Polypeptides as Neurotransmitters

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Many polypeptides of various sizes are found in the synapses of the brain. These are often called neuropeptides and are believed to function as neurotransmitters. Interestingly, some of the polypeptides that function as hormones secreted by the small intestine and other endocrine glands are also produced in the brain and may function there as neurotransmitters (table 7.8). For example, cholecystokinin (CCK), which is secreted as a hormone from the small intestine, is also released from neurons and used as a neurotransmitter in the brain. Recent evidence suggests that CCK, acting as a neurotransmitter, may promote feelings of satiety in the brain following meals. Another polypeptide found in spinal motor neurons that innervate skeletal muscles, the intravenous infusion of benzodiazepines acts to inhibit the muscular spasms in epileptic seizures and seizures resulting from drug overdose and poisons. Probably as a result of its general inhibitory effects on the brain, GABA also functions as a neurotransmitter involved in mood and emotion. Benzodiazepines such as Valium are thus given orally to treat anxiety and sleeplessness.

180 Chapter Seven

Table 7.8 Examples of Chemicals That Are Either Proven or Suspected Neurotransmitters

Category

Chemicals

Histamine

Serotonin

Catecholamines

Dopamine

(Epinephrine—a hormone) Norepinephrine

GABA (gamma-aminobutyric acid)

Glutamic acid

Glycine

Polypeptides

Glucagon Insulin

Somatostatin Substance P

ACTH (adrenocorticotropic hormone) Angiotensin II

Endogenous opioids (enkephalins and endorphins) LHRH (luteinizing hormone-releasing hormone) TRH (thyrotrophin-releasing hormone) Vasopressin (antidiuretic hormone) CCK (cholecystokinin)

Lipids

Endocannabinoids

Gases

Nitric oxide Carbon monoxide

many organs, substance P, functions as a neurotransmitter in pathways in the brain that mediate sensations of pain.

Synaptic Plasticity

Although some of the polypeptides released from neurons may function as neurotransmitters in the traditional sense (that is, by stimulating the opening of ionic gates and causing changes in the membrane potential), others may have more subtle and poorly understood effects. Neuromodulators has been proposed as a name for compounds with such alternative effects. An exciting recent discovery is that some neurons in both the PNS and CNS produce both a classical neurotransmitter (ACh or a cate-cholamine) and a polypeptide neurotransmitter. These are contained in different synaptic vesicles that can be distinguished using the electron microscope. The neuron can thus release either the classical neurotransmitter or the polypeptide neurotrans-mitter under different conditions.

Discoveries such as the one just described indicate that synapses have a greater capacity for alteration at the molecular level than was previously believed. This attribute has been termed synaptic plasticity. Synapses are also more plastic at the cellular level. There is evidence that sprouting of new axon branches can occur over short distances to produce a turnover of synapses, even in the mature CNS. This breakdown and re-forming of synapses may occur within a time span of only a few hours. These events may play a role in learning and conditioning.

Endogenous Opioids

The ability of opium and its analogues—that is, the opioids—to relieve pain (promote analgesia) has been known for centuries. Morphine, for example, has long been used for this purpose. The discovery in 1973 of opioid receptor proteins in the brain suggested that the effects of these drugs might be due to the stimulation of specific neuron pathways. This implied that opioids—along with LSD, mescaline, and other mind-altering drugs—might mimic the actions of neurotransmitters produced by the brain.

The analgesic effects of morphine are blocked in a specific manner by a drug called naloxone. In the same year that opioid receptor proteins were discovered, it was found that naloxone also blocked the analgesic effect of electrical brain stimulation. Subsequent evidence suggested that the analgesic effects of hypnosis and acupuncture could also be blocked by naloxone. These experiments indicated that the brain might be producing its own endogenous morphinelike analgesic compounds that served as the natural ligands of the opioid receptors in the brain.

These compounds have been identified as a family of polypeptides produced by the brain and pituitary gland. One member is called P-endorphin (for "endogenously produced morphinelike compound"). Another consists of a group of five-amino-acid peptides called enkephalins, and a third is a polypeptide neurotransmitter called dynorphin.

The endogenous opioid system is inactive under normal conditions, but when activated by stressors it can block the transmission of pain. For example, a burst in P-endorphin secretion was shown to occur in pregnant women during parturition (childbirth).

Exogenous opioids such as opium and morphine can produce euphoria, and so endogenous opioids may mediate reward or positive reinforcement pathways. This is consistent with the observation that overeating in genetically obese mice can be blocked by naloxone. It has also been suggested that the feeling of well-being and reduced anxiety following exercise (the "joggers high") may be an effect of endogenous opioids. Blood levels of P-endorphin increase when exercise is performed at greater than 60% of the maximal oxygen uptake (see chapter 12) and peak 15 minutes after the exercise has ended. Although obviously harder to measure, an increased level of opioids in the brain and cerebrospinal fluid has also been found to result from exercise. The opioid antagonist drug naloxone, however, does not block the exercise-induced euphoria, suggesting that the joggers high is not primarily an opioid effect. Use of naloxone, however, does demonstrate that the endogenous opioids are involved in the effects of exercise on blood pressure, and that they are responsible for the ability of exercise to raise the pain threshold.

Neuropeptide Y

Neuropeptide Y is the most abundant neuropeptide in the brain. It has been shown to have a variety of physiological effects, including a role in the response to stress, in the regulation of cir-cadian rhythms, and in the control of the cardiovascular system.

The Nervous System: Neurons and Synapses 181

Neuropeptide Y has been shown to inhibit the release of the excitatory neurotransmitter glutamate in a part of the brain called the hippocampus. This is significant because excessive glutamate released in this area can cause convulsions. Indeed, frequent seizures were a symptom of a recently developed strain of mice with the gene for neuropeptide Y "knocked out." (Knockout strains of mice have specific genes inactivated, as described in chapter 3.)

Neuropeptide Y is a powerful stimulator of appetite. When injected into a rat's brain, it can cause the rat to eat until it becomes obese. Conversely, inhibitors of neuropeptide Y that are injected into the brain inhibit eating. This research has become particularly important in light of the recent discovery of leptin, a satiety factor secreted by adipose tissue. Leptin suppresses appetite by acting, at least in part, to inhibit neuropeptide Y release. This topic is discussed in more detail in chapter 19.

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