Opposite effects of tolcapone on amphetamine-disrupted startle gating in low vs. high COMT-expressing rat strains

Differential sensitivity to the prepulse inhibition (PPI)-disruptive effects of dopamine agonists in Sprague–Dawley (SD) vs. Long Evans (LE) rats is heritable, reflects differential activation of DA signaling, and is associated with differences in the brain expression of specific genes, including those of the catecholamine catabolic enzyme, catechol-O-methyltransferase (COMT). In humans, both basal and drug-modified PPI differs significantly between individuals with polymorphisms conferring low- vs. high-activity of COMT. We used the COMT inhibitor, tolcapone, to assess the role of COMT activity in regulating the differential effects of the dopamine releaser, amphetamine (AMPH), on PPI in SD and LE rats. Acoustic startle and PPI were assessed in SD and LE male rats after pretreatment with tolcapone (vehicle vs. 30mg/kg ip) and treatment with AMPH (vehicle vs. 4.5mg/kg sc), using 10–120ms prepulse intervals. After tolcapone, AMPH significantly potentiated PPI in LE rats, and significantly disrupted PPI in SD rats. These patterns could not be explained by drug effects on pulse alone startle magnitude. The impact of COMT inhibition on AMPH-modified PPI was categorically different in strains exhibiting low vs. high levels of forebrain Comt expression, consistent with reports in humans that tolcapone has opposite effects on PPI among individuals with polymorphisms conferring low vs. high COMT activity. The present model provides a basis for understanding the mechanisms by which the effects of COMT inhibition on sensorimotor gating – and potentially, related neurocognitive and clinical functions – under hyperdopaminergic states are dependent on an individual's basal levels of COMT activity. •Tolcapone has opposite cognitive effects in humans with low vs. high COMT activity.•Here, tolcapone had opposite effects on amphetamine-modified PPI in two rat strains.•These strains have low vs. high Comt expression in brain regions that regulate PPI.•This model may clarify genotype-specific cognitive effects of tolcapone in humans.•This in turn will inform the procognitive uses of tolcapone in schizophrenia.