The effects in rats of lisdexamfetamine in combination with olanzapine on mesocorticolimbic dopamine efflux, striatal dopamine D2 receptor occupancy and stimulus generalization to a d-amphetamine cue

• Lisdexamfetamine and olanzapine increased dopamine efflux in cortex and accumbens more than either drug individually.
• Lisdexamfetamine did not affect olanzapine's ability to block striatal D2 receptors.
• The ability of lisdexamfetamine to generalize to a d-amphetamine cue was attenuated by olanzapine.

The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine's ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine.