Exam 4- Principles of Pharmacology

Neurobiological Models of Depression

1. The glucocorticoid hypothesis focuses on the stress-related neuro-endocrine abnormalities of depression. Depressed patients have abnormally high CRF secretion. The hypothalamic CRF neurons are normally controlled by other areas: the amygdala stimulates and the hippocampus has inhibitory control. When stress is prolonged and intense, glucocorticoid levels remain high, hippocampal neurons are damaged and no longer respond. Damage includes decreased dendritic branches and spines in the PFC and hippocampus. Formation of new hippocampal cells is inhibited. Cell loss in the hippocampus means reduced response to cortisol levels and loss of feedback inhibition of the HPA axis. Antidepressant drugs reduce levels of CRF and reverse loss of hippocampal dendrites in animal studies. 2. Neurotrophic hypothesis Low BDNF (brain-derived neurotrophic factor) may be responsible for the loss of dendritic branches and spines in the hippocampus and PFC and for reduced neurogenesis in the hippocampus. Antidepressants may prevent decrease of BDNF. Supporting evidence: •Chronic stress reduces BDNF in the hippocampus in rats. •Chronic but not acute antidepressant treatment increases BDNF in animals and humans. •Antidepressants prevent stress-induced reduction in BDNF and neuronal atrophy. Early life stress can lead to epigenetic changes that enhance CRF expression in the amygdala and hypothalamus and decreased glucocorticoid receptors in the hippocampus. The gene for BDNF can be modified by chromatin remodeling (epigenetic changes) that affect levels of gene expression. Stress results in methylation of BDNF genes, reducing expression. The antidepressant imipramine reverses suppression of BDNF expression by increasing histone acetylation. The drug also downregulates histone deacetylase (HDAC). This is being investigated for possible treatment approaches. Production of BDNF is dependent on the cAMP second-messenger system. Antidepressant drug treatment up-regulates several components of the system in the hippocampus and frontal cortex.

Mechanisms of Action- Cannabis

A cannabinoid receptor in the CNS was identified in 1988.Receptors occur in many brain areas. CB1 is the receptor found in the CNS. CB2 occurs in the brain's immune system and other tissues such as bone, adipose (fat) cells, and the GI tract. Cannabinoid receptors are metabotropic; they work via G proteins to inhibit cAMP formation, inhibit voltage-sensitive Ca2+ channels, and open K+ channels. CB1 receptors are located on axon terminals. By activating these presynaptic receptors, cannabinoids can inhibit the release of many neurotransmitters. Synthetic cannabinoid receptor agonists and antagonists have been developed for research and potential therapeutic use. THC given to mice induces reduced locomotor activity, hypothermia, catelepsy, and hypoalgesia—mediated through CB1receptors. Why do human brains have receptors for a compound made by plants? There must be an endogenous neurotransmitter-like substance that acts on the receptors. Several of these have now been discovered—the endocannabinoids. They are retrograde messengers—carry information in the opposite direction from normal (i.e., postsynaptic to presynaptic). They are synthesized and released in response to depolarization of the postsynaptic cell due to the influx of Ca2+. The endocannabinoids then cross the synaptic cleft, activate CB1 receptors on the nerve terminal, and inhibit Ca2+-mediated neurotransmitter release from the terminal. To determine the roles of anandamide and 2-AG, researchers use the the CB1 receptor antagonist rimonabant, and CB1 and CB2knockout mice. Pain perception: both approaches produce mice with hyperalgesia (increased pain sensitivity). Cannabinoid drugs have been used to treat pain and other medical conditions. Dronabinol (Marinol), a synthetic form of THC and the THC analog nabilone(Cesamet) are used to treat nausea and emesis in cancer chemotherapy patients. Nabiximols (Sativex) is a cannabis extract used to treat pain and spasticity in multiple sclerosis patients (not yet approved in the U.S.). Medical marijuana—smoked marijuana as a medication. Many states now permit legal use, but clinical studies of its efficacy have shown mixed results. Smoked marijuana has the potential for adverse health effects and abuse; most researchers favor development of cannabinoid-based drugs instead. Cannabinoids adversely affect cognitive function, which has been studied in animal models. Microinjection of THC or the synthetic cannabinoid agonist CP-55,940 into the hippocampus produced memory deficits in the radial arm maze. The effects can be completely blocked by the antagonist rimonabant. Learning and memory: some studies suggest endocannabinoids play a greater role in extinction of learned responses than in response acquisition. This has been demonstrated with auditory fear conditioning of rats and mice. CB1 knockout mice do not show normal extinction of the freezing response.

Animal Models of Affective Disorders

Behavioral despair or forced swim test requires rats or mice to swim in a cylinder from which there is no escape. After initial attempts to escape, the animal assumes a posture reflecting a sense of futility. Antidepressant drugs reduce the amount of time spent in the immobile posture. In the tail suspension test, mice are suspended by the tail from a lever, and the duration of movements (a period of agitation followed by immobility) is recorded. Learned helplessness test: animals are exposed to aversive events, such as inescapable foot shock for several hours or days. When placed in a new situation in which a response could alter an aversive event, they fail to make the appropriate Chronic stress tests are more difficult to perform but are considered to have greater validity. Chronic mild unpredictable stress exposes rodents to a series of physically stressful events—such as cold temperatures, wet bedding, restraint, and sudden loud noise—for several weeks. The animals show behaviors reminiscent of depressed individuals, including cognitive impairments, anxiety-like behaviors, social withdrawal, and reduced preference for sucrose that models human anhedonia. Chronic rather than acute antidepressant treatment is required to reverse the behaviors. Chronic social defeat stress uses the resident-intruder paradigm to create intense stress. The animal is placed in a dominant animal's cage, which generates nonlethal aggression. Exposure to the conflict is repeated over several days. Maternal separation can be used to simulate early life stress. Young animals are separated from their mothers for brief periods daily during the first few weeks of life.

THC Elimination

Blood THC levels decline rapidly after smoking marijuana, but complete elimination from the body is much slower because of persistence in fat tissues. The gradual movement of THC metabolites back out of fat stores means that urine screening tests can detect them more than 2 weeks after a single marijuana use.

Distribution of CB1 & CB2 receptors

CB1 -slide photo CB2 peripheral immunologic cells (modulation of cell migration) microglia

Dimethyltryptamine and 5-Methoxy-Dimethyltryptamine

Dimethyltryptamine (DMT) and 5-Methoxy-Dimethyltryptamine (5-MeO-DMT) are found in several plants indigenous to South America. Native tribes make hallucinogenic snuffs from plants containing these compounds, and also a drink called ayahuasca.

Drugs for Treating Anxiety

Drugs that relieve anxiety are anxiolytics. Sedative-hypnotic drugs are CNS depressants, and include the barbiturates, benzodiazepines, and alcohol. All of these drugs reduce neuron excitability. Anxiolytics often produce a calm and relaxed state, with drowsiness, mental clouding, and incoordination. At higher doses, they induce sleep, and are sometimes called hypnotics. At the highest doses, CNS depressants induce coma and death. The primary mechanism of action involves enhancing GABA transmission. GABA is the major inhibitory neurotransmitter; the GABAA receptor is a Cl- channel. GABA and GABA agonists allow Cl- to move into the cell and result in hyperpolarization. Benzodiazepines (BDZs) enhance the effect of GABA, but in the absence of GABA, they have no effect on channel opening. Barbiturates also increase the affinity of the GABAA receptor for GABA, and they can open the Cl- channel without GABA. This makes them potentially lethal, while the benzodiazepines are not. They have essentially been replaced by the benzodiazepines in the treatment of anxiety disorders. Barbiturate side effects:•Alter sleep by reducing the amount of REM sleep. •Mental clouding, loss of judgment, and slowed reflexes. •High doses lead to gross intoxication. Coma and death result from respiratory depression. They are extremely dangerous combined with alcohol. •Repeated use increases liver microsomal enzymes which enhances drug metabolism, producing lower blood levels (metabolic tolerance) and reduced effectiveness. •Cross-tolerance diminishes effectiveness of other drugs as well. •Barbiturates produce significant physical dependence and potential for abuse. Terminating drug use after extended treatment produces a potentially fatal withdrawal syndrome similar to that for alcohol. The first benzodiazepine (BDZ) to be introduced was chlordiazepoxide (Librium). It was the first true anxiolytic that targeted anxiety without producing excessive sedation, had low incidence of tolerance, less severe withdrawal than barbiturates, and a safe therapeutic index. All BDZs have a common molecular structure and similar mechanism of action. Onset of action is determined by lipid solubility; most soluble are quickest to be absorbed. The short-acting BDZs, such as temazepam (Restoril) and lorazepam (Ativan), are metabolized in one step. BDZs cannot be used for deep anesthesia, but are useful for pre-surgical anesthesia, dental work, and other procedures, to relax the patient. Rohypnol is marketed outside the U.S. as a sleep aid; it has become known as a "date rape" drug, especially when combined with alcohol. For anxiety, BDZs relieve the sense of worry and fearfulness and physical symptoms, with less mental clouding, loss of judgment, and motor incoordination than is typical of other sedative-hypnotics. In older patients with slower drug metabolism, confusion and reduced cognitive function may resemble senile dementia. Longer-acting BDZs are useful hypnotics to aid sleep. Some BDZs are useful muscle relaxants and others are anticonvulsants for the management of epilepsy. They can also prevent acute alcohol or barbiturate withdrawal symptoms. Second-generation anxiolytics were developed to have fewer side effects than BDZs. Buspirone (BuSpar) is less effective in reducing the physical symptoms of anxiety than the cognitive aspects of worry and poor concentration. Second-generation anxiolytics were developed to have fewer side effects than BDZs. Buspirone (BuSpar) is less effective in reducing the physical symptoms of anxiety than the cognitive aspects of worry and poor concentration. Advantages of buspirone:•It treats depression that often accompanies anxiety. •Anxiety reduction is not accompanied by sedation, confusion, or mental clouding. •Does not enhance CNS-depressant effects of alcohol or other CNS depressants. •It has little or no potential for recreational use or dependence. •No withdrawal syndrome has been reported. The onset of buspirone effectiveness in humans is quite long and its effectiveness in relieving anxiety is less than BDZs. This makes it less useful for patients who take the drug only when needed for situational anxiety. It does not show cross-tolerance or cross-dependence with BDZs or sedative-hypnotics, so it cannot be used as a substitution to treat alcohol or barbiturate withdrawal. It lacks hypnotic effects to treat insomnia, and has no muscle-relaxant effects to control seizures. Mechanism of action - agonist of 5HT1A receptors Antidepressant drugs can treat both anxiety and depression, which often occur together. Some can treat anxiety apart from depression; in OCD, SSRIs such as fluoxetine (Prozac) and sertraline (Zoloft) reduce symptoms, possibly because they enhance 5-HT function by blocking reuptake. Antidepressants including tricyclic antidepressants, MAOIs, and SSRIs, may be used to reduce the anxiety accompanying depression. SSRIs are the first choice because they have fewer troubling side effects, a high therapeutic index, and low abuse potential.

Acute Behavioral and Physiological Effects of Cannabinoids

Effects vary depending on dose, frequency of use, characteristics of the user, and the setting in which use occurs. Subjective and behavioral effects - four stages: "buzz," "high," "stoned," and "come-down. "The "high" is associated with feelings of euphoria and exhilaration, disinhibition. Relaxation is the most commonly reported effect of being "stoned." Physical responses include increased blood flow to the skin and flushing, increased heart rate, and increased hunger. Effects of marijuana are at least partially mediated by CB1 receptors—effects are significantly reduced by pretreatment with rimonabant. Smoking marijuana can sometimes produce transient psychotic symptoms such as depersonalization, derealization, agitation, and paranoia. Plasma THC levels peak much more rapidly after IV injection or marijuana smoking than after oral ingestion. In smokers, maximum intoxication occurs some time after the cigarette has been finished, when plasma THC is already declining—brain and plasma THC concentrations are not yet equilibrated when the plasma level peaks. Marijuana affects cognitive functions and psychomotor performance. Decreased performance for a variety of verbal, spatial, time estimation, and reaction time tasks has been noted. Cannabinoids appear to interfere with all aspects of memory processing. Heavy cannabis use over a long period may lead to impaired executive functioning for at least 2 to 3 weeks following cessation of use. Some data suggest that heavy, long-time users may continue to show impairment in decision-making, planning, and concept formation. Marijuana can affect psychomotor functioning under demanding task conditions, such as driving. Cannabinoids are reinforcing: In one study, regular marijuana users could discriminate THC-containing marijuana cigarettes from placebos with no THC, and all subjects preferred the marijuana with THC when given a choice. Animal studies have also demonstrated reinforcing properties. Lever pressing by squirrel monkeys for THC stopped when placebos were used. Lever pressing for THC was completely blocked by pretreatment with rimonabant, indicating that the reinforcing effect was dependent on CB1 receptor activation. Mechanisms for reinforcement: Activation of the mesolimbic dopamine (DA) system. Interactions between the cannabinoid and opioid systems may play a role in cannabinoid reward and reinforcement; opioid agonists enhance cannabinoid self-administration, and opioid antagonists have the opposite effect.

Neurobiology of Anxiety

Feelings of concern or worry, with responses such as increased muscle tension, restlessness, impaired concentration, sleep disturbances, and irritability. Activation of the sympathetic autonomic nervous system (ANS) produces increased heart rate, sweating, and other signs of the "fight-or-flight" response. Evolutionarily, anxiety is important to survival -warns of danger and activates fight-or-flight. In modern life, the fight-or-flight response is not always helpful (e.g., when required to make a speech or take and exam). Anxiety in small doses is a necessary stimulus for optimum performance in many everyday situations But when anxiety increases beyond a certain level, performance deteriorates noticeably. If high anxiety damages performance, our failures provide more reason to be anxious, creating an escalating circular pattern. Depression may develop. The amygdala central nucleus orchestrates the components of fear: -ANS activation-enhanced reflexes-increased vigilance -activation of the hypothalamic-pituitary-adrenal (HPA) axis... The physiology of anxiety may be somewhat different from that of fear. Amygdaloid processing plays a central role in anxiety, but behavioral responses may be initiated by the bed nucleus of the stria terminalis (BNST). The BNST projects to the same brain regions as the central nucleus. Fear response: central nucleus plays a role in response to sudden, aversive events. Anxiety: BNST initiates emotional response when stimuli are less precise predictors of potential danger. Produces a state of sustained preparedness for an unclear danger and prolonged anticipation of unpleasantness. In animals, anxiety in the elevated plus-maze is modulated by manipulations of the BNST. Chronic stress increases dendritic length and branching, and volume of the BNST. The amygdala aids in formation of emotional memories—conditioned fear or conditioned emotional response (CER). A CER makes an association between an environmental stimulus and an aversive stimulus. It is established quickly and is long-lasting. The prefrontal cortex (PFC) and anterior cingulate cortex exert inhibitory control over the primitive responses of subcortical regions, which allows us to cope with modern situations. Anxiety disorders are often considered to arise from an imbalance between emotion generating centers and higher cortical control. Many neurotransmitters modulate the anxiety response. 1. Corticotrophin-releasing factor (CRF) is released from the hypothalamus in response to stress. CRF induces the anterior pituitary to release adrenocorticotropic hormone (ACTH), which causes release of glucocorticoids such as cortisol from the adrenal cortex. Glucocorticoids induce physiological changes that help adapt to environmental challenges. High cortisol levels also act as negative feedback to the HPA system to bring cortisol levels back to normal. CRF also acts as a neurotransmitter in in multiple brain areas associated with anxiety. It causes behavioral signs of anxiety as well as altered ANS function. 2. Norepinephine (NE)The LC is a major cluster of noradrenergic cells that project to several brain areas. Several lines of evidence support the role of NE in anxiety:NE is the neurotransmitter released at the target visceral organs during sympathetic activation. Increased firing in the LC when presented with novel stimuli that signal threat or reward. Stimulation of the LC or administration of α2-autoreceptor antagonist yohimbine induces alerting and fear responses. Clonidine, an α2-autoreceptor agonist, has antianxiety effects. Patients with anxiety disorders have abnormal ANS response. NE and epinephrine are important in formation of emotional memories. 3. GABA - inhibitory neurotransmitter The GABAA receptor has a chloride (Cl-) channel that opens following GABA binding; Cl- enters cell and causes hyperpolarization. Benzodiazepines (BDZ) and barbituratescause sedation and reduced anxiety by binding to modulatory sites on the receptor complex The BDZ binding sites are widely distributed in the brain. They are in high concentration in the amygdala and cortex frontal lobe. A specific receptor antagonist, flumazenil, prevents the effects of BDZ binding but has no effect on the GABA receptor. Inverse agonists bind to BDZ sites and produce actions opposite of BDZ drugs—increased anxiety, arousal, and seizures. The β-carboline family produces extreme anxiety and panic. They are presumed to uncouple the GABA receptors from the Cl-channels so that GABA is less effective. Neuroactive steroids such as pregnenolone provide an additional modulatory role in anxiety. They bind to a separate site on GABAA receptors and increase the duration of GABA-induced Cl- channel opening. Neurosteroid levels tend to be low in people with generalized anxiety disorder and social phobia. 4. Serotonin plays a large role in anxiety modulation. Enhancing 5-HT function by blocking the reuptake transporter or stimulating 5-HT1Areceptors reduces anxiety. SSRIs, which enhance 5-HT function, are used to treat a variety of anxiety disorders. 5-HT may sometimes reduce anxiety, and at other times increase it. This may be explained by the subtype of 5-HT receptor involved, differences in acute and chronic treatment, or the specific brain regions involved. 5. Dopamine Plays a modulatory role in anxiety - significant DA projections from the VTA to the mPFC and limbic regions including the amygdala. Stress increases firing of mesocortical dopaminergic neurons and increases DA turnover in the prefrontal cortex. Genes and environment interact to determine the tendency to express anxiety. Animal and human studies have shown that early exposure to stress and neglect alters the developing brain and can produce a lifelong tendency for enhanced anxiety. Effects of early stress depend on timing—in what stage of development the stress occurs. Nervous system development continues throughout gestation and even after birth. Effects of prenatal stress are also gender-dependent. Women tend to have higher rates of anxiety disorders than men. Rhesus monkeys subjected to prenatal stress showed motor deficits, elevated ACTH and cortisol, and heightened signs of anxiety, as well as increased preference for alcohol at adolescence.

Characteristics of Anxiety Disorders

Generalized anxiety disorder (GAD) Individuals show signs of constant worry and continuously predict, anticipate, or imagine dreadful events. Life is generally stressful, and even minor events provoke worry. The chronic anxiety reduces the individual's performance on many tasks and decreases pleasure. Patients with GAD have increased volume of the amygdala, similar to that of laboratory animals exposed to repeated stressors. PET scans show greater amygdala activity with exposure to negative stimuli in GAD than in healthy individuals. Panic attacks—individual experiences all the effects of a fear reaction without a threatening stimulus, accompanied by strong arousal of the sympathetic ANS. Panic disorder—individual experiences both panic (individual attacks) and anticipatory anxiety over the possibility of having an attack in a place that is not safe. Anxiety associated with being in an "unsafe" place leads to agoraphobia, a fear of public places, and subsequent avoidance of many common situations. These people often lead very limited lives because they never leave the safety of their own homes. Phobias involve fears that the individual recognizes as irrational. They may focus on specific objects or situations, or relate to social situations. Phobias can affect daily existence and reduce quality of life. What people fear is at least partially determined by culture. In the Chinese culture, pa-leng is a morbid fear of the cold and loss of body heat. Social anxiety disorder (SAD)Extreme fear of being evaluated or criticized by others. Sufferers tend to avoid most interpersonal situations or, if unavoidable, suffer extreme anxiety, which may take the form of a panic attack. Onset is typically at a young age with half of affected individuals developing symptoms by age 11. Posttraumatic stress disorder (PTSD) After witnessing severely traumatic events in war, natural disasters, etc. an individual feels not only fear but also a sense of helplessness and horror. Individuals experience nightmares and flashbacks about the event. Also can be increased physiological reactivity to reminders of the trauma, sleep disturbances, and a numbing of emotional responses for many years. Some people have sudden outbursts of irritability. The probability of attempting suicide is significantly greater, as is the incidence of substance abuse, marital problems, depression, and feelings of guilt and anger. Obsessive-compulsive disorder (OCD) Recurring, persistent, intrusive thoughts or obsessions that the individual tries to resist but cause a great deal of anxiety, guilt, shame. Compulsions are repetitive rituals to relieve the tremendous anxiety generated by the obsessive thoughts. Other compulsions are unrelated to obsessions; they may involve meaningless repetitive acts like counting each crack in the sidewalk.

The potent form of cannabis called hashish

Hashish - cannabis derivative. Relatively pure resin preparation with very high [cannabinoid], or a solvent extract of leaves or resin. Hash oil is an alcoholic extract, placed on a tobacco or marijuana cigarette.

Background and History of Marijuana

In the 1930s, the US Bureau of Narcotics launched a public relations campaign to portray marijuana as a social menace that could destroy the youth of America. Marijuana remains a controversial subject in our society—castigated by many as a gateway to the so-called hard drugs, but praised by others as an unappreciated medical marvel. Marijuana is produced from flowering hemp (Cannabis sativa). Hemp has been a major source of fiber in many cultures for rope, cloth, and paper. Hemp seeds have been used for oil and animal / human food. Hemp also contains 70 unique compounds known as cannabinoids, plus more than 400 other identified compounds. The psychoactive compound Δ9-tetrahydrocannabinol (THC), is thought to account for the psychoactive effects. REALLY? Marijuana potency (in terms of THC content) varies widely, depending on the genetic strain of the plant and growing conditions. Potency can be increased by preventing pollination and seed production by the female plants. This marijuana is called sinsemilla("without seeds").

Cannabis Abuse and the Effects of Chronic Cannabis Exposure

Looking at usage from adolescence to age 37, investigators identified five patterns: 1. Non-users or experimenters 2. Occasional users 3. Quitters or decreasers 4. Chronic users 5. Increasing users Tolerance and Dependence Animals exposed to THC or other CB1 agonists develop tolerance to the behavioral and physiological effects of these compounds. Risk of dependence is related to drug use patterns. People who progress to daily use have a 50% probability of becoming dependent. Withdrawal symptoms include irritability, increased anxiety, depressed mood, sleep disturbances, heightened aggressiveness, and decreased appetite. Most cannabis users do not become dependent and do not seek treatment. Treatment in outpatient programs involves cognitive-behavioral therapy, relapse prevention training, and/or motivational enhancement therapy, but patients are very vulnerable to relapse. Effects of chronic cannabis use In young people, amount of cannabis use is inversely related to educational performance. Some research supports the hypothesis that heavy cannabis use leads to persistent cognitive deficits, impairing school performance. Alternatively, poor school performance and rejection of mainstream values such as educational achievement may increase cannabis use. Chronic cannabis use can also result in aimlessness, decreased motivation, lack of planning, and decreased productivity—amotivational syndrome. Other researchers question some of these results and suggest other interpretations of the relationship. 1.Association model—individuals who are already vulnerable to developing these issues have an increased likelihood of using cannabis when they are young. 2.Causal model—heavy use predisposes individuals to develop symptoms later in life. 3.Indicator-variable model—one or more other factors lead jointly to cannabis use and symptom proneness. Adverse health effects: There are no reports of death from overdose. Smoking marijuana can damage lungs—smoke contains tar, carcinogens, carbon monoxide, etc.

LSD

Lysergic acid diethylamide (LSD) is a synthetic compound based on fungal alkaloids. •First synthesized in 1938 from ergot, a parasitic fungus on rye. Ergot is very toxic. It produces powerful contractions of the uterus that can help trigger labor and reduce post-birth uterine hemorrhage. Some researchers tried LSD as a tool in psychotherapy or psychoanalysis. Psycholytic therapy—drug-induced "psycholysis," meaning psychic loosening or opening. Psychedelic therapy—patient was given a high dose of LSD in hopes of gaining insight into his or her problems.

Therapies for Affective Disorders

MAO inhibitors (MAOIs) The normal function of MAO is to metabolize monoamine neuro-transmitters in presynaptic terminals that are not contained in vesicles. Inhibition of MAO increases the amount of neurotransmitter available for release. Those biochemical changes occur within hours, but antidepressant effects require weeks of treatment. Neuron adaptation involving change in receptor density or second-messenger function must play an important part in these drug effects. Side effects of MAOIs include changes in blood pressure, sleep disturbances, and overeating/weight gain. More dangerous effects: •Because NE levels are elevated, drugs that enhance NE function (e.g., cold medications, antiasthma drugs, amphetamine, cocaine) will have a more intense effect. Tricyclic antidepressants (TCAs) are named for their three-ring structure. They act by binding to the presynaptic transporter proteins and inhibiting reuptake of neurotransmitters, which prolongs the duration of transmitter action at the synapse. The different TCAs have different NE and 5-HT reuptake-blocking potencies. Selective reuptake inhibitors have since been developed. Acute increase in synaptic activity is only the first step in antidepressant action; neuronal adaptation, occurring over a period of time, is necessary. Second-generation antidepressants are designed to be more selective and have fewer side effects. Selective serotonin reuptake inhibitors (SSRIs) block the presynaptic reuptake transporter for 5-HT. The antidepressant action of SSRIs are related to increased 5-HT function at some serotonergic receptors. At other receptors, however, this causes anxiety, restlessness, movement disorders, muscle rigidity, nausea, headache, insomnia, and sexual dysfunction. Serotonin syndrome: SSRIs have potentially life threatening effects when combined with other serotonergic agonists or drugs that interfere with metabolism of the SSRIs. These include severe agitation, disorientation, ataxia, muscle spasms, fever, shivering, chills, diarrhea, elevated blood pressure, and increased heart rate. SSRIs can also cause physical dependence. Withdrawal symptoms can last several weeks. Dual NE/5-HT modulators Current thinking suggests that enhancing both NE and 5-HT function is more beneficial than enhancing only one. Mirtazapine blocks α2-autoreceptors, increasing synaptic NE and α2-heteroreceptors on serotonergic cells, increasing 5-HT release. To reduce side effects, it blocks only selected 5-HT receptors. Third-generation antidepressants are currently in development and testing stages. •Goals: speed onset of effectiveness and reduce side effects. Two new approaches are CRF receptor antagonism and enhancement of the cAMP second-messenger system. The NMDA receptor antagonist ketamine is another new approach. Clinical trials have shown a rapid (within hours) reduction in depression symptoms for 65 to 70 percent of treatment-resistant patients. Effects lasted one to three weeks. NMDA antagonists that do not cause the transient psychosis-like symptoms and dissociative effects produced by ketamine are being investigated. For most patients with bipolar disorder, lithium carbonate is the most effective medication. While lithium has no effect on healthy individuals, it eliminates or reduces manic episodes without causing depression or producing sedation. It is particularly effective in reducing suicide in bipolar individuals. Lithium enhances 5-HT actions: it elevates brain tryptophan, 5-HT, and 5-HIAA (the 5-HT metabolite) and increases 5-HT release. It reduces catecholamine activity by enhancing reuptake and reducing release. Side effects of lithium: The therapeutic index is very low; blood levels of lithium must be monitored on a regular basis. Side effects are generally mild but may include increased thirst and urination, impaired concentration and memory, fatigue, tremor, and weight gain. Alternatives to lithium: Valproate (Depakote) is an anticonvulsant drug approved for treating acute mania. Effectiveness is similar to lithium, but side effects are different. It is teratogenic, so use in women of childbearing age is limited. Carbamazepine (Tegretol) is an anticonvulsant that resembles TCAs and inhibits NE reuptake. Its actions on intracellular signaling are similar to those of valproate and lithium, but side effects are different.

Characteristics of Schizophrenia

Mental disorders called psychoses are characterized by severe distortions of reality and disturbances in perception, intellectual functioning, affect, motivation, social relationships, and motor behavior. Schizophrenia is a thought disorder, characterized by illogical thinking, lack of reasoning, and inability to recognize reality. Auditory hallucinations are frequent, and are usually voices that are insulting or commanding. Historically, schizophrenia has been organized into subtypes: •Catatonic—alternating periods of immobility and excited agitation •Paranoid—characteristic delusions of grandeur or persecution •Disorganized—silly, immature emotions with disorganized behavior •Undifferentiated—cases not meeting the criteria of the other subtypes Another classification scheme is based on symptoms: Positive symptoms—delusions and hallucinations, bizarre behavior. Negative symptoms—reduced speech, flattened affect, loss of motivation, social withdrawal, and anhedonia. Cognitive symptoms—impaired working memory, executive functioning, and attention. Brain changes may be due to progressive deterioration during the illness rather than causing the illness. Or may be due to effects of antipsychotic medication used over many years. But most brain changes are not correlated with duration of time since onset of symptoms or the duration of time since hospitalization. Imaging studies show less blood flow to the frontal cortex when people with schizophrenia are performing cognitive tasks, such as the Wisconsin Card Sorting Test (WCST). Sort by: Color OR shape OR number

Mescaline

Mescaline is found in several species of cactus, such as Peyote (Lophophor williamsii) and San Pedro.

Hallucinogenic Drugs

Mescaline, Psilocybin, Dimethyltryptamine and 5-Methoxy-Dimethyltryptamine, LSD Hallucinogenic drugs produce unusual perceptual and cognitive distortions, which some people find novel, stimulating, or even spiritually uplifting. They produce these effects without producing a state of toxic delirium. Many are synthesized by plants or are based on plant-derived compounds.

Psilocybin

Mushrooms in several different genera produce alkaloids with hallucinogenic properties and are found in many places around the world. The dried mushrooms may be eaten raw or cooked or made into tea. The main compounds are psilocybin and related psilocin. After ingestion, psilocybin is converted to psilocin, the actual psychoactive agent. Hallucinogenic mushroom use also goes back thousands of years in several parts of the world. In 1955, Gordon Wasson participated in a mushroom-eating ritual in Oaxaca, Mexico, led by a Mazatec shaman. His experiences were described in a Life magazine article in 1957. Timothy Leary and Richard Alpert at Harvard experimented with psilocybin and LSD and helped to popularize these drugs.

Classic Neuroleptics and Atypical Antipsychotics

Neuroleptics is an older term for antipsychotic drugs. There are many of these drugs, and none are consistently more effective than the others. An individual may respond better to one drug than to another; several may have to be tested to find the one that is most effective. The classic antipsychotic drugs are phenothiazines and butyrophenones. Phenothiazines have a 3-ring nucleus plus variable side groups. Side chain structure determines potency, activity, and side effects. Competitive antagonists of dopamine D2receptors. Effectiveness of these drugs has been demonstrated hundreds of times, especially for positive symptoms. Negative and cognitive symptoms are more resistant to treatment. The law of thirds—one third of patients respond well, one third shows significant improvements, but may relapse, and one third fails to respond. After initial recovery, antipsychotic drugs are prescribed as maintenance therapy to prevent relapse. Unpleasant side effects cause many patients to stop treatment. Psychotherapy and group therapy are important additions to drug therapy. Antipsychotics also block D2 autoreceptors, which control firing rate, and synthesis of DA. Increased firing rate after antipsychotic administration is accompanied by increased turnover (synthesis, release, and metabolism) of DA. Under normal conditions, DA inhibits prolactin release from the pituitary. By blocking D2 receptors, neuroleptics stimulate prolactin secretion, which leads to lactation and breast enlargement, even in males. Measuring serum prolactin provides an easy measure of D2 receptor function in the CNS. Four dopamine pathways in the brain are important for understanding drug action: 1. Mesolimbic pathway—affects positive symptoms. 2. Mesocortical pathway—cognitive and negative symptoms. 3. Nigrostriatal pathway—motor side effects. 4. Tuberohypophyseal pathway—regulates pituitary hormone secretion; neuroendocrine effects. Parkinsonism: motor side effects that resemble symptoms of Parkinson's disease. Parkinson's is caused by loss of cell bodies in the substantia nigra, which gives rise to the nigrostriatal pathway. Lack of DA function in the striatum increases cholinergic cell activity, which causes the motor effects. Parkinson's disease is treated by reducing excess acetylcholine activity. Neuroleptic drugs with anti-cholinergic action, such as thioridazine, have been developed. Alternatively, antipsychotic drugs are combined with an anticholinergic drug such as benztropine (Cogentin). Tardive dyskinesia (TD) is characterized by stereotyped involuntary movements, particularly of the face and jaw, quick and uncontrolled movements of the arms and legs, and other motor effects. Incidence of TD increases with duration of treatment. Antipsychotic drugs cause little or no tolerance, physical dependence, or abuse potential, and have high therapeutic index. Lack of abstinence syndrome may be due to long half-life. However, abrupt termination of the drugs may unmask signs of TD. Atypical or second-generation drugs reduce positive symptoms of schizophrenia as well as classical drugs, but without significant extrapyramidal side effects. Some new drugs do not produce TD or increase prolactin secretion. These block 5HT2A, and have lower affinity for D2 than first-generation. Broad-spectrum antipsychotics block other receptor types in addition to D2 receptors. Clozapine has weak affinities for D1 and D2 and strong affinities for serotonergic, muscarinic, histaminergic, and D4 receptors. It is more effective for patients who do not respond to typical neuroleptics. Clozapine has many side effects because of its action on multiple receptors. There is little evidence to suggest superiority of the atypical drugs over conventional antipsychotics, although they do appear to reduce motor side effects (extrapyramidal side effects). Neither 1st nor 2nd generation antipsychotic drugs improve the cognitive impairments of schizophrenia. Some new approaches: 1. Enhancing acetylcholine. Clozapine is the only drug currently in use that enhances cognition; it increases ACh release in the hippocampus. 2. Selectively enhance D1 receptor signaling in PFC with D1 agonists. Hypofrontality is associated with reduced DA function in PFC, especially at D1 receptors. 3. Alternatively, increase DA function by inhibiting the enzyme catechol-O- methyltransferase (COMT), which degrades DA in the synapse.

Preclinical Models of Schizophrenia

No single animal model can mimic the complex symptoms of schizophrenia. Each one focuses on one aspect of the disorder to experimentally induce similar changes in animal behavior. Animal models are also used to test potential new drugs. They often depend on neurochemically induced behaviors that are known to respond to currently useful drugs. This method often fails to identify drugs with novel mechanisms of action. Amphetamine-induced stereotypy: High doses of CNS stimulants such as amphetamine produce symptoms similar to paranoid schizophrenia. In animals, it produces characteristic stereotyped sniffing, licking, and gnawing. Stereotyped behavior also occurs in humans on high doses, and is similar to the compulsive repetitions of behavior seen in schizophrenia. This method has been used for years to identify potential antipsychotic drugs. Another method compares dose-response curves for a drug's ability to block hyperactivity induced by apomorphine (a dopamine agonist) with the curve for the drug's effectiveness in producing catalepsy. Greater separation between curves means less likelihood that the effective antipsychotic dose will produce motor side effects in humans. The paw test: Animal's limbs are placed into separate holes, and time needed to remove fore- and hindpaws is recorded. The striatum regulates forepaw retraction; this is an analogue for motor side effects. The nucleus accumbens regulates rear paw retraction; longer drug-induced retraction time correlates with therapeutic efficacy. Rodent version of the WCST: animals are presented with 2 bowls, one of which contains food; they must discriminate based on odor or texture. Because of its similarity to the WCST, if this task is fully validated, it would have good translation to human behavior. Acoustic startle response: Based on evidence that schizophrenic individuals can't filter sensory stimuli and are overwhelmed by sights, sounds and odors in the environment. Reversal of induced sensory-filtering deficits predicts antipsychotic effects. Pre-pulse inhibition defect in human schizophrenic patients and animal models To study neurodevelopment, researchers subject pregnant rodents to inadequate diets, viral infections, stressors that elevate glucocorticoids; or create complications during delivery such as hypoxia. Neonatal ventral hippocampal lesion model(NVHL): Demonstrates how a single defect early in life can produce later physiological and behavioral abnormalities reminiscent of schizophrenia. The ventral hippocampus is lesioned at PND7. Early hippocampal lesions also affect development of other brain areas including the PFC, medial temporal lobe, and nucleus accumbens. Loss of hippocampal input to PFC is probably responsible for the decreased dendritic length and spine density characteristic of NVHL animals. Genetic models: Knockout, knockin, or transgenic mice may be useful in modifying schizophrenia susceptibility genes

PCP and Ketamine: Background and History

Phencyclidine (PCP) and ketamine are related compounds. PCP was developed in the 1950s as an anesthetic. It did not result in respiratory depression, as with barbiturates, but it produced unusual characteristics and sometimes severe reactions. Clinical use stopped in 1965. PCP became an illicit street drug with names such as "angel dust" and "hog." Popularity never rivaled that of marijuana or even cocaine or heroin, and PCP use declined to a rather low level. Ketamine was developed as a safer alternative to PCP, being less potent and shorter-acting. It is a valuable anesthetic for certain procedures, particularly in children, and is also used by veterinarians. It is currently marketed as a prescription medication under the trade names Ketalar, Ketaset, and Vetalar.

Cannabis (sativa, indica, ruderalis)

Plant-derived cannabinoids ∆9 -tetrahydrocannabinol (9) - THC ∆9 -tetrahydrocannabivarin - THCV Cannabidiol (7) - CBD Cannabigerol (6) Cannabichromene (5) Cannabicyclol (3) Cannabielsoin (5) Cannbitriol (9) Cannabinol Miscellaneous (11)

An 8000-year time line of cannabis use around the world

Probably came to the U.S. with Mexican and Caribbean immigrants in the early 1900s. Marijuana Tax Act - national registration, taxation system overturned in 1969, but cannabis is still tightly controlled.

Etiology of Schizophrenia

Some markers are potentially useful in diagnosing schizophrenia: •Eye-movement dysfunctions such as inability to visually track an object. Failure to track is also common in relatives of schizophrenic patients. The defective eye-tracking gene may be inherited along with the genes for schizophrenia. •EEG of a healthy person shows localized stimulus-induced electrical activity in a specific area of the brain depending on the nature of the stimulus. Persons with schizophrenia respond to specific stimuli with widespread electrical activity across large portions of the brain. Ancient disorder -1000 BC, but its causes remain unknown. A neurodevelopmental disorder with a strong genetic component. Importance of genetics is shown by many family, twin, and adoption studies. Genetic research tries to identify genes that predict vulnerability, to allow early intervention. It is difficult because many genes are involved. Some potential genes have been identified by linkage studies, which look for similarities at loci in families with affected members. Genes suspected to be involved are candidate genes: •Genetic correlates of characteristics typical of schizophrenia, such as eye-tracking dysfunction. •Alleles involved in neurotransmitters and receptors. •Gene mutations that affect brain development. New DNA techniques such as DNA microarrays and genome-wide association screening allow rapid screening of large amounts of genetic data. Alleles found more often in people with schizophrenia are "associated" with the disorder and singled out for further research. Epigenetic changes may also play a role. Stress, especially early in life, produces epigenetic modifications that alter neurodevelopment. Reelin is a glycoprotein secreted by neurons, that guides neuron positioning during fetal brain development. Reduction of reelin could explain the cell disorganization and morphological abnormalities in schizophrenic brains. Reelin is also reduced in adults and may contribute to cognitive deficits. Reduced reelin expression is due to epigenetic modulation of the RELN gene. Mutations of the DISC1 gene may contribute to risk of schizophrenia. It codes for proteins essential in neural development, and can be disrupted by a chromosome translocation. Various DISC1 polymorphisms are also associated with impaired cognitive function.

Mean time course of plasma THC concentrations

THC is easily absorbed by the lungs, and blood plasma levels rise quickly. In oral use, poor absorption results in low and variable plasma levels, probably due to degradation in the stomach and first-pass metabolism. Metabolized in the liver, accumulates in the body's fat stores

Chemical structure of 9-tetrahydro-cannabinol (THC)

THC was identified as the major active ingredient in 1964. Burning marijuana causes the THC to vaporize and enter the smoker's lungs in small particles. Effective dose and latency to onset of effects are influenced by the amount and potency of the plant used, and patterns of smoking (e.g., breath hold duration).

Legalization still prohibits the sale and use of cannabis products by those younger than 21 years. Why?

The adolescent brain is still developing. There is concern that the reward pathways and feedback loops may be altered if cannabis is used by those with still developing brains.

Pharmacology of Hallucinogenic Drugs

The different hallucinogens vary widely in potency, ranging from LSD as the most potent to mescaline as the least. Psychedelic effects generally begin 30 to 90 minutes after ingestion. An LSD "trip" can last 6 to 12 hours. Effects of smoked DMT and Salvia are felt within seconds, peak over a few minutes, and are gone within an hour. An LSD trip can be divided into four phases: (1) onset (2) plateau (3) peak and (4) come-down A hallucinogenic trip may be experienced as mystical and spiritually enlightening (a "good trip") or disturbing and frightening (a "bad trip"). Whether the user has a good or a bad trip depends on the dose and individual and social factors. One cannot predict in advance the outcome of an LSD trip. Flashbacks—re-experiencing the hallucinations some time after drug use has stopped. If they occur for a long time, the individual is considered to be suffering from hallucinogen persisting perception disorder (HPPD), which seems to be rare. Researchers make use of the Altered States of Consciousness (ASC) rating scale, or the Hallucinogen Rating Scale. The ASC has five dimensions: oceanic boundlessness, ego-disintegration, anxiety, visionary restructuralization, reduced vigilance, and auditory alterations. Most hallucinogenic drugs have either a serotonin-like or a catecholamine-like structure. The serotonin-like (indoleamine) hallucinogens include LSD, psilocybin, psilocin, DMT, 5-MeO-DMT, and the synthetic tryptamines. Phenethylamine hallucinogens: Mescaline is structurally similar to the neurotransmitter norepinephrine (NE) and amphetamine. Amphetamine can produce hallucinogenic effects with chronic high doses, and several analogs have even greater hallucinogenic properties. Salvinorin A is chemically known as a neoclerodane diterpene. A related drug called ketocyclazocine can also induce hallucinations. LSD binds with high affinity to at least eight different serotonergic receptor subtypes. The phenylethylamines also bind to some 5-HT receptors. Their common receptor subtypes are 5-HT2A and 5-HT2C. This suggests that they may play a central role in producing hallucinations. 5-HT2A receptors in the cortex are believed to be particularly important in the action of indoleamine and phenethylamine hallucinogens. A recent neuroimaging study found a correlation between intensity of subjective effects of psilocybin and drug occupancy of 5-HT2A receptors: 1. Activation of 5-HT2A receptors enhances glutamate-excitation of pyramidal neurons in layer V of the prefrontal cortex. The glutamate is released from thalamocortical afferents, interfering with thalamic filtering of sensory information, and resulting in overload at the cortical level. 2. Pyramidal cells in cortical layer V are directly stimulated by activation of 5-HT2A receptors and secondarily stimulated by glutamate released from other pyramidal cells in the deep cortical layers that project to layer V. This activation disrupts the normal functioning of glutamatergic networks in the prefrontal cortex. Most hallucinogens (except DMT and salvinorin A) produce rapid tolerance with repeated use. A likely mechanism is down-regulation of 5-HT2A receptors, which has been demonstrated in rats. Hallucinogens do not have high abuse potential; there are no withdrawal symptoms, and they are not effective reinforcers. Dependence does occur in a small number of users, especially if exposed at an early age.

Neurochemical Models of Schizophrenia

The dopamine hypothesis: excess DA function results in positive symptoms of schizophrenia. It was suggested by the fact that amphetamine can produce a psychotic reaction in healthy individuals that can be reversed by DA antagonists. There is a strong correlation between D2receptor blockade and reduction of schizophrenic symptoms. But evaluation of DA function in patients has been inconsistent. The DA imbalance hypothesis suggests that symptoms are due to reduced DA function in mesocortical neurons (negative symptoms and impaired thinking) along with excess DA function in mesolimbic neurons (positive symptoms). A neurodevelopmental model: Negative and cognitive symptoms are associated with reduced frontal lobe function. Excessive mesolimbic DA activity following early mesocortical cell loss can explain the positive symptoms. Early mesocortical cell loss due to genetics or environmental events that alter brain development are followed by loss of inhibitory control of mesolimbic cells and the onset of positive symptoms. This model can explain many pieces of the puzzle of schizophrenia, and provides testable hypotheses for further research. Other neurotransmitters also contribute to symptoms. Glutamate-DA interaction: •Inadequate glutamate may explain the apparent increase in mesolimbic DA and decrease in PFC. •Descending glutamatergic neurons influence both DA pathways.

Pharmacology of PCP and Ketamine

The subjective effects of PCP include feeling detached from the body, vertigo or floating sensation, numbness, a dreamlike state. Affective reactions include drowsiness and apathy, loneliness, negativism or hostility or, alternatively, euphoria and inebriation. All subjects exhibited cognitive disorganization—difficulty in maintaining concentration or focus, deficiencies in abstract thinking, and halting speech. Effects of PCP have been compared with the symptoms of schizophrenia, presumably accounting for the waning of the drug's popularity For ketamine, low doses yield reactions similar to those of PCP. Doses in the anesthetic range produce a dissociated state with many subjective effects reported. This state is called the "K-hole," and can be either spiritually uplifting or terrifying. PCP and ketamine are also considered dissociative anesthetics. PCP and ketamine are noncompetitive antagonists at NMDA receptors—ionotropic receptors for the excitatory neurotransmitter glutamate. The PCP/ketamine binding site is inside the receptor's ion channel, separate from the site at which glutamate or NMDA binds. Blockade of NMDA receptors in the cerebral cortex and hippocampus probably contributes to the cognitive deficits produced by PCP and ketamine. This may also increase presynaptic glutamate release (and thus excess glutamate transmission via non-NMDA receptors) within the cortex, a secondary result of NMDA receptor antagonism. PCP and ketamine are highly reinforcing, as shown by drug self-administration, and have high abuse potential. Both activate midbrain DA cell firing and stimulate DA release, particularly in the prefrontal cortex. In healthy volunteers without prior exposure to ketamine, researchers found dose-dependent increases in drug liking and desire for more drug. This confirmed that ketamine is rewarding in humans as well as laboratory animals. Use of ketamine has been growing because of the drug's popularity within the dance scene. But abuse dates back many years, by people in the medical or veterinarian professions, and by some intellectuals who favored it as a mind-expanding drug in the tradition of LSD. Dextromethorphan, a common ingredient in OTC cough and cold medications, is another noncompetitive NMDA receptor antagonist with abuse potential. Street names include "DXM,""DM," and "Robo." Drinking large quantities of cough syrup or taking Coricidin tablets containing dextromethorphan has serious side effects. Coricidin also contains chlorpheniramine, an antihistamine/anticholinergic. High doses are potentially fatal. But dextromethorphan can be extracted from cough syrup and repackaged in pills. Other potential therapeutic uses for ketamine: •A single IV dose has been shown to produce rapid, though temporary, improvement in clinically depressed subjects. •It may be useful as a non-opioid analgesic agent for a variety of chronic pain conditions.

Neurochemical Basis of Mood Disorders

There are different hypothesis for depression: The monoamine hypothesis originated with the observation that reserpine, which reduces high blood pressure, induces depression as a side effect. It prevents packaging of neuro-transmitters into vesicles, leaving them in the cytoplasm, where monoamine oxidase (MAO) degrades them. Thus, reserpine reduces the levels of DA, NE, and 5-HT. The antidepressants monoamine oxidase inhibitor (MAOIs) and tricyclic antidepressants (TCAs) acutely increase the function of NE and 5-HT and reverse reserpine-induced reduction in motor activity in animal models. Blood level of tryptophan, the 5-HT precursor, is another measure of serotonergic function that is frequently low in depressed patients. The tryptophan depletion challenge: subjects consume a tryptophan-deficient amino acid cocktail that transiently reduces 5-HT level in the brain by 70 to 80 percent. The serotonin reuptake transporter (SERT) gene has two alleles—long and short. The short allele is associated with reduced level and function of the transporter and in some cases with depression, although only in association with increased stressful life events. Challenge studies measure the magnitude of a biological response to agonists or antagonists (e.g., the agonist-induced increase in prolactin suggests that 5-HT receptors are less sensitive in depressed patients). Sensitivity to 5-HT is restored by chronic administration of antidepressants. Imaging techniques PET scans of blood flow in brains of depressed patients show increased activity in the orbitofrontal cortex and amygdala. Increased metabolic activity in the amygdala is correlated with severity of depression and returns to normal after antidepressant drug treatment. Antidepressants increase 5-HT by blocking reuptake, or inhibiting MAO. At first, the increase in synaptic 5-HT activates autoreceptors to slow cell firing and reduce synaptic 5-HT. But long-term administration of the antidepressant results in down-regulation of the autoreceptors, and synaptic 5-HT gradually increases. This may explain the delay in the therapeutic effects of antidepressants. The "serotonin-norepinephrine" hypothesis of depression: There are anatomical and functional interactions between NE neurons originating in the locus coeruleus and the 5-HT neurons in the raphe nuclei. Each system is capable of modulating the other.

Characteristics of Affective Disorders

There are two major types of affective disorders, both characterized by extreme and inappropriate exaggeration of mood (affect): Major depression—recurring episodes of dysphoria and negative thinking. Bipolar disorder—moods swing from depression to mania over time. Reactive depression—state of sadness in response to situations like loss of a loved one. Does not constitute mental illness, unless symptoms are disproportionate to the event or significantly prolonged. Pathological depression resembles an emotional state we have all experienced but differs significantly in intensity and duration. It is characterized by loss of interest in almost everything and inability to experience pleasure (anhedonia). Most patients feel hopelessness, sadness, worthlessness, guilt, desperation. Thoughts of suicide are common; one estimate suggests that 7 to 15 percent of depressed individuals commit suicide, in contrast to 1 to 1.5 percent of the overall population. Symptom clusters vary with individuals; there may be depression subtypes associated with distinct causes and pathophysiologies. There is an extensive overlap of depression with anxiety and alcohol dependence. Comorbidity is estimated at almost 60 percent. An anxiety disorder, particularly generalized or social anxiety, usually precedes depression. Most scientists agree that psychiatric disorders result from an interaction of genes and environmental events. Evidence for a genetic contribution to affective disorders comes from several sources: Adoption studies suggest a role for genetics, but results are inconsistent. If one monozygotic twin has a mood disorder, the likelihood of the other twin having a mood disorder is about 65 percent. For dizygotic twins, the rate is 20 percent. Linkage studies look for similarities in gene location on chromosomes in families with affected members. Anxiety and depression are closely related. Intense environmental stress and anxiety often precede episodes of depression, and altered patterns of stress hormone levels are frequently found in depressed patients. Life stresses may be perceived very differently by individuals. Many people seem resilient and capable of coping, despite extraordinary stresses, while others seem to succumb to relatively minor problems. Many depressed patients have elevated cortisol levels in response to greater-than-normal release of ACTH and CRF. In major depression, altered sleep rhythms are among the most common and persistent symptoms. Onset of sleep is delayed, and REM periods get shorter rather than longer as the night goes on. Depressed individuals show a shorter REM latency at all ages.

Chemical structures of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG)

Two main endocannabinoids have been found: arachidonoyl ethanolamide (AEA), or anandamide, 2-arachidonoylglycerol (2-AG).

Drug effects on locus coeruleus (LC) cell firing

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