Untitled Flashcards Set

Neurotransmitters/Drugs

·       Glutamate and GABA

o   Glutamate is an excitatory neurotransmitter mediating fast neurotransmission and acts as a go signal by depolarizing the postsynaptic membrane (i.e. influx of Na+ ions making the inside of the cell more positive)

o   GABA is an inhibitory neurotransmitter mediating fast neurotransmission and acts as a stop signal by hyperpolarizing the postsynaptic membrane (i.e. influx of Cl- ions making the inside of the cell more negative)

·       What determines if the amino acid neurotransmitter is excitatory or inhibitory?

o   The receptor determines if the amino acid neurotransmitter is excitatory or inhibitory and can be metabotropic and ionotropic

o   Metabotropic receptors are slow acting

o   Ionotropic receptors are fast acting

·       Other small molecule neurotransmitters

o   Acetylcholine was the first neurotransmitter discovered and is an excitatory neurotransmitter at neuromuscular junctions and autonomic nervous system synapses. It is an important neuromodulator in the brain, and nicotine is a drug that binds to acetylcholine receptors. Acetylcholine is degraded in the synaptic cleft by acetylcholine esterase.

o   Small molecule neurotransmitters are biogenic amines called monoamines, and include serotonin, considered to be an indoleamine, and dopamine, norepinephrine, and epinephrine, which are considered catecholamines. These are removed by reuptake and enzymatic degradation.

o   Serotonin is produced in the Raphe nuclei, is abbreviated as 5-HT, and plays important roles in sleep/wakefulness, and depression and anxiety. Pharmacological interventions include reuptake by serotonin transporters and degradation by monoamine oxidase. Prozac is a drug that prevents serotonin reuptake and prolongs neural responses to serotonin release.

·       Diffuse Modulatory Systems

o   Includes the biogenic amine neurotransmitters and acetylcholine. Small centers in the brain containing neurons projecting to many parts of the brain, and modulate overall brain states like mood, and arousal/sleep. An example is the Raphe nuclei, responsible for serotonin levels, are often found to be somewhat dysfunctional in patients with clinical depression.

·       Neuropeptides

o   Neuropeptides (opioids), many are also hormones, and play roles in modulating emotion, pain, stress, and homeostasis. They are also co-localized with small molecule neurotransmitters. Endogenous opioid peptides include endorphins, enkephalins, and dynorphins, which are co-localized with GABA or serotonin and tend to be depressants. They also act as analgesics to control pain, and are addictive, known to be agents of abuse.

o   True or False: Drugs are exogenous and not produced in the body – True

o   True or False: Transmitters are endogenous and are produced in the body - True

·       Measures of Drug Effectiveness and the goal of modern pharmacology

o   The goal of modern pharmacology is to develop drugs with high specificity and low toxicity.

·       Pharmacodynamics

o   Pharmacodynamics is the study of the physiological and biochemical interaction of drug molecules with cell receptors in target tissue

o   Receptors are proteins on cell surfaces or within cells

o   Ligands are molecules that bind to a receptor with some selectivity

o   True or False: Most drugs do not pass into neurons, but act on surface receptors - True

·       Agonists and Antagonists

o   Agonists are substances that increase the effectiveness of a neurotransmitter, whereas antagonists are substances that decrease the effectiveness of a neurotransmitter.

·       Drug Action at Synapses

o   Neurotransmitter release

■             Agonists: promote neurotransmitter release

■             Antagonists: decrease or block neurotransmitter release

o   Receptor Interaction

■             Agonists: stimulate receptors

■             Antagonists: block receptors

o   Degradation:

■             Agonists: Inhibit degrading enzyme

o   Reuptake

■             Agonists: block reuptake

Principles of psychopharmacology/Pharmacokinetics

·       Pharmacology

o   Drug action is the molecular change produced by a drug when it binds to a target site or receptor

o   Drug effects are the physiological or behavioral reactions

o   True or False: The site of the drug action is never different from the site of the drug’s effects - False

o   Therapeutic effects are the drug-target interaction that produces the desired physical or behavioral changes, whereas all other changes are considered to be side effects.

·       Pharmacokinetics

o   Bioavailability

■             Bioavailability is the amount of drug in the blood that is free to bind at target sites. Drug administration, absorption, distribution, binding, inactivation, and excretion all play roles in the bioavailability of a drug.

o   Routes of administration

■             Routes of administration are the way a drug enters and passes through the body, and include oral, injection, inhalation, topical application, or transdermal. To bypass the blood-brain barrier, inject into the cerebrospinal fluid or directly into the brain.

o   Absorption

■             Absorption is the movement of the drug from site of administration to the blood circulation, and is influenced by drug solubility, local conditions at the site of absorption, stomach contents, the concentration of the drug, circulation to the site of absorption, and the area of the absorbing surface.

o   Distribution:

■             Distribution highest concentration of a drug will occur where blood flow is greatest. Because the brain receives about 20% of the blood that leaves the heart, lipid-soluble drugs are readily distributed to the brain.

■             The blood-brain barrier limits movement of ionized molecules. Typical capillaries are designed to allow movement of materials between the blood and surrounding cells, whereas brain capillaries have no cleft, minimizing the movement of water-soluble molecules.

■             Drug molecules tied up in drug depots cannot reach active sites or be metabolized by the liver, but binding is reversible

■             Depot binding affects magnitude and duration of drug action: it reduces concentration of drug at its sites of action and delays effects

o   Inactivation and Elimination:

■             Half-life: amount of time required for removal of 50% of the drug (t½) and determines the interval between doses.

■             True or False: A longer half-life could lead to accumulation, which increases potential for side effects and toxicity - True

■             Metabolism

•      Metabolism is the process of destructing drug molecules (occurs in kidneys, liver, and intestines). Most biotransformation (drug metabolism) occurs in the liver.

•      First pass metabolism of drugs that are absorbed from the digestive system occurs in the liver and for some drugs also in the stomach and intestines. First pass metabolism can be avoided by alternative routes of administration, such as intravenous or inhalation.

■             Excretion

•      Excretion is the process of eliminating waste products and drugs are excreted in urine, feces, sweat, breast milk, and exhaled air

•      True or False: Feces is the most important route for drug elimination – False, it’s urine

•      The kidneys filter materials from the blood, unless they are large or bound to plasma proteins

Addiction

·       Psychoactive drugs produce an altered state of consciousness, and influence emotions perceptions, and behavior. Psychoactive drugs include stimulants, depressants, opiates, and hallucinogens.

·       Spectrum of use (Use, Misuse, Abuse, Dependence)

o   Use – Periodic non-problematic use

o   Misuse – Periodic use

o   Abuse – A pattern of misuse

o   Dependence – Compulsive problematic use, often with physiological dependence

·       Tolerance (Drug, Metabolic, Pharmacodynamic, and Behavioral)

o   Drug tolerance is the diminished response to a drug after repeated use.

■             True or False: Increasing dosages must be administered to obtain the same magnitude of biological effect - True

o   Metabolic tolerance is an increase in the number of enzymes used to break a substance down.

o   Pharmacodynamic tolerance are changes in nerve cell function to compensate for continued presence of drug.

o   Behavioral tolerance occurs when people learn to cope with being intoxicated.

·       Withdrawal

o   Withdrawal occurs with the sudden cessation of drug use, and can cause a variety of symptoms including sweating, nausea, anxiety, or loss of appetite.

·       Sensitization

o   Sensitization is the reverse of tolerance, when there is an enhancement of drug effects after repeated administration of the same dose and can persist over long periods of abstinence.

·       Drug Dependence

o   Drug dependence is a pattern of use in which the individual perceives the need to continue usage, occurring without medical need and can be compulsive.

o   Physical dependence has overt symptoms of withdrawal from chronic drug use and psychological dependence includes psychological drug craving brought on by triggers.

o   Psychological dependence includes psychological cravings for the drug brought on by triggers (associative learning mechanisms)

·       Drug addiction

o   Drug addiction is the term used to describe an overall pattern of compulsive drug abuse characterized by consistent preoccupation with drug consumption and a tendency to relapse after withdrawal.

·       Reward

o   Reward is a positive effect or feeling

o   Reinforcer is a substance, event, or activity that increases frequency/probability of a response the precedes it

·       Drug self-administration

o   Structures associated with reward circuit include the nucleus accumbens and the ventral tegmental area among other brain regions.

·       How do drugs affect our bodies?

o   Limbic system and neurotransmitters

o   Alter normal functioning of these systems

o   Increase in synaptic activity (dopamine)

o   Alterations of dopamine activity

·       D2 Receptors and Anhedonia

o   PET scans show lower dopamine D2 receptors in addiction

·       Drug Addiction: A complex behavioral and neurobiological disorder

o   Drugs, brain mechanisms, behavior, and environment contribute to drug addiction

Stimulants

·       Behavioral effects of cocaine

o   Sense of well-being, increased movement, and psychotic-like state (hallucinations, delusions)

·       Mechanisms of cocaine

o   Cocaine increases synaptic dopamine (DA) levels by binding to the plasma membrane DA transporter and blocking reuptake of the neurotransmitter.

o   Cocaine also increases frequency of DA release and inhibits NE uptake in the PFC, causing an NE receptor–mediated stimulation of glutamatergic neurons that project to the VTA.

o   At higher concentrations, cocaine also blocks voltage-gated Na+ channels which leads to a local anesthetic effect.

·       Behavioral effects of amphetamines

o   Amphetamines cause heightened alertness, increased confidence, feelings of exhilaration, reduced fatigue, and generalized sense of well-being. It also causes reduced REM sleep and permits sustained physical effort without rest or sleep.

o   Methylphenidate causes increased arousal, alertness, ability to concentrate, and elevated mood.

·       Mechanisms of amphetamine and methamphetamine action

o   Amphetamine and methamphetamine are indirect catecholamine agonists, stimulating DA and NE release from vesicles and blocking reuptake.

o   Methylphenidate, also known as Ritalin, activates catecholamine transmission by blocking DA and NE transporters, which increase extracellular levels of DA and NE.

·       Amphetamine and methamphetamine have therapeutic uses

o   Amphetamine and methamphetamine can be used in the treatment of narcolepsy, ADHD, and appetite suppression.

o   Methylphenidate is used to treat ADHD and also has therapeutic application to accelerate emergence from general anesthesia.

Nicotine

·       Route of administration effects

o   Inhaled nicotine reaches the brain in 7 seconds, faster than if it were injected with an IV.

o   Across the lining of the mouth or nose, such as chewing tobacco or snuff.

o   Transdermal patch, allowing nicotine to go through the skin into the bloodstream.

·       Nicotine metabolism

o   Mostly metabolized in the liver and then excreted via the kidneys

o   Nicotine and tar induce the production of liver enzymes which results in increased metabolism of other drugs

·       Nicotine toxicity

o   60mg is a lethal dose

o   “Low level” nicotine poisoning includes nausea, vomiting, dizziness, headache, confusion, and fainting

o   Acute nicotine poisoning includes tremors that develop into convulsions, and death by suffocation caused by paralysis of respiratory muscles

·       Behavioral and physiological effects of nicotine

o   Behavioral improvements in attention, cognition, motor, and memory

o   Physiological effects:

■             Increases activity of the sympathetic and parasympathetic branches of the autonomic nervous system

■             Increases heart rate and blood pressure

■             Weight loss due to decreased appetite and increased metabolism

■             Constriction of the blood vessels in the skin (smokers have cold hands, wrinkles)

·       How does nicotine affect the brain and body?

o   Nicotine is an agonist for nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels that respond to the neurotransmitter acetylcholine. These receptors let Na+, K+ and Ca2+ through, with a net effect of depolarizing the membrane.

·       Nicotine stimulates the reward pathway

o   Activation of receptors for nicotine (α4β2) in ventral tegmental area (VTA) cause VTA neurons to release more DA in the nucleus accumbens. Nicotine binds to α7 nicotinic presynaptic receptors on glutamate neurons in the VTA, stimulating glutamate release that in turn leads to DA release in the nucleus accumbens. Nicotine desensitizes α4β2 receptors on VTA GABA interneurons, which disinhibits VTA DA neurons and leads to DA release in the nucleus accumbens.

·       Behavioral and physiological effects of nicotine (continued)

o   Chronic exposure to nicotine induces tolerance and dependence

o   Acute tolerance is brief, due to desensitization of central nAChRs.

o   Chronic tolerance occurs from long-term exposure, which manifests as smokers showing an upregulation of nAChR levels in many brain areas.

o   Aversion is dependent on nAChRs containing the α5 subunit, which assembles α3 and β4 subunits.

o   Knocking out the α5 subunit enhances nicotine self-administration at high doses.

·       Nicotine withdrawal and addiction

o   Withdrawal symptoms include anxiety, decreased ability to enjoy things, cravings, and irritability.

·       Treatment

o   Strategies include prevention, self-help programs, and therapy programs. Pharmacological treatments include nicotine replacement, non-nicotine drugs, or nicotine vaccine.

o   While it is speculated that nicotine could help with memory and cognition in Alzheimer’s disease, schizophrenia, or ADHD, no medical applications for nicotine have been approved and the health risks from smoking to get nicotine far outweigh any benefits from the nicotine itself.

Caffeine

●      Pharmacokinetics of caffeine

○      Absorbed into bloodstream from digestive system in 30-60 minutes.

○      Metabolism of caffeine is increased by nicotine and decreased by alcohol

●      Behavioral effects of caffeine

○      At low to moderate doses, it increases alertness and energy, enhances cognitive function, and increases the ability to concentrate.

○      At higher doses, leads to anxiety and tension, can trigger panic attacks.

○      At really high doses, can cause caffeine poisoning, which can lead to irregular or rapid heartbeat, confusion, or seizures. These are off-target effects.

●      How does caffeine affect the brain?

○      Adenosine

■      Constituent of ATP. Builds up during wake, signaling to the brain that you’re “tired” through adenosine receptors.

○      Adenosine receptors

■      Caffeine’s main action on the brain is to block receptors for the neurotransmitter adenosine. Caffeine is an antagonist for adenosine receptors.

■      Adenosine receptors form complexes with DA receptors in the striatum. Blocking adenosine receptors, particularly A_2A subtype, underlies caffeine-induced behavioral stimulation.

●      Pharmacodynamic tolerance

○      At high doses, caffeine starts to have more off-target effects (all of which are excitatory)

○      Almost all the effects experienced from a reasonable daily dose are from blockade of adenosine A1 and A2A receptors

○      The A2A receptor type is especially prevalent in the striatum (nucleus accumbens), where it inhibits D2 dopamine receptors

○      True or False: Caffeine does NOT influence monoamine systems nearly as strongly as amphetamine-like drugs and cocaine do - True

●      Chronic caffeine use

○      As the action of adenosine receptors is inhibited through caffeine, more receptors are synthesized to maintain homeostasis.

○      Withdrawal symptoms are generally not severe (typically, headaches, fatigue, impaired concentration)

●      Caffeine combined with other drugs

○      Although caffeine does reduce alcohol-induced drowsiness, effects on manual dexterity, balance, reasoning, and verbal fluency remain.