I. The Transmitter Systems:

The drug-based treatment of behavioral and psychological disorders depends on their biological basis. All drugs with psychoactive properties change the activity of neurotransmitter signaling within the brain, whether they facilitate or impair it. Those that facilitate neurotransmitter activity are agonists and those that impair it are antagonists, as we discussed in Chapter Four. While there are over one hundred transmitter substances, we're going to focus on a few of the most well-studied and extensive ones in the central nervous system. Because of their widespread distribution in the brain they are involved in some of the key functions of the brain and have equally widespread involvement in psychological disorders.

Acetylcholine (ACh) is chemically known as a biogenic amine and is the single transmitter that depends on enzymatic degradation (done by acetylcholinesterase) in the synaptic cleft to terminate its signal. It is found in the brain, the parasympathetic nervous system as well as the nerve-muscle junction. It has important roles in regulating the processing of sensory information learning, memory and wakefulness. Dopamine (DA) is also a biogenic amine, but is further subcategorized chemically as a catecholamine. It is important in controlling voluntary motor movements, attention, behavioral control, reward, pleasure, learning, memory and hormonal responses. Norepinephrine (NE) is a biogenic amine and catecholamine and is important in attention and arousal, mood, and wakefulness. Serotonin (5HT) is a biogenic amine but it is not a catecholamine. It is an indolamine. It plays roles in mood, aggression, wakefulness, feeding, sexual desire, attention, body temperature and blood pressure. Glutamate (GLU) is an amino acid and is the primary excitatory neurotransmitter in the brain. As such glutamate is, at some level, involved in every brain function. It is especially important in learning and memory, specifically, and in any long-term synaptic signaling changes in the brain, in general. GABA is also an amino acid but it is the primary inhibitory neurotransmitter in the brain and because of that, it also is at some level involved in almost every brain function, but it is especially important in regulating learning and memory and fear or anxiety.

II. The Brain's Sources Of Some Key Transmitters

Some of these key transmitters are predominantly produced in only a relative few brain regions and distributed to the rest of the brain. The Basal Forebrain (BF) is the chief source of the brain's ACh particularly for the cortex and limbic system structures like the hippocampus and amygdala. However, the BF is not one structure but a small group of related structures that work together to produce and distribute ACh. Those structures include the nucleus basalis, the medial septum, the diagonal band of Broca and the substantia innominata (Latin for the unnamed substance). The Substantia Nigra (SN; Latin for the black substance) and the Ventral Tegmental Area (VTA) are the main sources for the forebrain's DA. Interestingly, their targets are fairly cleanly separated. The SN delivers its DA exclusively to the motor system, most notably the Basal Ganglia. In contrast, the VTA exclusively provides its DA to the limbic system and cortex, especially the prefrontal cortex. While the SN and the VTA produce the same transmitter, they do seem to not be composed of exactly identical cells. For instance, the SN got its name because, as an individual grows older, it accumulates a dark pigment that gradually changes its appearance to black. The VTA displays no such change in coloration as an individual grows older. The Locus Ceruleus (LC; Latin for the blue spot) is the brain's (as well as the spinal cord's) source for NE and is part of the reticular activating system involved in arousal and attending to novel stimuli or sudden changes in the environment. The Dorsal Raphe (DR; raphe is Latin for seam) is the brain's main source of 5HT and is also part of the reticular activating system and as such is also involved in arousal, novelty and motivation.

III. What's Going Wrong?

Alzheimer's disease (AD) attacks brain regions that are involved memory, reasoning and language. Estimates are that as many as 5 million Americans suffer from AD. The disease usually begins after age 60, and the incidence increases with age but there are some rare early-onset forms of AD, as well. While older people get AD, it is important to not that AD is not considered a normal or inescapable part of aging. AD is named after Dr. Alois Alzheimer, who first formally described it in 1906. He noticed changes in the brain tissue of a woman who had died with dementia, which is the loss of mental functions such as reasoning, memory, attention and behavioral control. He found unusual accumulations of a substance which stained dark with a silver-based stain. (Now known as beta-amyloid plaques) and tangled nerve fibers (now known as neurofibrillary tangles). Plaques and tangles in the brain are now considered the definitive signs of AD. The beta-amyloid in the plaques is toxic to neurons and leads to widespread cell death in the brain. Neurons die in areas of the brain that are vital to memory and other mental abilities such as the limbic system and temporal and frontal cortices. Among the hardest hit and first cells to die are the cells of the BF which leads to low levels of ACh in the brains of AD patients. We do not completely understand what causes AD. While beta-amyloid plaques apparently cause cell death in widespread areas, the primary sensory cortices and the primary motor cortex are spared as is the cerebellum. It is also unclear the degree to which the tangles cause or contribute to cell death, but they are clearly associated with it.

Age is the most important risk factor for AD. Family history is another risk factor. For example, the less common early-onset familial AD is inherited. However, the far more common late-onset form of AD does not seem to run in families. However, genetically inherited risk factors genes may interact with each other and with non-genetic factors to precipitate AD. There is increasing evidence that come cardiovascular disease risk factors such as high blood pressure, high cholesterol, and low levels of folic acid are positively correlated with the risk of AD. There is also evidence for negative correlations for physical, mental, and social activities with AD, suggesting that they may serve as protective factors against AD. For instance, exercise and educational achievement are negatively correlated with the development of AD. Early cognitive stimulation and development may also be protective. A longitudinal study of nuns cloistered in a Minnesota convent showed that their early linguistic ability demonstrated in their interviews to enter the order was associated with later development of AD; the greater their linguistic ability in their youth, the less of a risk of AD in their old age. Some autopsies even showed plaques and tangles in the brains of some the nuns with high early-life linguistic ability, even though they showed no symptoms of AD at their death.

The initial symptoms of AD may be forgetfulness, which may appear to be a simple age-related memory decline, though, most people with mild forgetfulness do not have AD. In the early stages of the disease individuals may have trouble remembering recent events or the names of people or they may not be able to solve simple math problems. However, as the disease progresses symptoms begin to interfere with daily life. People in the middle stages of AD may forget how to do simple tasks like grooming or dressing themselves. They may no longer be able to think clearly. They fail to recognize familiar people, places and things. They begin to have problems communicating, becoming less able to clearly speak, understand, read, or write. Later on, people with AD may become emotionally uninhibited, sometimes being anxious or aggressive, and may wander away from home and lose their way. Eventually, AD suffers need complete care. Typically, AD patients live from 8 to 10 years after they are first diagnosed, though some people may survive for as long as 20 years.

No currently known treatment can stop AD. However, for some people with early and middle stage AD, the drugs tacrine (Cognex, which is still available but no longer actively marketed by the manufacturer), donepezil (Aricept), rivastigmine (Exelon), or galantamine (Razadyne, previously known as Reminyl) may delay the progression of AD for a time. All of these drugs are acetylcholinesterase inhibitors and help make the most of whatever ACh the fewer and fewer surviving BF cells can produce. But they do not stop the widespread cell death. Eventually, there's no BF ACh-producing cells left for the drugs to work on. Another drug, memantine (Namenda), has been approved to treat moderate to severe AD, although it also is limited in its effects. It is an NMDA receptor antagonist which may slow down but not stop the process of programmed cell death triggered by beta-amyloid. Some hormones such as Nerve Growth Factor (NGF) seem to protect against beta-amyloid-induced cell death in cell-culture studies, but NGF is a protein that is too large to cross the blood-brain barrier is administered as a drug. Via the bloodstream.

Schizophrenia refers to the disorder characterized by disturbances of thought, attention, perception, and emotion accompanied by motor impairments and a withdrawal from reality that are severe enough to substantially impair ability to function normally and take care of one’s self. Brain scans of schizophrenics show results consistent with brain damage and DA overactivity (particularly from the VTA). The structure of the brain in schizophrenics shows much larger ventricles compared to controls which suggests diffuse neuronal damage and cell loss. Brain metabolic activity during a psychotic episode the frontal lobes of schizophrenics is lower than that of controls or even themselves when during a clear period or on their medication and symptom-free. Other studies have shown that schizophrenics also seem to have more DA D₂-like receptors than controls (The D₂, D₃ and D₄ receptors are in the D₂-like family). Also, long-term use of drugs which stimulate DA release and slow down its reuptake, like amphetamine and cocaine, can induce a schizophrenic-like psychosis that is virtually indistinguishable from schizophrenia. Even hallucinogenic drugs like psilocybin, which are 5HT agonists, support the role of DA overactivity in schizophrenic hallucinations, since the stimulation of forebrain 5HT receptors increases the release of DA in the forebrain as well.

Chronic schizophrenia, the most common type, is a heritable disorder though the specific genes have not been isolated. The role of genetics is clearly complicated by non-genetic environmental factors. For example, the incidence of schizophrenia in the general population is approximately 0.7%. When one identical twin has the disorder, the likelihood of the second identical twin having the disorder is 48%. Far more than random chance (0.7%) but far less than what would be expected if genetic factors were the only factor (100%).

Parkinson's disease (PD) results from of the loss of dopamine-producing brain cells in the SN. The hallmark symptoms of PD are tremor (trembling in hands, arms, legs, jaw, and face), rigidity (stiffness of the limbs and torso), bradykinesia (slowness of movement) and postural instability (impaired balance and coordination). The early symptoms occur gradually and are often difficult to notice. However, as they get worse patients may have difficulty walking and talking. In late stages the patients may even have difficulty swallowing and be essentially paralyzed. PD usually affects people over 50, though there are some rare exceptions (like Michael J. Fox). The rate of progression is variable, sometimes quicker and sometimes slower. However, the onset of symptoms is not thought to occur until approximately 90% of the SN neurons have already died. Apparently the cell death occurs gradually enough over the course of a lifetime that the motor system is able to compensate for the lower levels of DA by increasing the branching of terminal in the surviving cells and increasing the sensitivity of its DA receptors. When the compensatory mechanisms are no longer able to make up for the loss of SN cells the symptoms of PD begin to appear.

Currently, there is no cure for PD, but some medications provide relief from the symptoms. Usually, patients are given levodopa combined with carbidopa. Carbidopa delays the conversion of levodopa into DA until it reaches the brain. Once in the brain, neurons use levodopa to make DA and replenish the brain's dwindling supply. Although levodopa helps most Parkinsonian cases, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all. Other drugs, such as bromocriptine, pergolide, pramipexole, and ropinirole, mimic the role of DA in the brain, causing the neurons to react as they would to DA. However, the effectiveness of drug treatments may vary over time, with higher doses over time sometimes being required and in some cases the drugs may lose their effectiveness. And, as in AD, none of the treatments stop the loss of the cells which produce DA in the SN.

In some cases, surgery may be appropriate if the disease doesn't respond to drugs. A therapy called deep brain stimulation (DBS) has now been approved. In DBS, electrodes are implanted into the brain and connected to a small electrical device called a pulse generator that can be externally programmed. DBS can reduce the need for levodopa and related drugs, which in turn decreases the involuntary movements called dyskinesias that are a common side effect of levodopa. It also helps to alleviate fluctuations of symptoms and to reduce tremors, slowness of movements, and gait problems. DBS requires careful programming of the stimulator device in order to work correctly. Lesion surgeries such as thalamotomy and pallidotomy are also used to treat PD and can lead to a reduction in symptoms such as tremor, but they are not considered cures and the effects of the surgery eventually subside over the years.

Obsessive-Compulsive disorder (OCD) results in persistent, upsetting thoughts (obsessions) in people who use rituals (compulsions) to reduce the anxiety these thoughts produce. No specific genes for OCD have been identified but childhood-onset OCD runs in families. Also when an adult with OCD has children, there is a slightly increased risk that the child will develop OCD, although the risk is still low. When OCD runs in families, it is the general nature of OCD is inherited, not specific symptoms. Thus a child may have set of obsessions and compulsions, while the parent has a different set.

No definitive cause of OCD has been identified. Research suggests that OCD involves problems in communication between the frontal cortex and the basal ganglia. Early pharmacological treatments included antipsychotic medications used for schizophrenia, though currently serotonergic antidepressants (SSRIs) are more commonly used. However, we have seen in discussing schizophrenia that the5HT system may help regulate levels of DA release in the forebrain. PET scans show that the activity in brain regions involved in OCD return toward normal in those who improve after taking a serotonin medication or receiving cognitive-behavioral psychotherapy.

Tourette's syndrome (TS) is a neurological disorder characterized by repetitive, involuntary movements and vocalizations called tics. Tics are classified as either simple or complex. Simple motor tics are sudden, brief, repetitive movements such as eye blinking, facial grimacing, shoulder shrugging, and head or shoulder jerking. Simple vocal tics might include repetitive throat-clearing, sniffing, or grunting sounds. Complex tics are distinct, coordinated movements such as facial grimacing combined with a head twist and a shoulder shrug. Complex motor tics may actually appear purposeful, including sniffing or touching objects. Complex vocal tics include words or phrases. Perhaps the notorious tics in the public consciousness about TS include acts such as punching oneself in the face or coprolalia (uttering swear words) or echolalia (repeating the words or phrases of others). Some tics are preceded by an urge or sensation in the affected muscle group, commonly called a premonitory urge. Some individuals with TS will describe a need to complete a tic in a certain way or a certain number of times in order to relieve the urge or decrease the sensation. In this way, TS shows some similarity to OCD, and OCD and TS are sometimes comorbid (occurring in an individual at the same time). TS is also often comorbid with ADHD as well. Tics are also often worse with excitement or anxiety and better during calm, focused activities. However, they do not go away during sleep but are often significantly diminished.

Evidence suggests that TS is an inherited disorder. However, the pattern of inheritance is complex. Genetic studies also suggest that some forms of ADHD and OCD are genetically related to TS. It is important for families to understand that genetic predisposition may not necessarily result in full-blown TS; instead, it may express itself as a milder tic disorder or as obsessive-compulsive behaviors. It is also possible that the gene-carrying offspring will not develop any TS symptoms. The sex of the person also plays an important role in TS expression. At-risk males are more likely to have tics and at-risk females are more likely to have obsessive-compulsive symptoms.

Because tic symptoms are often not severe enough to cause impairment, the majority of people with TS take no medication. However, medications are available for individuals whose symptoms interfere with day-to-day life. Antipsychotics are often used for tic suppression. However as with chronic schizophrenia, a possible unpleasant side effect is tardive dyskinesia, a disorder with spontaneous uncontrollable writhing movements. This is presumed to occur because the motor system's D₂ receptors become overly sensitive to dopamine due to a constant blockade. Newer antipsychotic medications called novel antipsychotic avoid this side-effect. They seem do this by blocking D₄ receptors (a part of the D₂–like receptor family) which are found in the cortex but not in the motor system. However, they also block serotonin 5HT₃ receptors.

Depression is a multi-faceted disorder. Major depression seems to occur in some families; however, it can also occur in people who have no family history of depression. The original medical studies of depression indicated that there were low levels of metabolites of the monoamines (DA, NE, 5HT) present in the cerebrospinal fluid of patients which led to the development of antidepressant medications. There are now several types of antidepressant drugs used to treat depression. These include newer medications chiefly the selective serotonin reuptake inhibitors (SSRIs), the tricyclics (selective for NE), and the monoamine oxidase inhibitors (MAOIs; which can raise levels of DA, NE and 5HT). Symptoms are not typically relieved until at least ten days to two weeks of consistent administration and the maximum effects may not occur until 6 weeks or more of taking them has passed. Antidepressants are not drugs of abuse nor are the habit-forming. Unlike drugs like amphetamine, cocaine or MDMA, they do not increase the release of the transmitters they affect. They only increase available transmitter levels by blocking reuptake or in the case of MAOIs, preventing their degradation by MAO. For individuals whose depression is severe or life threatening and unresponsive to antidepressants or who cannot take antidepressants due to their side-effects, electroconvulsive therapy (ECT) is sometimes as a last resort. Patients are anesthetized before treatment, so the person receiving ECT does not consciously experience the event. For benefit, at least several sessions of ECT, typically given at the rate of 2-3 per week, are required. But while the mechanism is unknown, ECT does raise levels of monoamines in the CSF.

Epilepsy is a general term used for a group of disorders that cause disturbances in electrical signaling in the brain. Because of the special role of glutamate as the primary excitatory neurotransmitter in the brain, it also plays a key role in epilepsy. While seizures are characteristic of epilepsy, not all seizures are epileptic in nature. Drugs, fevers, head injuries, sudden drops in blood sugar, and other medical conditions can trigger seizures as well. However, one hallmark of epilepsy is that over the course of the disease the seizures usually get stronger and can occur more frequently. This is due to a "hijacking" of sorts of the glutamate receptors involved in the long term changes associated with learning and memory. In this case one can view epilepsy as an overactivity of the glutamate system. The NMDA glutamate receptor is involved in triggering the long lasting changes in signaling effectiveness at the synapse known as long-term potentiation (LTP). However, in epilepsy, the NMDA receptor and LTP are misappropriated and play a role in increasing the spread, duration and intensity of seizures. With anticonvulsant medications and in extreme cases, surgery, epilepsy is a manageable disorder. However, when untreated, epilepsy can be fatal in the case of a long-lasting intense seizure.

Anxiety disorders also seem to reflect in some way a misappropriation of LTP, but the culprit may be an under active GABA system, particularly in the limbic areas involved in emotion and especially in the amygdala. The amygdala is important in learning the emotional significance of stimuli, especially fear. Chemical or electrical stimulation of the amygdala in animals and humans has been shown to trigger fear and anxiety. The amygdala also has high levels of benzodiazepine binding sites on the GABA receptors found in it. It is thought that under normal conditions natural benzodiazepine-like compounds in the brain help to reduce the sensations and expressions of fear by increasing GABA activity in places like the amygdala. However, if GABA activity is under active in the amygdala and other limbic structures, the belief is that LTP may occur and strengthen the feelings of general fear, anxiety in dread in anxiety disorders such generalized anxiety disorder or panic attacks. In the case of phobias it's thought that the under active GABA system may lead to inadvertent LTP to form an unwarranted or unnecessary fear association to an object, person, place or event.