HT1A Agonists

Rasmussen, K.C.J. Nicotine withdrawal leads to increased sensitivity of serotonergic neurons to the 5-HT1A agonist 8-OH-DPAT. Psychopharmacology. 133 343, 1997. 

Becker, O.M., Dhanoa, D.S., Marantz, Y., Chen, D., Shacham, S., Cheruku, S., Heifetz, A., Mohanty, P., Fichman, M., Sharadendu, A., Nudelman, R., Kauffman, M. and Noiman, S. (2006) An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. Journal of Medicinal Chemistry, 49, 3116-3135. 

A therapeutic alternative for treatment of anxiety and depression is the use of 5-HT1A agonists. Azapirones comprise the major class of 5-HT1A agonists of which buspirone (Buspar [4]) is the only FDA-approved 5-HT1A selective agonist (relative to the other 13 serotonin receptor subtypes) for anxiety currently on the US market (Scheme 19.1). Buspirone has shown efficacy in randomized controlled trials of GAD for which it was approved [5-7]. Unlike benzodiazepines, buspirone is not addictive... 

Cheeta, S., Tucci, S., Sandhu, J., et al. Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils. Brain Res. 915, 170-175, 2001. 

Feeding behaviour 5-HT1A agonists enhance food consumption in experimental animals... 

Sexual behaviour 5-HT1B and 5-HT2 agonists cause hyperthermia in experimental animals 5-HT1A agonists both facilitate and inhibit sexual behaviour in male rats 5-HT1B agonists inhibit sexual behaviour in the male but facilitate this behaviour in the female rat... 

Sleep whereas the antagonists are hypotensives 5-HT1A agonists delay the onset of REM sleep... 

Koella has reviewed the evidence implicating the involvement of serotonin in the sleep-wake cycle but the involvement of specific serotonin receptor subtypes in sleep mechanisms is unclear. Experimental evidence suggests that 5-HT1A agonists delay the onset of REM sleep while 5-HT2 antagonists suppress REM and have variable effects on non-REM sleep. 

Glennon RA, Naiman NA, Pierson ME, Titeler M, Lyon RA. NAN-190 an arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydro y-2-(di- -propylamino)tetralin. Eur J Pharmacol 1988 154 339-341. 

Bianchi C, Siniscalchi A, Beani L. 5-HT1A agonists increase and 5-HT3 agonists decrease acetylcholine efflux from the cerebral cortex of freely-moving guinea-pigs. Br J Pharmacol 1990 101 448-452. 

Blier P, de Montigny C. Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone electrophysiological studies in the rat brain Synapse 1987 1 470-480. 

Kennett GA, Marcou M, Dourisch CT, Curzon G. Single administration of 5-HT1A agonists decreases 5-HT1A presynaptic, but not postsynaptic receptor-mediated responses relationship to antidepressant-like action. Eur J Pharmacol 1987 138 53-60. 

In Vivo and In Vitro Studies with 5-HT1A Agonists... 

Fig. 2. Hyperpolarizing effects of 5-HT on the medial prefrontal cortex and hippocampal pyramidal neurons. (A) Bath application of 5-HT (30 pM) elicited a hyperpolarizing response that was blocked by BMY 7378 (3 pM). The lower trace shows that the selective 5-HT1A agonist 8-OH-DPAT (30 M) induced a membrane hyperpolarization comparable to that elicited by 5-HT (30 pM). Reproduced with permission from ref. 75. (B) Bath application of 5-carboxyamidotryptamine (5-CT) and 5-HT produced a similar membrane hyperpolarization in CA1 hippocampal pyramidal cells. The lower panels show the inability of 5-HT and 5-CT to elicit the hyperpolarizing response in presence of the 5-HT1A receptor antagonist WAY-100635. Reproduced with permission from ref. 76.

Fig. 4. 5-HT neuron activity and 5-HT release in wild-type (WT) and 5-HT1A knockout (KO) mice in response to the systemic administration of the 5-HT1A agonist 8-OH-DPAT and the SSRI fluoxetine. (A,C) 8-OH-DPAT inhibited the firing rate of...

Casanovas JM, Lesourd M, Artigas F. The effect of the selective 5-HT1A agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain. Br J Pharmacol 1997 122 733-741. 

Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression Biol Psychiatry 2003 53 193-203. 

T Latency to feed li Response to chronic fluoxetine <=> Response to chronic imipramine <=> Response to chronic desipramine IT Response to 5-HT1A agonist IT Body temperature response IT Heart rate response <=> Body temperature response <=> Heart rate response li Body temperature response to 5-HT1A agonist... 

Stress-induced hyperthermia Body temperature response v=> Plasma corticosterone <=> Body temperature response to 5-HT1A agonist 66... 

HT II Response to 5-HT1A agonist ft Response to 5-HT1B agonist ft Response to fluoxetine with 5-HT1B/1D antagonist no effect in wild type 52... 

Dorsal raphe 5-HT <=> Basal <=> Response to local citalopram II Response to 5-HT1A agonist with citalopram 48... 

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