Technical advancements in recent years have allowed progress toward the understanding of the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
and how
drugsA psychoactive drug, psychopharmaceutical or psychotropic substance is a chemical substance that acts primarily upon the central nervous system where it alters brain function, resulting in changes in perception, mood, consciousness and behavior...
can be made to affect it. The term increasingly used to include all of the
biological scienceBiology is the natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy...
involved is,
Neuropsychopharmacology (Greek: neuron+psyche+pharmacon+logos => nerve - soul/mind - drug - study)
More precisely, neuropsychopharmacology is an interdisciplinary science related to
psychopharmacologyPsychopharmacology is the study of drug-induced changes in mood, sensation, thinking, and behavior....
(how drugs affect the mind) and fundamental
neuroscienceNeuroscience is the scientific study of the nervous system. Such studies span the structure, function, evolutionary history, development, genetics, biochemistry, physiology, pharmacology, informatics, computational neuroscience and pathology of the nervous system.The International Brain Research...
. It entails research of mechanisms of
neuropathologyNeuropathology is the study of disease of nervous system tissue, usually in the form of either small surgical biopsies or whole autopsy brains. Neuropathology is a subspecialty of anatomic pathology...
,
pharmacodynamics (drug action)Pharmacodynamics is the study of the physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...
,
psychiatric illnessA mental disorder or mental illness is a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as part of normal development or culture. The recognition and understanding of mental disorders has changed over time and...
, and states of
consciousnessConsciousness is subjective experience or awareness or wakefulness or the executive control system of the mind. It is an umbrella term that may refer to a variety of mental phenomena...
. These studies are instigated at the detailed level involving
neurotransmissionNeurotransmission , also called synaptic transmission, is an electrical movement within synapses caused by a propagation of nerve impulses...
/
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
activity,
bio-chemicalBiochemistry is the study of the chemical processes in living organisms. It deals with the structure and function of cellular components such as proteins, carbohydrates, lipids, nucleic acids and other biomolecules....
processes, and
neuralThe nervous system is a network of specialized cells that communicate information about an organism's surroundings and itself. It processes this information and causes reactions in other parts of the body. It is composed of neurons and other specialized cells called glial cells that aid in the...
circuitry. Neuropsychopharmacology supersedes
psychopharmacologyPsychopharmacology is the study of drug-induced changes in mood, sensation, thinking, and behavior....
in the areas of "how" and "why", and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes
psychiatric (psychoactive) as well as
neurologic (non-psychoactive) pharmacology-based treatments.
Developments in neuropsychopharmacology may directly impact the studies of
anxiety disorderAnxiety disorder is a blanket term covering several different forms of abnormal and pathological fears and anxieties which only came under the aegis of psychiatry at the very end of the 19th century. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders...
s, affective disorders, psychotic disorders,
degenerative disorderA degenerative disease is a disease in which the function or structure of the affected tissues or organs will progressively deteriorate over time, whether due to normal bodily wear or lifestyle choices such as exercise or eating habits...
s,
eating behaviorAn eating disorder is a condition which affects an individuals eating habits, either as a result of their own doing , or as a bodily reaction to the consumption of food. Eating disorders can range from mild mental anguish to life-threatening conditions, and can affect every aspect of an...
, and
sleep behaviorSleep is a naturally recurring state of relatively suspended sensory and motor activity, characterized by total or partial unconsciousness and the inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and it is more easily...
.
The rigorous way fundamental processes of the brain are being discovered is creating a field on par with other “
hard sciences” such as chemistry, biology, and physics, so that eventually it may be possible to repair mental illness with ultimate precision. An analogy can be drawn between the brain and an electronic device: neuropsychopharmacology is tantamount to revealing not only the
schematicright|thumb|300px|A schematic of the [[Washington Metro]]. The schematic is not drawn to scale; distances between stations are fixed and lines are drawn at 45 and 90-degree angles....
diagram, but the individual components, and every principle of their operation. The bank of amassed detail and complexity involved is huge; mere samples of some of the details are given in this article.
This account hangs on the assumption that
MaterialismThe philosophy of materialism holds that the only thing that exists is matter; that all things are composed of material and all phenomena are the result of material interactions. In other words, matter is the only substance. As a theory, materialism is a form of physicalism and belongs to the...
, the view that all mental states are reducible to brain states, is true.
History
Drugs such as
opiumOpium is a narcotic formed from the latex released by lacerating the immature seed pods of opium poppies . It contains up to 12% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade...
,
alcoholCharles Peter Kennedy MP is a British politician.From 9 August 1999 until 7 January 2006, he was the leader of the Liberal Democrats, the third largest political party in the United Kingdom....
, and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era nobody knew how these substances worked. The first half of the 20th century saw
psychologyPsychology is an academic and applied discipline involving the systematic, and sometimes scientific, study of human or animal mental functions and behavior...
and
psychiatryPsychiatry is a medical specialty officially devoted to the treatment and study of mental disorders. The term was first coined by the German physician Johann Christian Reil in 1808....
as largely
phenomenologicalThe term phenomenology in science is used to describe a body of knowledge which relates empirical observations of phenomena to each other, in a way which is consistent with fundamental theory, but is not directly derived from theory. For example, we find the following definition in the Concise...
, in that behaviors or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the
behavioralBehaviorism , also called the learning perspective , is a philosophy of psychology based on the proposition that all things which organisms do — including acting, thinking and feeling — can and should be regarded as behaviors...
branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as "software" errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields - until several developments after
World War IIWorld War II, or the Second World War , was a global military conflict which involved a majority of the world's nations, including all great powers, organized into two opposing military alliances: the Allies and the Axis...
began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as
MAO inhibitorsMonoamine oxidase inhibitors are a class of powerful antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression, and have also shown efficacy in smoking cessation....
,
tricyclic antidepressantTricyclic antidepressants are a class of psychoactive drugs used primarily as antidepressants, which were first discovered in the early 1950s, and subsequently introduced later in the decade...
s, thorazine and lithium which showed some clinical specificity for mental illnesses such as depression and schizophrenia. Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which
could directly affect brain circuitry and neurotransmitter levels were the
pre-frontal lobotomyPsychosurgery is a subset of neurosurgery intended to modulate the performance of the brain, and thus effect changes in cognition, with the intent to treat or alleviate severe mental illness...
, and
electroconvulsive therapyElectroconvulsive therapy , also known as electroshock, is a well-established, albeit controversial, psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect...
, the latter of which was conducted without muscle relaxants which often caused the patient great physical injury.
The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the
Hungarian College of Neuropsychopharmacology. This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information.
Overview
An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of
mindMind is the aspect of intellect and consciousness experienced as combinations of thought, perception, memory, emotion, will and imagination, including all unconscious cognitive processes. The term is often used to refer, by implication, to the thought processes of reason. Mind manifests itself...
, including both normal and drug-induced altered states, and diseases involving mental or cognitive
dysfunctionAbnormality, in the sense of something deviating from the normal or differing from the typical , is a subjectively defined behavioral characteristic, assigned to those with rare or dysfunctional conditions...
, have a
neuro-chemicalNeurochemistry is the specific study of neurochemicals, which include neurotransmitters and other molecules such as neuro-active drugs that influence neuron function. This principle closely examines the manner in which these neurochemicals influence the network of neural operation...
basis at the fundamental level, and certain circuit pathways in the
central nervous systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
at a higher level. (See also:
Neuron doctrineThe neuron doctrine is the now fundamental idea that the nervous system is made up of individual and discrete cells and was proposed by Heinrich Wilhelm Gottfried von Waldeyer-Hartz in 1891. Waldeyer-Hartz coined the term "neuron" to describe the individual cells. The "neuron doctrine" served to...
) Thus the understanding of nerve cells or
neuronA neuron is an excitable cell in the nervous system that processes and transmits information by electrochemical signaling. Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves...
s in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern
clinicalClinical psychology includes the scientific study and application of psychology for the purpose of understanding, preventing, and relieving psychologically-based distress or dysfunction and to promote subjective well-being and personal development...
and research methods such as
genetic manipulationGenetic engineering, recombinant DNA technology, genetic modification/manipulation and gene splicing are terms that apply to the direct manipulation of an organism's genes. Genetic engineering is different from traditional breeding, where the organism's genes are manipulated indirectly...
in animal subjects, imaging techniques such as
functional magnetic resonance imaging (
fMRIFunctional MRI or functional Magnetic Resonance Imaging is a type of specialized MRI scan. It measures the haemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging...
), and
in vitroA procedure performed in vitro is performed not in a living organism but in a controlled environment, such as in a test tube or Petri dish...
studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include radiological imaging such as
positron emission tomography (
PETPositron emission tomography is a nuclear medicine imaging technique which produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
) and
single-photon emission computed tomography (
SPECTSingle photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information...
). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10
-10 M such as found with extrastriatal D
1 receptor for dopamine.
One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of
neuro-pathologicalNeuropathology is the study of disease of nervous system tissue, usually in the form of either small surgical biopsies or whole autopsy brains. Neuropathology is a subspecialty of anatomic pathology...
conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop
drugsA psychoactive drug, psychopharmaceutical or psychotropic substance is a chemical substance that acts primarily upon the central nervous system where it alters brain function, resulting in changes in perception, mood, consciousness and behavior...
which act on very specific receptors within a neurotransmitter system. These "hyperselective-action" drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximizing the
efficacyEfficacy is the capacity to produce an effect. It is used to mean different specific things in different fields.- Healthcare :In a healthcare context, efficacy indicates the capacity for beneficial change of a given intervention Efficacy is the capacity to produce an effect. It is used to mean...
(or technically the
potency) of the drug within the clinical target and minimizing
adverse effectsIn medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect, and may result from an unsuitable or incorrect dosage or...
.
The groundwork is currently being paved for the next generation of
pharmacologicalPharmacology is the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and exogenous chemicals that alter normal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals...
treatments which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new
neuronA neuron is an excitable cell in the nervous system that processes and transmits information by electrochemical signaling. Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves...
s - the study of which, in addition to
neurotrophic factorsNeurotrophins are a family of proteins that induce the survival, development and function of neurons.They belong to a class of growth factors, secreted proteins, which are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the...
, may hold hope for neuro-degenerative diseases like Alzheimer's, Parkinson's,
ALSThe motor neurone diseases are a group of neurological disorders that selectively affect motor neurones, the cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body.-Terminology:In this article, MND refers to a group of...
, and types of
choreaChoreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from a Greek word χορεία , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term hemichoreia refers to...
. All of the proteins involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of
signal transductionIn biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another. Most processes of signal transduction involve ordered sequences of biochemical reactions inside the cell, which are carried out by enzymes and activated by second messengers,...
, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week.
Neurotransmission
So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the
action potentialAn action potential is a transient alteration of the transmembrane voltage across an excitable membrane generated by the activity of voltage-gated ion channels embedded in the membrane. Action potentials play multiple roles in several types of excitable cells such as neurons, myocytes, and...
may affect the firing of as many as a thousand other neurons in a process called
neurotransmission. In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an
EEGElectroencephalography is the recording of electrical activity along the scalp produced by the firing of neurons within the brain . In clinical contexts, EEG refers to the recording of the brain's spontaneous electrical activity over a short period of time, usually 20–40 minutes, as recorded from...
device.
By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained . These features are:
- The synthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
and storage of neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
substances,
- The transport of synaptic vesicles
A vesicle is a bubble of liquid within a cell. More technically, a vesicle is a small, intracellular, membrane-enclosed sac that stores or transports substances within a cell. Vesicles form naturally because of the properties of lipid membranes ...
and subsequent release into the synapse,
- Receptor
In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
activation and cascadeA biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
function,
- Transport
Monoamine transporters are structures in nerve-cell membranes that function as neurotransmitter transporters transferring monoamine neurotransmitters in or out of cells.-Types:There are several different monoamine transporters:*The dopamine transporter, DAT....
mechanisms (reuptake) and/or enzyme degradation
The more recent advances involve understanding at the
organicAn organic compound is any member of a large class of chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of compounds such as carbonates, simple oxides of carbon and cyanides, as well as the allotropes of carbon, are considered inorganic...
molecular level; biochemical action of the
endogenousThe word endogenous means "proceeding from within", the opposite of exogenous.-Biology:Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ligandsIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as...
,
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
s,
receptor proteins, etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterization of a large number of very specific sub-types of receptors. For the six more important neurotransmitters
Glu,
GABA,
Ach,
NE,
DA, and
5HT (listed at
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
) there are at least 29 major subtypes of receptor. Further "sub-subtypes" exist together with variants, totalling in the hundreds for just these 6 transmitters.
- (see serotonin receptorThe serotonin receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous system. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts...
for example.) It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.
It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the trans-membrane
ion channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of all living cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s which control the membrane currents via the ions
KPotassium is the chemical element with the symbol K , atomic number 19, and atomic mass 39.0983. Potassium was first isolated from potash...
+,
NaSodium is a metallic element with a symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1"...
+, and
CaCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
++, and of lesser importance
MgMagnesium is a chemical element with the symbol Mg, atomic number 12 and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the earth's crust by mass, although ninth in the Universe as a whole...
++ and Cl
-. The concentration differences between the inside and outside of the cell determine the membrane voltage.
Precisely how these currents are controlled has become much clearer with the advances in receptor structure and
G-protein-coupledG proteins, short for guanine nucleotide-binding proteins, are a family of proteins involved in second messenger cascades.G proteins are so called because they function as "molecular switches," alternating between an inactive guanosine diphosphate and active guanosine triphosphate bound state,...
processes. Many receptors are found to be pentameric clusters of five trans-membrane proteins (not necessarily the same) or
receptor subunits, each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the ionotropic type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.
The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying
gene transcriptionTranscription, or RNA synthesis, is the process of creating an equivalent RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA in the presence of the correct enzymes...
. The
synthesisProtein synthesis is the process in which cells build proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA which is then used as input to...
of cellular proteins from nuclear
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
has the same fundamental machinery for all cells; the exploration of which now has a firm basis thanks to the
Human Genome ProjectThe Human Genome Project was an international scientific research project with a primary goal to determine the sequence of chemical base pairs which make up DNA and to identify and map the approximately 20,000–25,000 genes of the human genome from both a physical and functional standpoint...
which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level.
Gene expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as rRNA genes or tRNA genes, the product is a functional RNA...
determines protein structures through type II
RNA polymeraseRNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
. So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from mRNA via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the
transcription initiation process by a variety of transcription factors produced from receptor activity.
Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of
gene knockoutA gene knockout is a genetic technique in which an organism is engineered to carry genes that have been made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.
Drugs
The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. "
Dirty DrugA dirty drug is an informal term used in pharmacology to describe drugs that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly negative side effects...
") and safe to consume. The 2005
Physicians' Desk ReferenceThe Physicians' Desk Reference is a commercially published compilation of manufacturers' prescribing information on prescription drugs, updated annually...
lists twice the number of
prescription drugA prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...
s as the 1990 version. Many people by now are familiar with "
selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders...
s", or
SSRI's which exemplify modern
pharmaceuticalsPharmacology is the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and exogenous chemicals that alter normal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals...
. These SSRI
anti-depressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors , tricyclic antidepressants , tetracyclic antidepressants , selective serotonin reuptake inhibitors , and serotonin-norepinephrine...
drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The
FDAThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
has approved drugs which selectively act on each of the major neurotransmitters such as
NENoradrenaline or norepinephrine is a catecholamine with dual roles as a hormone and a neurotransmitter....
reuptake inhibitor antidepressants,
DADopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D
1, D
2, D
3, D
4, and...
blocker
anti-psychoticsAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
, and
GABAγ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays an important role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone...
agonistAn agonist is a drug that binds to a receptor of a cell and triggers a response by the cell. An agonist often mimics the action of a naturally occurring substance.An agonist produces an action...
tranquilizerA tranquilizer, or tranquiliser , is a drug that induces tranquillity in an individual.The term "tranquilizer" is imprecise, and is usually qualified, or replaced with more precise terms:...
s (
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s).
New endogenous chemicals are continually identified. Specific receptors have been found for the drugs
THCThe acronym THC has several possible meanings:* Tetrahydrocannabinol, the main active chemical compound in Cannabis* Toronto Hemp Company, the world's largest Hemp and Cannabis Culture store, located in Toronto, Canada....
(cannabis) and
GHBγ-Hydroxybutyric acid , also known as 4-hydroxybutanoic acid and sodium oxybate, is a naturally-occurring substance found in the central nervous system, wine, beef, small citrus fruits, and almost all animals in small amounts. It is also a neuroprotective therapeutic nutrient that is...
, with endogenous transmitters anandamide and GHB. Another recent major discovery occurred in 1999 when
orexinOrexins, also called hypocretins, are the common names given to a pair of excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains....
, or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of
narcolepsyNarcolepsy is chronic sleep disorder, or dyssomnia. The condition is characterized by excessive daytime sleepiness in which a person experiences extreme fatigue and possibly falls asleep at inappropriate times, such as while at work or at school...
. Orexin agonism may explain the anti-narcoleptic action of the drug
modafinilModafinil is an analeptic drug manufactured by Cephalon, and is approved by the U.S...
which was already being used only a year prior.
The next step, which major
pharmaceutical companiesThe pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies can deal in generic and/or brand medications. They are subject to a variety of laws and regulations regarding the patenting, testing and marketing of drugs.-History:The...
are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents (
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
s) based on GABA
A(α2) agonists,
CRFCorticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response....
1 blockers, and 5HT
2c blockers. Another is the proposal of new routes of exploration for anti-psychotics such as
glycine reuptake inhibitors. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide
anatomical specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D
2 altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of
dyskinesiaDyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or chorea. Dyskinesia is a symptom of several medical disorders and is distinguished by the underlying cause...
s by their action on motor cortex.
Modern studies are revealing details of mechanisms of damage to the nervous system such as
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
(programmed cell death) and
free-radicalIn chemistry, radicals are atoms, molecules, or ions with unpaired electrons on an otherwise open shell configuration. These unpaired electrons are usually highly reactive, so radicals are likely to take part in chemical reactions...
disruption. PCP has been found to cause cell death in striatopallidal cells and abnormal
vacuolizationthumb|400px|Plant cell structurethumb|400px|Animal cell structureA vacuole is a membrane organelle which is present in all plant and fungal cells and some protist, animal and bacterial cells...
in
hippocampalThe hippocampus is a major component of the brains of humans and other mammals. It belongs to the limbic system and plays important roles in long-term memory and spatial navigation. Like the cerebral cortex, with which it is closely associated, it is a paired structure, with mirror-image halves in...
and other neurons. The
hallucinogen persisting perception disorderHallucinogen Persisting Perception Disorder or HPPD is a disorder characterized by a continual presence of visual disturbances that are reminiscent of those generated by the ingestion of hallucinogenic substances. Previous use of hallucinogens is needed, though not sufficient, for diagnosing...
(HPPD), also known as
post-psychedelic perception disorder, has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an
excitotoxicExcitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated...
response of 5HT
2 interneuronAn interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...
s. [Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself] As for MDMA, aside from persistent losses of 5HT and
SERTThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
, long-lasting reduction of serotonergic
axonAn axon or nerve fiber is a long, slender projectionof a nerve cell, or neuron, that conducts electrical impulsesaway from the neuron's cell body or soma....
s and terminals is found from short-term use, and regrowth may be of compromised function.
Neural circuits
It is a not-so-recent discovery that many functions of the brain are localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioral, and genetic correlates of receptor action, completing the knowledge of neural signalling
(see also: Human Cognome ProjectThe Human Cognome Project seeks to reverse engineer the human brain, paralleling in many ways the Human Genome Project and its success in deciphering the human genome. The HCP is a multidisciplinary undertaking, relevant to, among others: biology, neuroscience, psychology, cognitive science,...
). The signal paths of neurons are hyper-organized beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may been seen in the following abstracts.
Progress has been made on central mechanisms of
hallucinationA hallucination, in the broadest sense, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and...
believed to be common to
psychedelic drugA psychedelic substance is a psychoactive drug whose primary action is to alter the cognition and perception of the mind. Psychedelics are part of a wider class of psychoactive drugs known as hallucinogens, which also includes related substances such as dissociatives and deliriants...
s and
psychotic illnessPsychosis literally means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. It is likely the effect of partial agonistic action on the serotonin system. The 5HT
2A receptor and possibly the 5HT
1C are involved by releasing glutamate in the
frontal cortexThe frontal lobe is an area in the brain of mammals. It is located at the front of each cerebral hemisphere and positioned anterior to the parietal lobes and above and anterior to the temporal lobes...
, while simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. One hypothesis suggests that in the frontal cortex, 5HT
2A promotes late asynchronous
excitatory post-synaptic potentialsIn neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...
, a process antagonized by serotonin itself through 5HT
1 which may explain why SSRI's and other serotonin-affecting drugs do not normally cause a patient to hallucinate.
Circadian rhythmA circadian rhythm is a roughly-24-hour cycle in the biochemical, physiological or behavioral processes of living entities, including plants, animals, fungi and cyanobacteria...
, or sleep/wake cycling, is centered in the
suprachiasmatic nucleusThe suprachiasmatic nucleus, or nuclei, , a tiny region on the brain's midline in a shallow impression of the optic chiasm, is responsible for controlling endogenous circadian rhythms...
(SCN) within the hypothalamus, and is marked by
melatoninMelatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring hormone found in animals and in some other living organisms, including algae. Circulating levels vary in a daily cycle, and melatonin is important in the regulation of the circadian rhythms of several...
levels 2000-4,000% higher during sleep than in the day. A circuit is known to start with
melanopsinMelanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of...
cells in the eye which stimulate the SCN through glutamate neurons of the
hypothalamic tract. GABA-ergic neurons from the SCN inhibit the
paraventricular nucleusThe paraventricular nucleus is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin...
, which signals the
superior cervical ganglion (SCG) through
sympatheticThe Sympathetic Nervous System is a branch of the autonomic nervous system along with the enteric nervous system and parasympathetic nervous system. It is always active at a basal level and becomes more active during times of stress...
fibers. The output of the SCG, stimulates NE receptors (
βThe adrenergic receptors are a class of G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
) in the
pineal glandThe pineal gland is a small endocrine gland in the vertebrate brain. It produces melatonin, a hormone that affects the modulation of wake/sleep patterns and photoperiodic functions...
which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback
pathwayA neural pathway, or neural tract, connects one part of the nervous system with another and usually consists of bundles of elongated, myelin-insulated neurons, known collectively as white matter...
. Therefore, light
inhibits the production of melatonin which "
entrainsIn chronobiology, entrainment of a circadian system is the alignment of its own period and phase to the period and phase of an external rhythm. A common example is the entrainment of endogenous circadian rhythms to the daily light-dark cycle...
" the 24-hour cycle of SCN activity,. The SCN also receives signals from other parts of the brain, and its (approximately) 24 hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle
in vitro for many days. Additionally, (not shown in diagram), the
basal nucleus provides GABA-ergic inhibitory input to the
pre-optic anterior hypothalamus (PAH). When
adenosineAdenosine is a nucleoside composed of a molecule of adenine attached to a ribose sugar molecule moiety via a β-N
9-glycosidic bond....
builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity.
CaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that is a psychoactive stimulant drug. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819. He coined the term kaffein, a chemical compound in coffee, which in English became caffeine...
is known to block adenosine receptors, thereby inhibiting sleep among other things.
Research
Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the
American College of Neuropsychopharmacology (ACNP), the
European College of Neuropsychopharmacology (ECNP), and the
Collegium Internationale Neuro-psychopharmacologicum (CINP) to be established as a measure of focus.
The ECNP publishes
European Neuropsychopharmacology, and as part of the
Nature Publishing GroupNature Publishing Group is an international publishing company that publishes scientific journals. It is a division of Macmillan Publishers Ltd, which in turn is owned by the Georg von Holtzbrinck Publishing Group. NPG's flagship title is Nature, a highly-cited weekly multidisciplinary journal...
, the ACNP publishes the journal
NeuropsychopharmacologyNeuropsychopharmacology is a scientific journal published by the Nature Publishing Group. Since 1994, Neuropsychopharmacology has been the official publication of the ....
, and the CINP publishes the journal
International Journal of Neuropsychopharmacology with
Cambridge University PressCambridge University Press is a printer and publisher granted a Royal Letters Patent by Henry VIII in 1534. It is the world's oldest continually operating book publisher...
.
In 2002 the most recent comprehensive collected work of the ACNP, "Neuropsychopharmacology: The Fifth Generation of Progress" was compiled. It is one measure of the current state of knowledge, and might be said to represent a landmark in the century-long goal to establish the basic neuro-biological principles which govern the actions of the brain.
Many other journals exist which contain relevant information such as
Neuroscience.
Some of them are listed at
Brown University Library.
External links
- ACNP resources
- Organisations
- Journals