Chapter 4: Neurochemistry

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Neurochemistry
Focuses on the basic chemical composition and processes of the nervous system
Neuropharmacology
The study of compounds that selectively affect the nervous system
Frog heart experiment
Otto Loewi. Showed the role of the vagus nerve and the neurotransmitter acetylcholine in slowing heart rate. Ach was the first neurotransmitter discovered in the CNS and PNS.
Acetylcholine
Activates skeletal muscles in the somatic nervous system and may excite or inhibit internal organs in the autonomic nervous system
Epinephrine
EP or adrenaline. Chemical messenger that acts as a hormone to mobilize the body for fight or flight during times of stress and as a neurotransmitter in the CNS
Norepinephrine
NE or noradrenaline. Neurotransmitter found in the brain and in the parasympathetic division of the autonomic nervous system
Ligands
Fit receptors exactly and activate or block
Endogenous ligands
neurotransmitters and hormones.
Neurotransmitter: Chemical released by a neuron onto a target with an excitatory or inhibitory effect
• Outside the CNS, many of these chemicals circulate in the blood stream as hormones
Exogenous ligands
Drugs and toxins from outside the body
Invention of microscopy
1950s: invention of electron microscopy allowed view of synaptic structure for the first time
Projects a beam of electrons through a very thin slice of tissue
• Varying structure of the tissue scatters the beam onto a reflective surface where it leaves an image, or shadow, of the tissue
• Much better resolution than the light microscope
Synaptic Vesicle
Organelle consisting of a membrane structure that encloses a quantum of neurotransmitter
Quantum (pl. quanta)
Quantity, equivalent to the contents of a single synaptic vesicle, that produces a just observable change in postsynaptic electric potential
Synaptic Cleft
Gap that separates the presynaptic membrane from the postsynaptic membrane
Chemical Synapse
Junction where messenger molecules are released when stimulated by an action potential
Presynaptic Membrane
Membrane on the transmitter – output side of a synapse
Postsynaptic Membrane
Membrane on the transmitter – input side of a synapse
Storage granule
Membranous compartment that holds several vesicles containing a neurotransmitter
Electrical Synapse
aka Gap Junction
Fused presynaptic and postsynaptic membrane that allows an action potential to pass directly from one neuron to the next

Chemical synapses allow more flexibility in neuron-to- neuron communication

4 steps of neurotransmissions
Neurotransmitter must be:
1. Synthesized and stored in the axon terminal
2. Transported to the presynaptic membrane and released in response to an action potential
3. Able to activate the receptors on the target- cell membrane located on the postsynaptic membrane
4. Inactivated, or it will continue to work
indefinitely
Step 1 Neurotransmission
Synthesis and Storage
• Neurotransmitters are derived in two general ways
• Synthesized in the Axon Terminal
• Building blocks from food are pumped into cell via transporters:
protein molecules embedded within the cell membrane
• Synthesized in the Cell Body
• According to instructions contained in the DNA
• Transported on microtubules to axon terminal
Step 2 Neurotransmission
Neurotransmitter Release
• At the terminal, the action potential opens voltage-sensitive calcium (Ca2+) channels
• Ca2+ enters the terminal and binds to the protein calmodulin forming a complex
• Complex causes some vesicles to empty their contents into the synapse (exocytosis), and others to get ready to empty their contents
Exocytosis is mediated by specialized proteins. • SNAREs serve as tethers.
• v-SNAREs attach to vesicles.
• t-SNAREs attach to the presynaptic membrane.
• Synaptotagmin—a protein attached to the vesicle—is activated by Ca2+, triggering the fusion of the vesicle with the presynaptic membrane, thus releasing neurotransmitter.
Synaptotagmin
a protein attached to the vesicle—is activated by Ca2+, triggering the fusion of the vesicle with the presynaptic membrane, thus releasing neurotransmitter.
Step 3 neurotransmission
Receptor-Site Activation
• After being released, the neurotransmitter diffuses across the synapse and activates receptors on the postsynaptic membrane
• Transmitter-Activated Receptors
• Protein embedded in the membrane of a cell that has a binding site for a specific neurotransmitter
Neurotransmitter may
• Depolarize the postsynaptic membrane causing excitatory action on the postsynaptic neuron
• Hyperpolarize the postsynaptic membrane causing inhibitory action on the postsynaptic neuron
• Initiate other chemical reactions that modulate either the excitatory or inhibitory effect, or influence other functions of the receiving neuron
Autoreceptors
• “Self-receptor” on the presynaptic membrane that responds to the transmitter that the neuron releases
Ionotropic Receptor
Embedded membrane protein with two parts
• A binding site for a neurotransmitter
• A pore that regulates ion flow to directly and rapidly change membrane voltage
(Ligand gated channels)
Metabotropic Receptor
Embedded membrane protein with a binding site for a neurotransmitter but no pore
• Linked to a G protein that can affect other receptors or act with second messengers to affect other cellular processes
AKA: G-protein coupled receptor
G protein
Belongs to a family of guanyl-nucleotide-binding proteins coupled to metabotropic receptors that, when activated, bind to other proteins
Second Messenger
A chemical that carries a message to initiate a biochemical process
• Activated by a neurotransmitter (the first messenger)
• Examples:
• Alter ion flow in a membrane channel
• Formation of new ion channels
• Production of new proteins
Up-regulation
An increase in the number of receptors (in response to an antagonist)
Down-regulation
A decrease in the number of receptors (in response to an agonist drug)
Step 4 neurotransmission
Deactivation of the Neurotransmitter
Accomplished In At Least Four Ways
1. Diffusion away from synaptic cleft
2. Degradation by enzymes in the synaptic cleft
3. Reuptake into the presynaptic neuron for subsequent re-use
4. Taken up by neighboring glial cells
•Not mutually exclusive, a given neurotransmitter can be deactivated in multiple ways
A given neurotransmitter can be deactivated in multiple ways
• E.g. Serotonin
• Reuptake channels in presynaptic neuron
• Monoamine oxidase
Type I synapses
Excitatory
• Typically located on dendrites
• Round vesicles
• Dense material on membranes
• Wide cleft
• Large active zone
Type II synapses
Inhibitory
• Typically located on cell body
• Flat vesicles
• Sparse material on membranes
• Narrow cleft
• Small active zone
Criteria for identifying neurotransmitters:
1. The chemical must be synthesized in the neuron or otherwise
be present in it
2. When the neuron is active, the chemical must be released and produce a response in a target
3. The same response must be obtained when the chemical is experimentally placed on the target
4. A mechanism must exist for removing the chemical from its site of action after its work is done
Classes of neurotransmitters:
1. Amino acid transmitters
2. Amine transmitters
3. Peptide transmitters
4. Transmitter gases
Rate-Limiting Factor
• tyrosine hydroxylase
• restricts the rate at which all the catecholamines can be synthesized
Serotonin (5-HT)
• L-Tryptophan
• tryptophan hydroxylase
• 5-Hydroxy-L-Tryptophan (5-HTP)
• 5-Hydroxytryptophan decarboxylase • Serotonin (5-HT)
• degraded by Monoamine oxidase (MAO)
Amino Acid Transmitters
Glutamate: main
excitatory transmitter
• GABA: main inhibitory transmitter
Glutamate
• Major excitatory neurotransmitter
• Cannot pass blood- brain barrier
• Synthesized within the cell using glutamine released by glial cells
• Glial cells take up released glutamate and transform to glutamine
GABA
Major inhibitory neurotransmitter
• Synthesized in brain from glutamate

• GABAA—ionotropic, producing fast, inhibitory effects
• GABAB—metabotropic, slow inhibitory effects
• GABAC—ionotropic with a chloride channel

Neuropeptide
• A multifunctional chain of amino acids that act as a neurotransmitter
• Synthesized from mRNA on instructions from the cell’s DNA
• Do not bind to ion channels; do not have direct effects on the voltage of the postsynaptic membrane, act indirectly via G- protein coupled receptors
EX: • Opioids
• Neurohypophyseals
• Secretins
• Insulins
• Gastrins
• Somatostatins
• Corticosteroids
Transmitter Gases
Synthesized in cell, as needed
• Easily crosses cell membrane
• support metabolic processes
• Examples:
• Nitric Oxide (NO)
• vasodilation
• Carbon Monoxide (CO)
Activating System
Pathway that coordinates activity through a single neurotransmitter
Cholinergic Neuron
Neuron that uses acetylcholine (ACh) as its main
neurotransmitter
• Excites skeletal muscles to cause contractions
Nicotinic ACh Receptor
Ionotropic receptor (responsive to nicotine)
Four (five) activating systems
Cholinergic
• Dopaminergic (x2)
• Noradrenergic
• Serotonergic
Cholinergic System
ACh produced in nuclei in midbrain and basal forebrain
• Nicotinic ACh Receptor
• Ionotropic receptor (responsive to nicotine)
• Muscarinic ACh Receptor
• metabotropic receptor (responsive to muscarine)
Involved in attention, memory
• maintaining neuronal excitability
• helps maintain waking electroencephalog- raphic pattern
Alzheimer’s disease
• Degenerative brain disorder that first appears as progressive
memory loss and later develops into generalized dementia
• linked to decreased ACh synthesis
• treatment: acetylcholinesterase inhibitors
• increase amount of ACh remaining in synapse
Dopaminergic System
Two pathways:
• Mesostriatal (orange)
• originates in substantia nigra, projects to striatum (caudate, putamen)
• maintaining normal motor behaviour
• Mesolimbocortical (yellow)
• originates in ventral tegmentum, projects to nucleus accumbens, basal forebrain, frontal cortex
• reward, motivation ,addiction
Nigrostriatial: Parkinson’s Disease
• a degenerative disorder characterized by motor symptoms such as rigidity, slowness of movement, tremor, and abnormal gait
• loss of DA producing neurons in substantial nigra
• Treatment with L-dopa
Mesolimbic: Increased DA: Schizophrenia
• Behavioral disorder characterized by delusions, hallucinations, disorganized speech, blunted emotion, agitation or immobility, and a host of other symptoms
• positive symptoms (e.g., hallucinations) linked to over- activation of DA2 receptors
• a schizophrenia-like psychosis can be induced by drugs that increase DA (i.e., cocaine, amphetamines)
• Decreased DA: ADHD
• Treatment with DA stimulants (e.g., ritalin) reduces hyperactivity
Noradgrenergic System
Originates in locus coeruleus, projects throughout cortex (particularly to limbic system – amygdala, hippocampus, cingulate gyrus)
Decreased NE: Major depression
• Mood disorder characterized by prolonged feelings of worthlessness and guilt, the disruption of normal eating habits, sleep disturbances, a general slowing of behavior, and frequent thoughts of suicide
• Increased NE: Mania
• Elevated mood, arousal, basically the opposite of depression
• Some antidepressants that affect multiple transmitter systems (NE, DA, 5-HT) can trigger manic episodes in individuals with undiagnosed bipolar disorder
Sertotonergic System
Originate in raphe nuclei, project throughout brain
• Maintaining wakefulness
• Learning
Increased 5-HT: Obsessive-Compulsive Disorder
• Behavioral disorder characterized by compulsively repeated acts (e.g., hand washing) and repetitive, often unpleasant, thoughts (obsessions)
• Also tics, schizophrenia
• Decreased 5-HT: Depression
• Abnormalities in brainstem 5-HT neurons linked to sleep apnea and SIDS
Psychopharmacology
Study of how drugs affect the nervous system and behavior
• Drugs
• Chemical compounds administered to produce a desired change in the body
Psychoactive Drug
Substance that acts to alter mood, thought, or behavior
• used to manage neuropsychological illness
Routes of Drug Administration
Oral administration is the safest, easiest, and most common
route
• But oral administration is also the most complex as there are more barriers that the drug must cross to have its desired effect
• Other methods, such as inhalation or injection, produce much faster effects as there are fewer barriers for the drug to pass
• Fewest barriers are encountered if a psychoactive drug is injected directly into the brain.
• With each barrier eliminated en route to the brain, the dose of a drug can be reduced by another 90%.
Endothelial cells in capillaries located throughout the body are not tightly joined, so it is easy for substances to move into and out of the bloodstream
• Endothelial cells in the brain are tightly joined and the presence of astrocytes help keep most substances out
Small, uncharged molecules (e.g., oxygen and carbon dioxide) are fat soluble and can freely cross the BBB
• Larger, charged molecules (e.g., glucose, amino acids, fats) must be actively transported across the BBB
• Difficulty developing drugs for the brain
• They must be small and uncharged or they must be structurally similar to a substance that already has an active transporter that allows it to pass the BBB
• Estimated 98 percent of all drugs that may affect brain function and have therapeutic use, cannot cross the blood-brain barrier
How the Body Eliminates Drugs
Drugs are broken down in the kidneys, liver, and intestines
• The liver is especially active in catabolizing drugs
• Enzymes called the cytochrome P450 enzyme family are involved
in drug catabolism
• Liver is capable of catabolizing many different drugs into forms that are more easily excreted from the body
• Drugs are then excreted in urine, feces, sweat, breast milk, and exhaled air
• Some substances that cannot be removed may build-up in the body and become toxic
Agonist
Substance that ENHANCES the effectiveness of a neurotransmitter
Antagonist
Substance that BLOCKS/DECREASES the effectiveness of a neurotransmitter
7 stages of synaptic transmission
Synthesis of neurotransmitter in cell body, axon, or terminal
• Storageofneurotransmitter in granules or vesicles
• Release of transmitter from presynaptic terminal
• Receptor interaction in postsynaptic membrane
• In activation of excess neurotransmitter at the synapse
• Reuptake into the presynaptic terminal
• Degradation of excess neurotransmitter
Types of Ligands:
Agonists—mimiceffectsofanothertransmitter
• Antagonists—bindreceptorwithoutactivatingit
• Inverseagonists—bind to receptor and initiates opposite effect of usual transmitter
•Competitive ligands (bind to the same part of receptor molecules as endogenous ligand).
•Noncompetitive ligands (or neuromodulators) bind to modulatory sites that are not part of the receptor complex that normally binds the transmitter.
Binding affinity
The degree of chemical attraction between a ligand and a receptor.
A drug with a high affinity for its receptor will be effective at very low doses.
• Neurotransmitters are low-affinity ligands, allowing them to rapidly dissociate from receptors.
Efficacy
The ability of a bound ligand to activate the receptor.
Agonists have high efficacy
• Antagonists have low efficacy.
• Partial agonists produce a medium response regardless of dose.
Can be compared by evaluating maximal responses
Dose-response curve (DRC)
A graph of the relationship between drug doses and the effects.
• The DRC is a tool to understand
Can be nonmonotonic – indicating the point at which the drug is starting to have effects at lower-affinity receptors
Pharmacodynamics
The functional relationship between drugs and their targets.
Therapeutic Index
The separation between the effective dose and a toxic one.
• Toxic dose 50% (TD50)
• Dose at which 50% of animals show symptoms of toxicity
• Lethal dose 50% (LD50) • Dose at which 50% of animals die
• Drugs with wider therapeutic index are safer
Tolerance
Decrease in response to a drug with the passage of time
Lessening of response to a drug over time
• Larger dose is required to maintain the drug’s initial effect
Metabolic tolerance
Organ systems become more effective at eliminating the drug
• Increase in number of enzymes used to break down substance
Functional tolerance
Target tissues show altered sensitivity to the drug
• Activities of brain cells adjust to minimize effects of the substance
Subjects were given alcohol everyday for 13 weeks
Between days 12 and 20 of alcohol consumption, blood alcohol and the signs of intoxication fell even though participants maintained their intake.
Thereafter, blood alcohol levels and signs of intoxication fluctuated; one did not always correspond to the other.
relatively high blood alcohol level was sometimes associated with a low outward appearance of intoxication.
Cross-tolerance
Response to a novel drug is reduced because of tolerance developed in response to a related drug
• Suggests that the two drugs affect a common nervous system target
• Example: Barbiturates and benzodiazepines
Sensitization
occurs when drug effects become stronger with
repeated treatment
Classification of drugs
One can classify a drug by its most pronounced behavioral or psychoactive effect
I. Antianxiety Agents and Sedative Hypnotics
II. Antipsychotic Agents
III. Antidepressants and mood stabilizers
IV. Opioid Analgesics
V. Psychotropics
Group I: Antianxiety agents and sedative-hypnotics
• Benzodiazepines: • diazepam (Valium), • alprazolam (Xanax), • clonazepam (Klonopin)
• Barbiturates (anesthetic agents)
• alcohol
• Other anesthetics:
• gamma-hydroxybutyrate (GHB)
• ketamine (Special K)
• phencyclidine (PCP, angel dust)
Group II: Antipsychotic agents
• First generation • phenothiazines
• chlorpromazine (Thorazine)
• butyrophenones • haloperidol (Haldol)
• Second generation • clozapine (Clozaril) • aripiprazole (Abilify,
Aripiprex)
Group III: Antidepressants and mood stabilizers
• Antidepressants
• MAO inhibitors • Tricyclic antidepressants
• imipramine (Tofranil)
• SSRIs (atypical antidepressants)
• fluoxetine (Prozac)
• sertraline (Zoloft)
• paroxetine (Paxil, Seroxat)
• Mood stabilizers
• Lithium,
• sodium valproate
• carbamazepine (Tegretol)
Group IV: Opioid analgesics
• Opium derivatives
• morphine
• codeine
• heroin
• Endogenous opioid neuropeptides
• enkephalins
• dynorphins
• endorphins
Group V: Psychotropics
• Behavioral stimulants
• amphetamine
• cocaine
• General Stimulants: caffeine
• Psychedelic and hallucinogenic stimulants (listed by neurotransmitter)
• Acetylcholine psychedelics: atropine, nicotine
• Anandamide psychedelics: tetrahydrocannabinol (THC)
• Glutamate psychedelics: phencyclidine (PCP, angel dust), ketamine(Special K)
• Norepinephrine psychedelics: mescaline
• Serotonin psychedelics: Lysergic acid diethylamide (LSD), psilocybin, MDMA (Ecstasy)
Anxiolytics
tranquilizers, are depressants—drugs that reduce nervous system activity.
The GABAA Receptor
Excitation produces an influx of chloride (Cl ions, which hyperpolarizes the neuron
Has Two Sites:
• Sedative-Hypnotic Site: Alcohol and barbiturates
• Directly influences Cl- influx
• Antianxiety Site:Benzodiazepines
• Enhances binding effects of GABA
• Effect is dependent upon amount of GABA present
• Harder to overdose
GROUP I: ANTIANXIETY AGENTS
Benzodiazepines
• Minor tranquilizers
• Antianxiety agents
• Drugs that reduce anxiety (e.g., Valium, Xanax)
• Often used for temporary purposes (e.g., coping with stress due to a death in family)
GROUP I: SEDATIVE HYPNOTICS
Barbituates
• Produce sedation and sleep
• Can also produce general anesthesia, coma, and death
• Mostly replaced by benzodiazepines
GROUP I: SEDATIVE HYPNOTICS
Dissociative anesthetics
• Group of sedative-hypnotics developed as anesthetics
• Produce altered states and hallucinations
• Examples:
• GHB, flunitrazepam, ketamine • “Date rape” drugs
GROUP I: ALCOHOL
Similar neurochemical effects as barbiturates
• Activates GABAA receptors and increases inhibitory effects.
•contributes to social disinhibition and loss of motor coordination.
• Also stimulates dopamine pathways, causing euphoric effects.
• Chronic use causes liver damage and thiamine (vitamin B1) deficiency
GROUP II: ANTIPSYCHOTIC AGENTS
Psychosis is applied to behavioral disorders such as schizophrenia
• Antipsychotic drugs have improved functioning of schizophrenia patients and reduced number housed in institutions
First-generation / Typical antipsychotics such as chlorpromazine and haloperidol
• Major tranquilizer (neuroleptic)
• Drug that blocks the D2 dopamine receptor
• reduce the positive symptoms of schizophrenia, such as delusions and hallucinations
• Produce symptoms reminiscent of Parkinson’s disease
• Immediate effect of reducing motor activity
• After short period of use, there is a reduction in the symptoms of schizophrenia
• Negative side effect: Dyskinesia (impaired control of movement)
Second-generation / Atypical antipsychotics such as clozapine
• Weakly block D2 receptors but also block serotonin 5-HT2 receptors
• reduce negative symptoms (such as social withdrawal and blunted emotional responses) of schizophrenia
• Affect motivation and reduce agitation but may result in weight gain
Two other psychotropic drugs that produce schizophrenia- like symptoms, including hallucinations and out of body experiences, are phencyclidine (PCP or angel dust) and ketamine (Special K)
• Both drugs exert part of their action by blocking glutamate receptors, suggesting the involvement of excitatory glutamate synapses in schizophrenia
Dopamine hypothesis of schizophrenia
Proposal that schizophrenia symptoms are due to excess activity of the neurotransmitter dopamine
Evidence
• Antipsychotic drugs block D2 receptors
• Amphetamine promotes release of dopamine and can also produce symptoms similar to schizophrenia
GROUP III: ANTIDEPRESSANTS
Major Depression
• Mood disorder characterized by
• Prolonged feelings of worthlessness and guilt • Disruption of normal eating habits
• Sleep disturbances
• General slowing of behavior
• Frequent thoughts of suicide
• Common: ~6% of adult population
• Twice as common in women as in men
Although antidepressants affect synapses very quickly, their antidepressive actions take weeks to develop
• Prozac, an SSRI, enhances neurogenesis in the hippocampus
• ~20% of patients with depression fail to respond to antidepressants, suggesting that depression can likely have many causes
3 Classes of antidepressants
1. Monoamine Oxidase (MAO) Inhibitors
• Block the enzyme MAO from degrading neurotransmitters such as dopamine, noradrenaline, and serotonin
2. Tricyclic Antidepressants
• First-generation antidepressants with a chemical structure characterized by three rings that block serotonin reuptake transporter proteins
3. Second-Generation Antidepressants
• Action is similar to first-generation antidepressants, but is more selective in its action on the serotonin reuptake transporter proteins; also called atypical antidepressants
• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Block the reuptake of serotonin into the presynaptic terminal
GROUP III: MOOD STABILIZERS
Used to treat bipolar disorder
• Mutes the intensity of one pole of the disorder, thus making
the other pole less likely to recur
• Mechanism is not well understood
• Lithium may increase serotonin release • Valproate may stimulate GABA activity
GROUP IV: OPIOID ANALGESICS
Two natural sources of opioids
• Opium: used for thousands of years to produce euphoria,
analgesia, sleep, and relief from diarrhea and coughing
• The brain: peptides in the body that have opioid-like effects are collectively called endorphins (endogenous morphines)
Endorphins and their receptors are found in many regions of the brain and spinal cord
• Natural (morphine) and synthetic (heroin, oxymorphone, methadone, oxycodone, fentanyl) opioids mimic the endorphins
• Most synthetic opioids are prescribed for clinical use in pain management
• All opioids are potently addictive, and abuse of prescription opioids is growing more common
Some synthetic opioids prescribed for clinical use in pain management are hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone, and fentanyl.
If opioids are used repeatedly, they produce tolerance; within a few weeks the effective dose may increase tenfold.
• Many desired effects with respect to both pain and addiction no longer occur.
• Opioid ingestion produces wide-ranging physiological changes.
• Relaxation, sleep, euphoria, constipation
• Respiratory depression, decreased blood pressure, pupil
constriction, hypothermia
Opioids
Compound that binds to a group of brain receptors also sensitive to morphine
Endorphin
Peptide hormone that acts as a neurotransmitter and may be
associated with feelings of pain or pleasure
Three classes of endorphins
Endomorphins, enkephalins (meaning in the head), and dynorphins
Three receptors on which each endorphin is relatively specific
Mu,kappa,anddelta
Opioid Analgesic
Drugs with sleep-inducing (narcotic) and pain-relieving (analgesic) properties
Opiates
Many of these drugs are derived from opium, an extract of the seeds of the opium poppy
Pure substances derived from the poppy plant
Codeine: ingredient of cough medicines and pain relievers
Morphine: powerful pain reliever-> Heroin
Morphine
Most closely mimics the endomorphins and binds most selectively to the mu receptors.
• Synthetic opioids such as heroin affect mu receptors.
Herion
An opiate drug synthesized from morphine
• More fat soluble and penetrates the BBB faster than morphine, therefore it produces very rapid pain relief
GROUP V: PSYCHOTROPICS
Behavioral stimulants affect motor activity and mood.
• Psychedelic and hallucinogenic stimulants affect perception
and produce hallucinations.
• General stimulants mainly affect mood.
GROUP V: PSYCHOMOTOR STIMULANTS
Behavioral Stimulants
• Increase motor behavior and elevate a person’s mood and
level of alertness
• Rapid administration of behavioral stimulants is most likely to be associated with addiction
– Amphetamine
• Dopamine agonist
• Blocks dopamine reuptake transporter, leaving more dopamine available in the synaptic cleft
• Stimulates release of dopamine from presynaptic membrane.
• Both mechanisms increase the amount of dopamine available
in synapses to stimulate dopamine receptors
• Some Uses:
• Initially an asthma treatment
• Study aid
• Improvement of alertness and productivity
• Weight-loss aid
– Methamphetamine (amphetamine derivative)
• Relatively inexpensive, yet potentially devastating, drug
• neurotoxic (causes brain damage with prolonged use, damages both DA and 5HT neurons)
GROUP V: GENERAL STIMULANTS
Caffeine
• Inhibits the enzyme the normally breaks down the second
messenger cyclic AMP
• Increase in cAMP leads to an increase in glucose production within cells, which makes more energy available and allows for higher rates of cellular activity
• blocks the effect of adenosine, an endogenous neuromodulator that normally inhibits catecholamine release.
Adenosine
An endogenous neuromodulator that normally inhibits catecholamine release.
GROUP V: PSYCHEDELICS
Five main types
• Acetylcholine (e.g., atropine, nicotine)
• Norepinephrine (e.g., mescaline)
• Serotonin (e.g., LSD, psilocybin, ecstacy)
• Anandimide (THC)
• Glutamate (e.g., PCP, ketamine)
Hallucinogens
alter sensory perception and produce peculiar experiences.
• LSD (acid), mescaline (peyote), and psilocybin (magic mushrooms) have mainly visual effects.
• have diverse neural actions, including those on the noradrenergic (e.g., mescaline), serotonergic (e.g., mescaline, psilocybin, and LSD), Ach (e.g., muscarine), and opiate (e.g., Salvia) systems.
Potential medical uses of hallucinogens
OCD
Anxiety
Depression
PTSD
Acetylcholine psychedelics
These drugs either block (atropine) or facilitate (nicotine) transmission at ACh synapses.
Nicotine (from tobacco)
• Increases heart rate, blood pressure, hydrochloric acid
secretion, and bowel activity.
• Acts as an agonist on nicotinic ACh receptors in the body and brain.
• Rewarding effects are mediated by receptors in the ventral tegmental area.
• Nicotine in one cigarette can occupy 88% of the brains nicotinic receptors.
Norepinephrine psychedelics
Mescaline produces pronounced psychic alterations, including a sense of spatial boundlessness and visual hallucinations.
Serotonin psychedelics
LSD and psilocybin stimulate some serotonin receptors.
• Ecstasy elevates serotonin concentrations by blocking reuptake and stimulating release.
Endocannabinoids
homologs of marijuana produced in the brain —act as retrograde messengers and may influence neurotransmitter release from the presynaptic neuron.
Anandamide
endocannabinoid with many effects:
• Alters memory formation
• Stimulates appetite
• Reduces pain sensitivity
• Protects from excitotoxic brain damage
• Lowers blood pressure
• Combats nausea
• Lowers eye pressure from glaucoma
9-tetrahydrocannabinol (THC)
Effects vary—include relaxation, mood alteration, stimulation, hallucination, and paranoia
Two kinds of cannabinoid receptors (both metabotropic)
• CB1 receptors – only found in the CNS
• mediates the rewarding properties of cannabinoids.
• Concentrated in substantia nigra, hippocampus, cerebellar cortex, and cerebral cortex
• CB2 receptors are prominent in the immune system.
Glutamate psychedelics
• PCP (angel dust) and ketamine (Special K) can produce hallucinations and out-of-body experiences.
• They exert part of their action by blocking glutamate NMDA receptors involved in learning.
Drugs that have been associated with brain damage or cognitive impairments:
1. Amphetamines
• MDMA (“ecstasy”): Serotonin neurons
• Methamphetamine: Dopamine neurons
2. Cocaine:
• Blocks cerebral blood flow
3. Phencyclidine (PCP or “angel dust”):
• Blocks NMDA receptors
4. Chronic alcohol use associated with damage to the thalamus and limbic system
• not directly caused by alcohol
• Alcohol interferes with absorption of thiamine (vitamin B1) in intestines
• Thiamine plays a vital role in maintaining cell membrane structure
5. Doses of ecstasy approximating those taken by human users result in the degeneration of very fine serotonergic nerve terminals
Drugs that have NOT been associated with long-lasting brain damage
LSD
Opiates
Marijuana
• Marijuana plant contains at least 400 chemicals.
• Determining whether a psychotic attack is related to THC or to some other chemical in marijuana is almost impossible
Substance Abuse
Use of a drug for the psychological and behavioral changes that it produces aside from its therapeutic effects
Addiction
Desire for a drug manifested by frequent use of the drug, leading to the development of physical dependence in addition to abuse
Often associated with tolerance and unpleasant, sometimes dangerous, withdrawal symptoms upon cessation of drug use
Withdrawal symptoms
Physical and psychological behaviors displayed by an addict when drug use ends
• Examples: muscle aches and cramps, anxiety attacks, sweating, nausea, convulsions, death
Psychomotor Activation
Increased behavioral and cognitive activity
• At certain levels of consumption, the drug user feels energetic and in control
• Occurs with many drugs
Evidence for an Important Role of Dopamine in Drug Abuse
Rats will press a bar to receive electrical stimulation of the mesolimbic dopamine system and stop when the dopamine system is blocked
• Abused drugs seem to be dopamine agonists: they cause the release of dopamine or prolong its availability in the synapse
• Drugs that are dopamine antagonists (i.e. ,block the effect of dopamine) are not abused substances
Categories: Neurochemistry