History
Neuropharmacology
did not appear in the scientific field until, in the early part of the
20th century, scientists were able to figure
out a basic understanding of the nervous system and how nerves
communicate between one another. Before this discovery, there were drugs
that had been found that demonstrated some type of influence on the
nervous system. In the 1930s, French scientists began working with a
compound called phenothiazine in the hope of synthesizing a drug that
would be able to combat malaria. Though this drug showed very little
hope in the use against malaria-infected individuals, it was found to
have sedative effects along with what appeared to be beneficial effects
toward patients with Parkinson’s disease. This black box method, wherein
an investigator would administer a drug and examine the response
without knowing how to relate drug action to patient response, was the
main approach to this field, until, in the late 1940s and early 1950s,
scientists were able to identify specific neurotransmitters, such as norepinephrine (involved in the constriction of blood vessels and the increase in heart rate and blood pressure), dopamine (the chemical whose shortage is involved in Parkinson’s disease), and serotonin
(soon to be recognized as deeply connected to depression). In the
1950s, scientists also became better able to measure levels of specific
neurochemicals in the body and thus correlate these levels with
behavior. The invention of the voltage clamp in 1949 allowed for the study of ion channels and the nerve action potential.
These two major historical events in neuropharmacology allowed
scientists not only to study how information is transferred from one
neuron to another but also to study how a neuron processes this
information within itself.
Overview
Neuropharmacology
is a very broad region of science that encompasses many aspects of the
nervous system from single neuron manipulation to entire areas of the
brain, spinal cord, and peripheral nerves. To better understand the
basis behind drug development, one must first understand how neurons
communicate with one another. This article will focus on both behavioral
and molecular neuropharmacology; the major receptors, ion channels, and
neurotransmitters manipulated through drug action and how people with a
neurological disorder benefit from this drug action.
Neurochemical interactions
To
understand the potential advances in medicine that neuropharmacology
can bring, it is important to understand how human behavior and thought
processes are transferred from neuron to neuron and how medications can
alter the chemical foundations of these processes.
Neurons are known as excitable cells because on its surface membrane
there are an abundance of proteins known as ion-channels that allow
small charged particles to pass in and out of the cell. The structure of
the neuron allows chemical information to be received by its dendrites, propagated through the perikaryon (cell body) and down its axon, and eventually passing on to other neurons through its axon terminal.
Labeling of different parts of a neuron
These voltage-gated ion channels allow for rapid depolarization throughout the cell. This depolarization, if it reaches a certain threshold, will cause an action potential.
Once the action potential reaches the axon terminal, it will cause an
influx of calcium ions into the cell. The calcium ions will then cause
vesicles, small packets filled with neurotransmitters,
to bind to the cell membrane and release its contents into the synapse.
This cell is known as the pre-synaptic neuron, and the cell that
interacts with the neurotransmitters released is known as the
post-synaptic neuron. Once the neurotransmitter is released into the
synapse, it can either bind to receptors on the post-synaptic cell, the
pre-synaptic cell can re-uptake it and save it for later transmission,
or it can be broken down by enzymes in the synapse specific to that
certain neurotransmitter. These three different actions are major areas
where drug action can affect communication between neurons.
There are two types of receptors that neurotransmitters interact
with on a post-synaptic neuron. The first types of receptors are
ligand-gated ion channels or LGICs. LGIC receptors are the fastest types
of transduction from chemical signal to electrical signal. Once the
neurotransmitter binds to the receptor, it will cause a conformational
change that will allow ions to directly flow into the cell. The second
types are known as G-protein-coupled receptors or GPCRs. These are much
slower than LGICs due to an increase in the amount of biochemical
reactions that must take place intracellularly. Once the
neurotransmitter binds to the GPCR protein, it causes a cascade of
intracellular interactions that can lead to many different types of
changes in cellular biochemistry, physiology, and gene expression.
Neurotransmitter/receptor interactions in the field of neuropharmacology
are extremely important because many drugs that are developed today
have to do with disrupting this binding process.
Molecular neuropharmacology
Molecular
neuropharmacology involves the study of neurons and their neurochemical
interactions, and receptors on neurons, with the goal of developing new
drugs that will treat neurological disorders such as pain,
neurodegenerative diseases, and psychological disorders (also known in
this case as neuropsychopharmacology). There are a few technical words that must be defined when relating neurotransmission to receptor action:
- Agonist – a molecule that binds to a receptor protein and activates that receptor
- Competitive antagonist – a molecule that binds to the same site on the receptor protein as the agonist, preventing activation of the receptor
- Non-competitive antagonist – a molecule that binds to a receptor protein on a different site than that of the agonist, but causes a conformational change in the protein that does not allow activation.
The following neurotransmitter/receptor interactions can be affected
by synthetic compounds that act as one of the three above.
Sodium/potassium ion channels can also be manipulated throughout a
neuron to induce inhibitory effects of action potentials.
GABA
The GABA
neurotransmitter mediates the fast synaptic inhibition in the central
nervous system. When GABA is released from its pre-synaptic cell, it
will bind to a receptor (most likely the GABAA receptor) that
causes the post-synaptic cell to hyperpolarize (stay below its action
potential threshold). This will counteract the effect of any excitatory
manipulation from other neurotransmitter/receptor interactions.
This GABAA receptor contains many binding sites that
allow conformational changes and are the primary target for drug
development. The most common of these binding sites, benzodiazepine,
allows for both agonist and antagonist effects on the receptor. A common
drug, diazepam, acts as an allosteric enhancer at this binding site. Another receptor for GABA, known as GABAB,
can be enhanced by a molecule called baclofen. This molecule acts as an
agonist, therefore activating the receptor, and is known to help
control and decrease spastic movement.
Dopamine
The dopamine
neurotransmitter mediates synaptic transmission by binding to five
specific GPCRs. These five receptor proteins are separated into two
classes due to whether the response elicits an excitatory or inhibitory
response on the post-synaptic cell. There are many types of drugs, legal
and illegal, that effect dopamine and its interactions in the brain.
With Parkinson's disease, a disease that decreases the amount of
dopamine in the brain, the dopamine precursor Levodopa is given to the
patient due to the fact that dopamine cannot cross the blood–brain barrier
and L-dopa can. Some dopamine agonists are also given to Parkinson's
patients that have a disorder known as restless leg syndrome or RLS.
Some examples of these are ropinirole and pramipexole.
Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can be treated with drugs like methylphenidate (also known as Ritalin),
which block the re-uptake of dopamine by the pre-synaptic cell, thereby
providing an increase of dopamine left in the synaptic gap. This
increase in synaptic dopamine will increase binding to receptors of the
post-synaptic cell. This same mechanism is also used by other illegal
and more potent stimulant drugs such as cocaine.
Serotonin
The serotonin
neurotransmitter has the ability to mediate synaptic transmission
through either GPCR's or LGIC receptors. Depending on what part of the
brain region serotonin is being acted upon, will depend on whether the
output is either increasing or decreasing post-synaptic responses. The
most popular and widely used drugs in the regulation of serotonin during
depression are known as SSRIs or selective serotonin reuptake inhibitors.
These drugs inhibit the transport of serotonin back into the
pre-synaptic neuron, leaving more serotonin in the synaptic gap to be
used.
Before the discovery of SSRIs, there were also very many drugs that inhibited the enzyme that breaks down serotonin. MAOIs or monoamine oxidase inhibitors
increased the amount of serotonin in the pre-synaptic cell, but had
many side-effects including intense migraines and high blood pressure.
This was eventually linked to the drug's interacting with a common
chemical known as tyramine found in many types of food.
Ion channels
Ion
channels located on the surface membrane of the neuron allows for an
influx of sodium ions and outward movement of potassium ions during an
action potential. Selectively blocking these ion channels will decrease
the likelihood of an action potential to occur. The drug riluzole
is a neuroprotective drug that blocks sodium ion channels. Since these
channels cannot activate, there is no action potential, and the neuron
does not perform any transduction of chemical signals into electrical
signals and the signal does not move on. This drug is used as an
anesthetic as well as a sedative.
Behavioral neuropharmacology
Dopamine and serotonin pathway
One form of behavioral neuropharmacology focuses on the study of drug
dependence and how drug addiction affects the human mind. Most research
has shown that the major part of the brain that reinforces addiction
through neurochemical reward is the nucleus accumbens. The image to the right shows how dopamine is projected into this area. Chronic alcohol abuse can cause dependence and addiction. How this addiction occurs is described below.
Ethanol
Alcohol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on dopamine neurons in the mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc). One of alcohol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABAA receptors (e.g., enhanced GABAA receptor-mediated chloride flux through allosteric regulation of the receptor). At high doses, ethanol inhibits most ligand gated ion channels and voltage gated ion channels in neurons as well. Alcohol inhibits sodium-potassium pumps in the cerebellum and this is likely how it impairs cerebellar computation and body co-ordination.
With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors. The activation of these receptors triggers postsynaptic internal signaling events through protein kinase A which ultimately phosphorylate cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression.
With chronic alcohol intake, consumption of ethanol similarly
induces CREB phosphorylation through the D1 receptor pathway, but it
also alters NMDA receptor function through phosphorylation mechanisms; an adaptive downregulation of the D1 receptor pathway and CREB function occurs as well.
Chronic consumption is also associated with an effect on CREB
phosphorylation and function via postsynaptic NMDA receptor signaling
cascades through a MAPK/ERK pathway and CAMK-mediated pathway. These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the NAcc, where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is necessary and sufficient
for the development and maintenance of an addictive state (i.e., its
overexpression in the nucleus accumbens produces and then directly
modulates compulsive alcohol consumption).
Research
Parkinson's disease
Parkinson's disease is a neurodegenerative disease described by the selective loss of dopaminergic neurons located in the substantia nigra. Today, the most commonly used drug to combat this disease is levodopa or L-DOPA. This precursor to dopamine can penetrate through the blood–brain barrier,
whereas the neurotransmitter dopamine cannot. There has been extensive
research to determine whether L-dopa is a better treatment for
Parkinson's disease rather than other dopamine agonists. Some believe
that the long-term use of L-dopa will compromise neuroprotection and,
thus, eventually lead to dopaminergic cell death. Though there has been
no proof, in-vivo or in-vitro, some still believe that the long-term use of dopamine agonists is better for the patient.
Alzheimer's disease
While there are a variety of hypotheses that have been proposed for the cause of Alzheimer's disease,
the knowledge of this disease is far from complete to explain, making
it difficult to develop methods for treatment. In the brain of
Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh)
receptors and NMDA receptors are known to be down-regulated. Thus, four
anticholinesterases have been developed and approved by the U.S. Food and Drug Administration
(FDA) for the treatment in the U.S.A. However, these are not ideal
drugs, considering their side-effects and limited effectiveness. One
promising drug, nefiracetam,
is being developed for the treatment of Alzheimer's and other patients
with dementia, and has unique actions in potentiating the activity of
both nACh receptors and NMDA receptors.
Future
With
advances in technology and our understanding of the nervous system, the
development of drugs will continue with increasing drug sensitivity and specificity. Structure-activity relationships
are a major area of research within neuropharmacology; an attempt to
modify the effect or the potency (i.e., activity) of bioactive chemical
compounds by modifying their chemical structures.
