antipsychotics |
| 5-HT3 | Na+/K+/Ca2+ channel | 2-Methyl-5-HTa, SR 57227, mCPBGa | Ondansetrona, tropisetrona, Y-25130a, zacopride | Facilitation/stimulation of cellular function; in hippocampus, striatum, and superficial neocortex layers; involved in emesis, anxiety, and reward |
| 5-HT4 | Gs AC ↑ | BIMU 1,a BIMU 8,a ML10302,a RS 67506,a zacopride | GR 113808,a GR 125487,a RS 39604,a SB 204070,a SDZ 205,557a | Facilitation/stimulation of cellular function and excitatory function on cholinergic transmission; occurrence in nigrostriatal and mesolimbic system, and neocortex; involved in cognitive performance |
AC, adenylyl cyclase; spiroxatrine, 8-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (5-HT1A antagonist); ACTH, adrenocorticotropin; L-694,247, 2-[5-[3-(4-methylsulfonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethaneamine (5-HT1B agonist); NAS-181, (2R)-2-[[[3-(4-morpholinylmethyl)-2H-1-benzopyran-8-yl]oxy]methyl]morpholine (5-HT1B agonist); PLC, phospholipase C; α-methyl-5-HT, α-methyl-5-hydroxytryptamine (5-HT2 agonist); R-96544, (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]-1-methyl-3-pyrrolidinol hydrochloride (5-HT2A antagonist); WAY 161503, 8,9-dichloro-2,3,4,4-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride (5-HT2C agonist); SR 57227, 1-(6-chloro-2-pyridinyl)-4-piperidinamine hydrochloride (5-HT3 agonist); Y-25130, N-1-azabicyclo[2.2.2]-oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide hydrochloride (azasetron; 5-HT3 antagonist); ML10302, 2-(1-piperidinyl)ethyl-4-amino-5-chloro-2-methoxybenzoate (5-HT4 agonist); RS 39604, 1-[4-amino-5-chloro-2-(3,5-dimethoxyphenyl)methyloxy]-3-[1-[2-methylsulphonylamino]piperidin-4-yl]propan-1-one hydrochloride (5-HT4 antagonist); RS 67506, 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone (5-HT4 agonist)
↵ a Selective ligand at the respective receptor