Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression

Abstract

The dopamine system is unique among the brain's modulatory systems in that it has discrete projections to specific brain regions involved in motor behaviour, cognition and emotion. Dopamine neurons exhibit several activity patterns - including tonic and phasic firing - that are determined by a combination of endogenous pacemaker conductances and regulation by multiple afferent systems. Emerging evidence suggests that disruptions in these regulatory systems may underlie the pathophysiology of several psychiatric disorders, including schizophrenia and depression.

Figure 1. Tonic and phasic dopamine neuron regulation

a| The ventral pallidum (VP) provides a powerful GABAergic inhibitory input to ventral tegmental area (VTA) dopamine (DA) neurons, holding subsets of DA neurons in a hyperpolarized, nonfiring (silent) state. Pedunculopontine tegmentum (PPTg) input acts on glutamatergic NMDA receptors on DA neurons to generate phasic bursts of firing: these constitute the behaviorally salient rapid DA response. However, only neurons that are firing spontaneously can burst fire; hyperpolarized neurons exhibit a magnesium block of the NMDA channel and therefore will not be driven to burst fire. Thus input from the PPTg provides the phasic signal, whereas the VP, by controlling the number of DA neurons firing, determines the tonic gain, or the level of amplification, of the phasic signal. b| If an organism is in a safe, benign context, the number of DA neurons firing is kept low and the PPTg will only activate phasic bursting in a small population of neurons. As a result, a salient stimulus will trigger a calm orienting response. By contrast, in a threatening or opportunistic environment, such as that present when an animal is out hunting, the VP allows a large population of DA neurons to be active, increasing vigilance to the environment. Now the same salient stimulus will cause a much larger phasic response, enabling the organism to rapidly orient to the stimulus to prepare an appropriate response.

Figure 2. ilPFC Modulation of DA Neuron Activity

The infralimbic prefrontal cortex (ilPFC) provides bidirectional control over VTA DA neuron tonic population activity. Under normal circumstances, the ventral subiculum (vSub) of the hippocampus activates the nucleus accumbens (NAc) to inhibit the VP, driving VTA DA neuron tonic population activity and increasing the response to afferent drive. Activation of the ilPFC provides an indirect inhibition of the hippocampus vSub and simultaneously activates the BLA, which in turn activates the VP to decrease DA neuron tonic population activity. By contrast, inhibition of the ilPFC removes a tonic inhibition of the vSub, which would increase the drive to the NAc and result in inhibition of the VP, thereby driving up tonic DA neuron population activity. Therefore, ilPFC activation decreases the response of the DA system to phasic events via activation of the BLA, whereas inhibition of the ilPFC increases DA system responsivity via disinhibition of the vSub.

Figure 3. vSub dysfunction and schizophrenia symptomatology

Parvalbumin (PV)-labeled GABAergic interneurons in the ventral subiculum (vSub) are driven by glutamate acting on NMDA receptors, and provide a powerful inhibitory input to pyramidal neurons via stimulation of GABA-A receptors containing the alpha-5 subunit. The PV-pyramidal neuron interaction is necessary to drive gamma rhythmic activity. In the case of schizophrenia, there is a loss of a large number of PV interneurons, causing the pyramidal neurons to be hyperactive and dysrhythmic. This leads to an overdrive of the nucleus accumbens (NAc), which inhibits the ventral pallidum (VP) and increases responsivity of DA neurons primarily in the lateral ventral tegmental area (VTA) that projects to the associative striatum. This is proposed to underlie the DA-dependent positive symptoms of schizophrenia. However, if the vSub is hyperactive and dysrhythmic, it can also interfere with the function of other circuits. Thus, the vSub-prefrontal cortex (PFC) projection would lead to disruption of PFC activity and rhythmicity, leading to cognitive disruption. Moreover, the vSub-basolateral amygdala (BLA) projection would interfere with the BLA-limbic cortical control of emotional responses, possibly leading to negative symptoms. Therefore, a hyperactive, dysrhythmic vSub has the potential of disrupting multiple interconnected circuits, and could potentially contribute to all three symptom classes of schizophrenia. OFC, orbitofrontal cortex.

Figure 4. Depression circuitry and ketamine actions

a|. In depression in humans, there is reported hyperactivity in subgenual cingulate Area 25, which is functionally analogous to the rodent ilPFC. In animal models of depression, hyperactivity in the ilPFC drives the BLA. BLA activity, via the VP, attenuates reward-related medial VTA DA neuron activity^,,. As a result, normally reward-related stimuli that activate the PPTg should produce a significantly smaller DA neuron phasic response, leading to a failure to establish a link between stimulus and reward. In the learned helplessness depression model, control rats and nonhelpless rats both show stimulation-induced LTP in the vSub-NAc pathway (see inset) which can offset the BLA-VP inhibition of the VTA. However, in the helpless animals, stimulation instead produces a LTD, thereby removing this counterbalancing influence b| Ketamine, a fast-acting antidepressant drug, normalizes DA neuron firing and re-establishes stimulus-induced LTP in the vSub-NAc pathway (see inset), thus re-establishing the balance between the DA facilitatory and attenuating circuits.