Geeky Details in Dopamine System and Mental Illness


Regulation Of Dopamine System Responsivity And Its Adaptive And Pathological Response To Stress. Proc. R. Soc. B 282 2014 Anthony A. Grace

The dopamine system can play distinct roles in stress and psychiatric disorders. It is hypothesized that, even though the dopamine (DA) system forms the basis for a number of psychiatric disorders, the pathology is likely to originate in the afferent structures that are inducing dysregulation of the DA system.

1. Introduction

…it has become more and more evident that the dopamine (DA) system plays a key role in the response to stress, and in particular in the pathological response observed in many psychiatric disorders. The DA system plays a major role in the processing of natural and artificial rewards. Indeed, it has been proposed that mesolimbic DA mediates the hedonic aspects of rewarding stimuli, and that it acts as a learning signal for behavioural reinforcement.

… Disruption in the DA system has been implicated in numerous psychiatric and neurological disorders, including schizophrenia, Parkinson’s disease, drug abuse and major depressive disorders (MDDs). Although many studies have defined the basic and pathological function of the DA system in the brain, unravelling the complex afferent modulation of DA neuron activity is crucial to finding adequate and effective therapeutic approaches to treat several disorders. Indeed, many disorders are more likely to originate in afferent structures involved in the control of the DA system.

2. Stress and norepinephrine system

The catecholaminergic system has been repeatedly linked to stress responses…Maintained or repeated stressors produce morphological effects on the hippocampus and BLA

3. The dopamine system

  • Neurochemical studies have demonstrated that the DA system is activated by maintained stressful stimuli
  • Repeated restraint stress alters the response of the mesolimbic DA system to a stressor, and repeated stressors…facilitate the acquisition of self-administration of psychostimulants such as cocaine and amphetamine. …Of those that are firing spontaneously, two types of pattern are observed and regulated by different systems.
    • DA neurons display an irregular, single-spike firing pattern (or ‘tonic’ activity), as well as a burst firing pattern (or ‘phasic’ activity) The phasic pattern is dependent on glutamatergic afferent input
    • Phasic burst firing is believed to be the behaviourally salient output of the DA system that modulates goal-directed behaviour, and phasic changes in bursting occur in response to a conditioned stimulus, or after a primary reward, and have been shown to mediate prediction error response in conscious primates and rats.

4. Stressors And Environment
Responses to stress are dependent on the context. For example, if a rat is exposed to a stressor, such as during contextual fear conditioning, it will exhibit anxiety-like behaviours when returned to the same environmental context. The effect of a stressor on the DA system varies markedly depending on whether it is physiological, psychological or a noxious stimulus.

Stress has been shown to cross-sensitize with amphetamine, because the acute amphetamine-induced locomotor response, which is correlated with an increased VTA activity and an increased DA release in the NAc… This causes the DA system to be placed into a high responsive state to amplify the response to a stimulus when it is delivered in an activating context. Therefore, if a threat or specific situation requiring high vigilance is present, the vSub will set the DA system to a higher level of spontaneous activity, rendering it more reactive to deliver the appropriate response to a significant stimulus. When a stressor that had caused DA system activation is subsequently removed, the system exhibits an opposite response, a homeostatic event referred to as an opponent process.

… the initial activation of DA neurons during stress is followed by a depression of DA activity, in parallel with an attenuated amphetamine-induced locomotor response. Such a sequence of events would be expected to attenuate an emotional reaction…. chronic stress induces long-lasting changes in the regulation of neuronal activity of mesolimbic DA neurons. Therefore, the initial DA activity increase during stress predisposes the system to subsequent depression during withdrawal…

Pathological Stress Response And Psychiatric Disorders

As reviewed earlier, stressors can cause an acute activation of the DA system…followed by a withdrawal response with a decrease in the DA system activity driven by the amygdala. However, if this normal acute stress response is prolonged, it can lead to pathological consequences. Indeed, the deleterious consequences of chronic stress are likely to underlie several psychiatric conditions. (a) Stress and depression Anhedonia, or loss of interest or pleasure to normally rewarding events, is a major symptomofmany neuropsychiatric disorders, including MDD. Although depression has been historically associatedwith serotonin based on antidepressant drug actions, basic science investigations have consistently linked anhedonia to disruptions in the DA system…

The DA system is associated with reward prediction and motivation, and it is hypothesized that DA is necessary for the attribution of incentive salience to motivational stimuli, transforming the perception of a reward into a wanted incentive. This is consistent with disruptions of the motivation to seek out pleasurable experiences described in individuals diagnosed with MDD.

… The consequence of stress on the DA system might therefore be related to its predictable or unpredictable nature…There is substantial evidence that a significant association exists between acute or chronic stress and the motivation to abuse addictive substances…acute administration of psychostimulants such as cocaine or amphetamine increases mesolimbic DA, but chronic use and acute withdrawal downregulates the mesolimbic DA pathway, leading to decreases in basal DA levels.

According to the opponent process theory of motivation, the positive emotion caused by the reinforcing properties of a drug is followed by secondary compensatory anhedonic processes that are opposite in nature and longer in duration when compared with the initial emotion. Therefore, after chronic use, the negative affective state prevails during withdrawal, leaving the addicted individual in a negative affective state, increasing the risk of relapse even after protracted periods of time. This negative state has been observed only after chronic drug use; few studies have focused on the withdrawal- negative phase following acute drug injection. However, it has recently been shown that an acute injection of amphetamine induces a subsequent decrease of DA neuron population activity 18 h after the injection, with this decrease lasting for up to 72 h.

Moreover, either ketamine administration or BLA inactivation restores the decrease in DA neuron activity [130], suggesting that hyperactivity in the ilPFC!BLA!VP circuit, as observed in MDD models, might be responsible for the negative withdrawal state that increases the risk of relapse even after an acute injection of a psychostimulant. Therefore, the duration of the negative affective state during withdrawal is likely to be related to the duration of DA system activation. Indeed, these results suggest that chronic drug use should induce a prolonged risk of relapse, probably due to a prolonged decrease in DA neuron activity following withdrawal, whereas acute drug use, which also induces a decrease in DA neuron activity, might be responsible for a shorter withdrawal but will probably drive a drug-naive individual to take additional doses of the drug.


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