Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands.
Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.
National Medicines Institute, Chełmska 30/34, 00-725 Warszawa, Poland. z.chilmonczyk@nil.gov.pl.|Institute of Nursing and Health Sciences, University of Rzeszów, W. Kopisto 2A, 35-310 Rzeszów, Poland. z.chilmonczyk@nil.gov.pl.
Zdzisław
Z
Chilmonczyk
Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland. bojarski@if-pan.krakow.pl.
Andrzej Jacek
AJ
Bojarski
Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland. nfpilc@cyf-kr.edu.pl.
Andrzej
A
Pilc
Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, No-9037 Tromsø, Norway. ingebrigt.sylte@uit.no.
Ingebrigt
I
Sylte
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058990:Molecular Targeted Therapy / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000032:analysis / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D008024:Ligands; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
antidepressant activity; receptor trafficking; serotonin 1A receptors