Neuromodulation, Emotional Feelings and Affective Disorders

Dopamine: Pleasure

Dopamine has been related to brain rewarding processes since 1980, when the hedonic hypothesis was formulated (Bozarth et al., 1980[9]; Bozarth and Wise, 1980[10]). DA is a rewarding signal for salient stimuli such as food, sex and other needs. The reward depends on the needs of subjects, which were independently classified by Maslow (Maslow, 1943[63]).

Many pharmacological and behavioural studies on intracranial self-stimulation established the important role of medial prefrontal rewarding DA systems in positively motivated behaviour (Mora and Ferrer, 1986[70]). Drug addiction reshapes the reward system by affecting DA release and reuptake; decreased striatum DA responses were reported in detoxified cocaine abusers (Volkow et al., 1997[103]). Individuals with a history of abuse of alcohol, cocaine, heroin, or methamphetamine display lower levels of DA receptor binding compared to non-abusers (Volkow et al., 1997[104]; Diana, 2011[24]; Ron and Jurd, 2005[87]).

Over the past decades, theories concerning the role of midbrain DA on behaviour have changed. Although there is no doubt that DA is involved in hedonic experiences, its effects can be divided into more detailed aspects of behaviour (Redgrave et al., 1999[85]; Willuhn et al., 2010[106]). For example, global DA depletion does not impair the hedonic response to a primary reward such as preference for sucrose over water. These observations have led to considering the contribution of DA to motivated behaviour towards desired goals.

Mesolimbic DA is also involved in aversively motivated behaviours. Medial hypothalamic stimulation, which has been considered to cause a primary aversive state, causes a significant decrease in extracellular DA (Rada, Mark, and Hoebel, 1998[83]). However, when rats press a lever to escape the stimulation, DA levels in the nucleus accumbens (NAc) increased instead. This is similar to a finding by (Cabib and Puglisi-Allegra, 1994[11]) that when animals were allowed to control a painful shock experience, NAc DA metabolites increased.

Schultz et al. (1997[96]) studied the role of DA for reward and prediction in conditioning experiments, proposing that DA is a signal of salience of the stimulus; for example, DA neurons are activated when animals touch a small morsel of apple or receive a small quantity of fruit juice as reward. These phased activations do not discriminate between different types of rewarding stimuli, but aversive stimuli like air puffs to the hand or drops of saline to the mouth do not cause the same transient activations.

The unconditioned reaction can be connected to other stimuli.[13] For example, if the presentation of light is consistently followed by food, a rat will learn that light predicts the future arrival of food. Only the light with food will induce DA release. The prediction-based explanation is that the light fully predicts the food that arrives. Surprisingly, once the stimulus-reward association is learned, reward delivery no longer elicits an increase in the activity of DA neurons, as expected (Schultz et al., 1997[96]). It appears therefore that learning is driven by deviations or ‘errors’ between the predicted time and amount of rewards. Hence, the authors proposed that DA encodes expectations about external stimuli or reward, especially when it is uncertain or deviation or error (predication error).

From the above experimental evidence, we hypothesize that DA is a signal for salient stimuli such as food, sex and other needs, participating in the generation of the feeling of pleasure.

Serotonin (5-hydroxytryptamine): Displeasure

5-hydroxytryptamine has been related to depression for decades, mostly because of being targeted by antidepressant drugs; however, most prescribed drugs for depression do alter 5-HT levels. 5-HT is mostly released in the gut (about 90% of body release), where enterochromaffin cells release it in response to noxious substances in the food, making the gut move faster, thus causing vomiting or diarrhoea. Plant seeds with 5-HT exploit this reaction to speed the passage of seeds through the digestive tract. Animals such as wasps and scorpion can induce pain by means of 5-HT and other substances present in their venom.

Even in phylogenetically distant animals like the mollusc, 5-HT release is involved in the regulation of avoidance behaviour (Inoue et al., 2004[44]). Drugs that block 5-HT receptors make the body unable to shut off appetite and are associated with increased weight gain (Wheeler et al., 1996[105]). People with low 5-HT are at risk of showing aggressive behaviour, not caring about punishments (LeMarquand et al., 1998[57]).

It was found that depressed subjects with low cerebrospinal fluid (CSF) concentrations of a 5-HT metabolite were found to display a history of suicide attempts (Roy et al., 1990[88]); Engstrom et al., 1999[28]; Jokinen et al., 2007[53]; Lidberg et al., 1985[59]; Moberg et al., 2011[68]). The correlation between low CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations and increased risk for suicide has become one of the most reproducible findings in biological psychiatry (Engstrom et al., 1999[28]; Jokinen et al., 2007[53]; Lidberg et al., 1985[59]; Moberg et al., 2011[68]).

Some other studies have suggested that the deficits in 5-HT functioning within the frontal cortex may underlie other behaviour disturbances, such as impaired impulse control and increased incidence of violent episodes (Higley et al., 1996[39]; Miller, 1992[67], Holmes et al., 2002[41]; Siegel et al., 2007[98]).

Some studies even suggested that low 5-HIAA in the CSF is a marker for the predisposition to a wide array of psychopathological problems such as impulse control, suicide, impulsive fire setting, violent criminal behaviour, alcohol intake and dependence (Plutchik, 1962[82], Virkkunen et al., 1987[102]; Carlborg et al., 2009[14]).

In the central nervous system (CNS), 5-HT is mostly produced by neurons in the raphe nuclei and released into the extracellular space between neurons in medial prefrontal cortex, amygdala and hippocampus. It is involved in appetite, sleep and mood (Pakalnis et al., 2009[75]). Opinion on these functions has been revised in the past few years. One of the main arguments related to insomnia was based on the destruction of the midbrain raphe nuclei in the cat (Saponjic, 2011[91]); but it is currently accepted that 5-HT predominantly promotes wakefulness and inhibits rapid eye movement (REM) sleep (Monti, 2011[69]), because the activity of serotonergic neurons of the dorsal raphe nuclei decreases from waking through slow wave sleep to REM sleep. Only under some circumstances does it contribute to increase in sleep propensity (Monti, 2011[69]).

5-hydroxytryptamine may indirectly act as a tranquilliser. Tryptophan, which is easily converted to 5-HT in the body, is used as a tranquilliser; and it has been proved that 5-HT is involved in the biology of torpor and hibernation, and inhibits mitochondrial respiration. Abundant evidence points to a decrease of 5-HTergic activity in anxiety, phobias, panic attacks, post-traumatic stress, and depression disorders based on effects of treatments that enhance 5-HT. The most popular kind of antidepressant increases the action of 5-HT in the brain; however, it has been difficult to establish a primary role for 5-HT deficiency in the above diseases (Fernandez and Gaspar, 2012[30]).

Selective 5-HT reuptake inhibitors may also have depression-like side effects, such as apathy, nausea/vomiting, drowsiness, weight loss and diminished libido. Actually, these drugs also affect other modulators (DA, NE); for example, in the first generation of antidepressants, the monoamine oxidase inhibitors had a similar effect on all catecholamines. Pharmaceutical companies have been looking for 5-HT-specific reuptake inhibitors. However, while it is true that these drugs increase the actions of 5-HT, it is hard to find their effects on depression. These drugs’ improvement of depressive symptoms, sometimes better than placebo, might be the result of increased social interaction subsequent to a reduction in fear and avoidance (Dempsey et al., 2009[22]). Injecting 5-HT or increasing its activity can cause sedation and helplessness.[48] Learned helplessness, a behavioural depression caused by exposure to inescapable stress, is considered to be an animal model of human depressive disorder. Cortical 5-HT excess is causally related to the development of learned helplessness (Petty et al., 1994[80]), and learned helplessness patients have high levels of 5-HT (Kobayashi et al., 2008[54]; Petty, Kramer and Moeller, 1994[79]; Petty et al., 1994[80]).

Chemicals that antagonize 5-HT do seem to function as antidepressants (Martin, Gozlan and Puech, 1992[62]). It has been found that l-tryptophan depresses while levodopa intensifies emotional reactivity, the former lowering the level of endogenous 5-HT. And it was also found that lack of 5-HT enhances the emotional reactivity to learned fear memories (Dai et al., 2008[18]). The major benefit of 5-HT drugs seems to be alleviating anxiety.

Genetic studies also support this viewpoint. Pet1 is specifically expressed in the 5-HT neurons and directly activates the transcription of genes implicated in the serotonergic machinery.[73] Compared to WT and Pet +/− littermates, Pet −/−mice have an 80% reduction in 5-HT tissue levels, with no significant changes in the levels of DA (Hendricks et al., 2003[38]). These mice showed normal ambulatory activity in a novel arena; however, they explored more the aversive areas, which suggests lacking of a dislike marker due to low 5-HT. In addition, these mice showed increased levels of aggression as measured by the resident-intruder assay (Hendricks et al., 2003[38]).

The hydroxylation of tryptophan into 5-hydroxy-tryptophan is the rate-limiting step in the synthesis of 5-HT. Two isoforms of the enzyme tryptophan hydroxylase, Tph1 and Tph2, are responsible for catalysing this reaction. Tph2 is exclusively expressed in the 5-HT neurons of the raphe nuclei. Genetic deletion of Thp2 was obtained in several groups. The depressive-like behaviour of the Thp2 −/− mice was evaluated (Savelieva et al., 2008[94]), which finds that these mice spent less time immobile in the test, a result that is suggestive of an antidepressant effect.

Another example is the vesicular monoamine transporter (Vmat) 2, which transports monoamines into the synaptic vesicle. The homozygote Vmat2 −/− induced a major depletion of all monoamines and died within a few days after birth (Zhang et al., 2005[107]). In contrast, heterozygote Vmat2 +/− mice, having a 34% decrease in brain 5-HT, were viable and showed normal growth rate and behaviour. These animals also showed a significant reduction in the level of DA 42% and NE, 23%. Interestingly, they showed pronounced depressive-like phenotype characterised by increased immobility (Fukui et al., 2007[31]). In contrast, no anxiety phenotype was detected in a large battery of tests. To overcome the lack of specificity, a conditional knockout mouse was created by crossing Sert mice with Cmat2, allowing for the deletion of the Vmat2 gene specifically in 5-HT neurons (Narboux-Neme et al., 2011[72]). No depression-like phenotype was observed; instead they showed less latency to reach out for the food pellet in a novelty suppressed feeding test, suggesting an anxiolytic-like phenotype.

Overall, both pharmacological and genetic studies reviewed above suggest that 5-HT action is related to generation of the feeling of displeasure.

Norepinephrine: Fear/anger

An event is anticipated (expected) or not anticipated (surprising). If what happens was anticipated, people feel calm; if it happens surprisingly, the first reaction is to be scared and angry. For example, the door was knocked very loudly while you were focusing on your reading; the first reaction is that you become scared, and then angry. After opening the door, you may feel happy (if the person knocking the door is someone you like) or sad (if the person is not liked). The neuromodulator underlying both fear and anger is NE.

In the peripheral autonomous nervous system, NE acts as a sympathetic neurotransmitter. Together with hypothalamic-pituitary-adrenal hormones, NE induces the stress that underlies ‘fight-or-flight’ responses, directly increasing heart rate, triggering the release of glucose, and increasing blood flow to skeletal muscles. In the CNS, the NE system is considered to play an important role in attention, sleep/wakefulness, emotion and central responses to stress. It might also be involved in anxiety disorders, especially in panic/fear disorders (Itoi and Sugimoto, 2010[46]).

Norepinephrine release induces fight/anger or flight/fear, which are early evolutionary adaptations to allow better coping with dangerous and unexpected situations. When a deer meets a lion, NE is released in both brains, but the reaction of the deer is flight/fear while the reaction of a lion is fight/anger. These are twin emotions supported by NE release.

Norepinephrine is released from the locus coeruleus (LC) in the case of stressful events to keep the brain alert to the unexpected stimuli and inhibit irrelevant stimuli, a function that has been described as increasing ‘signal to noise’ rate in the afferents[23] (Morilak et al., 2005[71]; Avery et al., 2012[5]; George et al., 2013[33]).

The LC is the largest NE nucleus in the brain, projecting axons to almost all brain regions. Many studies have been conducted to show its implication in sleep, attention and alertness, anxiety and stress response (Bremner et al., 1996a[11], 1996b[12]; Itoi, 2008[45]). Robust activation of the LC has been reported after stressful stimuli in cats: an increase in firing was observed following exposure to noxious air puff stimuli or visual threat (Rasmussen, Morilak, and Jacobs, 1986[84]). Electrical stimulation of LC resulted in behaviours observed in fearful or threatening situations in the wild (Levine, Litto, and Jacobs, 1990[58]; Sara and Bouret, 2012[92]).

It has been recognised that the amygdala plays a prominent role in stress-elicited fear and anxiety (LeDoux, 1998[56]). Electrical stimulation of the amygdala promotes stress-like behavioural and autonomous reactions, whereas ablation shows a marked increase of tameness, loss of motivation, decrease of fear response to aversive stimuli and a more rapid extinction of conditioned avoidance responses acquired preoperatively (Shumake et al., 2010[97]). NE and DA may be released together to induce anger and aggressive behaviours. The interaction between NE and 5-HT is less documented. Serotonergic neurons in the raphe nuclei project to fear-related amygdala areas (Graeff et al., 1993[35]; Asan, Steinke, and Lesch, 2013[3]).

A considerable amount of research has focused on the finding of low 5-HT metabolite levels in abnormal aggression, but the mechanism is not clear. We can conjecture that at low levels of 5-HT people are likely to feel more anger when surprised, inducing impulsive behaviours, violent or aggressive. Loud noise increases midbrain tryptophan hydroxylase activity (Boadle-Biber et al., 1989[7]; Azmitia, Liao, and Chen, 1993[6]), but is blocked by a lesion of the central amygdala (Singh et al.,1990[99]; Armbruster et al., 2010[2]).

Within the circuits of fear, it has been proposed that central serotonergic activity plays a crucial role by enhancing fear through the raphe nuclei-amygdala pathway (Graeff et al., 1993[35]; Ling et al., 2009[60]; Goel et al., 2014[34]). Serotonergic cells in raphe nuclei firing activity rises with restraint and confrontation (Jacobs, 1991[49]; Jacobs and Fornal, 1991[50]; Ling et al., 2009[60]; Goel et al., 2014), and 5-HT levels rise during inescapable shock treatment but not during escapable shocks (Maswood et al., 1998[64]), when DA is released. Considering these dynamical aspects of emotion, there is uncertainty regarding whether a stimulus will predict threat or reward.

In summary, NE release has been experimentally related to ‘fight or flight’ behaviours, inducing the emotional feelings of fear and anger.

Acetylcholine: Calmness/willingness

Although there are few reports about cholinergic involvement in emotional feelings, ACH is a major player in the affective space since it sets the pace for cognitive operations that stabilize affective drives. In the peripheral nervous system, ACH acts as a parasympathetic neurotransmitter, being responsible for stimulation of ‘rest and digest’ activities that occur when the body is at rest, including sexual arousal, salivation, tears, urination, digestion and defecation. In the CNS, ACH can boost cognitive functions; its uptake inhibitors have been used for Alzheimer’s disease. It might, therefore, be conceived as the cognitive part of emotion, regulating the expectation of rewards (Delgado, Gillis, and Phelps, 2008[21]).

The opposite emotional feelings for fear/anger are calmness/willingness, or ‘cholinergic emotions’. Darwin used related words in his book about emotions (Ekman, 2003[27]). He found that even bees get angry and described angry dogs as retracting upper lips, exposing teeth for biting. In a similar fashion, dogs stand erect, hairs on its back upright to appear large, thus appearing threatening. On the contrary, the dog gets down close to the ground to show affection or submission. Hence, the opposite emotional feeling for anger would be ‘affectionate’, and the opposite emotion for fear might be ‘courage’. ACH underlies these emotions by inhibiting the excitability of the cortex (Eggermann and Feldmeyer, 2009[26]; Gulledge et al., 2007[37]). The significant of ACH-related emotional feelings lies in that they can help people relax from stressful events. For example, ACH-related emotions help psychological therapy with phobic, manic and anxious patients. In addition, nostalgic music (not sad music) can make people calm down. Furthermore, long-term stressful events usually lead to back pain, because of long time back stance.

This is not to say that ACH-related emotions are all positive: Apprehension and worrying should also belong to this group. Actually, cholinergic involvement in depression has long been suggested, since 1972 (Janowsky et al., 1972[50]). At the time when the hypothesis was first published, the primary evidence was that a number of cholinesterase inhibitors had been shown to induce depression (Janowsky, 2011[52]), presumably by increasing central ACH levels (Janowsky, el-Yousef, and Davis, 1974[51]). For example, physostigmine, a centrally acting cholinesterase inhibitor, was shown to decrease manic symptoms and increase depressed reaction. Later on, many studies provided information that largely supported the hypothesis (Houlihan et al., 2002[43]; Janowsky, 2011[52]; Mearns, Dunn, and Lees-Haley, 1994[66]). The theory was further supported by animal studies showing that mice bred specifically for sensitivity to cholinergic agents demonstrated depression-like behaviours (Overstreet, 1993).

Other studies found that learned stress, a widely used preclinical model of depression, could be induced (Dilsaver and Alessi, 1987[25]). In addition, the mood depressing effects of monoamine reserpine, which has been used to support the monoamine hypothesis of depression, are remarkably similar to those of the cholinesterase inhibitors. Overlapping symptoms include apathy, lassitude, slowed down thinking, psychomotor retardation, lack of interest, fatigue, lethargy, nightmares and depression. In addition, reserpine has been reported to have central cholinergic properties. The reserpine-induced effect might be due to a combination of monoamine depletion and cholinergic activation, shifting NE-ACH balance to a cholinergic dominance (Curro Dossi, Pare, and Steriade, 1991[17]).

There are many reports about the interaction between ACH and catecholamines. For example, the antagonistic effects of NE and ACH in affective disorders were reflected in their synaptic wiring in the amygdala (McGaugh and Cahill, 1997[65]): ACH carries the influence of the amygdala to other brain structures; NE inhibits the activity of ACH (Packard, Cahill, and McGaugh, 1994[74]). Through these synaptic wires, the amygdala filters its incoming sensory streams of information, looking for ‘dangerous’ stimulus features, which would require the organism to engage in certain species-specific instincts, such as freezing or starting (Samson, Frank, and Fellous, 2010[90]). Similar synaptic wiring can be found in the substantia nigra, where the interaction between DA and ACH is well-documented for cases of Parkinson’s disease. The inhibition of ACH on DA is also involved in the predication error experiments. As we know, ACH is involved in conditioned learning: after learning, a stimulus (e.g., light) will not induce DA release because ACH dominates and inhibits DA release. Similarly, DA released during feeding signals food reward, and the increase of ACH in NAc has a role in the onset of satiation (Avena et al., 2006[4]). This increase in ACH is attenuated with sham feeding, where food is drained from a gastric fistula after ingestion. Thus, food-induced DA release goes unopposed by ACH. Hoebel and colleagues (Hoebel, Avena, and Rada, 2007[40]) suggested that the DA and ACH balance in NAc may affect motivation: While DA enables a person to start moving, ACH acts as a control to prevent over-responding and facilitates stopping.

An interaction between ACH and 5-HT has also been reported. The selective 5-HT reuptake inhibitor fluoxetine has demonstrated the ability to alleviate behavioural depression in the forced swim test, one of the potential mechanisms being to suppress cholinergic activities in the NAc (Chau et al., 2011[15]). Tobacco smoking also supports the relationship between ACH and depression. Depression rates are much higher in smokers with a history of major depression; they have a harder time quitting smoking and are at risk of developing a major depression episode. Smokers also have lower levels of monoamine oxidase A (Dani and Harris, 2005[20]). Many patients with depression fail to derive sufficient benefit from available treatment options and up to a third never reach remission, despite multiple trials of appropriate treatment. ACH uptake inhibitors might be an alternative drug for aggression, phobia or mania. Novel antidepressant drugs targeting ACH receptors appear to hold promise (Philip et al., 2010[81]).

The brain circuits of neuromodulation are displayed in Figure 2. NA is released in the brain stem and spreads first to anterior regions and cerebellum, and second to posterior cortical areas. ACH is released from the basal and medial nuclei and spreads in all directions. DA is released from the substantia nigra, reaching the amygdala, nucleus acumbens and striatum. 5-HT is released from the raphe and takes a pathway similar to NA, spreading to anterior areas and cerebellum, and then to posterior cortex