Acute ketamine withdrawal disrupts memory and monoaminergic neurotransmission in adolescent female rats

Abstract

Adolescence is a period of profound behavioral changes associated with high brain vulnerability to negative stimuli including psychotropic drugs misuse which may contribute to the development of psychiatric disorders. Ketamine, an NMDA receptor antagonist, is an anesthetic agent used in a recreational manner in night clubs and raves, especially by intranasal route. The psychedelic effects of ketamine include euphoria, reward and mood swings, leading to an altered state of consciousness. Ketamine use has increased among adolescents and young adults, becoming a relevant global public health concern. At these events, drug consumption is often episodic but intense, which may disrupt diverse neuromodulation processes leading to behavioral impairments. Here, we investigated the mnemonic consequences of ketamine withdrawal following recreational exposure in adolescent female rats. To mimic weekend recreational use, adolescent female Wistar rats (n = 8 animals per group) received intranasal ketamine or saline (10 mg/kg/day) for three consecutive days. Twenty-four hours after the last ketamine administration, animals were submitted to a battery of behavioral tasks including novel object recognition, social recognition and Y-maze paradigms to assess episodic, social and working memories. Hippocampal and prefrontal cortex samples were collected for neurochemical analysis. Early ketamine withdrawal following acute exposure impaired all memory types evaluated in the current study. Additionally, a significant reduction in serotonin and norepinephrine levels were observed in the hippocampus and prefrontal cortex of ketamine exposure rats. These findings indicated cognitive and monoaminergic impairments in adolescent female rats at early ketamine withdrawal periods following acute exposure.