Dopamine is another neuromodulator.
It is produced by only a small number of cells in the brain,
perhaps a few hundred thousand, but dopaminergic neurons
send projections very broadly, over almost the entire brain.
The major divisions of the dopamine system are called ???pathways???,
and include the so-called mesocortical pathway, the mesolimbic pathway,
the nigrostriatal pathway and the tuberoinfundibular pathway.
Each pathway targets a different set of brain areas
and plays a distinct functional role in our daily lives.
For instance, dopamine neurons originating in the substantia nigra
(from Latin for ???dark substance???) are involved in regulating movement.
These cells are lost in Parkinson???s disease,
for reasons we don???t understand yet.
Parkinson???s disease is characterized by a host of symptoms,
beginning with stiffness and trembling of the limbs.
A variety of other diseases, such as encephalitis or certain kinds
of poisoning can also kill these same cells, producing similar symptoms.
Since dopaminergic neurons die off in Parkinson???s disease,
a common treatment is to try to supplement dopamine.
The drug L-Dopa is a chemical precursor to dopamine,
which the body can convert into dopamine.
This drug can have dramatic effects in Parkinson???s,
in some cases resulting in dramatic ???awakenings???
of previously catatonic patients.
Unfortunately, these effects are usually short-lived as the L-Dopa gradually
becomes less and less effective.
Nobel prizes were won in both 2000 and 2001 for discoveries surrounding
L-Dopa, and understanding and seeking a cure for Parkinson???s is an area
of active research.
Other dopaminergic pathways target other brain systems.
For instance, dopamine is thought to play an important role
in reward-motivated behavior, and reinforcement learning.
Dopaminergic neurons in an area called the ventral tegmental area project
to many areas of the brain, and together with areas like the nucleus accumbens
form an important reward ???subsystem???
in the brain.
These reward circuits are the target of many recreational drugs.
Cocaine blocks the reuptake of dopamine from the synaptic cleft,
thus increasing the time this neurotransmitter spends
in the synaptic cleft and increasing the likelihood
of exerting its postsynaptic action.
As a result, cocaine ???turns up??? the effect of the dopaminergic system.
The addictive nature of cocaine and other drugs
is a complex and not fully-understood phenomenon,
but it is largely driven by neurons adapting
to the higher levels of dopamine present at synapses.
One mechanism for such adaptation is the down-regulation
of receptors in the postsynaptic neuron.
The effect of such down-regulation is two-fold: first,
more and more of the drug is required to achieve the same effect???
and second, when *not* taking the drug, the dopamine system works
at lower-than-normal levels.
This means that, in time, drug users need to take some amount of the drug
just to achieve normal levels of dopamine.
There are also dopaminergic pathways involved in other functions,
such as endocrine or hormonal regulation.
So you see, that???s a lot of different functions for one neuromodulatory
substance!
[ Cholinergic ]
Of course, there are other neuromodulatory systems
that have broad and diverse effects.
The cholinergic system is one of them.
You might recall that acetylcholine is an important neurotransmitter
in the peripheral nervous system, but it also
plays an important neuromodulatory role in the brain.
As with other neuromodulatory systems, cholinergic outputs
arise from a relatively small number of cells,
but act on a variety of brain areas in the neocortex, hippocampus, but also
the brainstem and deeper nuclei.
Acting mainly through so-called M1 receptors,
the cholinergic system affects a variety of systems related to muscle and motor
control, learning, short-term memory, and arousal.
Chances are you???ve had first-hand experience modulating the cholinergic
system with drugs.
The common allergy medication diphenhydramine,
marketed in the United States under the brand name ???Benadryl???
is anti-histamine that also has potent anticholinergic effects.
These anticholinergic effects are responsible for a number
of the unpleasant side effects of the drug, including dry mouth.
Such off-target effects are common in drugs
that affect more than one neuromodulatory system, though given
the breadth of different actions that even a single neuromodulator can have,
multiple, often unrelated effects from systemic administration of drug
are the rule, rather than the exception.
Even more potent anticholinergic agents can have even more dramatic effects.
For instance, because the cholinergic system plays an important role
in memory formation, some anticholinergic drugs can even lead
to a limited form of amnesia, called ???anterograde???
amnesia, wherein the patient fails to remember
events that occurred while the drug was in the system.
Scopolamine is an example of such a drug.
It is synthesized naturally by the Borrachero tree, which grows wild
in Columbia, and legend states that even being around the pollen of the tree
is said to lead to unusual dreams.
Over the years, scopolamine has been used for a variety of purposes in both
research and in the clinic, but it???s also a drug that???s in various forms
of criminal enterprise, for instance in Columbia,
where the substance originates.
In Columbia, scopolamine also goes by the name ???Devil???s Breath???,
and it???s pretty scary stuff: a small amount of the drug slipped into a drink
can cause an unfortunate victim to enter a dissociative state where they are
unable to form plans and even unable to exercise free will.
Worse yet, because of scopolamine???s amnesic effects,
victims don???t remember what happened to them while they were under
the influence of the drug.
It???s a pretty stark reminder of how much we are at the mercy
of our biology.
Because neuromodulatory systems have such broad effects,
they???re a prime target to be hijacked to produce profound effects
on behavior.