Single binge dosing of 4-Methylethcathinone (4-MEC) induces sturdy and durable cognitive impairment in mice

Synthetic cathinones (SC), the second largest class of New Psychoactive Substances monitored by the EMCDDA, are derivatives of the naturally occurring beta-ketone amphetamine analogue found in the leaves of khat plant (Catha edulis). Their similitude of psycho-/stimulant effects to those of methylenedioxy-methamphetamine (MDMA), amphetamines and cocaine make them to be often used as substitutes. According to users, ingestion of these SC usually produces fast-acting but short-lived stimulant effects, hence inducing higher desire of redosing and potential risk of overdosing. Current information on the short- and long-term cognitive function implications arising from SC use remains limited, and even scarcer when frequent administration during a single exposure event (binge exposure) is thought.

Therefore, the aim of this study was to evaluate the cognitive effects of SC arising from this type of binge exposure. Hence, the short and long-term effect on learning/memory ability of mice exposed to SC single binge was evaluated by the Morris watermaze (WM) a specific test used to evaluate spatial learning and memory effects in rodents.

The popular ring-substitute cathinone 4-Methylethcathinone (4-MEC), a SC heavily marketed at the beginning of the 2010s as mephedrone substitute, and described as weaker and short lived usually leading to more frequent administrations compared to mephedrone, was selected to be studied. The 4-MEC single-binge (2x64mg/kg, 2h interval) induced learning/memory effects assessed in a WM setup starting 24h after binge session. Animals were trained in the WM, which consisted of a circular pool (100cm diameter) filled with water (22±1°C). Four positions around the edge of the tank, designated as north (N), south (S), east (E), and west (W), were dividing the tank into 4 quadrants: NE, SE, SW, and NW, providing alternative start positions. A platform (9cm diameter), always located in the SW quadrant, was submerged. Mice received a training session during 5 days, consisting of four trials/day using a semi-random set of start locations. On the D6 a probe trial (no platform) was conducted. The path taken by each mouse and the escape latency (the time needed by each mouse to find the platform, in s) was video-recorded. The results show that 4-MEC single binge induced significant gap in scape latency from D2 onwards compared with controls, and even when trained 25 days post exposure no significant recover was observed in learning ability. This leaning impairment compromised the memory score of exposed mice at short-/lÁlvaroong-term. In conclusion, 4-MEC-binge exposure induced short-term learning/memory impairment, which was sustained for long-term. These results suggest a potential risk of sustained cognitive impairment from binge exposure to SC, hence its use may pose a considerable cognitive and mental health concern.