Making Sense of: Sensitization in Schizophrenia

Abstract

Sensitization is defined as a process whereby repeated intermittent exposure to a given stimulus results in an enhanced response at subsequent exposures. Next to robust findings of an increased dopamine synthesis capacity in schizophrenia, empirical data and neuroimaging studies support the notion that the mesolimbic dopamine system of patients with schizophrenia is more reactive compared with healthy controls. These studies led to the conceptualization of schizophrenia as a state of endogenous sensitization, as stronger behavioral response and increased dopamine release after amphetamine administration or exposure to stress have been observed in patients with schizophrenia. These findings have also been integrated into the neurodevelopmental model of the disorder, which assumes that vulnerable neuronal circuits undergo progressive changes during puberty and young adulthood that lead to manifest psychosis. Rodent and human studies have made an attempt to identify the exact mechanisms of sensitization of the dopaminergic system and its association with psychosis. Doing so, several epigenetic and molecular alterations associated with dopamine release, neuroplasticity, and cellular energy metabolism have been discovered. Future research aims at targeting these key proteins associated with sensitization in schizophrenia to enhance the knowledge of the pathophysiology of the illness and pave the way for an improved treatment or even prevention of this severe psychiatric disorder.

Keywords: PHNO; amphetamine; dopamine; positron emission tomography; psychosis.

Figure 1.

Sensitization leads to an increase in drug effects. The dose of a drug producing half-maximal response (ED50) decreases with sensitization, so that a lower dose is needed to produce half-maximal drug effects (ED50S). Alternatively, the original ED50 will cause larger effects in the sensitized state. The opposite is found in tolerance, where the efficiency of a drug decreases and a higher dose (ED50T) is now needed to produce half-maximal effects, or where the original ED50 will now induce smaller effects.

Figure 2.

Adjacent transversal slices of a positron-emission tomography image using the dopamine D_2/3 receptor agonist radioligand [¹¹C]-(+)-PHNO. Bright areas show binding to dopamine D_2/3 receptors in the human striatum and brainstem substantia nigra/ventral tegmental area.