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Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands.

Chilmonczyk Z, Bojarski AJ, Pilc A, Sylte I - Int J Mol Sci (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: National Medicines Institute, Chełmska 30/34, 00-725 Warszawa, Poland. z.chilmonczyk@nil.gov.pl.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Adult 5-HT raphe-PFC circuitry in anxiety and depression model (according to Albert et al.) [161]. The model shows 5-HT neurons (brown) projecting to prefrontal cortex GABAergic interneurons (yellow) and glutamatergic pyramidal neurons (blue) with transmitter release illustrated as small circles of the same colors. Receptors: 5-HT1A (green), 5-HT2A (light green), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-glutamate (purple) and GABAA receptors (blue). The response in the target neurons (red ovals): stimulatory (+), inhibitory (−). (↑)—elevation, (↓)—decrease. 5-HT1A heteroreceptors and GABAA receptors reduce the activity of the pyramidal neurons while 5-HT2A receptors activate the neurons.
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ijms-16-18474-f005: Adult 5-HT raphe-PFC circuitry in anxiety and depression model (according to Albert et al.) [161]. The model shows 5-HT neurons (brown) projecting to prefrontal cortex GABAergic interneurons (yellow) and glutamatergic pyramidal neurons (blue) with transmitter release illustrated as small circles of the same colors. Receptors: 5-HT1A (green), 5-HT2A (light green), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-glutamate (purple) and GABAA receptors (blue). The response in the target neurons (red ovals): stimulatory (+), inhibitory (−). (↑)—elevation, (↓)—decrease. 5-HT1A heteroreceptors and GABAA receptors reduce the activity of the pyramidal neurons while 5-HT2A receptors activate the neurons.

Mentions: Albert et al. proposed a simplified model of raphe and PFC circuitry involvement in anxiety and depression (Figure 5) [161]. It was suggested that there are two major sub-populations of heteroreceptors in PFC: 5-HT1A receptors on pyramidal glutamatergic neurons and on GABA interneurons that inhibit the activity of both neuron types [162]. In rodent PFC, ~50% of pyramidal neurons and ~25% of GABAergic interneurons express 5-HT1A receptors [163], and this proportion is even higher (up to 80%) in upper cortical layers of primate and human PFC [162]. It should also be noted that 5-HT1A receptors are abundantly coexpressed (in ca. 80%) with excitatory 5-HT2A receptors in rodent PFC [161]. 5-HT2A receptors have 10-fold lower affinity for 5-HT and with maturation 5-HT1A receptor inhibition predominates over 5-HT2A excitatory function. In this model the activity of the GABA interneurons exhibits inhibitory activity on glutamatergic pyramidal neurons while 5-HT1A heteroreceptors diminish the GABAergic activity. In the anxiety model, under normal conditions both 5-HT1A heteroreceptors on pyramidal and interneurons are engaged, resulting in a balance between 5-HT1A-mediated inhibition and dys-inhibition on pyramidal neurons. On the basis of evidence from human imaging studies, it was suggested that different sub-populations of PFC neurons with different targets mediate anxiety vs. depression behavior. Due to these differences, the serotonin circuitry model for depression involves similar components but is slightly different from the anxiety model. First, opposite to anxiety, activation of the pyramidal neuron is associated with reduced depression and increased resilience. Second, it was proposed that the 5-HT2A receptor is weakly active in the mature pyramidal neurons controlling depression. The model predicts elevated anxiety at the low and high serotonin levels and elevated depression at the lack of serotonin and its low levels [162].


Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands.

Chilmonczyk Z, Bojarski AJ, Pilc A, Sylte I - Int J Mol Sci (2015)

Adult 5-HT raphe-PFC circuitry in anxiety and depression model (according to Albert et al.) [161]. The model shows 5-HT neurons (brown) projecting to prefrontal cortex GABAergic interneurons (yellow) and glutamatergic pyramidal neurons (blue) with transmitter release illustrated as small circles of the same colors. Receptors: 5-HT1A (green), 5-HT2A (light green), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-glutamate (purple) and GABAA receptors (blue). The response in the target neurons (red ovals): stimulatory (+), inhibitory (−). (↑)—elevation, (↓)—decrease. 5-HT1A heteroreceptors and GABAA receptors reduce the activity of the pyramidal neurons while 5-HT2A receptors activate the neurons.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581256&req=5

ijms-16-18474-f005: Adult 5-HT raphe-PFC circuitry in anxiety and depression model (according to Albert et al.) [161]. The model shows 5-HT neurons (brown) projecting to prefrontal cortex GABAergic interneurons (yellow) and glutamatergic pyramidal neurons (blue) with transmitter release illustrated as small circles of the same colors. Receptors: 5-HT1A (green), 5-HT2A (light green), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-glutamate (purple) and GABAA receptors (blue). The response in the target neurons (red ovals): stimulatory (+), inhibitory (−). (↑)—elevation, (↓)—decrease. 5-HT1A heteroreceptors and GABAA receptors reduce the activity of the pyramidal neurons while 5-HT2A receptors activate the neurons.
Mentions: Albert et al. proposed a simplified model of raphe and PFC circuitry involvement in anxiety and depression (Figure 5) [161]. It was suggested that there are two major sub-populations of heteroreceptors in PFC: 5-HT1A receptors on pyramidal glutamatergic neurons and on GABA interneurons that inhibit the activity of both neuron types [162]. In rodent PFC, ~50% of pyramidal neurons and ~25% of GABAergic interneurons express 5-HT1A receptors [163], and this proportion is even higher (up to 80%) in upper cortical layers of primate and human PFC [162]. It should also be noted that 5-HT1A receptors are abundantly coexpressed (in ca. 80%) with excitatory 5-HT2A receptors in rodent PFC [161]. 5-HT2A receptors have 10-fold lower affinity for 5-HT and with maturation 5-HT1A receptor inhibition predominates over 5-HT2A excitatory function. In this model the activity of the GABA interneurons exhibits inhibitory activity on glutamatergic pyramidal neurons while 5-HT1A heteroreceptors diminish the GABAergic activity. In the anxiety model, under normal conditions both 5-HT1A heteroreceptors on pyramidal and interneurons are engaged, resulting in a balance between 5-HT1A-mediated inhibition and dys-inhibition on pyramidal neurons. On the basis of evidence from human imaging studies, it was suggested that different sub-populations of PFC neurons with different targets mediate anxiety vs. depression behavior. Due to these differences, the serotonin circuitry model for depression involves similar components but is slightly different from the anxiety model. First, opposite to anxiety, activation of the pyramidal neuron is associated with reduced depression and increased resilience. Second, it was proposed that the 5-HT2A receptor is weakly active in the mature pyramidal neurons controlling depression. The model predicts elevated anxiety at the low and high serotonin levels and elevated depression at the lack of serotonin and its low levels [162].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: National Medicines Institute, Chełmska 30/34, 00-725 Warszawa, Poland. z.chilmonczyk@nil.gov.pl.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus