Neuropharmacology is the study of how drugs affect cellular function in the nervous system. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.
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, however, that had been found that demonstrated some type of influence on the nervous system. In the 1930’s, 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, where 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 how a neuron processes this information within itself.
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 between 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.
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.
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 effect 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 LGIC’s. 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 GPCR’s. These are much slower than LGIC’s 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 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—this is when a molecule binds to a receptor protein and activates that receptor
- Competitive antagonist—this is when a molecule binds to the same site on the receptor protein as the agonist, preventing activation of the receptor.
- Non-competitive antagonist—this is when a molecule 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.
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.
The dopamine neurotransmitter mediates synaptic transmission by binding to five specific GPCR's. These five receptor proteins are separated into two classes due to whether the response elicits a 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 process is also used by other illegal stimulant drugs such as cocaine.
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 SSRI's 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 SSRI's, there were also very many drugs that inhibited the enzyme that broke down serotonin. MAOI's 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 interacting with a common chemical known as tyramine found in many types of food.
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 can not 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 along with sedative properties.
One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. (see neuropsychopharmacology for human behavior and drug development) 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 and serotonin are projected into this area. Chronic alcohol abuse can cause major dependence and addiction. How this addiction occurs is described below.
The behavior effects of alcohol are primarily produced through its actions on the brain. Intoxication is a short-term result of alcohol present in the brain that is attributed to changes in neuronal communication. Tolerance and dependence are more long-term results that involve molecular and cellular changes due to increased exposure to alcohol. Researchers have found many areas in neuronal function that alter due to chronic alcohol exposure. In the GABAergic system, the GABAA receptor is modified effecting the efficiency and timing of inhibitory synaptic transmission. This is also usually accompanied by an increase or decrease in the release of the neurotransmitter GABA causing many of the neurons in the brain to become hyper-excitable during withdrawal from alcohol. Since GABA, for the most part, is an inhibitory neurotransmitter, a decrease in its amount will result in a feeling of anxiety. Along with GABA, there have been many links to other neurotransmitters that are affected by long-term use of alcohol, including dopamine, serotonin, and glutamate.
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 better long-term use of dopamine agonists be better for the patient.
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.
With an increase in technology and our understanding of the nervous system, the development of drugs will continue to rise with an increase in drug sensitivity and specificity. Structure-activity relationship or SARs is a major area of research within neuropharmacology which tries to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structure.
- Structure-activity relationship
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