This model of antidepressants MOA makes some senses with SSRI but not with 5HT1a direct agonists imho (or Serotonin releasers like MDMA). If I understand correctly, 5HT1a DRN autoreceptors basically function as sensors in a feedback loop to regulate released 5HT levels in synapse by inhibiting its further release and ending neuron firing. Serotonin transporter (SERT) on the other hand removes 5HT released within the synaptic cleft and transport it back to the neuron for storage (and reuse?) It saves energy compared to de nuovo synthesizing serotonin every time the neuron needs it to fire. So the 2 mechanisms of regulating serotonin levels (and the firing of serotonergic neurons) are working together to regulate serotoninergic firing.
Now, SSRIs prevents the reuptake of released 5HT which will have no effect as long long as the HT1a autoreceptors are in the basal state ie fully sensitized: 5HT levels will still be regulated via 1a autoreceptors feedback loop. Of course, chronic activation leading to desensitization of 1a autoreceptors would lead to "increase" (or at least persistent signaling) serotonin levels since you now have blockade of the 2 modes of regulating 5HT. That might explain the time lag of SSRI to work. Another way to achieve same effect is simply blockade of 1a autoreceptors which may explain the antidepressant effect of some 5HT1a antagonists like pindolol. Sure, if you were to block 1a autoreceptors AND inhbibit reuptake the neurotransmitter at the same time, you get more bang for your money (5HT reuptake inhbition + disinhibition of 5HT release).
Having said that, activation of 1a autoreceptors by direct agonists will lead to inhibition of further serotonin release (NOT THE AGONIST). The agonist is still available to bind and activate postsynaptic receptors and lead to AnxiolyticAD response that would have been coming from the endogenous serotonin binding to post-synaptic 5HTRs! So you'll have serotonergic response regardless of 5HT1a levels. At least the response mediated by the 5HT1a subpopulation of 5HTs. The challenge is that if you are dealing with a selective 1a agonist, you'll now have less serotonergic activation of the other 13 different or so 5HT subtypes (5HT1D/B, 5HT2, 5HT3, 5HT6..etc etc) because by activating autoreceptors, the agonist is decreasing overall serotonin available. It is as if direct 5HT1a autoreceptors agonists are also indirectly antagonist of other serotonergic subtypes (pretty complex!).
As I said, chemically ( as far as rational drug design concerned) it is incredibly difficult to come up with a molecule that is selective post-synaptic 5HT1A agonist: the drug molecule cannot differentiate between auto and heteroreceptors: it would bind (and activate both) without discriminating although with opioids as I mentioned above, activation by different agonists may lead to different downtream signaling like morphine compared to endorphins. Difficult but not impossibe, afaik nobody has yet come up with a rationale on what makes a molecule functionally slective: you'll just have to random screen millions of molecules(at ca $200/molecule that's lots of money!! way beyond my payscale as a homeless person working daylabor). Another approach is manipulating pharmacokinetic parameters of the drug molecule so that it selectively distributes to one or the other brain regions (difficult to predict a priori!!). As I mentioned, you can easily get molecules cross BBB and get in the brain but hard to tell them where to go once there!!
As for the anxiolytic effect of 5HT1a activation by agonists, it seems unrelated to the observed AD effect. Here is a recent review:
Association of 5-HT1A Receptors with Affective Disorders
By Cesar Soria-Fregozo, Maria Isabel Perez-Vega, Juan Francisco Rodríguez-Landa, León Jesús Germán-Ponciano, Rosa Isela García- Ríos and Armando Mora-Perez
Imho, the best anxiolytic/antidepressant 5HT1a agonist drug would be one that is also serotonin releaser (releaser not uptake inhibitor!). With SRAs (serotonin releasers like MDMA exctasy) autoreceptors activation would not be relevant since the level of released serotonin in the synaptic cleft would just be baseline ie autoreceptors activation by the agonist regulate 5HT level to baseline and activation of postsynaptic 5HTa brings about the intended anxiolytic/serenic/antidepressant effect without f...g up other 5HT receptors subtypes states... but who knows?
NB: actually one such drug I came across is
mepiprazole (or its cousin
tolpiprazole . It is an anxiolytic (minor tranquilizer) developed in the 70s in Germany and was (is?) used in Spain as anxiolytic to treat "neurosis" aka stressthe syout. It is a 5HT DA NE releaser (more selective for 5HT than DA/NE) and a 5HT1a agonist. I am not sure if it is still prescribed in Spain (if anybody please let me know). It was probably displaced with the introduction of benzodiazepines anxiolytics (t’was the craze with Valium & co back then right?). I would certainly bet this molecule would be the perfect “chill pill”. Unlike benzodiazepines and other GABAergic, activation of 5HT1a by anxiolytics (at least as seen with Buspar) does not lead to sedation, drowsiness, tolerance, withdrawal, is faster and safer than with benzos.. (cf this ref here)...The only issue is priapism aka the “exploding penis” (would look at that issue further if it is related to 5HT1a agonism per se or specifically with Buspar though)..