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Outlined on this page are the neurophysiological pathways by which diseases are manifested or by which drugs and supplements work. Before mechanisms of action are discussed some general background information on the nervous system, neurons and neurotransmitters is given. Following the general information, the sections are broken down by disease or supplement for ease of reference.

The nervous system monitors and controls almost every organ system in the body through a series of feedback loops. The main function of the nervous system is to receive and integrate input from internal and external environments and to respond to stimuli.

The nervous system is divided into two main parts- the central and peripheral. The central nervous system (CNS) is made up of the brain and spinal cord, while the peripheral nervous system (PNS) connects the CNS to other parts of the body through nerves. The brain is divided into many different regions that each perform a different function. The function of the parts of the brain that are discussed will be mentioned in the text.

The nervous system can be further divided into several parts. The portion of the nervous system that deals with sensation and voluntary movement is called the somatic division. The portion concerned with digestion, metabolism, circulation and involuntary movements is called the autonomic division. Both divisions have afferent (moving inward toward the body) and efferent (moving out or away from the body) portions. AfferentThe efferent portion of the autonomic nervous system is further divided into two more subdivisions: sympathetic and parasympathetic. The sympathetic system prepares the body for the “fight or flight” response, while the parasympathetic system handles the “rest and digest” responses.

Neurons are the basic functional unit of the nervous system. They are specialized cells that carry information from one part of the body to another through electrical impulses called action potentials. There are three main types of neurons- the sensory neurons, motor neurons and interneurons. The sensory neurons carry messages to the central nervous system (CNS), while the motor neurons carry information from the CNS to the muscles, and the interneurons connect neuron to neuron.

While most of the diseases, conditions, drugs and supplements discussed on this page deal with neurotransmitters and the nervous system, in some cases an understanding of the endocrine system and hormones is necessary. The functional unit of the endocrine system is the hormone. A hormone is a molecule that is secreted into the bloodstream by an endocrine gland. Each hormone acts on its target cell by attaching to the appropriate receptor. An endocrine gland is a ductless gland whose secretory products are picked up by capillaries in the region. Exocrine glands, on the other hand, secrete their products into the external environment through ducts that empty into the gastrointestinal lumen. The binding of a hormone to its target causes the receptor to modify the activity of the target cell. Most hormones are classified according to the gland from which it was secreted. On this page, the gland from which the hormone was secreted, as well as the function of the hormone will be mentioned in context.

The basic structure of a neuron includes a soma, an axon, and dendrites. The soma is the central cell body that contains the nucleus, and it is where most of the activity takes place. Axons and dendrites are projections that extend away from the soma, and serve to transport electrical signals. Neurons have only one axon but many dendrites.

Action potentials, the electrical depolarizations and repolarizations of the plasma membrane that serve to transport messages, are usually carried in one direction with dendrites receiving the signal and axons carrying the signal away from the cell body. Branches off the end of an axon, called synaptic knobs, form connections with target cells, that is, the cell receiving the information. When an action potential reaches the synaptic knob, chemical messengers called neurotransmitters are released and travel across the synaptic cleft, a gap between cells, to the target cell with the help of glial cells (Zigmond, 2004). Glial cells are non-neuronal cells in the nervous system that help regulate the external environment, including the uptake of neurotransmitters from synapses.

An action potential is a unidirectional wave of depolarization of the plasma membrane of neurons. The resting membrane potential is an electric potential across the plasma membrane of -70milivolts. The voltage is caused by an unequal distribution of ions inside and outside the membrane. In the axon there are more negative charges inside the membrane which results in the negative voltage.

The Na +/K + ATPase pump and potassium leak channels are required to establish resting membrane potential. The Na +/K + ATPase pumps three sodium ions out of the cell and two potassium ions into the cell using one ATP. Currently, it is believed that the pump functions in the following way: The pump binds 3 Na + ions (ATP is already bound). ATP is then hydrolyzed leading to the phosphorylation of the pump and the release of ADP. The release of ADP results in a conformational change which causes the release of the Na ions. The pump then binds two K + ions which leads to dephosphorylation. ATP binds again and released K + ions inside the cell ( Colorado State, 2004). This results in a sodium gradient with high sodium outside the cell and a potassium gradient with high potassium in the cell (Zigmond, 2004).

Depolarization is a change in membrane potential from resting membrane potential of -70mV to a less negative or positive potential. Voltage-gated sodium channels in the plasma membrane of the axon open in response to a change in the membrane potential. The channels allow sodium ions to flow down a gradient into a cell and depolarize that portion of the membrane. The channels open around -50mV, which is called the threshold potential. Once the threshold is reached the channels open fully and sodium flows into the cell down its concentration gradient to depolarize the membrane to about +35mV. Some sodium ions flow down the axon and depolarizes the membrane slightly (Zigmond, 2004).

After depolarization the membrane is re-polarized by a series of factors: 1) the voltage-gated sodium channels slam shut after they open and remain inactive until resting membrane potential is re-established. 2) Voltage-gated potassium channels open in response to membrane depolarization; as potassium ions leaves the cell the membrane potential become more negative. 3) Potassium leak channels and the Na +/K + ATPase continue to function bringing the membrane back to resting potential (Zigmond, 2004).

The axons of many neurons are wrapped in a myelin sheath. Myelin is created by glial cells, called Schwann cells, that exist in conjunction with neurons. The myelin speeds up the movement of action potentials by limiting the area where ions can enter or exit a neuron. Places not covered by myelin, the nodes of Ranvier, are areas of concentrated voltage-gated sodium channels (Zigmond, 2004). The action potential “jumps” from node to node speeding up the reaction.

Neurotransmitters are endogenous substances that are released from neurons. They usually act on receptors on post-synaptic cells and produce a functional change in the target cell. In order to classify something as a neurotransmitter it must be synthesized and released from a neuron. For most neurotransmitters, the pre-synaptic cell must contain the transmitter and the enzymes responsible for synthesizing the neurotransmitter. Neurotransmitters must also be released from nerve terminals in a chemically identifiable form and, there should be active mechanisms to terminate the action of neurotransmitters.

A synapse is a junction between the axon and dendrites of two neurons. There are two types of synapses: electrical and chemical. Electrical synapses occur when two cells are connected by gap junctions, or the separation of cells by pores. When two cells are joined by electrical synapses, the action potential will spread directly from one cell to another. When a signal is transmitted across a chemical synapse, on the other hand, a variety of steps must occur. First the action potential must reach the synaptic knob at which point the presynaptic membrane is depolarized and voltage-gated Ca 2+ channels open. Calcium ions then must flow into the presynaptic cell, which causes the release of neurotransmitters stored in secretory vesicles. The neurotransmitters then diffuse across the synaptic cleft and bind to receptors on the postsynaptic membrane. The receptors are ligand-gated ion channels and binding causes the ion channels to open and the membrane polarization to alter. If the depolarization reaches the threshold an action potential is initiated. The neurotransmitter in the synaptic cleft then degrades or is taken up by the presynaptic cell. Excitatory neurotransmitters are those that depolarize the postsynaptic membrane after their release. In contrast, inhibitory neurotransmitters induce hyperpolarization of the postsynaptic membrane (Zigmond, 2004). Chemical synapses are the type dealt with most on this page.

Catecholamines are organic compounds that contain a benzene ring with two hydroxyl substitutions in the nucleus (catechol nucleus) and an amine group. The term usually refers to dopamine (dihydroxyphenylethylamine), norepinephrine, and epinephrine (Zigmond, 2004). In the CNS there are specific neurons for each of the catecholamines mentioned. They each also have a role in the PNS; however, the functions in the PNS will not be discussed.

Catecholamines are formed in the brain, adrenal cells and sympathetic nerves. Phenylalanine and tyrosine are precursors to catecholamines. Catecholamines are released by a calcium ion-dependent process at the synapses, or can be released by a reversal of the catecholamine transporters which can occur in response to certain drugs (Zigmond, 2004).

Serotonin was originally isolated from blood platelets and the intestinal tract. It is also found in mast cells (cells of connective tissue) and enterochromaffin cells (a group of cells found in the gut). When purified and crystallized it was found to be 5-hydrozytryptamine which is now called serotonin (Zigmond, 2004). The biosynthesis of serotonin is similar to that of the catecholamines. Tryptophan, the precursor amino acid, enters a serotoninergic neuron and is hydroxylated. The product, 5-hydroxytryptophan is then decarboxylated by aromatic amino acid decarboxylase. Serotonin is primarily stored in vesicles and is released exocytotically, that is, the vesicle fuses with the membrane and then releases its contents. The vesicular amine transporter is similar to that which transports catecholamines except it may contain a serotonin-binding protein (Zigmond, 2004).

Serotonin neurons are sensitive to changes in the plasma levels of tryptophan, and therefore dietary changes can regulate serotonin levels in the brain. Serotonin auto-receptors regulate serotonin release and synthesis. The autoreceptor is the 5-HT1a receptor. In the brain, serotonin can be regulated in a variety of ways. One of the ways of regulation requires altering the activity of the presynaptic serotonergic auto-receptors, specifically the 5-HT1A and 5-HT1B receptors. The 5-HT1A auto-receptors control serotonergic neuronal firing while the 5-HT1B auto-receptors are involved in the local inhibitory control of serotonin release (Tsai, 2004). Released serotonin is taken up by a plasma membrane carrier, the serotonin transporter. The enzyme monoamine oxidase is responsible for the degradation of serotonin.

γ-Aminobutyric acid or GABA, is an amino acid that fills the requirements of a neurotransmitter. Amino acid neurotransmitters are derived from intermediary glucose metabolism and are accumulated in glial cells as well as neurons. GABA is derived from aminated and decarboxylated α-ketoglutarate, an intermediate in the citric acid cycle (Zigmond, 2004).

The predominant GABA receptor is GABA A. The regulation of GABA is somewhat ambiguous because of confusion over whether it interacts with an autoreceptor or heteroreceptor (Zigmond, 2004).

Researchers have found that in the CNS, serotonin has implications on sleep, appetite, memory, learning, temperature regulation, mood, sexual behavior, eating and aggression. Serotonin has also been noted to produce an inhibitory effect on the nervous system that calms, soothes, and generates feelings of general contentment and satiation. Also, the indole structure of serotonin is similar to LSD and other psychotropic indoleamines which led researchers to believe that serotonin was linked to psychiatric disorders including depression and schizophrenia.

Until recently, scientists did not know the causes of major depressive disorder (MDD), but most believed that a serotonergic dysfunction was related (Tsai, 2004). They based their claim on evidence that studies of depressed patients revealed decreased brain concentrations of serotonin and decreased cerebrospinal concentrations of 5-hydrozyindoleacetic acid. The effectiveness of selective serotonin-reuptake inhibitors (SSRIs) has also lent evidence to the serotonin deficiency theory of MDD. Serotonin auto-receptors have been suggested to play a role in the pathogenesis of MDD (Tsai, 2004), and are the source of the antidepressant effects of the drug class (SSRIs). The autoreceptors, 5-HT 1A and 5-HT 1B, control and regulate serotonin release, respectively (Gardier, 1996). SSRIs function by blocking the serotonin transporter (Gardier, 1996). The SSRIs inhibit serotonin reuptake which results in increased serotonin concentration in the synapse (Schatzberg, 1987). The drug class of SSRIs includes the drugs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, among others.

Though there has been significant evidence on the effectiveness of SSRIs for patients with MDD, some evidence has been contradictory. For instance, low and normal concentrations of serotonin have been found in the brains of suicide victims (Asberg, 1976). Tryptophan, a precursor of serotonin, is claimed by some to have antidepressant effects while others disagree (Asberg, 1976). Thus, despite considerable evidence on the effectiveness of SSRI therapy, there are some who do not believe the drug is efficacious, nor that serotonin dysfunction is involved in depression at all.

An article published in the New Scientist in May 2004, highlights research on brain structure that has led to some remarkable new information about depression. A scientist at Washington University in St. Louis received a grant to take brain scans of 10 women with depression. Upon studying the scans she found that the hippocampus of all the women was up to 15% smaller than normal. She also found that hippocampus size decreased corresponding to the amount of time that the women had experienced depressive symptoms. To explain her findings, the scientist, Yvette Sheline, turned to a study performed at Stanford University that found that the hippocampus of animals shrank due to chronic stress (Farley, 2004). In response to stress, the adrenal gland is stimulated to release the steroid cortisol. Over a long period of time, cortisol can actually damage the brain by degrading dendrite endings or killing cells completely (Farley, 2004).

Cortisol levels are elevated in depressed patients, which may explain the shrunken hippocampus, but the hippocampus is involved in memory and learning, which are not major problems in depression. However, the hippocampus also connects with parts of the brain that controls mood and emotion, but scientists did not believe that damage to the hippocampus alone could cause the symptoms seen in depressed patients. When searching for answers to this problem, scientists found that another area of the brain, the prefrontal cortex, differed in depressed patients as well. The prefrontal cortex is thought to play a role in the negative thought patterns of depression. The prefrontal cortex was found to have very small neurons and fewer glial cells than normal. The amygdala, the part of the brain that controls fear and anxiety, also appeared to be enlarged in depressed patients (Farley, 2004).

These discoveries do not discount or discredit the serotonin theory of depression, however. In fact, SSRIs such as Prozac, were found to increase brain concentrations of brain-derived neurotrophic factor (BDNF) in the hippocampus. The role of BDNF is to protect neurons in the brain. Another discovery found that neurons could be regenerated through a process called neurogenesis. From this discovery, researchers found that SSRIs actually induce neurogenesis. In fact, the same amount of time that it takes for SSRIs to reduce depressive symptoms (3-4 weeks) is precisely the amount of time that it takes to induce neurogenesis (Farley, 2004).

Thus, SSRI treatment is not obsolete, but the process by which it works is perhaps not a previously thought. Raising serotonin in the body, it was found, increases the levels of a protein known as CREB (cAMP response element-binding protein), which increases BDNF levels which gives rise to neurogenesis. These new discoveries about brain physiology in depressed patients create promising new treatment options for depressed patients. New treatments, it is thought, will deal directly with chemical cascades inside the cell, rather than with neurotransmitter manipulations (Farley, 2004).

SSRIs are effective in the treatment of anxiety disorders, however, SSRIs may not be considered the ideal treatment (Goodman, 2004). There has been a link between GABA and anxiety (Nestoros, 1984). GABA is one of the principal inhibitory neurotransmitters in the brain. Benzodiazepines are a class of drugs that have been shown to have anti-anxiety effects. They are found to promote presynaptic inhibition in the spinal cord. Since GABA mediates the presynaptic inhibition in the spinal cord, it was hypothesized that GABA was responsible for anxious behaviors (Nestoros, 1984).

Upon inspection, benzodiazepines did, in fact, cause synaptic transmission in neurons that contain GABA as its neurotransmitter. Benzodiazepines failed, however, to stimulate inhibitory effects of dopamine and serotonin, two other mood related neurotransmitters. Thus, it is believed that benzodiazepines act on GABA (Nestoros, 1984). There are a number of ways in which GABA can be affected by the drug: blockage of GABA reuptake, cause GABA release or directly affect the postsynaptic membrane (Nestoros, 1984). After a number of experiments were run, scientists came to believe that the most likely site of action was on the postsynaptic membrane because a benzodiazepine receptor was discovered (Nestoros, 1984).

The proposed mechanism of action is that benzodiazepines act on a GABA receptor regulator unit, which has a GABA recognition site, a benzodiazepine site, a protein modulator, and a chloride channel (Nestoros, 1984). Basically, benzodiazepines cause a cascade of reactions that leads to increased GABA concentrations in the synapse which reduces anxiety levels.

There has been a trend in linking obsessive compulsive disorder (OCD). As a result of the theorized link, scientists began to assess whether markers for depression might also be present in OCD (Zohar, 1987). Recently a drug called clomipramine, a tricyclic antidepressant (not used in the U.S.), that has a high potency for serotonin reuptake has had effects on OCD behaviors. Scientists found that the plasma levels of clomipramine, but not the plasma level of its primary metabolite (blocks serotonin and norepinephrine reuptake) correlates with a reduction in OCD behaviors (Zohar, 1987). There was also a correlation in the reduction of OCD symptoms and the serotonin metabolite 5-HIAA and platelet serotonin. Tryptophan was also shown to reduce OCD symptoms, which also suggests that serotonin plays a role in obsessive compulsive behavior, since tryptophan is the precursor to serotonin (Zohar, 1987).

Norepinephrine is thought to play a role in bipolar disorder. In experimental tests, levels of norepinephrine in patients with affective disorders were higher than patients without disorders (Leszczynska-Rodziewicz, 2002; Lake, 1982). Manic patients had the highest norepinephrine levels.

Lithium is a common drug prescribed to bipolar patients. It is believed that lithium works by interfering with the release of norepinephrine, and increasing the re-uptake of norepinephrine by the presynaptic neuron (Ebadi, 2002). Some scientists have found that lithium has a large range of targets, not just norepinephrine, and hinders a wide range of cell processes (Harwood, 2003). Based on these two studies of lithium, it is difficult to say what the actual mechanism of action of lithium is. As a result, there is a push to create new mood stabilizing drugs, especially for bipolar disorder.

Dopamine plays an important role in normal attention and in attention disorders. A major site of action for stimulant drugs is the dopamine synapse. Some of the drugs used to treat attention deficit (hyperactivity) disorder (ADD/ADHD) stimulate the release and/or block the re-uptake of dopamine (Swanson, 2000). This causes an increase of dopamine in the synapse. The increased concentration of dopamine is the cause of decreased activity, inattention and impulsivity. As a result, dopamine was concentrated on as a site of action for treating ADHD (Swanson, 2000).

There is some evidence that people with ADD/ADHD have underactive frontal lobes and basal ganglia. The basal ganglia controls fine motor control and movement (hyperactivity), while the frontal lobes are involved in memory, impulse control, decision making and social behavior (attention). Judging strictly by the roles of the frontal lobe and basal ganglia, it would make sense that any sort of defect in those two regions of the brain could cause ADD/ADHD symptoms. It turns out that dopamine pathways link the basal ganglia and frontal cortex (Elster, 2000). ADD/ADHD medications, such as methylphenidate (Ritalin), serve to increases the concentration of dopamine in the synapse by blocking dopamine reuptake receptors (Brookhaven, 2002). Increased dopamine serves to activate the frontal lobes and basal ganglia and restore normal attention to a patient.

Ginko biloba leaf extracts (EGb) may have improving affects on memory and dementia. It is believed that Ginko has vasoregulatory effects and inhibits platelet aggregation, as well as acts as an antioxidant and increases cerebral blood flow. It is also believed to inhibit a platelet activating factor, lipid peroxidase and protein kinase C (Fugh-Berman, 1999). There are several mechanisms by which EGb may improve memory (Shah, 2003).

Another study suggests that EGb may be effective against stress. In this experiment, EGb was given to stressed individuals, and the concentrations of catecholamines and serotonin showed a marked decrease (Shah, 2003). There are many postulated mechanisms of action for each of the processes mentioned above, however the true mechanism of the drug is still unknown (Shah, 2003).

St John’s wort, the extract of the plant Hypericum perforatum L., has been found to have anti-depressant effects. SJW extract is composed of flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones (Butterweck, 2003). Many studies have been performed on SJW and many different results have been found. Originally, it was thought that SJW inhibits the re-uptake of serotonin, dopamine and norepinephrine with equal affinity. However, it is now believed that SJW has affinity for adenosine, GABA and glutamate receptors (Butterweck, 2003). Recent studies suggest that SJW is involved in the regulation of genes that control hypothalamic pituitary-adrenal axis function (Butterweck, 2003). Another study suggests the SJW inhibits monoamine oxidase in vitro, but this effect has not been noted in vivo. SJW’s largest affect appears to be on GABA A and GABA B receptors. The mechanism of action is unknown.

Flaxseed oil is thought to have anti-inflammatory, anti-thrombotic and anti-proliferative activities, as well as improve memory. Flax oil is a rich source of α-linolenic acid ( ALA). ALA is an omega-3, all cis polyunsaturated fatty acid containing 18 carbons and 3 double bonds (PDRhealth, 2004). Omega-3 fatty acids have been used to treat a number of psychiatric disorders such as depression, bipolar disorder, schizophrenia and ADD/ADHD. Omega-3 fatty acids have been found to increase the density of serotonin receptors in the frontal cortex ( Logan, 2003). Increased serotonin levels can alleviate depressive symptoms as noted in the “depression” section. Omega-3s can also increase membrane fluidity by displacing cholesterol. Certain fluidity is required for neurotransmitter binding and signaling, so omega-3s can actually improve neurotransmitter action by acting on the membrane ( Logan, 2003).

Valerian had been used to treat insomnia, anxiety and depression. Valerian works by stimulating the release and inhibiting the reuptake of GABA, thereby increasing the concentration of GABA in the synaptic cleft (Ebadi, 2002).

Under stressful situations catecholaminergic activity increases and is thought to stimulate the brain-pituitary-adrenal axis (Stoppler, 2004). The hormone cortisol, a steroid hormone made in the adrenal glands, is secreted during stressed states. Cortisol normally functions to regulate blood pressure, cardiovascular function, as well as regulate the use of proteins, carbohydrates and fats (Stoppler, 2004). When secreted, cortisol causes a breakdown of muscle protein to the corresponding amino acids, which are then used by the liver in gluconeogenesis. Cortisol is controlled though a feedback mechanism involving adrenocorticotropin (ACTH) and corticotrophin releasing hormone (CTH). ACTH is synthesized in the pituitary gland. Upon synthesizing ACTH, the pituitary signals the hypothalamus to form and release CTH. CTH signals the pituitary to release ACTH, and ACTH signals the adrenal glands to increase cortisol production (Stoppler, 2004)

Drug addiction is a brain disease. Dopamine is the neurotransmitter most often linked to the rewards from abusive drugs that lead to addiction, specifically psychomotor stimulants and opiate drugs (Bozarth, 1994). Drugs of abuse can increase extracellular dopamine levels. In its mechanism of action, dopamine binds to the dopamine receptor, which is expressed on both the target neurons and the dopamine containing neurons. To terminate dopamine action, the neurotransmitter must be taken up by the pre-synaptic cell (Bozarth, 1994).

There are seven transmembrane domain proteins on dopamine that belong to the G-protein family. The receptors can be divided into two subfamilies: the D 1 family and the D 2 family. The D 1 receptor is widely expressed in the brain. Mice with a mutant D 1 receptor experienced heightened baseline locomotor activity. In the mice, the D 1 receptor also appears to be crucial in mediating the locomotor effects on cocaine. The D 3 receptor is thought to play an inhibitory role in locomotor stimulation by cocaine and amphetamines. The D 1 receptor is thought to inhibit the locomotor stimulant and subjective effects of cocaine (Xu, 2004).

When withdrawing from an addictive drug, the blood levels of dopamine decrease which may be responsible for the intense cravings that patients experience. The ventral tegmental dopamine system may provide the neurochemical interface where exogenous opiate (heroin, morphine, etc.) and endogenous opioid peptides (endorphins, enkephalins) activate brain mechanisms involved in craving and reward (Bozarth, 1994). Following chronic drugs use, patients may experience decreased dopaminergic function.

Caffeine is a drug of choice for many Americans. It is a CNS stimulant that induces wakefulness, increases attention, and affects locomotor activity.

Adenosine is a purine that functions as an inhibitor of neuronal activity. Despite its effects on the CNS, adenosine does not fit into the criteria normally used to define a neurotransmitter. It is not accumulated into vesicles and not released from nerve terminals in a calcium-dependent fashion. It is a product of the breakdown of adenine nucleotides such as ATP. Synthesis also occurs intracellularly by means of cytoplasmic 5’-nucleotidase or by hydrolysis of S-adenosyl-homocysteine (Fisone, 2004). Intracellular adenosine is converted to AMP by adenosine kinase. The extracellular concentration of adenosine is controlled by Na +-dependent equilibrative transporters, which maintain similar intra- and extracellular concentrations of nucleosides. Usually the activity of intracellular adenosine kinase is high enough to maintain low levels of adenosine (Fisone, 2004).

Adenosine receptors are found in the brain; to date, four G-protein-coupled receptors for adenosine have been identified. They have been named A 1, A 2A, A 2B, and A 3. The affinity for adenosine of the A 2B and A 3 receptors is low, and basal level of activation is negligible (Fisone, 2004). Thus, under normal conditions caffeine cannot act via blockade of these receptors. However, the receptors A 1 and A 2A bind to caffeine with high affinity and are activated by small concentrations of adenosine which are normally present in the brain (Fisone, 2004).

At the cellular level, the majority of adenosine A 1 receptors are located on presynaptic nerve terminals where they mediate the inhibition exerted by adenosine on the release of neurotransmitters including glutamate, dopamine and acetylcholine. It is thought that caffeine stimulates arousal by blocking the A 1 receptor-mediated inhibition of mesopontine cholinergic projection neurons involved in the regulation of cortical activity (Fisone, 2004).

One of the major effects of caffeine as a psychostimulant is a prolonged increase in motor activity. Because of that, the basal ganglia and the striatal spiny neurons may play an important role in the mechanism of caffeine (Fisone, 2004). The basal ganglia is a station where information coming from limbic, prefrontal, oculomotor, and motor cortex is collected and integrated. The spiny neurons give rise to two outputs responsible for fine motor control. Both pathways contain GABA. Evidence suggests that caffeine exerts its motor stimulant effect by acting on striatal medium spiny neurons (Fisone, 2004).

The locomotor stimulant effect of caffeine has been attributed to the blockade of adenosine A 1 receptors. The receptors inhibit dopamine release and caffeine has been reported to increase extracellular dopamine in the striatum (Fisone, 2004).

Alcohol addiction may be partially due to genetics as well as neurotransmitters. Ethanol acts on the dopamine system and mediates its reinforcing or addictive properties. Studies have shown that alcoholics have a higher incidence of TAQ1 allele. Not only does this study suggest the genetic nature of alcoholism, but also explains the effect of ethanol on the body, as lower concentrations of the D2 receptors have been linked to TAQ1 as well (Volkow, 1996).

Studies have also shown that alcoholics have up to 20% fewer D2 receptors than normal patients. (The association of the TAQ1 allele for the D2 receptor gene may be present in other addictive disorders.) Decreases in D2 receptors have been attributed to changes in the striatal GABAergic cells. GABA modulates dopamine activity in the brain. Increases in GABA reduce the dopamine response to stress, while decreases in GABA increase the response. Stress is thought to play an important role in the facilitation of alcohol consumption. It is believed that alcohol reduces stress through its GABA-enhancing properties (Volkow, 1996). Increased synaptic GABA concentrations have anti-anxiety effects. Alcohol decreases GABA reuptake, thus causes there to be more GABA in the synapse. Chronic alcohol consumption decreases brain GABA levels and decreases the density of GABA receptor sites. As a result, those who consume alcohol regularly must drink more in order to achieve the same calming effect and often to avoid withdrawal symptoms (Volkow, 1996).

Nicotine is one of the most widely abused drugs in the world, which could be due in part its addictive effect. Nicotine has been linked to the dopamine system, which is responsible for reward and addiction. When bound to the ventral tegmental region, nicotine induces dopamine release in that region, as well as in the nucleus accumbens. Both the ventral tegmental area and the nucleus accumbens are regions of the brain that deal with reward, pleasure, and addiction. Serotonin and norepinephrine may also play a role in the addictive aspect of nicotine. Serotonin receptor antagonists antagonize the “nicotine-conditioned place preference”, while serotonin receptor agonists trigger the release of dopamine (Singer, 2004). Norepinephrine may also be involved in the reward process, as the lack of norepinephrine receptors completely desensitized mice to the effects of psychostimulants and opiates (Singer, 2004).

Despite the evidence that nicotine is neurochemically proven to be addictive, there may be other reasons for the continued use of nicotine; it may have cognitive effects. Nicotine increases the acetylcholine levels in the cortex and hippocampus, and increases dopamine in the hippocampus, and frontal cortex (Singer, 2004). The hippocampus is involved in memory and learning while the frontal cortex is involved in higher brain functions, such as memory, thought and reasoning. Thus, people may abuse nicotine for its effects on cognitive function (Singer, 2004).

Serotonin has been proven to play a role in reward as demonstrated by its ability to increase the amount of dopamine in the nucleus accumbens. Serotonin also plays a role in cognition as demonstrated by an experiment with rats; when serotonin levels are decreased, the rats failed at maze and avoidance tests (Singer, 2004). Norepinephrine, as well, is involved in both reward and cognition. When norepinephrine levels are decreased in the prefrontal cortex, dopamine levels were found to increase in the nucleus accumbens. The increase in dopamine may have been mediated by inhibitory GABA neurons, glutamatergic projects or excitatory prefronto-cortical projections (Singer, 2004). All of those processes are involved in cortical function, thus norepinephrine is linked to cognition and reward as well.

Exercise activates the sympathetic nervous system. Norepinephrine, as a result, is able to innervate the adrenal medulla, which causes increased release of norepinephrine and epinephrine. The increase of these two catecholamines causes the following physiological effects on the body: increased heart rate, vasoconstriction of the systemic system, and vasodilation in muscle and the liver (Harber, 1984). The increase can also cause mental effects, such as heightened mood.

β-endorphin, what is know simply as endorphin today, is a 31-residue peptide sequence cleaved from a larger peptide called pro-opiocortin (ACTH is derived from the same peptide). The β-endorphin sequence was cleaved because it was found to have potent opioid activity. Upon exercising, the body is signaled to release endorphins, which bind to opiate receptors in the brain. The endorphins are thought to have several physiological effects on the body, such as heightened mood, reduced anxiety, and altered pain perception (Harber, 1984). There is some doubt however, that the rise in endorphin concentration is not actually the cause of the euphoric state. Scientists have postulated that only if the CNS concentrations of endorphins are shown to be elevated could the heightened mental state be achieved. In most cases, however, endorphins do not cross the blood-brain barrier. When endorphins are injected into a patient, the patient experiences no euphoric state, however, when injected into the cerebral ventricle, patients experience a higher pain tolerance. There have been some unpublished studies that suggest that if exercise is intense enough, that endorphins can indeed cross the blood-brain barrier and cause a heightened state (Harber, 1984).

An endorphin antagonist, naloxone, has been used in many studies to determine if blocking endorphins has an effect of mental state. Scientist found that with exercise, patients experience an elevated mood state with less depression, less tension and less anger. However, when the drug naloxone was administered after exercise, patients saw no change in mood (Harber, 1984).

Endorphins, along with other endogenous opioids, are believed to modulate the serum concentrations of stress hormones. The pituitary hormone ACTH, is secreted in response to stressful situations, and is involved in gluconeogenesis. Also during exercise, the adrenal medulla discharges more hormones corresponding to the intensity of the work. CTH, is a hormone released from the adrenal medulla that regulates ACTH. It has been found that when responding to identical stimuli, ACTH and endorphins are released simultaneously. It is believed that endorphins regulate the secretion of CTH, since naloxone by itself leads to increased ACTH (Harber, 1984).

From reading this page alone it becomes evident that many of these diseases and mechanisms of action are linked. The body and mind are quite complex, and one change in one area most often affects other areas as well.

There are a number of other disorder, drugs and supplements that aren’t mentioned on this page. However, those mentioned are some of the most common and most used by the U.S. population. As noted by the mention of the article in New Science, research on these topics is continuing each day, and major breakthroughs on the mechanism of particular drugs or the neurochemistry behind disorders are just around the corner.

Questions or Comments, email Dr. Verna Case

This website was created as part of a Davidson College biology course.


Figure 2: Schematic diagram of synapse. Permission granted by Dr. Carl Erickson. http://www.utexas.edu/research/asrec/neuron.html		Figure 3: Schematic diagram of the interactions between two neurons. Permission granted by Dr. Carl Erickson. http://www.utexas.edu/research/asrec/neuron.html

Brain Physiology