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

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.

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Circuits regulating pleasure and happiness: evolution and role in mental disorders

Acta Neuropsychiatrica ◽

10.1017/neu.2017.8 ◽

2017 ◽

Vol 30 (1) ◽

pp. 29-42 ◽

Cited By ~ 8

Author(s):

Anton J.M. Loonen ◽

Svetlana A. Ivanova

Keyword(s):

Mental Disorders ◽

Insular Cortex ◽

Evolutionary Origin ◽

Evolutionary Development ◽

Extrapyramidal System ◽

Reward Seeking ◽

Starting Point ◽

Emotional Behaviour ◽

Hippocampal Complex ◽

Striatal System

Taking the evolutionary development of the forebrain as a starting point, the authors developed a biological framework for the subcortical regulation of human emotional behaviour which may offer an explanation for the pathogenesis of the principle symptoms of mental disorders. Appetitive-searching (reward-seeking) and distress-avoiding (misery-fleeing) behaviour are essential for all free-moving animals to stay alive and to have offspring. Even the oldest ocean-dwelling animal creatures, living about 560 million years ago and human ancestors, must therefore have been capable of generating these behaviours. Our earliest vertebrate ancestors, with a brain comparable with the modern lamprey, had a sophisticated extrapyramidal system generating and controlling all motions as well as a circuit including the habenula for the evaluation of the benefits of their actions. Almost the complete endbrain of the first land animals with a brain comparable with that of amphibians became assimilated into the human amygdaloid and hippocampal complex, whereas only a small part of the dorsal pallium and striatum developed into the ventral extrapyramidal circuits and the later insular cortex. The entire neocortex covering the hemispheres is of recent evolutionary origin, appearing first in early mammals. During the entire evolution of vertebrates, the habenular system was well conserved and maintained its function in regulating the intensity of reward-seeking (pleasure-related) and misery-fleeing (happiness-related) behaviour. The authors propose that the same is true in humans. Symptomatology of human mental disorders can be considered to result from maladaptation within a similar amygdalo/hippocampal–habenular–mesencephalic–ventral striatal system.

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A Manual of Cognitive Behaviour Therapy for People with Learning Disabilities and Common Mental Disorders – Therapist VersionA Manual of Cognitive Behaviour Therapy for People with Learning Disabilities and Common Mental Disorders – Therapist Version

Nursing Standard ◽

10.7748/ns2012.09.27.2.29.b1410 ◽

2012 ◽

Vol 27 (2) ◽

pp. 29-29

Author(s):

Simon Jones

Keyword(s):

Learning Disabilities ◽

Mental Disorders ◽

Cognitive Behaviour Therapy ◽

Common Mental Disorders ◽

Behaviour Therapy ◽

Cognitive Behaviour

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The Prospect of Cure: Implications for Mental Health Planning

Behaviour Change ◽

10.1017/s0813483900006173 ◽

1992 ◽

Vol 9 (4) ◽

pp. 246-253 ◽

Cited By ~ 2

Author(s):

Gavin Andrews

Keyword(s):

Mental Health ◽

Mental Disorders ◽

Mental Health Professionals ◽

Health Planning ◽

Clinical Care ◽

Patient Treatment ◽

Health Staff ◽

Behaviour Therapy ◽

Mental Health Staff ◽

Cognitive Behaviour

The treatment of persons with mental disorders is advancing rapidly. New epidemiological information has allowed the magnitude of the task to be specified. A census of mental health professionals has allowed the workloads to be determined and organisational models which focus on treatment in the community established. As diagnosis is the first step in treatment it is timely that new, computerised structured diagnosis interviews are available. Treatment evaluation likewise is able to suggest that medication and cognitive behaviour therapy backed by good clinical care are the keys to good patient treatment. The two major problems that follow mainstreaming of the treatment of persons with mental disorders are the reallocation of money to treatment in the community, and the education of mental health staff to diagnose and deliver the proven effective treatments.

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A Manual of Cognitive Behaviour Therapy for People with Learning Disabilities and Common Mental Disorders - Therapist VersionA Manual of Cognitive Behaviour Therapy for People with Learning Disabilities and Common Mental Disorders - Therapist Version

Nursing Standard ◽

10.7748/ns2012.09.27.2.29.s37 ◽

2012 ◽

Vol 27 (2) ◽

pp. 29-29

Author(s):

Simon Jones

Keyword(s):

Learning Disabilities ◽

Mental Disorders ◽

Cognitive Behaviour Therapy ◽

Common Mental Disorders ◽

Behaviour Therapy ◽

Cognitive Behaviour

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Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2017.10.006 ◽

2017 ◽

Vol 92 ◽

pp. 202-209 ◽

Cited By ~ 6

Author(s):

Hugo R. Arias ◽

Xiaotao Jin ◽

Dominik Feuerbach ◽

Ryan M. Drenan

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Inhibitory Activity ◽

Acetylcholine Receptors ◽

Nicotinic Acetylcholine ◽

Medial Habenula

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Nucleus accumbens cholinergic interneurons oppose cue-motivated behavior

10.1101/520817 ◽

2019 ◽

Cited By ~ 3

Author(s):

Anne L. Collins ◽

Tara J. Aitken ◽

I-Wen Huang ◽

Christine Shieh ◽

Venuz Y. Greenfield ◽

...

Keyword(s):

Nucleus Accumbens ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Female Rats ◽

Nucleus Accumbens Core ◽

Cholinergic Interneurons ◽

Reward Seeking ◽

Motivated Behavior ◽

Male And Female Rats ◽

Seeking Behavior

ABSTRACTBackgroundEnvironmental reward-predictive stimuli provide a major source of motivation for adaptive reward pursuit behavior. This cue-motivated behavior is known to be mediated by the nucleus accumbens core (NAc). The cholinergic interneurons in the NAc are tonically active and densely arborized and, thus, well-suited to modulate NAc function. But their causal contribution to adaptive behavior remains unknown. Here we investigated the function of NAc cholinergic interneurons in cue-motivated behavior.MethodsTo do this, we used chemogenetics, optogenetics, pharmacology, and a translationally analogous Pavlovian-to-instrumental transfer behavioral task designed to assess the motivating influence of a reward-predictive cue over reward-seeking actions in male and female rats.ResultsThe data show that NAc cholinergic interneuron activity is necessary and sufficient to oppose the motivating influence of appetitive cues. Chemogenetic inhibition of NAc cholinergic interneurons augmented cue-motivated behavior. Optical stimulation of acetylcholine release from NAc cholinergic interneurons prevented cues from invigorating reward-seeking behavior, an effect that was mediated by activation of β2-containing nicotinic acetylcholine receptors.ConclusionsThus, NAc cholinergic interneurons provide a critical regulatory influence over adaptive cue-motivated behavior and, therefore, are a potential therapeutic target for the maladaptive cue-motivated behavior that marks many psychiatric conditions, including addiction and depression.

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Lateral habenula mediates defensive responses only when threat and safety memories are in conflict

10.1101/2020.11.12.378612 ◽

2020 ◽

Author(s):

Geronimo Velazquez-Hernandez ◽

Francisco Sotres-Bayon

Keyword(s):

Learning And Memory ◽

Latent Inhibition ◽

Brain Structure ◽

Choice Behavior ◽

Extinction Learning ◽

Lateral Habenula ◽

Emotional Conflict ◽

Reward Seeking ◽

Defensive Responses ◽

Behavioral Tasks

SummarySurvival depends on the ability to adaptively react or execute actions based on previous aversive salient experiences. Although lateral habenula (LHb) activity has been broadly implicated in the regulation of aversively motivated responses, it is not clear under which conditions this brain structure is necessary to regulate defensive responses to a threat. To address this issue, we combined pharmacological inactivations with behavioral tasks that involve aversive and appetitive events and evaluated defensive responses in rats. We found that LHb pharmacological inactivation did not affect cued threat and extinction learning and memory, anxiety-like or reward-seeking behaviors. Surprisingly, we found that LHb inactivation abolished reactive defensive responses (tone-elicited freezing) only when threat (conditioning) and safety memories (extinction and latent inhibition) compete. Consistently, we found that LHb inactivation impaired active defensive responses (platform-mediated avoidance), thereby biasing choice behavior (between avoiding a threat or approaching food) towards reward-seeking responses. Together, our findings suggest that LHb activity mediates defensive responses only when guided by competing threat and safety memories, consequently revealing a previously uncharacterized role for LHb in experience-dependent emotional conflict.

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