Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment

A very dense and long article but a good overview of how several of the medications in trial might normalize gabaergic transmission and hippocampal hyperactivity.

aberrant dopamine transmission and associated SCZ symptoms have been proposed as a consequence of disruption in afferent brain regions that regulate the dopamine system, mainly cortical and hippocampal regions. Hence, treatment at the site of pathology could be a more effective therapeutic avenue than current antipsychotics that target D2 receptors.

For example, in the hippocampus a functional loss of PV interneurons has been associated with hippocampal hyperactivity that is proposed to underlie the hyperdopaminergic state observed in SCZ [54,55]. A hyperactive hippocampus can also interfere with the function of other circuits leading to cognitive deficits and negatives symptoms (Figure 1). Thus, targeting excitatory–inhibitory balance may alleviate positive, negative, and cognitive symptoms of SCZ [54]. Therefore, one potential approach for treating a broad range of SCZ symptoms is to modulate abnormalities in glutamate and GABA neurotransmission, as will be discussed below.

A further approach that could potentially normalize the functional loss of PV interneurons would be the modulation of Kv3.1 potassium channels on these cells. The Kv3.1 channel is part of the family of Kv3-type voltage-gated potassium channels (Kv3.1-Kv3.4) that have fast-spiking properties [74]. Kv3.1 channels are abundantly expressed in PV interneurons and play an important role in regulating their activity by allowing these cells to fire at high frequency and, thus, enabling the synchronized activity of pyramidal neurons and generation of gamma oscillations [75,76], which is dramatically impaired in SCZ [53]. Therefore, the modulation of these channels could potentially normalize the impaired activity of these interneurons in SCZ

Another approach that could compensate for decreases in PV interneuron functionality is to increase GABA neurotransmission. One target that has shown some promise is the GABAA receptor containing the α5 subtype (α5-GABAA) [81], which is highly expressed in limbic brain regions, mainly in the hippocampus and to a lesser extent in the neocortex [82,83,84]. A proposed function of α5-GABAA receptors is the tonic regulation of inhibitory inputs to pyramidal neurons, coordinating spike timing of these neurons and balancing excitation [85,86,87]. Of particular interest is the involvement of the α5-GABAA receptor present on pyramidal neurons regulating GABA inputs arising from perisomatic targeting PV-expressing interneurons (Figure 2). Preclinical studies have supported the potential use of α5-GABAA receptors positive allosteric modulator (PAM) to treat SCZ.

Several mechanisms have been proposed to explain how agonists of mAChR M4 could counteract a hyperdopaminergic state. The activation of mAChR M4 on cholinergic interneurons in the striatum reduces local cholinergic tone within the striatum, which reduces striatal dopamine levels [122,123]. Similar outcomes were found by Foster and colleagues, where the activation of mAChR M4 receptors on D1 receptor-spiny projection neurons may increase the release of the endocannabinoid 2-arachidonoylglycerol that, through the activation of cannabinoid CB2 receptors located in presynaptic terminals of dopamine neurons, leads to sustained inhibition of dopamine release [124]. In addition, the activation of presynaptic mAChR M4 located in laterodorsal tegmental nuclei cholinergic neurons projecting to the VTA reduces local cholinergic tone, which may modulate dopamine neuron activity.

Trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptor activated by endogenous trace amines that are structurally related to monoaminergic neurotransmitters. The expression of TAAR1 was reported in several brain regions, such as the prefrontal cortex, striatum, amygdala, nucleus accumbens, and ventral tegmental area [125]. It is proposed that the activation of TAAR1 modulates presynaptic dopamine synthesis capacity [126], which may produce antipsychotic-like effects. Moreover, TAAR1 may alter D2 receptor-mediated signaling through the formation of heterodimers [127].

In mice, SEP-363856, a TAAR1 agonist developed by Sunovion Pharmaceuticals, reduced dopamine synthesis capacity induced by repeated treatment with ketamine [128]. SEP-363856 was also found to inhibit neuronal firing and decrease excitability in the ventral tegmental area [129]. In addition to TAAR1, SEP-363856 also acts as a 5-HT1A receptor agonist [129]. Recent clinical trials have evaluated SEP-363856 for SCZ. In a phase-II, randomized, double-blind, placebo-controlled 4-week, SEP-363856 was superior to placebo for reducing both positive and negative symptoms of SCZ without inducing side effects of current antipsychotics [130]. Phase 3 clinical trials are ongoing. Clinical trials investigating the effects of ralmitaront (RO6889450), a TAAR1 partial agonist, in SCZ are also ongoing.

They also suggest NAC and suforaphane as preventative treatments.