The atypical dopamine transporter inhibitor CE-158 enhances dopamine neurotransmission in the prefrontal cortex of male rats: a behavioral, electrophysiological and microdialysis study.

BACKGROUND: Dopamine plays a key role in several physiological functions such as motor control, learning and memory, motivation and reward. The atypical dopamine transporter inhibitor CE-158 has been recently reported to promote behavioral flexibility and restore learning and memory in aged rats.

METHODS: Adult male rats were intraperitoneally administered for 1 or 10 days with CE-158 at the dose of 1 or 10 mg/kg, and tested for extracellular dopamine in the medial prefrontal cortex (mPFC) by means of intracerebral microdialysis and single unit cell recording in the same brain area. Moreover, the effects of acute and chronic CE-158 on exploratory behavior, locomotor activity, prepulse inhibition (PPI), working memory and behavioral flexibility were also investigated.

RESULTS: CE-158 dose-dependently potentiates dopamine neurotransmission in the mPFC as assessed by intracerebral microdialysis. Moreover, repeated exposure to CE-158 at 1 mg/kg is sufficient to increase the number of active pyramidal neurons and their firing frequency in the same brain area. In addition, CE-158 at the dose of 10 mg/kg stimulates exploratory behavior to the same extent after acute or chronic treatment. Noteworthy, the chronic treatment at both doses did not induce any behavioral alterations suggestive of abuse potential (e.g., motor behavioral sensitization) or pro-psychotic-like effects such as disruption of sensorimotor gating or impairments in working memory and behavioral flexibility as measured by PPI and Y maze.

CONCLUSIONS: Altogether, these findings confirm CE-158 as a promising pro-cognitive agent and contribute to assessing its preclinical safety profile in a chronic administration regimen for further translational testing.