Although in the past, explanations for neuroleptic-induced movement disorders have focused on the dopamine system and basal ganglia, these models have provided insight into only some of the motor side effects of antipsychotic drugs (e.g. Parkinson like syndromes). The problematic management of the motor side effects of neuroleptic drug treatment and the limitations of existing theories and treatments emphasize the need to consider alternatives. One such alternative involves the role of sigma binding sites in the motor side effects of antipsychotic drug treatment. Many neuroleptics have marked affinities for sigma binding sites in addition to their interactions with dopamine receptors. Sigma binding sites in the CNS are found in highest concentration in brainstem motor structures and functional studies have shown that these sites, particularly the sigma-2 subtype, are involved in motor control. In the present proposal, the role of various sigma receptor subtypes in the motor side effects of antipsychotic drugs will be evaluated using a series of radioligand binding, behavioral, and electrophysiological studies. In initial studies, the affinities of neuroleptics for the various sigma subtypes will be evaluated since this information is currently unknown. Next, behavioral and electrophysiological studies will be conducted to evaluate the extent to which neuroleptics affect motor control via brainstem sigma sites. These studies will be conducted in the red nucleus because this structure l) has a well established role in motor control, 2) is rich in sigma receptors but virtually devoid of other receptors with which non-selective sigma ligands interact (e.g. contains almost no dopamine, PCP or opiate receptors), and 3) microinjection of sigma ligands, including haloperidol, into this structure elicits quantifiable dystonic reactions that are mediated through sigma binding sites. To determine whether certain sigma subtypes are preferentially involved in the effects of neuroleptics, the potency of the neuroleptics in producing their functional effects will be correlated with their binding affinities for the different sigma subtypes. A series of drug interaction studies will also be conducted to further assess the contribution of different sigma subtypes in the functional effects of neuroleptics. Finally, the effects of chronic neuroleptic treatment on binding to the different sigma subtypes and the functional ramifications of these changes will be measured.
