I haven't been obsessed with serotonin since the late '60s when she kept me busy for several years. That exciting decade saw the preliminary evidence separating norepinephrine effects from those of 5-HT. Glowinski and Iverson and many others tried to create compounds that eliminated one or the other transmitter. Psychologists performed tandem studies as soon as a chemical was available, then retracted as various alpha-meta-nor-this or that was subsequently identified. Para-chlorophenylalanine promised to deplete serotonin rather than NE and an astounding range of behavioral phenomena occurred, even if sometimes transient.
There was, and still is, a substantial case for 5-HT's having a significant role in sensory inhibition (1). Pearce told me once that serotonin is perhaps the phylogenetically oldest transmitter. Notion was once that 90% of the stuff is in our gut; if so, then psychological adaptations related to food, to temperature, or safety might well be elaborations of the original digestive functions.
My suggestion about 5-HT and rejection sensitivity (RS) is more than intuition, but perhaps not much more. Peter Kramer gives credit to Don Klein for developing the concept of RS; Kramer certainly pulled it out in some very meaningful ways in "Listening to Prozac," a fairly difficult book for a best seller. You can call it "guilt" or "rejection sensitivity" or "shame" or any number of other labels; by whatever label, people seem less inhibited by social consequences when taking an SSRI. I suspect but cannot prove, that some impulsive (ADHD) people become more forgetful at lower doses of an SSRI, doses lower than those that elicit similar forgetfulness at higher doses in other people. My behavioral suspicion is that embarrassment is less a motive to remember various appointments; mental rehearsal drops off for the tasks of daily living just as it does for other, more clinical obsessions.
I've also noticed that with less guilt or RS, self-esteem rises. (Kramer also picked up on this reciprocity. I often like to address self-esteem with procedures that should enhance a client's competence, procedures such as getting him/her into situations where he/she can exercise special talents. Lying to someone in order to elevate self-esteem is useless; few believe the lie and we discredit ourselves with either a child or an adult client. Most of us calibrate very well where we stand in a group on a variety of traits.) If self-esteem rises sufficiently, one of the checkoffs for clinical mania, for children or for adults, is satisfied. Thus, it's entirely possible that SSRIs can do more than correct for a "deficiency," they can also push the client into a state of grandiosity, a fact that has significant implications for self-regulation.
The complimentary manipulation, that of limiting serotonin activity, is recently possible. Risperidone appears to limit 5-HT availability at specific receptor sites. It also appears to cut into grandiosity in several teen males that I know. They do start listening to teachers, carrying groceries for mom, or fretting that they are doing poorly in school. Graffiti and high speed driving drop in frequency or assume more socially acceptable forms. (Regulating these things can be difficult and require a lot of time. One young man responded well to risperidone in the summer when on a manic roll; he seems to have cycled back to average with the fall and drifted into substantial guilt, shame, and apprehension, emotional reactions that abated when his previously successful dose of risperidone was cut in half. (Grandiosity bloomed when he stopped it altogether.)
You're right that dopamine is a very active lady and appears to modulate a lot of things in extrapyramidal systems. (Glutamate makes them all shirkers as does GABA! I've never bothered with distinctions between a "neurotransmitter" and a "modulator." Nerves can function as regulatory pipelines as well as informational wires. It seems a waste of time and perhaps a linguistic artifact to separate the two functions.) DA may give us some handles on ADHD as well as Parkinsons or schizophrenia. Since the SSRIs are our most convenient handle at the moment for many phenomena, it seems convenient to think about serotonin rather than things happening a synapse further along. (Time delays vary tremendously between clients, especially with children.)
Stuart Kauffman gives some hint that simplicity may also be accurate. (2) He develops an impressive model that ranges from molecules to IBM and to star systems. The model predicts the stability of developing systems as a function of the number of elements and the number of links that each element has to other elements. Thus, a network of 100,000 light bulbs maintains a static pattern if there is one and only one connection from any bulb to another bulb. There is no variety in the pattern of light generated. A second connection for each bulb allows only 317 different patterns to be run before repetition occurs. A 4th connection quickly moves the repetitions to a random sequence that takes many, many years or centuries to stabilize (become repetitive). He posits that biological systems operate of logical and evolutionary necessity in this "phase transition" between being static and moving into chaos.
If his model is valid, then all psychopathology might be developmentally traceable to very few events. Fractal experiences can result in later, more elaborate "trees" of phenomena, all deriving from originally from a single cause. Such trees may not be evolutionarily flexible if there is a change in the fitness landscape. (Once there may have been one serotonin role; I understand from some rumor that we are up to 30 or 40 identified receptor types for 5-HT.)
Fun stuff! Thanks for the inspiration!
1) Brody JF (1970) Behavioral effects of serotonin depletion and of p-chlorophenylalanine (a serotonin depletor) in rats. Psychopharmacologia, 17, 14-33. Demonstrated changes in behavioral reactivity to low intensity foot shock in active and passive avoidance tasks, as well as to taste, visual, and auditory stimuli. There were also increases in thirst as measured by ad lib drinking, a phenomenon attributed at the time to a direct effect of PCPA. However, I've also seen increased open field exploration after 5-HT depletion. It may be that cutting 5-HT availability makes a wide range of Psychological Adaptations more likely to be expressed. There were several studies demonstrating increased breeding or aggression when PCPA was given. It may be that "instinctive" responses of any sort become more probable, less inhibited, as a function of the eliciting situation as well as 5-HT depletion. Put a rat in a breeding situation, cut his 5-HT, and he may be more likely to have sex; put the same rat with a dominant male and get a fight.
"Naturally," there will be substantial interactions with the animal studied as well as with various strains of animal. Oakley Ray built a large scientific following by putting 6 different strains of rat in the same training situation or with the same drug manipulation and getting 6 different acquisition or extinction curves. I once had a friend who was impervious to morphine; so was her father as he discovered in combat in the Philippines.
The human application of all this stuff is tenuous. I linked my '70 work to observations by Jouvet that implicated 5-HT in sleep regulation. I argued that a continuum exists for reactivity to external stimulation. Even when apparently awake, we can seem more alert to our outer world and less so to our inner preoccupations (cut 5-HT and get fewer obsessions!). Deprive most of us of sleep for the right period and watch reactivity increase.
2) Kauffman S. (1995) At Home in the Universe: The Search for the Laws of Self-Organization and Complexity. NY: Oxford.