Chemical Signaling by Neurotransmitters and Hormones

Chemical Signaling between Nerve Cells

Neurotransmitter Synthesis, Release, and Inactivation

• Synapses may occur on the dendrite (axodendritic), cell body (axosomatic), or axon (axoaxonic) of the postsynaptic cell.
• Most neurotransmitters fall into one of the following categories (with acetylcholine as a notable exception): amino acid transmitters, monoamine transmitters, lipid transmitters, neuropeptide transmitters, and gaseous transmitters.
• Neurons commonly synthesize and release two or more neurotransmitters, often from different categories.
• Classical neurotransmitters (amino acids, monoamines, and acetylcholine) are mainly synthesized in the nerve terminal and then are transported into synaptic vesicles; neuropeptides are synthesized and are packaged into vesicles in the cell body.
• Neurotransmitters are released from nerve terminals by a Ca²⁺-dependent process called exocytosis.
• Synaptic vesicles are replenished by recycling processes. Three models have been proposed to explain vesicle recycling at low to moderate rates of neuronal activity: clathrin-mediated endocytosis, ultrafast endocytosis, and kiss-and-run. At very high rates of activity, a fourth process called bulk endocytosis comes into play to retrieve and recycle large amounts of vesicle membrane that has fused with the nerve terminal membrane.
• Lipid and gaseous transmitters are synthesized upon demand, are not stored in synaptic vesicles, and often function as retrograde messengers by signaling from the postsynaptic to the presynaptic cell.
• Neurotransmitter release is controlled by the rate of cell firing, the release probability at a specific synapse, and inhibitory terminal and somatodendritic autoreceptors.
• Depending on the neurotransmitter, termination of transmitter action is accomplished by the processes of uptake (including reuptake by the presynaptic cell) and/or enzymatic breakdown.

Neurotransmitter Receptors and Second-Messenger Systems

Pharmacology of Synaptic Transmission

Synaptic Plasticity

• Neurotransmitter receptors serve the purpose of signaling information from the presynaptic to the postsynaptic cell. Unlike transporters, they do not carry neurotransmitter molecules across the cell membrane.
• Most neurotransmitters make use of multiple receptor subtypes.
• Neurotransmitter receptors fall into two categories: ionotropic and metabotropic.
• Ionotropic receptors are composed of multiple subunits and form an intrinsic ion channel that is permeable either to cations such as Na⁺ (and sometimes also Ca²⁺) or to anions such as Cl^–. These receptors respectively mediate fast excitatory or fast inhibitory transmission.
• Metabotropic receptors are coupled to G proteins in the cell membrane and mediate slower transmission involving ion channel opening (e.g., inhibitory K⁺ channels) or second-messenger synthesis or breakdown.
• Allosteric modulators are molecules that either increase or decrease receptor activity by binding to sites on the receptor protein separate from the agonist binding site.
• Second messengers work by activating protein kinases that phosphorylate target proteins in the postsynaptic cell.
• Some important second-messenger systems and their respective kinases are the cAMP (protein kinase A), cGMP (protein kinase G), Ca²⁺ (calcium/calmodulin kinase II), and phosphoinositide (protein kinase C) systems.
• The second messengers cAMP and cGMP are inactivated by enzymes called phosphodiesterases (PDEs). Inhibitors of specific PDEs are being tested for their potential efficacy in treating various CNS disorders.
• Neurotrophic factors like NGF and BDNF work by activating tyrosine kinase receptors.
• Psychoactive drugs usually exert their subjective and behavioral effects by modifying synaptic transmission in one or more of the following ways: (1) increasing or decreasing transmitter synthesis, (2) reducing transmitter inactivation by inhibiting enzymatic breakdown or blocking reuptake, (3) stimulating transmitter release, and (4) acting as agonists or antagonists at transmitter receptors on the postsynaptic or presynaptic (i.e., autoreceptors) cell.
• Synaptic plasticity refers to functional and structural changes in synaptic connectivity. Components of the MAP kinase system such as the extracellular signal-related kinase (ERK) play an important role in the molecular mechanisms of synaptic plasticity. Structurally, synaptic plasticity is manifested by changes in the size, shape, and/or number of dendritic spines, and such changes are found both in neuropsychiatric disorders and in drug and alcohol dependence and withdrawal.

The Endocrine System

• Hormones are released into the bloodstream, where they may travel long distances before reaching target cells in the body. Despite important differences between synaptic and endocrine communications, the same substance is sometimes used as both a neurotransmitter and a hormone.
• The adrenal gland is composed of the inner medulla and the outer cortex, both of which are activated by stress. The chromaffin cells of the adrenal medulla secrete the hormones EPI and NE, whereas the adrenal cortex secretes glucocorticoid steroids such as cortisol and corticosterone.
• Other steroid hormones that are synthesized and released by the gonads include estrogens and progesterone from the ovaries in females, and androgens such as testosterone from the testes in males. These gonadal steroids are responsible for many of the secondary sex characteristics that appear after puberty; testosterone is additionally involved in sexual differentiation of the brain during early development, as well as in stimulation of sexual motivation later in life.
• The islets of Langerhans and the thyroid gland secrete hormones important in energy metabolism. Insulin and glucagon are released from separate populations of cells within the islets of Langerhans, and together these two peptide hormones regulate the disposition of glucose and other sources of metabolic energy. Lethargy and excessive energy are behavioral symptoms of hypothyroidism and hyperthyroidism, respectively, and are due to abnormally low or abnormally high levels of the two thyroid hormones, thyroxine and triiodothyronine.
• The pineal gland, which is situated just over the brainstem, synthesizes the hormone melatonin using 5-HT as a precursor. Melatonin has been implicated in the regulation of various types of rhythmic activity, including sleep.
• The pituitary gland is found just under the hypothalamus and is connected to it. The pituitary is divided into two separate glands, the anterior and posterior pituitary glands, which serve different functions.
• The anterior pituitary secretes TSH, ACTH, FSH, LH, GH, and PRL. TSH and ACTH stimulate the thyroid and adrenal glands (cortex), respectively, whereas FSH and LH together control the growth and functioning of the gonads. GH stimulates skeletal growth during development, and PRL plays an important role in promoting milk production during lactation.
• The hypothalamic releasing hormones TRH, CRH, and GnRH are neuropeptides synthesized within the hypothalamus that trigger the release of TSH, ACTH, and the gonadotropins FSH and LH. Because of this organizational structure, in which several glands must stimulate each other until the final hormone product is secreted, the endocrine system works much more slowly than chemical communication by neurotransmitters.
• The posterior pituitary secretes two small peptide hormones, vasopressin and oxytocin. Vasopressin enhances water retention by the kidneys, whereas oxytocin stimulates uterine contractions during childbirth and also triggers milk letdown from the breasts during lactation. These hormones may also promote affiliative behaviors in some species.
• The actions of hormones are mediated by several different kinds of receptors. Some are metabotropic receptors similar to those discussed for various neurotransmitters. Others are intracellular receptors that function as transcription factors that control gene expression, and still others are tyrosine kinase receptors.
• The endocrine system is important to pharmacologists for several reasons. These include the fact that (1) drugs can adversely alter endocrine function, (2) hormones may alter behavioral responses to drugs, (3) hormones themselves sometimes have psychoactive properties, and (4) the endocrine system can be used as a window to the brain to help us determine the functioning of a specific neurotransmitter system by measuring changes in hormone secretion under appropriate conditions.