Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention

Abstract

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

Keywords: antipsychotics; dopamine; glutamate; hippocampus; parvalbumin; psychosis; stress.

Figure 1

The anterior limbic hippocampus in humans, which is homologous to the ventral hippocampus (vHipp) of the rodent, is proposed to be hyperactive and dysrhythmic in SCZ due to a decreased PV interneuron (PVI) inhibition of pyramidal (Pyr) neurons. This is thought to lead, through a ventral striatum-ventral pallidum (VP) pathway, to an overdrive in the activity of VTA dopamine neurons that project to the associative striatum. The resulting striatal hyperdopaminergic state has been linked to the positive symptoms of SCZ. Additionally, a hyperactive hippocampus can also interfere with the function of other circuits. For instance, disruption of prefrontal cortex (PFC) and basolateral amygdala could potentially lead to cognitive deficits and interfere with emotional responses leading to negative symptoms, respectively. Therefore, a hyperactive dysrhythmic limbic hippocampus potentially disrupts multiple circuits and could contribute to the three main symptom clusters of SCZ.

Figure 2

Targeting the dysregulation of excitatory–inhibitory balance in SCZ include compounds that may compensate for the functional loss of PV interneurons (PVI) and attenuate the potentially increased activity of pyramidal (Pyr) neurons as well as the resulting increase in glutamate release. A hypofunction of NMDA receptors on PVI is proposed to underlie SCZ symptoms. (1) Compounds that facilitate NMDA receptor activity without triggering excitotoxicity, such as compounds that act through the glycine site, have the potential to increase PVI drive. A further approach that could normalize the functional loss of PVI is the modulation of Kv3.1 potassium channels on these cells. These channels play an important role in regulating PVI activity by allowing these cells to fire at high frequency. (2) Another approach that could compensate for decreases in PVI functionality is to increase postsynaptic GABA actions. One target that has shown some promise is the GABA_A receptor containing the α5 subtype (α5-GABA_A). (3) A decreased PVI inhibition of pyramidal neurons leads to a greater glutamate release. Therefore, another target is the use of agents that decrease presynaptic glutamate release, such as group II metabotropic glutamate receptor (mGluR2/3) agonists have attracted great interest as a novel treatment for SCZ.

Figure 3

It is proposed that during childhood/adolescence PV interneurons (PVI) are not “mature” and are not yet protected by perineuronal nets (PNNs), a glycosaminoglycan matrix sheath that surrounds PVI to end the plastic phase, but also protect PVI from metabolic and oxidative damage. Thus, during periods when PNNs are not yet fully formed, PVI are more vulnerable to stress-induced damage. This vulnerability continues until adulthood. During adolescence, exposure to stress can increase oxidative stress and cause aberrant excitation onto PVIs leading to PVI damage/loss. This, in turn, results in deficits in the excitatory/inhibitory (E/I) balance producing circuit deficits that lead to SCZ-related changes. Therefore, treatments that mitigate the impact of stress, through stress management approaches and/or attenuation of oxidative stress with antioxidants, may protect PVI from damage and potentially prevent SCZ development.