Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transporter-mediated monoamine efflux with weak to no activity at pre- or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS

Chronic psychostimulant exposure to adult, but not periadolescent rats reduces subsequent morphine antinociception

Preweanling methylphenidate (MPH) exposure produces a long lasting enhanced sensitivity to opioids. Two important questions are whether this enhancement is specific to the age of psychostimulant exposure and the type of psychostimulant. To answer these questions periadolescent (PD 35) and adult (PD 55) rats received daily injections of saline, MPH, or methamphetamine (METH) for 10 consecutive days. Two weeks later, acute morphine antinociception was assessed on the hot plate using a cumulative dose response procedure. Following acute antinociceptive testing, morphine tolerance was induced in half the animals by administering morphine twice a day over two days. Rats pretreated with MPH and METH during the periadolescent period of ontogeny showed no change in acute morphine antinociception, but rats exposed to a relatively high METH dose (3 mg/kg) displayed enhanced morphine tolerance compared to saline pretreated controls. MPH and METH pretreatment during adulthood led to a reduction in morphine antinociceptive potency and an apparent reduction in morphine tolerance. When combined with our previously published findings, these data indicate that the developmental stage during which MPH and METH exposure occurs differentially alters adult morphine responsiveness. That is, psychostimulant exposure to preweanling rats enhances morphine antinociception and facilitates the development of tolerance, whereas psychostimulant exposure to adult rats reduces subsequent morphine antinociception and tolerance. These alterations indicate that it could be important for physicians to know about prior psychostimulant use when prescribing opioids for pain relief