The evolutionary old forebrain as site of action to develop new psychotropic drugs

Abstract

Background: Previously, the authors have developed a model of how reward-seeking and distress- avoiding behaviour is regulated by the human brain. The forebrain's evolution in vertebrates was taken as a starting point.

Aims: The authors want to inspire colleagues to study in particular the pharmacological effects on the described ancient forebrain structures in order to modify specific symptoms of mental disorders.

Methods: Compilation of data and ideas of previous articles, with examples to illustrate.

Results: A primary (lamprey-like), secondary (frog-like) and tertiary (mammal-like) forebrain can be distinguished, organized according to a Russian doll model. The first constituent is primarily involved in producing the emotional response, while the last is principally concerned with constructing conscious cognitive behaviour (including verbal and written communication). Mental disorders comprise (partly related and partly unrelated) biological and rational phenomena. The secondary system regulates the intensity of reward-seeking and distress-avoiding behaviour. An essential component of the primary forebrain evaluates the results of behavioural actions: the lateral habenula-projecting pallidum. These neurons regulate the activity of ascending dopaminergic pathways. The authors suggest that these habenula-projecting pallidum neurons are targeted by subanaesthetic dosages of ketamine. The medial habenula is enriched with nicotinergic acetylcholine receptors and regulates the activity of ascending adrenergic and serotonergic neurons. This may link varenicline-induced hostility to selective serotonin reuptake inhibitor-induced aggression.

Conclusions: Studying the effects of new compounds on the primary and secondary brains in lampreys and frogs may yield interesting new treatments of mental disorders.

Keywords: Amygdala; GPh; habenula; ketamine; varenicline.

Figure 1.

Scheme showing the connectivity of the amygdalo-hippocampal system to the midbrain through the habenular complex (adapted from Loonen and Ivanova, 2016b). CTX: cerebral cortex; DR: dorsal raphe nucleus; DTg: dorsal tegmental nucleus; GPh: habenula-projecting part of the globus pallidus; IPN: interpeduncular nucleus; LHb: lateral habenula; MHb: medial habenula; PHC: parahippocampal cortex; RMTg: rostromedial tegmental nucleus; VTA: ventral tegmental area.

Figure 2.

Scheme showing the initiation and execution of the emotional response. BST: bed nucleus of the stria terminalis; CA: corticoid amygdala; CM: centromedial amygdala; dPFC: dorsolateral prefrontal cortex; MC: motor cortex; mPFC: medial prefrontal cortex; PAG: periaqueductal grey; PMC: premotor cortex; SMC: supplementary motor cortex.

Figure 3.

Simplified representation of the connectivity through the epithalamus. GPh: habenula-projecting globus pallidus; IPN: interpeduncular nucleus; LHb: lateral habenula; MHb: medial habenula; RMTg: rostromedial tegmental nucleus; SNc: substantia nigra, pars compacta; VTA: ventral tegmental nucleus.