Physiology
SECTION 2: NEURONS AND NEUROTRANSMITTERS
Neuron
Axon
Neurotransmitter molecules
Receptor
Synapse Dendrites
Electrical impulses
FIGURE 2.2 Image of a central neuron receiving input from an upstream neuron and communicating with a downstream neuron through a synapse.
Source: U.S. National Institutes of Health, National Institute on Aging.
neurons, are autoreceptors. Autoreceptors are found on the cell body of the very neuron that released the neurotransmitter. Autoreceptors monitor the behavior of the neuron’s own activity. Autoreceptors con-stitute a negative feedback system, which decreases the probability that
the neuron will release a great deal of neurotransmitters within a short period of time.
The Life Cycle of a Neurotransmitter
Generally, neurons use only one neurotransmitter to communicate. The neuron must produce (synthesize) its neurotransmitter. Once produced, the neurotransmitter must be packaged into vesicles, ready for delivery down the axon and release into the synaptic cleft. How is the neurotrans-mitter removed from the synaptic cleft? Sometimes it is broken down by an enzyme in the synaptic cleft. Some neurotransmitters (serotonin, dopamine, and norepinephrine) are transported back into the presynap-tic neuron by a protein, called a transporter. The neurotransmitter is then ready to be repackaged into a vesicle and reused. Sometimes, not all of the neurotransmitter inside the cell gets repackaged. Some of the neu-rotransmitter can get degraded inside the cell by another enzyme.
How Are the Functions of Neurotransmitters Investigated?
The neurons that utilize serotonin, norepinephrine, acetylcholine, and dopamine are located in clusters. Neuroscientists can destroy (ablate) the entire cluster. After this specific destruction, researchers investigate how the animal’s behavior has changed.
As mentioned, neurons utilizing the neurotransmitters serotonin, norepinephrine, and dopamine (the monoamines) are found in clusters.
Neurons making other types of neurotransmitters are located much more diffusely throughout the brain. For example, neurons utilizing gamma-aminobutyric acid (GABA), the brain’s major inhibitory neurotransmitter, and glutamate, the brain’s major excitatory neurotransmitter, are found throughout the brain.
Presently, for just about every known receptor type, chemicals that will activate the receptor (agonist) or deactivate the receptor (antagonists) are available. Neuroscientists, because they can bore into a live animal’s brain, can provide targeted delivery of an agonist or antagonist and then examine how behavior is affected.
Scientists have procedures for finding the location of neurons with receptors for particular neurotransmitters. They can find out which
neurotransmitter any neuron is waiting for. Antibodies are molecules that bind to specific molecules, in our case, a receptor for a particular neurotransmitter. Biologists know how to make antibodies to receptors for a particular neurotransmitter. They can tag the antibody with a mol-ecule that shines when given a light source. Slices of the brain can be prepared. The antibody sticks to the receptor. It is then possible to look at where the antibody sticks in the brain to identify which neurotransmitter the neurons in various locations are waiting for.
For each neurotransmitter, there are multiple subtypes of receptors (each produced from a different gene) waiting for that neurotransmit-ter. Receptor subtypes vary in their sensitivity to the neurotransmitter, that is, their affinity for the neurotransmitter. Some receptor types need a great amount of neurotransmitter to respond to the message. Others, with high affinity, respond to low amounts of the neurotransmitter.
Particular subtypes of receptor can also vary in terms of the impact they will have on the receiving neuron. For the most part, this book will not detail receptor subtypes. However, if there is a number next to the recep-tor (e.g., dopamine receprecep-tor type 2), this just provides information on the particular receptor subtype.
Because much of the discussion that follows refers to particular sub-structures in the brain. Table 2.1 lists the basic function of most of the structures mentioned in this chapter and elsewhere in the text.
Figure 2.3 provides a map of particular nuclei found in the brain stem.
Figure 2.4 offers a side or lateral view of outer brain structures. Figure 2.5 is a view of brain structures from the front facing the brain, called a coronal view. Figure 2.6 gives a lateral view of deeper brain structures.
Figure 2.7 offers a view of what are referred to as limbic structures, which will be further explained later in the text. These images can be consulted to determine the location of particular structures in the brain.
Specific Neurotransmitters
In Chapter 3, we will cover psychotropic drugs. Psychotropic drugs are drugs that alter mood or behavior. Psychotropic drugs are generally referred to as agonists or antagonists for a particular neurotransmitter system. As previously pointed out, an agonist increases the function of
TAbLE 2.1
brief Explanation of Some Major brain Structures
Structure General Function
Amygdala Evaluates the emotional significance of stimuli;
best known for its role in signaling fear Basal ganglia: caudate,
putamen, globus pallidus, subthalamic nucleus
Involved in fine-tuning movement; involved in habits
Bed nucleus of the stria terminalis (BNST)
Output structure of the amygdala; whereas the amygdala is needed for fear, the BNST is needed for anxiety (distinction is explained in the section Creating Anxiety/Fear in this chapter)
Brain stem: medulla, pons,
midbrain Area of the brain containing nuclei of the autonomic nervous system; nuclei producing the catecholamines and the raphe producing serotonin
Cerebellum Coordinates fine movements providing feedback on motor plans generated
elsewhere in the brain; plays role in allocating attention
Corpus callosum Fiber tracks connecting the right and left hemispheres of the cortex
Dorsal anterior cingulate Registers pain from psychological and physical sources; sometimes referred to as an error detector or a conflict monitor
Fornix Output structure extending from the
hippocampus to the hypothalamus
Habenula Area in the brain that receives information from the retina to set up wake–sleep cycles; plays a major role in learned helplessness
Hippocampus Creates and retrieves memories about what happened where (episodic memories); restrains the HPA
Hypothalamus Regulates appetite and thirst, controls pituitary gland function, controls the autonomic response to complex stimuli; some areas involved in sexual behavior, caretaking of young, and rage
Insula Area that receives information from internal organs; needed to experience disgust
(continued)
TAbLE 2.1 (continued)
Medial forebrain bundle Axons from ventral tegmental area, raphe, and locus coeruleus and other brain stem nuclei projecting broadly and with output to the lateral hypothalamus; axons carry information between areas
Nucleus accumbens Area that receives input from the ventral tegmental area
Periaqueductal gray Area around the aqueduct (hollow space filled with cerebrospinal fluid in midbrain); plays a role in sexual function, caring for young, and freezing behavior (ventral area) or fighting/
fleeing (dorsal area)
Pineal gland Responds to information about daylight; releases melatonin to increase the propensity toward sleep
Pituitary gland Master gland in the body; releases hormones that influence output of other glands in the body.
ACTH, a hormone that controls cortisol release, is discussed in this chapter
Striatum Region of the mid brain; the dorsal striatum contains the basal ganglia; the ventral striatum contains the nucleus accumbens
Substantia nigra Area of dopaminergic neurons in the midbrain that project to the basal ganglia in the dorsal striatum
Thalamus The “Delta hub” of the brain; the area into which sensory information is fed before it is sent to areas of the cortex, which will interpret the information
Ventral tegmental area Area in the midbrain containing dopaminergic neurons that project to the nucleus accumbens and broadly to the cortex
Ventricles Hollow spaces in brain filled with cerebrospinal fluid
ACTH, adrenocorticotropic hormone; HPA, hypothalamic–pituitary–adrenal axis.
the neurotransmitter; an antagonist decreases the function. In this chap-ter, we will cover some of the major neurotransmitters in the brain that inform where the neurons that synthesize or make the neurotransmitters are found and what the function of the neurotransmitter might be. This information is presented so that when, for example, you are told that a
FIGURE 2.3 Brain stem.
Source: Wolters Kluwer: Lippincott Williams & Wilkins; published in Lane et al. (2009b).
Ventral tegmentum Locus coeruleus Periaqueductal gray Parabrachial nucleus Raphe nuclei Solitary tract nucleus Dorsal motor nucleus Nucleus ambiguus Medulla
Pons Thalamus
FIGURE 2.4 Lateral view of outer brain structures.
Source: Wolters Kluwer: Lippincott Williams & Wilkins; published in Lane et al. (2009b).
Primary motor cortex
Primary sensory cortex
Parietal
Occipital Temporal
Cerebellum Insula
Orbital prefrontal cortex
Parietal
Occipital Temporal
Cerebellum
FIGURE 2.5 Coronal view of the brain.
Source: Wolters Kluwer: Lippincott Williams & Wilkins; published in Lane et al. (2009b).
Corpus callosum
Caudate nucleus Putamen
Globus pallidus Nucleus accumbens
Amygdala Hypothalamus
Insula Thalamus
Basal gangila:
FIGURE 2.6 Midsagittal view of the brain.
Source: Wolters Kluwer: Lippincott Williams & Wilkins; published in Lane et al. (2009b).
Putamen Corpus callosum
Prefrontal cortex Forebrain
Nucleus accumbens Amygdala
Pituitary Hippocampus Midbrain
Pons Cerebellum Medulla Hindbrain
Caudate Fornix
Cingulate cortex Hypothalamus
Thalamus
Ventral tegmentum
drug is a dopamine agonist in Chapter 3, you can predict how the drug will affect mood and behavior and you can predict which brain struc-tures might be impacted by the drug.
Dopamine
There are four major circuits for dopamine in the brain (Figure 2.8). One pathway (the tuberoinfundibular pathway) controls the release of hor-mones from a gland located inside the brain (the pituitary). (The path-way is at the base of the hypothalamus, just above the pituitary.) In this pathway, dopamine inhibits the release of prolactin, a hormone that con-trols milk production in the breast (Dunlop & Nemeroff, 2007). With dop-amine depletion, as occurs in heavy cocaine abusers or with blockade of dopamine receptors by antipsychotic drugs, breast development in men may occur.
A second dopamine pathway (the nigrostriatal pathway) is important for controlling movement and habit learning. Neurons in the midbrain (substantia nigra pars compacta) project to the striatum, an area control-ling movement. In Parkinson’s patients, the midbrain substantia nigra neurons die. The result is an extreme movement disorder. The muscles are flexed, but are unable to move. Resting tremor and pill-rolling move-ments in the fingers are observed. The facial muscles are motionless and eye blink is gone. Disruption of this pathway also impairs habit learning and the learning of stimulus response associations (Dunlop & Nemeroff, FIGURE 2.7 Limbic structures of the brain.
Source: Wolters Kluwer: Lippincott Williams & Wilkins; published in Lane et al. (2009b).
Anterior cingulate cortex
Subgenual anterior cingulate cortex Orbital
prefrontal cortex
Hypothalamus
Amygdala
Hippocampus Fornix Posterior cingulate cortex Mid-cingulate cortex
2007; O’Doherty et al., 2004; Treadway & Zald, 2011). Antipsychotic drugs, which are dopamine antagonists, also cause Parkinson’s disease symptoms.
A third pathway (the mesolimbic pathway) has been intensely stud-ied because all drugs of abuse (alcohol, nicotine, cocaine, amphetamine, and opioids) increase activity in this pathway. Here, dopamine neurons from the ventral tegmental area (VTA; in the midbrain) project to the nucleus accumbens. Dopamine is released into the nucleus accumbens with ingestion of drugs of abuse, the opportunity for food, opportu-nities for copulation, and the occurrence of unexpected rewards (see Chapter 8, “Addictions”).
Consideration of the context in which dopamine release occurs led to some hypothesizing about the significance of dopamine. The first hypothesis was that dopamine release was associated with pleasure.
This hypothesis was discarded because of the work of Kent Berridge.
First, Berridge and others observed that when an animal is about to be shocked, dopamine is also released into the nucleus accumbens (Faure, Reynolds, Richard, & Berridge, 2008; Pruessner, Champagne, Meaney, &
Dagher, 2004; Salamone, Correa, Farrar, & Mingote, 2007). Second, FIGURE 2.8 The dopaminergic systems. Midline sagittal section demon-strating the projections. Inset: Axial section of the midbrain demondemon-strating the location of the dopaminergic neurons.
Source: Nadeau et al. (2004).
Projections to the
striatum Nigrostriatal
dopaminergic system
Substantia nigra
Substantia nigra Ventral tegmental
area Ventral
tegmental area Mesolimbic dopaminergic
system Mesocortical
dopaminergic system Projections
to the ventral striatum
Amygdala
dopamine release occurs as the animal works to find food or sex, not while the animal is consuming food or copulating (Baldo & Kelley, 2007;
Berridge & Robinson, 1998). Finally, when Berridge and colleagues wiped out the dopamine neurons in the VTA, the animal clearly displayed signs of enjoyment if force fed; however, the animal would no longer work for the food (Berridge & Robinson, 1998; Robinson & Berridge, 2008).
Salamone, Correa, Farrar, and Mingote (2007) showed that when dop-amine input into the nucleus accumbens is inhibited, animals become lazy and lethargic. The current view is that dopamine is the neurotrans-mitter of motivation. It is the neurotransneurotrans-mitter of “wanting” rather than the neurotransmitter for “liking” (Berridge, 2009b).
The fourth pathway (the mesocortical pathway) refers to neurons from the VTA that project broadly throughout the cortex, including to the hip-pocampus (where memories are formed) and the prefrontal cortex (PFC) (where executive function occurs; Treadway & Zald, 2011). In the pocampus, dopamine plays a major role in changing synapses in the hip-pocampus to create memories. When these dopaminergic VTA neurons are active, the animal is more alert and maintains vigilance. The animal is ready to learn about the environment, particularly about how stimuli are related to consequences (O’Doherty et al., 2004). As stated by Der-Avakian and Markou (2012, p. 5), “one role of dopamine is to transfer positive incentive value from the reward to the cue that predicts reward.”
Another way of characterizing the VTA projections to the prefrontal cortex is that dopamine is involved in appreciating the emotional significance of stimuli (Dunlop & Nemeroff, 2007; Rilling, Sanfey, Aronson, Nystrom, &
Cohen, 2004). The VTA dopaminergic neurons (in addition to the “want-ing neurons”) are sometimes referred to as the “incentive salience sys-tem.” The projections from the VTA to the cortex are about learning what is important, that is, assigning significance to the stimuli that surround us (Robinson & Berridge, 2008).
A second function of dopamine in the mesocortical pathway may be to focus attention and maintain information in working memory (short-term memory is required to hold ideas in awareness sufficiently long to figure things out). In the cortex, receptors are primarily of the D1 type.
They are found on GABA neurons as well. They probably function to help a person ignore irrelevant stimuli (Ledoux, 2014).
Panksepp, Wright, DÖbrÖssy, Schlaepfer, and Coenen (2014) summarize the dopamine tracks emerging from the VTA (called the medial forebrain
bundle) as “a general-purpose neuronal system that coaxes animals and humans to move energetically (enthusiastically) from where they are to the places where they can find and consume resources needed for sur-vival. It permits learning by readily assimilating predictive reward in the world” (Panksepp et al., 2014).
Serotonin
Serotonin-producing neurons are located at the midline of the brain stem in an area called the raphe (Figure 2.3). Research investigation of the sero-tonin system has yielded puzzling, contradictory results. For example, particular antidepressant drugs increase levels of serotonin. Presumably, antidepressants decrease distress, but in the short term these drugs can increase anxiety and precipitate suicidal ideation. The research of Chris Lowry and colleagues (Hale & Lowry, 2011; Hale, Shekhar, & Lowry, 2012) has cleared up some of the mystery. Lowry identified multiple serotonergic circuits for the neurons in the raphe. One of these circuits creates anxiety, whereas other circuits enhance regulation of emotion and decrease anxiety. Each circuit operates independently of other circuits.
The function of serotonin is therefore difficult to characterize, because it plays different roles depending on the circuit.
In the section on brain circuits in this chapter (Section 4: Circuits:
Creating Learned Helplessness), the learned helplessness circuit will be described. When subjected to uncontrollable shock, animals exhibit anx-iety and depression. Serotonin is vital for the creation of learned help-lessness. If serotonergic neurons in a particular section of the raphe (the caudal part of the dorsal raphe) are destroyed, the animal will not dis-play learned helplessness behaviors of anxiety and “giving-up” (Hale, Raison, & Lowry, 2013; Maier & Watkins, 2005).
Another set of serotonergic neurons in the raphe (interfascicular part of the dorsal raphe nucleus and neurons near the ventrolateral peri-aqueductal gray [PAG]) are the antipanic neurons (Hale & Lowry, 2011;
Hale et al., 2012; Hanusch et al., 2013; Paul, Johnson, Shekhar, & Lowry, 2014). They project to the prefrontal cortex and to the dorsal PAG. A reli-able way to induce panic in most animals is to infuse the animal with lactic acid. Those animals that fail to panic exhibit stronger activity of the serotonin antipanic neurons (Hale et al., 2012, 2013). The antipanic serotonergic neurons respond to an anti-inflammatory white blood cell
hormone (interleukin 10, discussed later) and to warm and cold tempera-tures. This may explain why sitting in warm sunlight reduces anxiety.
The brain contains many hollow spaces (called ventricles) that are filled with cerebrospinal fluid (CSF). Yet another set of serotonergic neu-rons control cilia (hair-like projections) on the cells lining the ventricles.
Here serotonin increases the movement of the cilia so that CSF is moved through the system at a faster rate, allowing for pathogens or toxic chem-icals associated with stress to be quickly removed from the brain. Finally, another group of serotonergic neurons controls sleep stages (Hale &
Lowry, 2011).
In the literature, many studies have involved the assessment of sero-tonin metabolites in the CSF. A consistent finding is that those with low levels of serotonin metabolites in their CSF are more impulsive and aggres-sive (Korte, Koolhaas, Wingfield, & McEwen, 2005). Those who have been violent or who have committed suicide in a violent manner also are dis-tinguished by low levels of serotonin metabolites in their CSF (Davidson, Putnam, & Larson, 2000). Unfortunately, measuring serotonin metabolites in the CSF does not inform about which circuit the metabolite came from.
However, the findings suggest that some circuits that use serotonin may perform an inhibitory function on negative mood or impulses.
Norepinephrine/Noradrenaline
The locus coeruleus is a group of neurons in the brain stem that is the major producer of norepinephrine in the brain (Figure 2.3). Neurons in the locus coeruleus fire more rapidly during high arousal states as contrasted with low arousal states (Brennan & Arnsten, 2010). During normal levels of arousal, neurons in the prefrontal cortex are activated by norepinephrine through a specific type of norepinephrine receptor. These normal levels of arousal improve memory (Brennan & Arnsten, 2010). Under stress, neu-rons in the locus coeruleus increase the tonic firing rate to even higher lev-els. Under stress, norepinephrine activates another set of norepinephrine receptors in the prefrontal cortex and impairs memory (Brennan & Arnsten, 2010). Thus, norepinephrine can have opposing effects on the PFC depend-ing on the rate of release and the subtype class of norepinephrine receptor that receives the message. At midlevels of arousal, memory improves. At very high levels, memory deteriorates (Brennan & Arnsten, 2010).
Norepinephrine is also the signal to the astrocytes (a type of supporting cell) to release fuel (which can be converted to sugar) for working neu-rons. Dysfunction of the release of fuel by the supporting cells has been implicated in attention deficit hyperactivity disorder (ADHD; Killeen, Russell, & Sergeant, 2013). Norepinephrine also tones down inflamma-tion in the brain by influencing microglia, a type of white blood cell that is resident in the brain (Kalinin et al., 2012). It is known that norepineph-rine neurons are destroyed early on in Alzheimer’s disease, allowing for more inflammation in the brain. Inflammation, which entails activated white blood cells spewing out damaging molecules, is a big factor in Alzheimer’s disease (Levey, 2014).
Acetylcholine
Acetylcholine is released in the brain, where it plays a role in memory.
Acetylcholine is also used by neurons outside the brain. Acetylcholine is the neurotransmitter involved in the division of the peripheral nervous system that controls internal organs (the involuntary, autonomic nervous system). In the voluntary peripheral nervous system, acetylcholine is the neurotransmitter that commands striated muscle tissue so that one can move around (Nolte, 2009).
As mentioned previously, all drugs leading to compulsive use result in the release of dopamine into the nucleus accumbens (see Chapter 8,
“Addictions”). Nicotine, for example, is a drug that operates on acetylcho-line receptors (the nicotinic subtype). In the brain, nicotinic acetylchoacetylcho-line receptors (α4β2 receptors) are present on dopaminergic neurons and con-trol the release of dopamine into the nucleus accumbens (Lüscher, 2013;
Purves et al., 2012). Thus, acetylcholine plays a role in appetitive struc-tures, largely dopaminergic strucstruc-tures, described later.
Glutamate
Glutamate is the brain’s major excitatory neurotransmitter. Although glu-tamate uses both metabotropic and ionotropic receptors, the ionotropic receptors are relevant for the excitatory function. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and N-methyl-d-aspartate (NMDA) receptors are two types of receptors for glutamate that
open an ion channel. Interestingly, the ionotropic receptors, AMPA and NMDA receptors, work together. NMDA receptors are called silent recep-tors unless they are near an AMPA receptor. When glutamate binds to an AMPA receptor and sufficient ions move through the AMPA channel, then a magnesium atom blocking the NMDA receptor-associated chan-nel is displaced out of the ion chanchan-nel. When glutamate next binds to the NMDA receptor, calcium enters the cell making it very likely to fire. After this, the AMPA receptor moves nearer to the NMDA receptor, strength-ening the sensitivity of the neuron to glutamate. The synchrony between the NMDA and AMPA receptors makes their conjoint activity “coinci-dence detectors.” AMPA and NMDA receptors are critical players in the formation of long-term potentiation, meaning the way in which the brain encodes new memories (Purves et al., 2012). The NMDA receptor also needs glycine to bind on part of the receptor to respond to glutamate.
Glutamate is key to formation of new memories and learning. Because most of us want to improve our ability to learn, neuroscientists have focused on understanding glutamate. Neuroscientist Joe Tsien and col-leagues created a mouse called the “Doogie Howser mouse” (in reference to the 1980 television program about a boy genius) by mutating the recep-tor for glutamate (Tang et al., 1999). The mutant mouse then performed much better on thinking tasks. Tsien speculated about why nature had not just created all mice as super-smart. The trade-off is that too much signaling through a glutamate receptor provokes a seizure. There is a critical threshold between brilliance and death from a seizure. Much cur-rent investigational work on performance-enhancing drugs involves glu-tamate receptors; it is a risky business.
After release of glutamate into the synaptic cleft, glial cells (support cells) pick up the excess glutamate (Nolte, 2009, p. 193). Astrocytes, a type of support cell, which are near the blood vessels in the brain, can thus detect where in the brain activity is occurring and shift blood supply to brain areas where more activity is occurring (Nolte, 2009, p. 135).
Gamma-Aminobutyric Acid
GABA is the brain’s major inhibitory neurotransmitter. GABA neurons are dispersed throughout the brain. When GABA binds to its receptor, a channel for chloride opens. With more chloride inside the neuron, the neuron is less likely to fire. Although GABA generally inhibits neurons,
sometimes GABA’s function is to ensure that only a strong signal from inputting neurons activates receiving neurons (Saar, Reuveni, & Barkai, 2012).
Cannabinoids
The brain has ligands (binding partners) that will bind at cannabinoid receptors (marijuana receptors). The molecules produced by the brain that bind at receptors for marijuana are called endocannabinoids, “endo” refer-ring to internal or within. Unlike many other neurotransmitters, which are modifications of amino acids (building blocks for proteins), endocannab-inoids are altered polyunsaturated fatty acid chains. They are released after cleavage from the neuron’s cell membrane. Endocannabinoids are not packaged into a vesicle. Cannabinoid receptors, which are metabotro-pic, are found in many areas of the brain. In addition to neurons, recep-tors are also found on support cells in the brain (astrocytes, microglia, and oligodendrocytes; Marco et al., 2011).
Cannabinoids play major roles in decreasing anxiety. They are essen-tial for being able to extinguish fear memories. They potentiate GABA inhibition in the amygdala, a structure involved in anxiety (Figure 2.7 of the limbic system showing structures involved in emotional activity.) They decrease the stress hormone (cortisol). They also operate in the hypo-thalamus, a structure involved in the control of food intake (think, the munchies). Particular enzymes (hydrolases) degrade the endocannabi-noids (Marco et al., 2011).
Opioids
Opioid receptors were so named because opium binds to these receptors.
Opiate derivatives (morphine, heroin, and codeine) also bind to these receptors. There are natural opiates in the brain: endorphins, enkepha-lins, and dynorphins. There are three types of opioid receptors: mu receptors for the natural endorphin’s binding partners, delta receptors for the natural enkephalin’s binding partners, and kappa receptors for the natural dynorphin’s binding partner.
Opioid receptors are found in many places, including the spinal cord, where they decrease pain transmission. The dorsal anterior cingulate
cortex (dACC), an alarm center in the brain, is full of opioid receptors where opioids function to decrease alarm and physical pain. In fact, persons carrying a particular allele for the mu-opioid receptor expe-rience both more physical and emotional pain. They exhibit stronger activation of the dACC in response to social rejection (Way, Taylor, &
Eisenberger, 2009).
Opioid receptors are found on the GABA interneurons in the caudal dorsal raphe, the serotonergic structure involved in producing anxiety and defeat after exposure to uncontrollable shock (called learned help-lessness). Opioids increase the release of GABA into the serotonin-releas-ing neurons, whose cell bodies are found in the caudal dorsal raphe. The serotonergic neurons in the caudal dorsal raphe are inhibited by opioids.
The anxious behavior following inescapable shock is reduced (Maier &
Watkins, 2005).
In the VTA, opioid receptors are found on the GABA neurons. GABA neurons in the VTA synapse onto dopaminergic neurons. GABA inhib-its dopamine release from dopaminergic neurons, which release into the nucleus accumbens. The opioids decrease the release of GABA from the GABAnergic neurons. When GABA release is inhibited, the inhibition of dopamine release is gone. Effectively, opiates are a break on a break.
Thus, when opiates hit their receptors in VTA, more dopamine is released from VTA neurons into the nucleus accumbens. The effect increases loco-motion and movement (Lüscher, 2013).
As will be discussed in the section on pleasure (see Section 5: Emotions:
Specific Emotions; Pleasure), opioids play a role in mediating the sen-sual pleasure produced by activity in another area of the brain (the ven-tral pallidum and parabrachial area; Berridge, 2009a, 2009b; Berridge &
Kringelbach, 2008; Trezza, Baarendse, & Vanderschuren, 2010).
Dynorphin, a naturally occurring opiate, is also produced in the nucleus accumbens. Dynorphin counters the effects of endorphins and enkepha-lins. Dynorphins decrease dopamine release and generally increase dis-comfort (Bruijnzeel, 2009).