Dopamine System Dysregulation by the Ventral Subiculum as the Common Pathophysiological Basis for Schizophrenia Psychosis, Psychostimulant Abuse, and Stress

Abstract

The dopamine system is under multiple forms of regulation, and in turn provides effective modulation of system responses. Dopamine neurons are known to exist in several states of activity. The population activity, or the proportion of dopamine neurons firing spontaneously, is controlled by the ventral subiculum of the hippocampus. In contrast, burst firing, which is proposed to be the behaviorally salient output of the dopamine system, is driven by the brainstem pedunculopontine tegmentum. When an animal is exposed to a behaviorally salient stimulus, the pedunculopontine tegmentum elicits a burst of action potentials in the dopamine neurons. However, this bursting only occurs in the portion of the dopamine neuron population that is firing spontaneously. This proportion is regulated by the ventral subiculum. Therefore, the ventral subiculum provides the gain, or the amplification factor, for the behaviorally salient stimulus. The ventral subiculum itself is proposed to carry information related to the environmental context. Thus, the ventral subiculum will adjust the responsivity of the dopamine system based on the needs of the organism and the characteristics of the environment. However, this finely tuned system can be disrupted in disease states. In schizophrenia, a disruption of interneuronal regulation of the ventral subiculum is proposed to lead to an overdrive of the dopamine system, rendering the system in a constant hypervigilant state. Moreover, amphetamine sensitization and stressors also appear to cause an abnormal dopaminergic drive. Such an interaction could underlie the risk factors of drug abuse and stress in the precipitation of a psychotic event. On the other hand, this could point to the ventral subiculum as an effective site of therapeutic intervention in the treatment or even the prevention of schizophrenia.

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

“…Ultimately, the loss of functionality of this subset of GABAergic interneurons projecting to pyramidal cell neurons likely accounts for the HPC hyperactivity and secondary increases in DA population response in the VTA. This is also consistent with clinical data showing that patients with schizophrenia demonstrate abnormal resting state activation in the HPC (Heckers et al, 1999;Nordahl et al, 1996) that correlates with psychosis (Grace, 2010). Therefore, abnormally increased ventral HPC excitability appears to drive the increased DA neuron population activity that we propose correlates with psychosis in schizophrenia.…”

Stress and neurodevelopmental processes in the emergence of psychosis

“…Other neurotransmitter systems, including GABA and glutamate, are likely involved, and there are undoubtedly individual differences among patients in the confluence of factors that trigger psychotic symptoms. While space does not permit greater discussion of the numerous alternatives, other authors have speculated on some of them in detail (Phillips et al, 2007; Bennett, 2008; Grace, 2010; Lodge and Grace, 2011). …”

“…Stress sensitization refers to the augmenting effects of stress/trauma exposure on subsequent behavioral and biological responses to stress (Grace, 2010; Valenti et al, 2011). Several studies of large samples have documented this effect at the behavioral level in humans.…”

“…For example, research on rodents has shown that exposure to severe or persistent stress/trauma can heighten HPA reactivity and DA augmentation in response to subsequent stressors (Yuii et al, 2007; Grace, 2010; McLaughlin et al, 2010). These postulated mechanisms are discussed further below.…”

Evidence for an anterior–posterior differentiation in the human hippocampal formation revealed by meta-analytic parcellation of fMRI coordinate maps: Focus on the subiculum

“…Continuous with the CA1 region of the hippocampus, but located within the parahippocampal gyrus in humans (Duvernoy, 2005), the subiculum provides a central role in the integration of information within the hippocampus (Naber et al, 2000) as well as its transmission to other brain regions (Witter, 2006). The subiculum has also gained attention in the context of pathophysiological models for a variety of psychiatric conditions, in particular those with a component reflecting maladaptive responses to stress (Herman and Mueller, 2006), including schizophrenia, addiction and mood disorders (Belujon and Grace, 2014; Grace, 2010). Consistent with the presence of functional differentiation across the structure, distinct behavioral consequences of dorsal and ventral subiculum manipulations have been observed in rodents (Andrzejewski et al, 2006; Caine et al, 2001).…”