Posted by Astounder on November 2, 2007, at 12:43:49
In reply to Re: Dopamine agonists cause sedation. But why?? » Astounder, posted by amigan on November 2, 2007, at 6:36:00
> I see that 5HT2A and 5HT2C antagonists increase dopamine. Does this mean that certain antidepressants like mirtazapine are expected to do the job? Are there any more potent 5HT2A/C antagonists than this drug?
Mirtazapine, a potent 5-HT2a/c antagonist, immediately and robustly increases DA firing in some areas, like the frontal cortex and the ventral tegmental area, which are involved in executive functioning and reward, respectively.
The most potent 5-HT2a blocking antidepressant is the tricyclic amitripytline (Elavil). It has higher affinity than serotonin itself, which explains why, even though a highly effective serotonin and norepinephrine reuptake inhibitor, it does not cause the serotonin syndrome in combination with a full MAOI (multiple reuptake inhibitors, like Effexor, clomipramine, and imipramine usually seem to cause a worse serotonin syndrome than pure SSRIs). Nefazodone and trazodone are both also 5-HT2a antagonists.
Many of the typical antipsychotics, such as chlorpromazine (Thorazine), and the antihistamine cyproheptadine are highly efficacious at this site, which is why they're used to treat the serotonin syndrome. Low dose (0.5-1 mg) Risperdal (along with its active metabolite) is probably the most selective 5-HT2a antagonist on the market with its with subnanomolar affinity; most other atypicals have a high affinity for this site, including clozapine, olanzipine, sertindole, ziprasidone, aripiprazole.
At 5-HT2c, most of the typical and atypical neuroleptics that have strong 5-HT2a blocking also have strong action here, though you can't go by the binding data alone, since some work as inverse agonists. Again, cyproheptadine and Elavil bind strongly, with Elavil acting as an inverse agonist. The pipeline antidepressant/anti-insomnic drug agomelatine (Valdoxan) is selective for 5-HT2c receptors in addition to M1 & M2 melatonin receptors.
Any drug that results in prolonged stimulation of both the 5-HT1 & 5-HT2 series receptors--SSRIs, SNRIs, MAOIs--is going eventually cause the downregulation of 5-HT2 series receptors. Conversely, blockers of the 5-HT2 receptors also result in their downregulation.
I would stay away from 5-HT2c antagonists honestly, unless you're OCD or anorexic, since they can cause massive weight gain. If you work out though, they can help in bulking up. Drugs with stimulate these receptors are not always anxiogenic: MDMA's psychomotor stimulating & wakefulness promoting effects are partly through 5-HT2a stimulation, and this receptor may play a part in MDMA's release of oxytocin (which is responsible for its anxiolytic, empathogenic, and disinhibiting effects). Stimulation of the 5-HT2c receptor is responsible for the actions of the serotonergic anorectics, like megadose (900 mg/d) 5-HTP, reuptake inhibitors like sibutramine, and releasers like fenfluramine.
Atypical opiates like tramadol, levorphanol, and methadone have functional, naloxone-reversible 5-HT2a/c blocking actions, which explains why they can be used long term to treat OCD & Tourettism. Opposite direct 5-HT2c blockers, opiate abuse has been known to cause weight loss, though withdrawal can cause weight gain. This is probably because opiates substitute for food-induced reward in animal studies.
poster:Astounder
thread:791344
URL: http://www.dr-bob.org/babble/20071027/msgs/792959.html