Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets

Abstract

Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated.

Keywords: antipsychotic; dopamine; schizophrenia.

Figure 1

Dopamine neuron activity is driven by a pacemaker conductance that maintains their firing, which is offset by inhibition from the ventral pallidum. (A) In the baseline state, approximately half of the dopamine neurons are spontaneously firing, with the other half held in a hyperpolarized state due to GABAergic inhibition from the ventral pallidum. Activity in the limbic hippocampus provides an excitatory drive to the nucleus accumbens, which in turn can inhibit the ventral pallidum to modulate the inhibitory drive on ventral tegmental area dopamine neurons [78]. (B) In schizophrenia, a loss of parvalbumin GABAergic neurons in the limbic hippocampus causes this region to be tonically hyperactive; this leads to increased accumbens inhibition of the ventral pallidum. This releases the dopamine neurons from inhibition, causing the entire population of dopamine neurons to be in the active, responsive state.

Figure 2

In schizophrenia, a loss of parvalbumin GABAergic neurons in the limbic hippocampus, via a circuit involving the nucleus accumbens and ventral pallidum leads to a disinhibition of VTA dopamine neurons and dopamine overdrive in the associative striatum; this appears to underlie the positive psychotic features of the disorder. By causing depolarization block of the ventral tegmental dopamine neurons, first- and second-generation antipsychotic drugs reverse dopamine neuron hyperactivity to relieve psychosis; in addition, first-generation drugs also cause depolarization block in the substantia nigra dopamine neurons to lead to extrapyramidal side effects. However, when the hippocampus is hyperactive and dysrhythmic, it can also lead to pathological activity changes in its other targets. Thus, it will impact the amygdala-cingulate cortex to lead to negative symptoms, and the prefrontal cortex to induce cognitive deficits; all characteristics of schizophrenia that are not effectively treated by dopamine antagonist first- and second-generation antipsychotic drugs. Novel mechanism antipsychotic drugs that act directly at the site of pathology in the hippocampus could be effective at reversing the negative and cognitive deficits as well as the positive symptoms of schizophrenia. * Site of pathology in schizophrenia; ↓ PV reduction in the hippocampus.

Figure 3

Phasic dopamine neuron burst firing is believed to be the behaviorally salient output of the dopamine system. (A) Burst firing is driven by a glutamate input from the pedunculopontine tegmentum acting on dopamine neuron n-methyl-D-aspartate (NMDA) receptors to drive burst firing. However, for NMDA to drive burst firing, the neuron must be in a depolarized, spontaneously active state; otherwise in hyperpolarized, inactive neurons there is a magnesium blockade of the NMDA channel. Therefore, only spontaneously active dopamine neurons can be driven by the pedunculopontine tegmentum into burst firing. The ventral pallidum, by controlling the number of dopamine neurons active, can determine the level of amplification, or the gain, of the phasic response. This is thought to be adjusted depending on the demands of the environment; in highly salient or dangerous conditions, the hippocampus increases the number of dopamine neurons in the responsive, active state, thereby enabling a salient stimulus to activate the pedunculopontine tegmental-driven burst firing across a large number of dopamine neurons, facilitating an immediate response to the threat. (B) In the case of schizophrenia, an overactive hippocampus removes tonic inhibitory drive of dopamine neurons, causing a massive increase in the number of responsive neurons independent of environmental contingencies. Under these conditions, both salient and nonsalient stimuli will cause a maximal phasic response. Therefore, with an overdriven dopamine system, every stimulus will be perceived as a threat, causing the patient to be overwhelmed and unable to filter salient from nonsalient stimuli. This leads to a state of aberrant salience, or the inappropriate attribution of salience to a normally benign object.