Posts Tagged ‘ neuromodulator


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.

Neurons and Neurotransmitters

Fundamentally, the nervous system is simple. It receives sensory input, then translates this into an appropriate response. Things get a bit more complicated when we try to find out just what happens in between those two events. Sensory impulses travel through neurons, brain cells that can be thought of as switches, turning on or off depending on their input. It is important to realize that no overall response is determined solely by one structure of the brain or even one system, and it is not a simple yes-no decision but the interaction of many yes-no decisions. Like the collapse of a building or the stampede of a crowd, it is the influence of many small factors or decisions that cause a critical yet vague threshold to be reached.

The brain can be thought of somewhat as a tangled web of neurons, with dendrites connecting to axons. At the receiving end, a single neuron thrusts out many dendrites, which bring signals toward the nerve cell. They reach out for stimuli, like branches of a tree toward the sun. Their twigs swarm with tiny receptors. Receptors are small structures designed to recognize and lock on to certain chemical compounds released by other nerve cells. The junction between these dendrites and other axons is called a synapse, and this is where the chemical release and recognition occur.

If a receptor is activated by one of these chemical signals, it adjusts the flow of ions through the membrane of the underlying nerve cell. If many receptors are activated and the flow of ions changes significantly, the nerve cell may lose its polar, charged electrical properties. Instantly the whole depolarized cell fires, sending a signal down the axon causing the release of specific chemical signals. These molecules pour out of tiny round storage packets called vesicles, and deliver this chemical message at the synapse to another dendrite. This process continually echos throughout our brain.

In general, when the first primary chemical messengers reach their receptors, they change the way the next cell acts in one of three ways.

Chemical messengers can act as transmitters. In this case the chemical messenger acts directly and is the prime mover. It quickly transfers the signal from the near side of the synapse (presynaptic side) to the far side of the synapse (postsynaptic side). To transmit its fast excitatory messages, the brain usually uses molecules of acetylcholine or glutamate. They increase the excitability of the next cell (and hence the likelyhood to fire) by depolarizing it. Other primary neurotransmitters decrease the next cells excitability. GABA, for instance, excels in this role and hyperpolarizes the next cell.

The nerve cell which released its transmitter into the synapse quickly prepares to fire again. It recaptures most of its transmitter molecules, recycles them back up into storage vesicles, and releases them again. Many nerve cells fire as fast as the wingbeat of a hummingbird, firing several hundred times a second.

We can refer to this as neurotransmission, and think of it like a private telephone line. Two people are conducting a brisk and efficient conversation, on a hardwired private link which corresponds to the synapse.

Chemical messengers can act as modulators. Instead of being the prime movers, these messengers merely modify the way other primary neurotransmitters are acting. They nudge whatever excitation or inhibition is underway in one direction or the other, but with less influence than the primary neurotransmitter. For instance, norepinephrine (NE) can act as a modulator. Some NE receptors cover the terminal endings of acetylcholine nerve cells, and can stop them from releasing their acetylcholine.

In a broad generalization, norepinephrine enhances sensate responses (including those from noxious stimuli), dopamine energizes, and serotonin enters into mood-related behaviours. Neuromodulators can be thought of as a volume knob - given an ongoing conversation, they can either amplify it or mute it.

Chemical messengers can act as neurohormones. A nerve cell may release a hormone into tissue fluids, and it may diffuse a long distance before it can find the specific receptor it binds to, and it needs no synapse to act. We can think of neurohormonal communication like a radio station broadcasting across the country. The messages travel widely, but only specific radio sets tuned into a certain station will receive any information.

The brain has trillions of these receptors, attached to dendrites, cell bodies, and axon terminals. They are precisely shaped structures that will attach to a single neurotransmitter. Each receptor can be thought of as “voting” for excitation or inhibition of the nerve cell. The result determines whether the cell fires, how frequently the cell fires, and for how long the burst of firing will last.

Each chemical messenger is used in many different circuits throughout the brain. No one modulator, no one transmitter, no one receptor can be said to be the sole cause of any behavior. A given chemical messenger does two major things:

  1. It subtly influences many behaviors by acting at many levels simultaneously in the brain.
  2. It increases or decreases the contributions made by other chemical messengers and their receptor systems.

As a result of this feedback on multiple levels, the brain is gifted with a huge array of functions and experiences, each subject to wide variation and gradation.