First, it's always confusing in the literature when they talk about striatal vs. mesolimbic/nucleus accumbens dopamine because the mesolimbic system and Nucleus accumbens/ventral striatum are PART OF the striatum. Anyways, I have more info now (the tentative answer to your last comment can be found in the last two "my conclusions":
"In vivo microdialysis and electrophysiological techniques were used to elucidate the role of the 5-HT(2) receptor family on the control of mesolimbic dopaminergic system exerted by serotonin (5-HT). Administration of RO 60-0175 (1 mg/kg, i.p.), a selective 5-HT(2C) receptor agonist, significantly decreased dopamine (DA) release by 26+/-4% (below baseline) 60 min after injection. Moreover, RO 60-0175 (80-320 microg/kg, i.v.) dose-dependently decreased the basal firing rate of DA neurons in the ventral tegmental area (VTA), reaching its maximal inhibitory effect (53.9+/-15%, below baseline) after the dose of 320 microg/kg. The selective 5-HT(2C) receptor antagonist SB 242084 completely blocked the inhibitory action of RO 60-0175 on accumbal DA release and on the firing rate of VTA DA cells. On the contrary, both (+/-)-DOI, a mixed 5-HT(2A/2C) receptor agonist, and the selective 5-HT(2B) agonist BW 723C86, did not affect either DA release in the nucleus accumbens or the firing rate of VTA DA cells. Taken together, these data confirm that central 5-HT system exerts an inhibitory control on the mesolimbic DA system and that 5-HT(2C) receptors are involved in this effect."
My conclusion: 5-ht2c agonism alone will decrease mesolimbic dopamine. BUT 5-h2a+2c agonism together will not affect mesolimbic dopamine.
"In conclusion, we have demonstrated that a selective 5-HT2C receptor antagonist does not produce rewarding effects by itself, but can potentiate the positive CPP produced by a low dose of amphetamine. These results indicate that selective 5-HT2C receptor antagonists developed for depression and anxiety could lead to abuse if given in combination with medications that have psychostimulant-like properties. Furthermore, this study illustrates the need for extensive study of 5-HT2C receptor drugs using conditioned place preference or other tests of reward, with concomitant study of dopamine release and dopamine releasing drugs."
My conclusion: 5-ht2c antagonists on their own do not increase mesolimbic dopamine, but when combined with low-dose amphetamine (and potentially other stimulants) it will increase it. I guess we can assume that it will increase it with high dose amphetamine as well. This contradicts what I posted in my last comment, although it was a 5-ht2c+2b antagonist in the last comment, not just 5-ht2c. Maybe the 5-ht2b antagonism has an impact.
The effects of (±)-DOI (1-(2,5-dimethoxy-4-iodophenyl)-aminopropane) hydrochloride, a mixed 5-HT2A/2C receptor agonist, on the release of dopamine (DA) following d-amphetamine sulfate (AMP) or a DA D2 autoreceptor selective dose of (−)-apomorphine hydrochloride (APO), were investigated in rat striatum (STR) and nucleus accumbens (NAC), using in vivo microdialysis. AMP (1.0 mg/kg, s.c.) produced marked increases in extracellular DA levels in both the STR and the NAC whereas DOI (2.5 mg/kg, i.p.) alone had no significant effect on extracellular DA levels in either region. Pretreatment with DOI 30 min prior to AMP, further enhanced the AMP-induced increase in striatal extracellular DA levels. On the other hand, DOI pretreatment attenuated the APO (50 μg/kg, s.c.)-induced decrease in extracellular DA levels in the STR. Pretreatment with DOI did not affect the ability of either AMP or APO to modulate extracellular DA levels in the NAC. These results provide further evidence that 5-HT2A/2C receptors modulate the release mechanisms of DA in the STR. Possible mechanisms are discussed.
My conclusion: 5-ht2a+2c (together) agonism alone will not increase dopamine in the striatum or NAC/mesolimbic system. 5-ht2a+2c (together) agonism combined with amphetamine potentiates amphetamine-induced dopamine release in the striatum but has not effect on amphetamine-induced dopamine increase in the NAC.
The 5-HT2A agonists DOI and LSD did not produce amphetaminelike responding at any dose tested or time of administration. Simultaneous administration of DOI or LSD with amphetamine was not significantly different from the response produced by amphetamine alone. Preadministration of DOI (3 hours) or of LSD (2 hours) before amphetamine, however, evoked significant enhancement of the amphetamine cue. The results suggested that the enhanced behavioral response to amphetamine may be due either to an increased sensitivity of dopaminergic neurons in the mesolimbic area, or to an enhanced release of dopamine by amphetamine. These studies all show that activation of the 5-HT2A receptor can enhance the response to a drug that produces indirect release of dopamine from neuron terminals. Whether or not these findings would extrapolate to schizophrenia is at present an unknown, but highly relevant issue. If basal dopaminergic tone is enhanced through some pathological process, will the activation of serotonin systems further amplify dopaminergic function? Enhanced efficacy of antipsychotic agents possessing 5-HT2A antagonist activity certainly suggests a parallel to the studies cited above.
My conclusion: DOI and LSD are 5-ht2a+2c agonists, not just 5-ht2a. So, 5-ht2a+2c agonism seem to have the potential to be able to potentiate amphetamine-induced dopamine release in the mesolimbic system (NAC), contradicting the study above. Would 5-ht2a agonism alone be able to do that, I don't know. Couldn't find any research on it online...
"Subjects receiving 5-HT2A agonists report a range of experiential phenomena. Most common are hallucinations, synesthesia, and ego dissolution: the experience of a diminished sense of self; Nour et al., 2016; Tagliazucchi et al., 2016)." "Studies utilizing 5-HT2A agonists raise legitimate ethical and safety concerns due to risks associated with their hallucinogenic properties."
My conclusion: In the article from which I took this quote, not once do they mention "dopamine"... 5-ht2a agonists (that includes a lot of psychedelic drugs) are not famous for inducing effects similar to psychostimulants or for being addictive, meaning that they don't seem to be increasing mesolimbic dopamine, which is the mechanism by which most drugs are thought to be addictive). They are famous for inducing hallucinogenic and transcendental effects. Does 5-ht2a agonism have the potential to indirectly end up affecting mesolimbic dopamine? I don't know for sure but I'd say maybe since psychedelic drugs led me to develop psychosis, and have done it for many other schizophrenics. Psychosis is thought to be related mainly to increased mesolimbic dopamine activity (although I think as of today that they have discovered other mechanisms which might lead to psychotic symptoms), so I guess 5-ht2a agonism could potentially end up affecting mesolimbic dopamine, at least in people genetically vulnerable to mental illnesses like schizophrenia.
"5-HT2A receptors located on dopaminergic and/or GABAergic neurons within the striatum and nucleus accumbens might provide an anatomical substrate for a serotonin-mediated psilocybin-induced dopamine release (Palacios et al. 1991)." ### "The serotonin agonist psilocybin binds with high affinity at 5-HT2A (Ki = 6 nM) and to a lesser extent at 5-HT1A (Ki = 190 nM) (McKenna et al. 1990) receptors." "Since psilocybin also acts upon 5-HT1A receptors (Buckholtz et al. 1990; McKenna et al. 1990) and stimulation of 5-HT1A autoreceptors is expected to enhance the dopaminergic tone (Neal-Beeliveau et al. 1993), one might speculate that psilocybin increases striatal dopamine release through a concomitant stimulation of both 5-HT1A and 5-HT2Areceptors. This hypothesis is supported by the finding that 5-HT1A agonists can facilitate dopamine release in the striatum and nucleus accumbens (Benloucif and Galloway 1991), while 5-HT1A antagonist have been reported to inhibit dopamine release in these brain regions (Parson and Justice 1993; Boulenguez et al. 1996; Nomikos et al. 1996)." ### "Nevertheless, the present findings suggest that stimulation of 5-HT, presumably 5-HT2 and 5-HT1 receptors, can lead to an increase in striatal dopamine efflux which may contribute to the psychotomimetic effects of psilocybin. Of particular interest to the present study are indications that abnormalities in the number of 5-HT1A and 5-HT2A receptors have been found in the frontal cortex, nucleus accumbens, striatum, and hippocampi of schizophrenic patients (Mita et al. 1986; Arora and Meltzer 1991; Joyce et al. 1993; Laruelle et al. 1993; Gurevich and Joyce 1997)." ### "Thus, it may be argued that, in psilocybin psychosis, specifically those aspects of psychotic symptoms related to euphoria and alertness may be mediated by striatal dopamine release, but that striatal dopamine release alone cannot account for the occurrence of psilocybin-induced psychotic symptoms. In this respect, it is of note that haloperidol had virtually no effect on psilocybin-induced hallucinations (VUS) and even increased anxious ego-dissolution (AIA) in psilocybin subjects, while ketanserin, a preferential 5-HT2A receptor antagonist, dose-dependently prevented psilocybin psychosis (Vollenweider et al. 1998)." ### " Furthermore, consistent with this possibility, we recently found that the D2 antagonist haloperidol attenuated psilocybin-induced depersonalisation, derealisation and euphoria (Vollenweider et al. 1998)."
My conclusion: We cannot know how much of the 5-ht1a agonism vs 5-ht2a agonism is responsible for euphoric symptoms (i.e. indirect increase in mesolimbic dopamine) in the psilocybin mushroom experience (I guess psychedelic drugs can induce euphoria and in that regard be similar to psychostimulants after all). Psychosis induced by psilocybin was prevented by 5-ht2a antagonism alone so I guess it's safe to say that 5-ht2a plays a large role in the overall psychosis induced by the drug (including the euphoria I guess)
Edited by Ihaveanhedonia, 10 October 2017 - 02:40 AM.