LSD as a DA/NE partial agonist and MK801/PCP/Ketamine as a D2 agonist

[nuke]

Been thinking more about LSD and dopamine and psychosis and antipsychotics and stumbled on some papers. It seems that LSD is not a full agonist and blocks the effects of endogenous dopamine and norepinephrine to some extent. This is from a very old study from nature. My thought is, if LSD has such a high affinity for D2 receptors, why hasn't anyone bothered producing an ultrapotent antipsychotic D2 antagonist from an ergoline? Structural alterations make the effects on serotonin easy to abolish (or perhaps a 5HT2A antagonizing effect could also be added).

What's also surprising is how high an affinity dizocilpine has for dopamine and how it induces a hyperlocomotive effect that is blockable by haloperidol and clozapine (especially clozapine, making it an intriguing model for schizophrenia as clozapine has the highest efficacy for the disorder). However, the use of dizocilpine in humans has been described as inherently dysphoric despite having an apparently strong effect at D2 (the dopamine receptor implicated in schizophrenia). These are affinities for the receptors themselves though rather than reuptake, however these affinities in PCP and ketamine are both similarly much greater than their NMDA receptor affinities, with also greater ratios of DA:NMDA than dizocilpine. PCP and ketamine both also appear to be D2 agonists, so perhaps the abuse potential of both the drugs is not with their effect on the dopamine transporter but rather the ratio of D2 binding and agonism to NMDA binding and antagonism. However, another study from nature reports different binding/affinity.

Also interesting is the following from that nature study:
"When S-ketamine was compared to its racemic mixture in parallel runs, S-ketamine showed a two- to three-times higher affinity for both the high-state of the dopamine D2 receptor defined by [3H]raclopride (0.7 ± 0.3 M vs 2.3 ± 0.3) as well as for the NMDA receptor defined by [3H]-MK-801 (0.5 M vs 1.4 uM)."

DXM (dextromethorphan) is not known for its dopaminergic effect and may be why it has a somewhat lower abuse potential.

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocllpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2High, their dissociation constants (K,) were obtained on [3H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2High with a Ki of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a K, of 313nM, as labeled by [3H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2High with a Ki of 55 nM, an affinity higher than its 3100 nM Ki for the NMDA sites. Dizocilpine had a K, of 0.3 nM at D2High, but a Kd of 1.8 nM at the NMDA receptor. LSD had a K, of 2 nM at D2High. Because the psychotomimetics had higher potency at D2High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given In vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis.

http://cat.inist.fr/?aModele=afficheN&cpsidt=17042427

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors implications for models of schizophrenia

Ketamine and PCP are commonly used as selective NMDA receptor antagonists to model the putative hypoglutamate state of schizophrenia and to test new antipsychotics. Recent findings question the NMDA receptor selectivity of these agents. To examine this further, we measured the affinity of ketamine and PCP for the high-affinity states of the dopamine D2 and serotonin 5-HT2 receptor and found that ketamine shows very similar affinity at the NMDA receptor and D2 sites with a slightly lower affinity for 5-HT2 (0.5 M, 0.5 M and 15 M respectively), while PCP shows similar affinity for the NMDA and 5-HT2 sites, with a slightly lower affinity for the D2 site (2 M, 5 M and 37 M respectively). Further, ketamine and PCP in clinically relevant doses caused a significant increase in the incorporation of [35S]GTP--S binding in CHO-cells expressing D2 receptors, which was prevented by raclopride, suggesting a partial agonist effect at the D2 receptor. Thus, ketamine and PCP may not produce a selective hypoglutamate state, but more likely produce a non-selective multi-system neurochemical perturbation via direct and indirect effects. These findings confound the inferences one can draw from the ketamine/PCP models of schizophrenia.

Ketamine had an affinity (Ki of 1.0 ± 0.2 M for the dopamine D2receptors (using [3H]raclopride and striatal tissue) and an affinity of 0.5 ± 0.2 M (using cloned receptors and [3H]-dopamine). This was comparable to its affinity for the NMDA receptors labeled with [3H]MK-801 (0.5 ± 0.15 M). Ketamine also showed appreciable affinity for the high-affinity state of the serotonin 5-HT2 receptors (15 ± 5 M) (Figure 2). When S-ketamine was compared to its racemic mixture in parallel runs, S-ketamine showed a two- to three-times higher affinity for both the high-state of the dopamine D2 receptor defined by [3H]raclopride (0.7 ± 0.3 M vs 2.3 ± 0.3) as well as for the NMDA receptor defined by [3H]-MK-801 (0.5 M vs 1.4 uM).

PCP showed a similar high-affinity for the high-affinity state of the serotonin 5-HT2 receptors (5 ± 2 M), as it did for the NMDA receptor as labeled with [3H]MK-801 (2 ± 0.5 M) (Figure 3). And while its affinity for the D2 receptor was relatively lower (37 ± 10 M), it is still high enough to preclude selectivity at clinically relevant concentrations.

When cloned D2 receptors were exposed to ketamine and PCP they showed a significant, dose-dependent increase in the binding of [35S]GTP--S with an EC50 of 0.9 ± 0.4 M for ketamine and 4 ± 1 M for PCP (Figure 4). This increase was selective for CHO cells expressing the D2 receptors and was not seen in cells without D2 receptors. The increase for ketamine was in the range of 80% of that produced by dopamine, while that of PCP was in the range of 50% of the dopamine effect, suggestive of a partial agonist effect in this functional assay. The addition of raclopride dose-dependently (EC50 2-5 nM) reversed this incorporation induced by ketamine and PCP, consistent with this incorporation being mediated selectively via the D2 receptor.

http://www.nature.com/mp/journal/v7/n8/full/4001093a.html

Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice

Direct or indirect stimulation of dopamine receptors increases locomotor activity in mice. Determining the role played by D1 and D2 dopamine receptors in the mediation of this activity can be difficult due to the wide variety of experimental paradigms used to investigate these phenomena. Objectives: This study set out to compare the role of selective antagonism of dopamine D1 and D2 receptors on the hyperactivity induced by a range of stimulants. Methods: Mice were habituated to perspex locomotor activity boxes (30×30× 30 cm) and activity was measured via photobeam interrupts. Results: Haloperidol and clozapine both reduced the hyperactivity induced by MK-801. Haloperidol did so only at a dose that also decreased spontaneous activity (0.1 mg/kg), whereas clozapine reduced MK-801-induced hyperactivity at a dose that had no effect on spontaneous activity (1.25 mg/kg). The D1 antagonist SCH23390 (0.01 mg/kg) reduced hyperlocomotion induced by amphetamine (2.5 mg/kg), cocaine (10 mg/kg) and C-APB (1.0 mg/kg) at doses that did not consistently alter spontaneous activity, whereas the selective D2 antagonist raclopride only attenuated the hyperlocomotion induced by amphetamine, cocaine and C-APB at doses in excess of the minimum dose required to attenuate spontaneous locomotor activity significantly. The latency to peak levels of hyperlocomotion induced by MK-801 (0.3 mg/kg) was delayed by SCH23390 (0.1 mg/kg) but peak levels of activity were not reduced. Conclusions: The results of the present study suggest that selective blockade of D1 receptors suppresses amphetamine and cocaine-induced hyperactivity in mice but not MK-801-induced locomotor activity.

http://www.springerlink.com/content/n65wx15kvq7h822f/

Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia

It has previously been reported that the glutamate ionotropic antagonist phencyclidine directly inhibits the release of prolactin in anterior pituitary cells in culture, suggesting that phencyclidine has a dopamine (DA)-like action on prolactin-releasing cells. It has also been reported that the glutamate metabotropic agonist LY379268 can stimulate the incorporation of [35S]GTP--S into DA D2Long receptors. The present study was done to examine whether such glutamatergic drugs had similar actions on the DA D2Short receptor. The present results show that phencyclidine, ketamine, and LY379268 also stimulated the incorporation of [35S]GTP--S into D2Short receptors. The proportion of D2Long and D2Short receptors existing in the high-affinity state were both markedly reduced by NaCl. While phencyclidine and LY379268 each stimulated the incorporation of GTP--S into D2Long and D2Short receptors, this stimulation was reduced by NaCl, with D2Short being much more sensitive than D2Long to the inhibition by NaCl. The binding of phencyclidine and LY379268 to D2High receptors in vivo was directly confirmed by the i.v. injection of phencyclidine and LY379268 in which 50% inhibited the binding of [3H]PHNO to the striatum ex vivo at 0.25 and 1.5 mg/kg, respectively. The results confirm that glutamate agonists and antagonists have a significant affinity for DA D2High receptors. The psychotogenic action of phencyclidine may stem from a combination or synergistic action of glutamate receptor antagonism and DA D2 agonism. In addition, the antipsychotic clinical action of LY379268 congeners such as LY404039 may be related to a combined or synergistic action of glutamate receptor stimulation together with a partial DA agonist action that reduces endogenous DA neurotransmission. Synapse 62:819-828, 2008. © 2008 Wiley-Liss, Inc.

http://www3.interscience.wiley.com/journal/121384062/abstract?CRETRY=1&SRETRY=0

LSD as an agonist and antagonist at central dopamine receptors.
Nature 1974
von Hungen K, Roberts S, Hill DF
Agonistic and antagonistic activities of D-LSD (D-lysergic acid diethylamide) at cerebral dopamine receptors were studied. Method The effects of D-LSD, L-LSD and 2-bromo-D-lysergic acid diethylamide (BOL) on the activation of adenyl cyclase induced by L-noradrenaline plus dopamine and those of D-LSD, chlorpromazine, haloperidol, i-methyl-D-lysergic acid diethylamide (MLD), BOL, propranolol or cyproheptadine on dopamine- and D-LSD-induced activation of adenyl cyclase were determined in particulate fractions from cerebral cortex or corpus striatum of male rats (-6 weeks, 225 g). Results The conversion of 14G-ATP to cyclic AMP (i.e. the adenyl cyclase activity) was completely blocked by 10 M D-LSD, and 10 M dopamine plus 10 M noradrenaline had additive effects on adenyl cyclase activity. The response to dopamine and noradrenaline was also inhibited by 10 M BOL. The stimulation of the enzyme activity by either dopamine or noradrenaline was also inhibited by L-LSD in particulate hippocampal preparations from rat--brain. Although hypothalamic, brain stem and cerebellar cell-;free fractions did not Show any activation of adenyl cyclase activity in response to D-LSD, this effect could be elicited in cell-free fractions obtained from striatal tissue with very low D-LSD concentrations (0.1 M). 10 M D-LSD was about half as effective in enhancing enzyme activity in particulate preparations from corpus striatum of adult rats as equimolar doses of dopamine. 10 M of D-LSD, however, completely abolished the effects of 10 M dopamine. 10 M of chlorpromazine or haloperidol, 100 M of BOL or MAD or cyproheptadine almost completely abolished the effects of equimolar doses of either D-LSD or dopamine. D-LSD or dopamine-induced enhancement of adenyl cyclase in striatal tissue was not inhibited by propranolol The enzyme activity in striatal tissue was not stimulated by any of the blocking agents themselves, except D-LSD.

 

[grue]

The very interesting NMDA partial antagonist memantine also possesses D2High agonist activity, similar in magnitude to its affinity for NMDA antagonism by at least one report.

It's odd (I say this not "seeing" the chemical kinetics) that all of these NMDA molecules also have an affinity for D2. I believe that NMDA antagonism is generally going to provoke dopamine release as a downstream effect. I wonder if it is somehow possible that the D2 agonism is simply a relic of this. Not possible, you will assert though...?

DXM (dextromethorphan) is not known for its dopaminergic effect and may be why it has a somewhat lower abuse potential.

DXM is sometimes asserted to block the dopamine reuptake transporter; I haven't actually seen any data on this. I actually, personally, tend to find DXM considerably more euphoric (and stimulant-like) than ketamine (or memantine, alone); I haven't had a chance to take PCP or MK-801.

 

[fastandbulbous]

It's odd (I say this not "seeing" the chemical kinetics) that all of these NMDA molecules also have an affinity for D2. I believe that NMDA antagonism is generally going to provoke dopamine release as a downstream effect. I wonder if it is somehow possible that the D2 agonism is simply a relic of this. Not possible, you will assert though...?

Well if you view the arylcyclohexylamine derivatives as being derivatoives if benzylamine, you only have to look at BZP to highlight any dopaminergic effects

 

[hugo24]

Shit I haven't seen this before.Guess I haven't consumed any psychedelic for too long 8) . Or I have reached the same biblical age as f&b where every brain cell is holy

There comes Another memory back,I remember seeing compounds made for obesity projects which had the Phencyclidin structure but the piperidine replaced by a piperazine (plus a rest but the structures are property).Interesting.

 

[LuxEtVeritas]

have you used memantine recreationally and if so please relate details...?

DXM is sometimes asserted to block the dopamine reuptake transporter; I haven't actually seen any data on this. I actually, personally, tend to find DXM considerably more euphoric (and stimulant-like) than ketamine (or memantine, alone); I haven't had a chance to take PCP or MK-801.

 

[kaskelot]

The very interesting NMDA partial antagonist memantine also possesses D2High agonist activity, similar in magnitude to its affinity for NMDA antagonism by at least one report.

It's odd (I say this not "seeing" the chemical kinetics) that all of these NMDA molecules also have an affinity for D2. I believe that NMDA antagonism is generally going to provoke dopamine release as a downstream effect. I wonder if it is somehow possible that the D2 agonism is simply a relic of this. Not possible, you will assert though...?



DXM is sometimes asserted to block the dopamine reuptake transporter; I haven't actually seen any data on this. I actually, personally, tend to find DXM considerably more euphoric (and stimulant-like) than ketamine (or memantine, alone); I haven't had a chance to take PCP or MK-801.

So this could be one way to explain some of the antidepressive effects that some people use ketamine and DXM for?

I recall seeing someone here on BL promoting ketamine as an antidepressant, my memory does not do my wishes at this moment though. In low recreational doses DXM is pretty stimulant in me.

Interesting thread.

 

[nuke]

So this could be one way to explain some of the antidepressive effects that some people use ketamine and DXM for?

I recall seeing someone here on BL promoting ketamine as an antidepressant, my memory does not do my wishes at this moment though. In low recreational doses DXM is pretty stimulant in me.

Interesting thread.

Yes, I think Jamshyd was the one who had the ketamine regimen. I use DXM in low doses to deal with anxiety and depression, though for me it's not really euphoric or stimulating but it is anxiolytic.

It's hard to see how DXM works at dopamine yet but my thoughts are that it is a partial agonist or ineffective at the dopamine receptor because it can antagonize the dopaminergic effect of other drugs. Its DAT and D2 affinity have not been extensively evaluated as far as I know, though.

It's very weird that s-ketamine would be greater at both receptors in an equivalent amount; D2R and NMDAR (and DAT) are either very promiscuous or very close in structure or both.