rational exploration of the underground

Serotonin (5-hydroxytryptamine, ST, 5HT) is a hydroxylated tryptamine, a class of compounds which rose to widespread fame in the psychedelic drug community with the publication of Alexander Shulgin’s work “Tryptamines I Have Known and Loved“. Most of the body’s serotonin (80%+) is produced and contained in the digestive tract, where it regulates intestinal movements. The remainder is synthesized in Raphe cells deep along the midline core of the brainstem, where it is involved in activities such as mood, appetite, sleep, muscle contraction, memory, and learning. Raphe cells start to fire slowly, and their firing also tails off slowly. This reflects a system designed to modulate slower state-dependent activities, rather than a quick response to external stimuli.

Serotonin is present in all bilaterally symmetric animals, and acts to modulate digestive movements and is involved in the perception of resource availability. For very simple animals resources could only mean food, but in more advanced animals such as primates this also includes social status (or lack of it). Serotonin can modulate an animal’s rate of growth, desire to reproduce, and overall mood in relation to the perceived abundance or scarcity of these resources. In roundworms serotonin is released as a signal in response to positive events such as finding a new grazing ground or meeting a suitable mate. Lobsters injected with serotonin begin to display dominant social behavior, regardless of previous social status.

There are at least three major families of serotonin receptors. Many psychedelic drugs, such as psilocybin, act as partial serotonin agonists primarily active at the 5HT2 receptor. But there is some action at additional receptors, including not surprisingly the 5HT3 receptor involved in feelings of nausea. 5HT3 antagonists such as ondansetron are used during chemotherapy and are considered the gold standard in anti-nausea treatment.

In primates, many serotonin terminals end in the fourth layer of the visual cortex, where they can influence visual perception. Additionally, the temporal lobe is rich in serotonin nerve cell endings, meaning serotonin action has a significant influence on the stream of visual interpretations and association arising from external stimuli. Serotonin tends to act generally as an inhibitor in the cortex, where it reduces the excitatory responses evoked by other sensory stimuli. It also tends to preserve the general noise level of firing in the background, reducing the signal to noise ratio in contrast to the action of norepinephrine.

In humans, low serotonin levels are correlated with certain states of depression. This is reinforced by the fact that consumption of the serotonin precursor 5-hydroxytryptophan (5HTP) causes alleviation of depressive symptoms in some patients. The brain normally has a dense concentration of postsynaptic 5HT2 receptors in the prefrontal cortex, the location in the brain thought to play an “executive” role in coordinating sensory response. Patients who have had a major depressive incident tend to have even higher numbers of these receptors, which is thought to be a result of the brain compensating for lower serotonin levels. In the brain stems of depressed subjects, autopsies have also shown reduced serotonin levels.

Increases in serotonin levels tend to have the opposite effect, increasing outward social behaviours. In monkeys, serotonin agonist drugs increase the approaching, grooming, resting, and eating activities typical of the dominant males. They also reduce inward social solitary, vigilant, and avoidance behaviors. This is reflected in humans under the influence of MDMA, an amphetamine derivative which simultaneously releases large amounts of serotonin while blocking its reuptake. Subjects become much more social and talkative, empathy towards others is increased, and anxiety and paranoia disappear. This has made MDMA and related compounds ideal for psychiatric therapy, particularly for couples and those who have experienced intensely traumatic events.

But the “serotonin as happiness” message sold by drug companies pushing antidepressants is not a complete story. A depressed person may have decreased serotonin levels in response to environmental or other factors, and an antidepressant will certainly raise them. But if these stress factors do not change along with the serotonin levels (through changes in behavior or the environment itself), it is unlikely to create lasting positive change. Serotonin appears to act to regulate the extent or intensity of moods, with less influence on the direct attitude of the mood itself. Similar to the use of MDMA in therapy, these drugs should be regarded as a catalyst to move in the correct direction, and not a magic bullet.

Dopamine (DA) is a neurotransmitter present in many animals, from the honeybee to the dolphin. It is involved in many behaviors associated with motivation and reward. The majority of dopamine in humans is released from two areas.

First is the the substantia nigra, whose darkly pigmented cell bodies supply dopamine to the deep motoric nuclei of the basal ganglia. Dopamine concentrations in one nuclei, the putamen, exceed anywhere else in the brain reaching a level of 5740 nanograms per gram. Dopamine released in this nigrostriatal pathway helps us quickly execute our motor patterns and associated movements. For instance, if dopamine drops to very low levels on one side of this system Parkinsonian symptoms will arise, with sluggish arm and leg movements on one side of the body.

Second is the ventral tegmental system. Its cells send much of their dopamine up to the nucleus accumbens in the ventral striatum, and a separate pathway supplies the limbic system. Two other branches supply dopamine to the cortex in the prefrontal and cingulate regions. An especially dense network of dopamine fibers covers the inner part of the prefrontal lobe, the same region where the thalamus sends its major input. The intersection of these two pathways in the prefrontal cortex remains one of the brain’s most constant features, dating back to the tree shrew and reminding us of our origins in the forest.

Suppose you take a rat, normally a social animal, and reduce its social stimuli over a prolonged period making it a hermit in a cage. The different dopamine systems react in different ways - the metabolic activity of the dopamine cells supplying the frontal lobes slows, whereas metabolism increases in dopamine cells projecting up to the dorsal and ventral striatum. Even though the isolated rats have now quieted down and show few spontaneous behaviors (frontal lobes), they jump more when an electrical shock is delivered to the foot (dorsal and ventral striatum). Increased social exposure causes a reversal of these effects - more active and less nervous rats.

Each person’s brain is unique, as the number and distribution of dopamine receptors varies widely. Early in life, brain development responds to male or female hormones present. Male rats already show more evidence of dopamine receptors in their cortex and amygdala only a few days after being born.

There are five known dopamine subreceptors in humans. The most abundant dopamine subreceptor in the nervous system is the D1 receptor, which regulate neuronal growth and development and mediates some behavioral responses. It also stimulates adenylyl cyclase and activates cyclic AMP-dependent protein kinases, involved in the regulation of glycogen, sugar, and lipid metabolism. D2 receptors are gaining prominence as potential keys to certain diseases, as increased D2 receptor levels have been linked to schizophrenia, certain Parkinson’s symptoms, and narcolepsy.

The major functional role of dopamine systems in the human brain appears twofold. First, there are prominent motoric effects. Decades of research on rats and mice have shown that any cause of indirect release of dopamine into the nucleus accumbens causes rats to engage in specific motor sequences: they move around more, they sniff more, and engage in repetitive grooming behaviors. This is not unlike a human who has experienced dopamine increase caused by cocaine or other drug consumption, as they fidget, sniff and lick their lips, run their fingers through their hair, or pick at the skin.

But there is more than just a general mobilizing or energizing effect. This became clear when experiments were undertaken as animals pressed on a lever, working to receive food as a reward. Drugs which increased dopamine levels caused the animals to become more selective and efficient, suggesting that dopamine helps to sustain goal directed behavior. While dopamine was initially dubbed the “pleasure” neurotransmitter, recent research suggests that pleasure is a less appropriate term than “motivation”. As any speed freak will tell you, after a certain point self-administration of the drug becomes distinctly dysphoric, but the desire to continue dosing remains strong and is not correlated with the level of
“pleasure” (if any) that the next dose will produce.

There are also interesting correlations to personality. “Extroverted” personalities tend to show higher spinal fluid levels of dopamine breakdown products, and a set of aggressive patients also showed the same evidence of higher dopamine turnover. After practicing yoga meditation for six months however, the levels of dopamine breakdown products of the aggressive patients fell from an average of 51 nanograms per liter to 41 nanograms per liter.

Nerve cells are designed to fire repetitively, and are subject to a barrage of stimuli. The brain prevents itself from spiraling out of control into hyperexcitable states by inhibition, a way of “turning down the volume” in the brain. The major workhorse for this is gamma animobutyric acid, or GABA. In a strange parallel, the brain synthesizes GABA in one step from glutamate, the brain’s major excitatory neurotransmitter. Excitation can therefore be efficiently followed by the capacity for inhibition, two naturally opposing processes depending on, and counterbalancing, the other. GABA and glutamate are the yin and yang of our nervous system.

There is hardly a single behavior that does not involve GABA. It is estimated to be involved in one third of all transmissions at synapses, and GABA nerve cells alone make up 40 percent of the total population of nerve cells, with glutamate cells adding perhaps another 30 percent. Broadly, the brain applies its fast acting GABA circuits at all levels to hold in check the local excitatory processes. Some GABA cells inhibit pivotal nerve cells that directly command other essential nerve cell populations. GABA mechanisms hold aggressive behavior in check in many animal species. If rats are made hyperactive by injection of dopamine into the nucleus accumbens, they will quickly quiet down after GABA is injected into the same nucleus.

GABA agonists include alcohol and benzodiazepines such as Xanax. Widely used for their tranquilizing, anti-anxiety, or sleep producing properties, they can create an incredibly risky state of addiction if used too frequently. Unlike other drugs that when withdrawn simply cause the perception of extreme suffering, cold turkey withdrawal causes GABA action to drop precipitously, inducing states of extreme agitation or convulsions, possibly causing death. A slow tapering of the drug, allowing natural GABA to rebound slowly, is the typically recommended course of action.

The inhibitory effects of GABA can be related to the “tunnel vision” experienced during states of drunkenness, where the visual field is reduced and attention is paid only to the objects directly in front of the subject. In contrast, bicluculline is a drug that stops the inhibitory role of GABA. When applied to the visual cortex, it expands the apparent visual fields by three to five times.

A traveller taking a benzodiazepine for a long haul flight and a frat boy on his 21st birthday both may experience periods of retrograde amnesia. This emphasizes the fact that when GABA systems become overactive, they can block the way a person accesses recently produced memories.

The anti-anxiety properties of GABA agonism are not limited to the “higher” civilized frustrations of the overworked executive as well. They can also relieve the deep primal anxiety of a baby monkey separated from his mother. Diazepam, a benzodiazepine, quickly stops their agitated behavior and cries of distress. High brain levels of dopamine are reduced, as well as high blood levels of ACh and cortisol which are correlated with stressful experiences.