Baseline prepulse inhibition expression predicts the propensity of developing sensitization to the motor stimulant effects of amphetamine in C57BL/6 mice

Rationale

The startle reflex to a sudden intense acoustic pulse stimulus is attenuated if the pulse is shortly preceded by a weak prepulse stimulus. This represents a form of sensory gating, known as prepulse inhibition (PPI), observable across species. PPI is modulated by dopamine and readily disrupted by acute amphetamine. Prior repeated exposures to amphetamine also disrupt PPI even when the drug is not present during test, suggesting that a sensitized mesolimbic dopamine system—inducible even by a single exposure to amphetamine—might be responsible. However, this causative link has been challenged by inconsistent efficacy between different amphetamine pre-treatment regimes, which all robustly sensitize the behavioral response to amphetamine.

Methods

Here, the presence of such a link in reverse was tested by comparing the propensity to develop amphetamine sensitization between high- and low-PPI expressing individuals identified within a homogeneous cohort of C57BL/6 mice. Comparison of dopamine content including its metabolites was performed separately in drug naïve mice by post-mortem HPLC.

Results

Behavioral sensitization was substantially stronger in the low-PPI group compared with the high-PPI group, while the magnitude of their response to the first amphetamine challenge was similar. Dopamine content within the nucleus accumbens and medial prefrontal cortex was significantly higher in low-PPI relative to high-PPI mice.

Conclusion

Individuals with weak sensory gating characterized by low basal PPI expression may be more susceptible to the development of dopamine sensitization and therefore at greater risk of developing schizophrenia. Conversely, high baseline expression might predict a resistance to dopaminergic sensitization.