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KEY CONCEPTS

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  • The monoamine neurotransmitters (dopamine [DA], norepinephrine [NE], epinephrine, serotonin, and histamine), the related small molecule neurotransmitter, acetylcholine (ACh), and the neuropeptides, orexin A and B, have an unusual but functionally significant organization in the brain. Their cell bodies are restricted to a small number of nuclei in the brainstem, hypothalamus, and basal forebrain, but their axons project widely throughout the central nervous system. This widely projecting organization permits each of these neurotransmitters to modulate activity in diverse circuits, sometimes in a coordinated fashion.

  • For example, these systems play critical roles in sleep, arousal, and attention, and in survival responses to relevant stimuli.

  • Widely projecting DA neurons have their cell bodies in the midbrain, within the substantia nigra pars compacta and the ventral tegmental area. DA is also produced by neurons in the arcuate nucleus of the hypothalamus, and by local circuit neurons in the retina. Midbrain DA neurons project widely to the forebrain and influence motivation, motor behavior, and multiple forms of memory. DA released from the hypothalamus suppresses synthesis and release of prolactin by the anterior pituitary.

  • NE is synthesized in nuclei within the medulla and pons, the most prominent of which is the locus ceruleus (LC). The LC provides virtually all of the NE to the cerebral cortex. NE regulates arousal, attention, vigilance, and memory. Descending NE fibers modulate afferent pain signals.

  • Serotonin (5HT or 5-hydroxytryptamine) is synthesized by neurons within the raphe nuclei of the midbrain. Their axons project very widely in the brain to influence diverse circuits involved in arousal, sensory processing, mood, and emotions.

  • ACh is the neurotransmitter at the neuromuscular junction (nerve–muscle synapses). In the brain it is produced by widely projecting neurons with cell bodies in the brainstem and in the basal forebrain that project to the cerebral cortex and hippocampus. It is also produced by interneurons in the striatum. ACh in the forebrain influences many processes including motivation, learning, and memory.

  • Histamine is produced by neurons in the tuberomammillary nucleus that lies within the posterior hypothalamus. These neurons project throughout the brain to regulate arousal. Inactivity of histamine neurons promotes sleep. Peripherally, histamine in the stomach promotes secretion of gastric acid via H2 receptors; histamine released from mast cells is involved in allergic responses mediated via H1 receptors.

  • Orexin A and B (also known as hypocretin 1 and 2) are related neuropeptides that regulate sleep and wakefulness by interacting with monoaminergic and cholinergic neurons that in turn regulate arousal, emotion, motivation, and feeding. Orexin neurons have cell bodies in the lateral hypothalamus, and project widely throughout the brain. Among the major recipients of orexinergic projections are the LC, a source of NE, and the tuberomammillary nucleus of the hypothalamus, the source of histamine.

  • All receptors for DA, NE, and histamine and 12 of the 13 5HT receptors are G protein–coupled receptors. The 5HT3 receptor is a ligand-gated ion channel. ACh receptors are divided into two major classes: nicotinic receptors, which ...

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