Circuits Regulating Pleasure and Happiness-Mechanisms of Depression

According to our model of the regulation of appetitive-searching versus distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side, to the centromedial amygdala on the other side, controls the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure). Hyperactive motivation to exhibit behavior related to avoidance of misery results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. In clinical depression, a mismatch exists between the activities of these two circuits: the balance is shifted to the misery-avoiding side. Five theories have been developed to explain the mechanism of depressive mood disorders, including the monoamine, biorhythm, neuro-endocrine, neuro-immune, and kindling/neuroplasticity theories. This paper describes these theories in relationship to the model (described above) of the regulation of reward-seeking versus misery-avoiding behaviors. Chronic stress that leads to structural changes may induce the mismatch between the two systems. This mismatch leads to lack of pleasure, low energy, and indecisiveness, on one hand, and dysphoria, continuous worrying, and negative expectations on the other hand. The neuroplastic effects of monoamines, cortisol, and cytokines may mediate the induction of these structural alterations. Long-term exposure to stressful situations (particularly experienced during childhood) may lead to increased susceptibility for developing this condition. This hypothesis opens up the possibility of treating depression with psychotherapy. Genetic and other biological factors (toxic, infectious, or traumatic) may increase sensitivity to the induction of relevant neuroplastic changes. Reversal or compensation of these neuroplastic adjustments may explain the effects of biological therapies in treating depression

Five theories of the mechanism of depression

The neurobiology of mood disorders has been already for decades the subject of intensive experimental and clinical research. Several theories have been developed to explain the genesis of these disorders. We believe that the different mechanisms implicated by these theories are not independent from one another. Therefore, we will try to describe, how these different theories are interrelated. This will bring us finally to a model how two different brain structures induce low mood. We believe that a dysfunctioning of two different cortical-subcortical circuits is involved in major depressive disorders. The five theories of mood disorders give the mechanisms of how these circuits are affected by genetic and environmental circumstances

Neurobiological mechanisms associated with antipsychotic drug-induced dystonia

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors

Circuits Regulating Pleasure and Happiness: A Focus on Addiction, Beyond the Ventral Striatum

A recently developed anatomical model describes how the intensity of reward-seeking and misery-fleeing behaviours is regulated. The first type of behaviours is regulated within an extrapyramidal cortical–subcortical circuit containing as first relay stations, the caudate nucleus, putamen and core of the accumbens nucleus. The second type of behaviours is controlled by a limbic cortical–subcortical circuit with as first stations, the centromedial amygdala, extended amygdala, bed nucleus of the stria terminalis and shell of the accumbens nucleus. We hypothesize that sudden cessation of hyperactivity of the first circuit results in feelings of pleasure and of the second circuit in feelings of happiness. The insular cortex has probably an essential role in the perception of these and other emotions. Motivation to show these behaviours is regulated by monoaminergic neurons projecting to the accumbens from the midbrain: dopaminergic ventral tegmental nuclei, adrenergic locus coeruleus and serotonergic upper raphe nuclei. The activity of these monoaminergic nuclei is in turn regulated through a ventral pathway by the prefrontal cortex and through a dorsal pathway by the medial and lateral habenula. The habenula has this role since the first vertebrate human ancestors with a brain comparable to that of modern lampreys. The lateral habenula promotes or inhibits reward-seeking behaviours depending upon the gained reward being larger or smaller than expected. It is suggested that the ventral pathway is essential for maintaining addiction based on the observation of specific cues, while the dorsal pathway is essential for becoming addicted and relapsing during periods of abstinence

Circuits regulating pleasure and happiness:The evolution of reward-seeking and misery-fleeing behavioral mechanisms in vertebrates

The very first free-moving animals in the oceans over 540 million years ago must have been able to obtain food, territory, and shelter, as well as reproduce. Therefore, they would have needed regulatory mechanisms to induce movements enabling achievement of these prerequisites for survival. It can be useful to consider these mechanisms in primitive chordates, which represent our earliest ancestors, to develop hypotheses addressing how these essential parts of human behavior are regulated and relate to more sophisticated behavioral manifestations such as mood. An animal comparable to lampreys was the earliest known vertebrate with a modern forebrain consisting of old and new cortical parts. Lampreys have a separate dorsal pallium, the forerunner of the most recently developed part of the cerebral cortex. In addition, the lamprey extrapyramidal system (EPS), which regulates movement, is modern. However, in lampreys and their putative forerunners, the hagfishes, the striatum, which is the input part of this EPS, probably corresponds to the human centromedial amygdala, which in higher vertebrates is part of a system mediating fear and anxiety. Both animals have well-developed nuclear habenulae, which are involved in several critical behaviors; in lampreys this system regulates the reward system that reinforces appetitive-seeking behavior or the avoidance system that reinforces flight behavior resulting from negative inputs. Lampreys also have a distinct glutamatergic nucleus, the so-called habenula-projection globus pallidus, which receives input from glutamatergic and GABAergic signals and gives output to the lateral habenula. Via this route, this nucleus influences midbrain monoaminergic nuclei and regulates the food acquisition system. These various structures involved in motor regulation in the lampreys may be conserved in humans and include two complementary mechanisms for reward reinforcement and avoidance behaviors. The first system is associated with experiencing pleasure and the second with happiness. The activities of these mechanisms are regulated by a tract running via the habenula to the upper brainstem. Identifying the human correlate of the lamprey habenula-projecting globus pallidus may help in elucidating the mechanism of the antidepressant effects of glutamatergic drugs