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Synthetic cathinones (SCs) are β‐keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5‐HT(2A) receptors (5‐HT(2A)R) and muscarinic M(1) receptors (M(1)R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M(1)R (minimal displacement of [~K(d)] [3H]scopolamine up to 10 μM). However, two SCs, α‐pyrrolidinopropiophenone (α‐PPP) and 4‐methyl‐α‐PPP, had low μM K(i) values at 5‐HT(2A)R. In 5‐HT(2A)R–phosphoinositide hydrolysis assays, α‐PPP and 4‐methyl‐α‐PPP displayed inverse agonist activity. We further assessed the 5‐HT(2A)R functional activity of α‐PPP, and observed it competitively antagonized 5‐HT(2A)R signaling stimulated by the 5‐HT(2)R agonist (±)‐2,5‐ dimethoxy‐4‐iodoamphetamine (DOI; K(b) = 851 nM). To assess in vivo 5‐HT(2A)R activity, we examined the effects of α‐PPP on the DOI‐elicited head‐twitch response (HTR) in mice. α‐PPP dose‐dependently blocked the HTR with maximal suppressiont 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α‐PPP. To corroborate a 5‐HT(2A)R mechanism, we also tested 3,4‐methylenedioxy‐α‐PPP (MDPPP) and 3‐bromomethcathinone (3‐BMC), SCs that we observed had 5‐HT(2A)R K(i)s > 10 μM. Neither MDPPP nor 3‐BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α‐PPP has antagonist interactions at 5‐HT(2A)R in vitro that may translate at physiologically‐relevant doses in vivo. Considering 5‐HT(2A)R antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α‐PPPs unpopularity compared to other monoamine transporter inhibitors.

Parkinson’s Disease (PD) is the second most common neurodegenerative disease throughout the United States. Dopamine (DA) Replacement Therapy is the standard treatment for the motor symptoms of PD. ...

USPHS National Institute on Drug Abuse National Institute on Alcohol Abuse and Alcoholism The objective of the present study was to further elucidate the mechanisms involved in the wake-promoting effects of psychomotor-stimulants. Many previous studies have tightly linked the effects of stimulants to dopamine neurotransmission, and some studies indicate that serotonin 2A receptors modulate these effects. However, the role of dopamine in arousal is controversial, most notably because dopamine neurons do not change firing rates across arousal states. in the present study, we examined the wake-promoting effects of the dopamine-releaser amphetamine using non-invasive telemetric monitoring. These effects were evaluated in rhesus monkeys as a laboratory animal model with high translational relevance for human disorders of sleep and arousal. To evaluate the role of dopamine in the wake-promoting effects of amphetamine, we used in vivo microdialysis targeting the caudate nucleus, as this approach provides clearly interpretable measures of presynaptic dopamine release. This is beneficial in the present context because some of the inconsistencies between previous studies examining the role of dopamine in arousal may be related to differences between postsynaptic dopamine receptors. We found that amphetamine significantly and dose-dependently increased arousal at doses that engendered higher extracellular dopamine levels. Moreover, antagonism of serotonin 2A receptors attenuated the effects of amphetamine on both wakefulness and dopamine overflow. These findings further elucidate the role of dopamine and serotonin 2A receptors in arousal, and they suggest that increased dopamine neurotransmission may be necessary for the wake-promoting effects of amphetamine, and possibly other stimulants. Yerkes Natl Primate Res Ctr, Div Neuropharmacol & Neurol Dis, Atlanta, GA USA Universidade Federal de São Paulo UNIFESP, Dept Psicobiol, São Paulo, Brazil NIDA, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA NIAAA, NIH, Bethesda, MD USA Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA Universidade Federal de São Paulo UNIFESP, Dept Psicobiol, São Paulo, Brazil USPHS: DA010344 USPHS: DA012514 USPHS: RR000165 Web of Science

The central dogma of pharmacology posits that ligands that function as agonists of a protein receptor will activate all effectors coupled to that receptor in equal proportions. A new conceptualizat...