Interesting that it's been suggested here that S-ketamine is less stimulating, because that was always the opposite of my experience. I guess without a polarimeter I can't even say that I had S-ketamine for certain, but I purchased a batch labeled as such and it seemed brighter, more colorful, and more stimulating than the racemic batch I purchased. Also, I had Anesket vials last summer which are racemic and those felt like the racemic batch I had previously—more sedating and just darker overtones on the whole compared to S isomer.
The scientific literature suggests that not only that S-isomer ketamine would be more stimulating (e.g. striatal D2 binding in nonhuman primates decreases after S-ketamine but not R-ketamine), but also that the stereospecificity of the stimulating effects is conserved within the ACH class. This is evidenced by a
paper which found S-MXE increases locomotor activity, while R-MXE doesn't.
But to get back to the original point of this thread, it's definitely interesting to consider how D2 antagonists might combine with dissociatives. I did find a couple of papers suggesting that D2 antagonists block MK-801 increases in acute locomotor activity. I'm not sure if it was already mentioned in this thread, but the Seeman studies found that MK-801 was a D2 agonist as well.
The purpose of this study was to evaluate the role of endogenous dopamine in the hypermotility response to MK801. The administration of MK801 (0.1 mg/kg, SC) to rats produced an intense stimulation of coordinated locomotor activity, which was not associated with stereotyped behavior. This stimulatory response was inhibited by pretreatment with either reserpine (5 mg/kg, IP) or alpha-methyl-p-tyrosine (2 doses of 250 mg/kg, IP). Similarly, pretreatment with the D2 antagonist eticlopride (0.03 mg/kg, SC) or the D1 antagonist SCH23390 (0.1 mg/kg, SC) produced a marked inhibition of MK801-stimulated hypermotility, and the combination of eticlopride (0.03 mg/kg, SC) and SCH23390 (0.03 mg/kg, SC) produced a greater inhibition of MK801-stimulated locomotion than either agent alone.
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Of course, whether you can dissociate D2 activation from the desirable effects of dissociatives is a concern in its own right. The subjective experience of "liking something" would appear to be quite important for producing drug induced euphoria, and this experience appears to mediated by the ventral pallidum. The ventral pallidum receives inputs from the nucleus accumbens (which is rife with D2 receptors) and in turn projects to the mediodorsal thalamic nucleus.
The most prominent MK-801-induced changes in glutamate release occur in the mediodorsal thalamic nucleus, while the D2 activation (whether direct or indirect) would be especially affecting the nucleus accumbens. As the ventral pallidum is sandwiched (from a connectivity standpoint) between these regions which appear to be strongly affected by NMDAR antagonists, I would guess that it's extremely important for mediating their euphoric effects.
Another point is that dopamine is an extremely important learning signal and codes for prediction errors, and altering its physiological function likely contributes to ketamine-induced perceptual disturbances.
Getting back to the the D2 antagonist blocking the MK-801 increases in locomotor activity, here's another one of those papers:
The effects of typical and atypical neuroleptics on MK-801-induced locomotor activity and stereotyped sniffing were tested. Pretreatment with the typical neuroleptic haloperidol (0.01, 0.05, 0.1, 0.5 mg/kg SC) and the dopamine D2 receptor selective antagonist eticlopride (0.005, 0.01, 0.05 mg/kg SC) each resulted in significant and dose-dependent reductions of locomotor activity and sniffing. The atypical neuroleptic clozapine (1.0, 5.0, 10.0 mg/kg SC) was somewhat unique in that all doses reduced locomotor activity, but only the highest dose (10.0 mg/kg) significantly reduced sniffing.
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Also, if you're interested in how they quantified locomotor activity.
Fifteen minutes following the MK-801 administration, each rat was placed in the center of the open field and was observed for a 1rain period immediately and thereafter at 5min intervals for the remaining 60rain. Locomotor activity was quantified by counting the total number of crossovers a rat made from one of the twelve rectangular areas to another during each 1min observation period. All four paws must have crossed for a crossover to be scored.
And yeah, lots of atypical antipsychotics do block 5-HT2A as well, which is interesting since 5-HT2A antagonists can block locomotor sensitization to ketamine. My personal hunch is that locomotor sensitization contributes to the long-term tolerance that people observe with dissociatives. People generally desire the sedating effects of these substances which become more elusive over time, and all the while the effects become more stimulating. At least that meshes with my personal experience.
Although you probably can't completely dissociate the acute 5-HT2A activation from the desirable effects of dissociatives, I think it may be less of a contributor than other 5-HT receptors. Mainly this is because, from a purely somatosensory standpoint, I think the "5-HT-esque" effects of dissociatives have more in common with something like MDMA rather than psychedelics. Which is to say they are more cuddly and warm, as compared to the somatosensory effects of psychedelics which can be more cold and standoffish.
Mechanistically too, dissociatives would be expected to work on the 5-HT system in a fashion more similar to MDMA, since they would have to increase 5-HT release along endogenously defined pathways. This would be especially important in superficial cortex, where the vast majority of 5-HT synapses are located and signal through 5-HT3 receptors. In contrast, psychedelics activate deeper regions of the cortex which are exposed to lower concentrations of 5-HT due to the absence of 5-HT synapses there.