Нейрофармакология: Изучение влияния лекарств на нервную систему и поведение.

Field of study
the journal
Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. 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 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.

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 affect communication between neurons.

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 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 affect 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.

The neurotransmitter serotonin has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. The excitatory or inhibitory post synaptic effects of serotonin are determined by the type of receptor expressed in a given brain region. The most popular and widely used drugs for 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. Before the discovery of SSRIs, there were also drugs that inhibited the enzyme that breaks down serotonin. MAOIs or monoamine oxidase inhibitors increased the amount of serotonin in the synapse, but had many side effects including intense migraines and high blood pressure. This was eventually linked to the drugs 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 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.

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. Long term excessive alcohol use can cause dependence and addiction. How this addiction occurs is described below.

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. With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors.

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.

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 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.