kolbintro5e

5-3 Neurotransmitter Systems and Behavior

When researchers began to study neurotransmission, they reasoned that any given neuron would contain only one transmitter at all its axon terminals. Newer methods of analysis revealed that this hypothesis isn’t strictly accurate. A single neuron may use one transmitter at one synapse and a different transmitter at another synapse. Moreover, different transmitters may coexist in the same terminal or synapse. Neuropeptides have been found to coexist in terminals with small-molecule transmitters, and more than one small-molecule transmitter may be found in a single synapse. In some cases, more than one transmitter may even be packaged within a single vesicle.

All these findings allow for multiple combinations of neurotransmitters and receptors for them. They caution as well against assuming a simple cause-and-effect relation between a neurotransmitter and a behavior. What are the functions of so many combinations? The answer will likely vary, depending on the behavior that is controlled. Generally, neurotransmission is simplified by concentrating on the dominant transmitter within any given axon terminal. The neuron and its dominant transmitter can then be associated with a function or behavior.

We now consider some links between neurotransmitters and behavior. We begin by exploring the three peripheral nervous system divisions: SNS, ANS, and ENS. Then we investigate neurotransmission in the central nervous system.

Neurotransmission in the Somatic Nervous System

Nicotinic ACh Receptor

Research from J. E. Heuser and T. Reese, 1977, in E. R. Kandel, ed, The Nervous System, vol. 1, Handbook of Physiology. Oxford University Press, p. 266.

Motor neurons in the brain and spinal cord send their axons to the body’s skeletal muscles, including the muscles of the eyes and face, trunk, limbs, fingers, and toes. Without these SNS neurons, movement would not be possible. Motor neurons are also called cholinergic neurons because acetylcholine is their main neurotransmitter. At a skeletal muscle, cholinergic neurons are excitatory, producing muscular contractions.

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Just as a single main neurotransmitter serves the SNS, so does a single main receptor, a transmitter-activated ionotropic channel called a nicotinic acetylcholine receptor (nAChr). When ACh binds to this receptor, its pore opens to permit ion flow, thus depolarizing the muscle fiber. The nicotinic receptor pore is large enough to permit the simultaneous efflux of K⁺ and influx of Na⁺. The molecular structure of nicotine, a chemical found in tobacco, activates the nAChr in the same way that acetylcholine does, which is how this receptor got its name. The molecular structure of nicotine is sufficiently similar to that of ACh that nicotine acts as a mimic, fitting into acetylcholine receptor binding sites.

Acetylcholine is the primary neurotransmitter at skeletal muscles, but other neurotransmitters also occupy these cholinergic axon terminals and are released onto the muscle along with ACh. One is a neuropeptide called calcitonin gene–related peptide (CGRP), which acts through CGRP metabotropic receptors to increase the force with which a muscle contracts.

Dual Activating Systems of the Autonomic Nervous System

The complementary ANS divisions, sympathetic and parasympathetic, regulate the body’s internal environment. The sympathetic division rouses the body for action, producing the fight-or-flight response. Heart rate ramps up and digestive functions ramp down. The parasympathetic division calms the body down, producing an essentially opposite rest-and-digest response. Digestive functions ramp up, heart rate ramps down, and the body is ready to relax.

Figure 5-16 shows the neurochemical organization of the ANS. Both divisions are controlled by acetylcholine neurons that emanate from the CNS at two levels of the spinal cord. The CNS neurons synapse with parasympathetic neurons that also contain acetylcholine and with sympathetic neurons that contain norepinephrine. In other words, cholinergic neurons in the CNS synapse with sympathetic NE neurons to prepare the body’s organs for fight or flight. Cholinergic neurons in the CNS synapse with autonomic ACh neurons in the parasympathetic division to prepare the body’s organs to rest and digest.

Figure 5-16: FIGURE 5-16 Controlling Biological Functions in the Autonomic Nervous System The neurotransmitter in all the neurons leaving the spinal cord is acetylcholine. Left: In the sympathetic division, ACh neurons activate autonomic norepinephrine neurons in the sympathetic ganglia. NE stimulates organs required for fight or flight and suppresses activity in organs used to rest and digest. Right: In the parasympathetic division, ACh neurons from the spinal cord activate ACh neurons in the parasympathetic ganglia near their target organs to suppress activity in organs used for fight or flight and to stimulate organs used to rest and digest. To review the ANS divisions and connections in detail, see Figure 2-30.

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Which type of synapse is excitatory and which inhibitory depends on the particular body organ’s receptors. During sympathetic arousal, norepinephrine turns up heart rate and turns down digestive functions, because NE receptors on the heart are excitatory, whereas NE receptors on the gut are inhibitory. Similarly, acetylcholine turns down heart rate and turns up digestive functions because its receptors on these organs are reversed: on the heart, inhibitory; on the gut, excitatory. Neurotransmitter activity, excitatory in one location and inhibitory in another, mediates the sympathetic and parasympathetic divisions, forming a complementary autonomic regulating system that maintains the body’s internal environment under varying circumstances.

Enteric Nervous System Autonomy

The ENS can act without input from the CNS, which is why it has been called the second brain. It uses all four classes of neurotransmitters, more than 30 transmitters in total. Most are identical to those employed by the CNS. Chief among the small-molecule neurotransmitters used by the enteric nervous system are serotonin and dopamine.

Sensory ENS neurons detect mechanical and chemical conditions in the system. Via intestinal muscles, motor neurons in the ENS control the mixing of intestinal contents. Secretion of digestive enzymes is also under ENS control.

Four Activating Systems in the Central Nervous System

Just as there is an organization to the neurochemical systems of the PNS, there is an organization of neurochemical systems in the CNS. These systems are remarkably similar across a wide range of animal species, which allowed for their identification, first in the rat brain and then in the human brain (Hamilton et al., 2010).

For each of the four activating systems that we describe here, a relatively small number of neurons grouped together in one or a few brainstem nuclei send axons to widespread CNS regions, suggesting that these nuclei and their terminals help to synchronize activity throughout the brain and spinal cord. You can envision an activating system as analogous to the power supply in a house. The fuse or breaker box is the source of the power, and from it transmission lines go to each room.

Just as in the ANS, the precise action of the CNS transmitter depends on the brain region that is innervated and on the types of receptors the transmitter acts on at that region. To continue our analogy, precisely what the activating effect of the power is in each room depends on the electrical devices in that room.

Each of four small-molecule transmitters participates in its own neural activating system—the cholinergic, dopaminergic, noradrenergic, and serotonergic systems. Figure 5-17 locates each system’s nuclei, with arrow shafts mapping the axon pathways and arrowheads indicating axon terminal locales.

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Figure 5-17: FIGURE 5-17 Major Activating Systems Each system’s cell bodies are gathered into nuclei (shown as ovals) in the brainstem. Their axons project diffusely through the CNS and synapse on target structures. Each activating system is associated with one or more behaviors or diseases.

As summarized on the right in Figure 5-17, each CNS activating system is associated with numerous behaviors. Associations among activating systems, behavior, and brain disorders are far less certain. All these relations are subjects of ongoing research. Making definitive correlations between activating systems and behavior or activating systems and a disorder is difficult, because the axons of these systems connect to almost every part of the brain and spinal cord. They likely have both specific functions and modulatory roles. We detail some of the documented relations between the systems and behavior and disorders here and in many subsequent chapters.

Cholinergic System

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Figure 5-18 shows in cross section a rat brain stained for the enzyme acetylcholinesterase (AChE), which breaks down Ach in synapses, as diagrammed earlier in Figure 5-10. The darkly stained areas have high AChE concentrations, indicating the presence of cholinergic terminals. AChE permeates the cortex and is especially dense in the basal ganglia. Many of these cholinergic synapses are connections from ACh nuclei in the brainstem, as illustrated in the top panel of Figure 5-17.

Figure 5-18: FIGURE 5-18 Cholinergic Activation Drawing at left shows the cortical location of the micrograph at right, stained to reveal AChE. Cholinergic neurons in the rat’s basal forebrain project to the neocortex, and the darkly stained bands in the cortex show areas rich in cholinergic synapses. The darker central parts of the section, also rich in cholinergic neurons, are the basal ganglia.

Ian Whishaw

The EEG detects electrical signals the brain emits during various conscious states; see Sections 7-2 and 13-3.

The cholinergic system participates in typical waking behavior, attention, and memory. For example, cholinergic neurons take part in producing one form of waking EEG activity. People affected by the degenerative Alzheimer disease, which begins with minor forgetfulness, progresses to major memory dysfunction, and later develops into generalized dementia, show a profound loss of cholinergic neurons at autopsy. One treatment strategy for Alzheimer disease is drugs that stimulate the cholinergic system to enhance alertness. But the beneficial effects of these drugs are minor at best (Herrmann et al., 2011). Recall that ACh is synthesized from nutrients in food; thus, the role of diet in maintaining acetylcholine levels also is being investigated.

Focus 14-3 details research on Alzheimer disease. Section 16-3 reviews dementias’ causes and treatments.

The brain abnormalities associated with Alzheimer disease are not limited to the cholinergic neurons, however. Autopsies reveal extensive damage to the neocortex and other brain regions. As a result, what role, if any, the cholinergic neurons play in the progress of the disorder is not yet clear. Perhaps their destruction causes degeneration in the cortex or perhaps the cause-and-effect relation is the other way around, with cortical degeneration causing cholinergic cell death. Then too, the loss of cholinergic neurons may be just one of many neural symptoms of Alzheimer disease.

Dopaminergic System

Rhythmic movement helps Parkinson patients restore the balance between neural excitation and inhibition—between the loss and the release of behavior. Some patients participate in a specially designed Dance for PD (http://danceforparkinsons.org/) class for people with Parkinson’s (PwP). Participants at the Mark Morris Dance Center, pictured here, report that moving to music helps them regain muscle control.

Figure 5-17 maps the dopaminergic activating system’s two distinct pathways. The nigrostriatal dopaminergic system plays a major role in coordinating movement. As described throughout this chapter in relation to parkinsonism, when dopamine neurons in the substantia nigra are lost, the result is a condition of extreme muscular rigidity. Opposing muscles contract at the same time, making it difficult for an affected person to move.

Parkinson patients also exhibit rhythmic tremors, especially of the limbs, which signals a release of formerly inhibited movement. Although the causes of Parkinson disease are not fully known, it can actually be triggered by the ingestion of certain toxic drugs, as described in Clinical Focus 5-4, The Case of the Frozen Addict. Those drugs may act as selective neurotoxins that specifically kill dopamine neurons in the substantia nigra.

Dopamine in the mesolimbic dopaminergic system may be the neurotransmitter most affected in addiction—to food, to drugs, and to other behaviors that involve a loss of impulse control. A common feature of addictive behaviors is that stimulating the mesolimbic dopaminergic system enhances responses to environmental stimuli, thus making those stimuli attractive and rewarding. Indeed, some Parkinson patients who take dopamine receptor agonists as medications show a loss of impulse control that manifests in such behaviors as pathological gambling, hypersexuality, and compulsive shopping (Moore et al., 2014).

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CLINICAL FOCUS 5-4

The Case of the Frozen Addict

Patient 1: During the first 4 days of July 1982, a 42-year-old man used 4½ grams of a “new synthetic heroin.” The substance was injected intravenously three or four times daily and caused a burning sensation at the site of injection. The immediate effects were different from heroin, producing an unusual “spacey” high as well as transient visual distortions and hallucinations. Two days after the final injection, he awoke to find that he was “frozen” and could move only in “slow motion.” He had to “think through each movement” to carry it out. He was described as stiff, slow, nearly mute, and catatonic during repeated emergency room visits from July 9 to July 11. (Ballard et al., 1985, p. 949)

Patient 1 was one of seven young adults hospitalized at about the same time in California. All showed symptoms of severe Parkinson disease that appeared very suddenly after drug injection. These symptoms are extremely unusual in this age group. All who were affected reportedly injected a synthetic heroin that was being sold on the streets in the summer of 1982.

J. William Langston (2008) and his colleagues found that the synthetic heroin contained a contaminant called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) resulting from poor technique during its synthesis. The results of experimental studies in rodents showed that MPTP was not itself responsible for the patients’ symptoms but was metabolized into MPP⁺ (1-methyl-4-phenylpyridinium), a neurotoxin.

The autopsy of one individual who was suspected of having died of MPTP poisoning showed that the brain had selectively lost dopamine neurons in the substantia nigra. The rest of the brain appeared healthy. Injecting MPTP into monkeys, rats, and mice produced similar symptoms and a similar selective loss of dopaminergic neurons in the substantia nigra. Thus, the combined clinical and experimental evidence indicates that a toxin can selectively kill dopamine neurons and that the die-off can induce Parkinson disease.

In 1988, Patient 1 received an experimental treatment at University Hospital in Lund, Sweden. Living dopamine neurons taken from human fetal brains at autopsy were implanted into the caudate nucleus and putamen (Widner et al., 1992). Extensive work with rodents and nonhuman primates in a number of laboratories had demonstrated that fetal neurons, before they develop dendrites and axons, can survive transplantation, mature, and secrete neurotransmitters.

Patient 1 had no serious postoperative complications and was much improved 24 months after the surgery. He could dress and feed himself, visit the bathroom with help, and make trips outside his home. He also responded much better to medication. The accompanying diagrams contrast DA levels in the brain of a Parkinson patient before (left) and 2 years, 4 months after implantation (right).

Transplantation of fetal neurons to treat Parkinson disease typically does not work. Unlike the case of the frozen addict, Parkinson disease is associated with a continuing, active process that destroys dopaminergic neurons, including transplanted neurons, in the substantia nigra. Because Parkinson disease can affect as many as 20 people per 100,000, scientists continue to experiment with new approaches to transplantation and with genetic approaches for modifying remaining dopamine neurons (Lane et al., 2010).

These diagrams represent PET scans that contrast DA levels in a Parkinson patient’s brain before, and 28 months after, implantation.

Research from “Bilateral Fetal Mesencephalic Grafting in Two Patients with Parkinsonism Induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyradine (MPTP),” by H. Widner, J. Tetrud, S. Rehngrona, B. Snow, P. Brundin, B. Gustavii, A. Bjorklund, O. Lindvall, and J. W. Langston, 1992, New England Journal of Medicine, 327, p. 151.

Sections 6-3, 6-4, and 12-3 describe drug effects on the mesolimbic DA system. Sections 6-2 and 7-4 discuss schizophrenia’s possible causes and Section 16-4, its neurobiology.

Excessive mesolimbic dopaminergic activity is proposed as well to play a role in schizophrenia, a behavioral disorder characterized by delusions, hallucinations, disorganized speech, blunted emotion, agitation or immobility, and a host of associated symptoms. Schizophrenia is one of the most common and most debilitating psychiatric disorders, affecting about 1 in 100 people.

Noradrenergic System

Norepinephrine (noradrenaline) may participate in learning by stimulating neurons to change their structure. Norepinephrine may also facilitate healthy brain development and contribute to organizing movements. A neuron that uses norepinephrine as its transmitter is termed a noradrenergic neuron (derived from adrenaline, the Latin name for epinephrine).

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In the main, behaviors and disorders related to the noradrenergic system concern the emotions. Some symptoms of major depression—a mood disorder characterized by prolonged feelings of worthlessness and guilt, the disruption of typical eating habits, sleep disturbances, a general slowing of behavior, and frequent thoughts of suicide—may be related to decreased activity of noradrenergic neurons. Conversely, some symptoms of mania (excessive excitability) may be related to increased activity in these same neurons. Decreased NE activity has also been associated both with hyperactivity and attention-deficit/hyperactivity disorder (ADHD).

Serotonergic System

The serotonergic activating system maintains a waking EEG in the forebrain when we move and thus participates in wakefulness, as does the cholinergic system. Like norepinephrine, serotonin plays a role in learning, as described next in Section 5-4. Some symptoms of depression may be related to decreased activity in serotonin neurons, and drugs commonly used to treat depression act on 5-HT neurons. Consequently, two forms of depression may exist, one related to norepinephrine and another related to serotonin.

Likewise, some research results suggest that various symptoms of schizophrenia also may be related to increases in serotonin activity, which implies that different forms of schizophrenia may exist. Decreased serotonergic activity is related to symptoms observed in obsessive-compulsive disorder (OCD), in which a person compulsively repeats acts (such as hand washing) and has repetitive and often unpleasant thoughts (obsessions). Evidence also points to a link between abnormalities in serotonergic nuclei and conditions such as sleep apnea and sudden infant death syndrome (SIDS).

5-3 REVIEW

Neurotransmitter Systems and Behavior

Before you continue, check your understanding.

Question 1

Although neurons can synthesize more than one _______, they are usually identified by the principal _______ in their axon terminals.

Question 2

In the peripheral nervous system, the neurotransmitter at somatic muscles is _______; in the autonomic nervous system, _______ neurons from the spinal cord connect with neurons for parasympathetic activity and with _______ neurons for sympathetic activity.

Question 3

The two principal small-molecule transmitters used by the enteric nervous system are _______ and _______.

Question 4

The four main activating systems of the CNS are _______, _______, _______, and _______.

Question 5

How would you respond to the comment that a behavior is caused solely by a chemical imbalance in the brain?

Answers appear in the Self Test section of the book.