Schizophrenia is a highly complex neuropsychiatric disorder with heterogeneous symptoms that typically fall into three distinct symptom domains: positive symptoms like hallucinations and delusions, negative symptoms like blunted affect and avolition, and cognitive impairments including deficits in learning, memory, and executive functions. While currently marketed antipsychotics are generally effective at addressing positive symptoms, ∼30% of patients receive no therapeutic benefits from first-line antipsychotic treatment (Nucifora et al., 2019), and these drugs are associated with debilitating side effects, including severe movement disorders like Parkinsonism (characteristic of classical antipsychotics like haloperidol) and metabolic syndromes like weight gain, high cholesterol, and Type 2 diabetes (associated with atypical antipsychotics like olanzapine; Stroup and Gray, 2018). The inadequate efficacy and severe side effects limit adherence to these medications. Therefore, there is a clear need for novel antipsychotic drugs with greater efficacy and more tolerable side effects.
Converging evidence suggests that dopaminergic dysfunction is the final common pathway leading to schizophrenia symptomatology. Specifically, hyperdopaminergic tone in the striatum leads to the activation of dopaminergic D2 receptors and the expression of positive symptoms (Howes et al., 2012). Indeed, all currently marketed antipsychotic drugs antagonize D2 receptors. Dopamine D2 receptors are expressed primarily on a subset of GABAergic medium spiny neurons (MSNs), which make up ∼95% of striatal neurons, and cholinergic interneurons (CINs), which make up ∼1–2% of striatal neurons (Kreitzer, 2009). While D2 receptors on MSNs are thought to be the target responsible for antipsychotic efficacy, recent studies have highlighted the critical importance of D2 receptors expressed on CINs in regulating motor functions and in producing haloperidol-induced catalepsy in mice (Kharkwal et al., 2016), a murine analog of human motor syndromes. Therefore, specifically modulating D …
Correspondence should be addressed to Cassandra J. Hatzipantelis at cjhatzipantelis{at}ucdavis.edu.
