The concept of synapses

Cajal: anatomically demonstrated narrow gap separating neurons
Sherrington: physiologically demonstrated communication between neuron and next differs from communication along single axon
Synapse –> specialized gap between neurons
The Properties of Synapses
Reflexes: autonomic muscular responses to stimuli. In leg flexion reflex, sensory neuron excites 2^nd neuron  excites motor neuron  excites muscle
Reflex arc: circuit from sensory neuron to muscle response
Reflex must require communication between neurons
Properties of reflexes suggest special process at junction between neuron
1. Reflexes slower than conduction along axon
2. Several weak stimuli presented at slightly different times/locations produce stronger reflex than single stimulus
3. When one set of muscles becomes excited  different set relaxes Speed of a Reflex and Delayed Transmission at the Synapse
Impulses have to travel up an axon from skin receptor to spinal cord, then impulse travels from spinal cord back down leg to the muscle
Speed of conduction through reflex arc ~15 m/s; conduction down an axon is 40 m/s (AP velocities along sensory/motor nerves)  delay must occur where one neuron communicates with another Temporal Summation
Repeated stimuli within brief time has cumulative affect (summation over time)
Presynaptic neuron: delivers transmission
Postsynaptic neuron: neuron receiving transmission
Sub-threshold excitation in postsynaptic neuron decays over time, can combine with 2^nd excitation that follows quickly
With rapid successions of pinches, each adds effect, until combo exceeds threshold of the postsynaptic neuron  AP

After brief stimulation of axons of presynaptic neurons  slight depolarization of the membrane of postsynaptic cell

Slight depolarization is graded potential; can be excitatory depolarization, excitatory post-synaptic potential (EPSP), or inhibitory hyperpolarization
Results from flow of Na ions into neuron Spatial Summation
Synaptic inputs from separate locations combine effects on a neuron (summation over space)
Pinching 2 points activated separate sensory neurons  axons converged onto neuron in spinal cord (not enough to reach threshold)  combo of excitations exceeded threshold, produced AP.
EPSPs from several axons summate their effects on a postsynaptic cell
Sensory input to brain arrives at synapses  individually produce weak effects; each neuron receives many incoming axons that produce synchronized responses  ensures sensory stimulus stimulates neurons enough to activate them
Temporal and spatial summation usually occur together; neuron might receive input from several axons at approx. same time; different order  different results

Inhibitory Synapses

Interneuron: (intermediate neuron) in spinal cord  excite motor neurons connected to flexor muscles of leg
At these synapses, input from axon hyperpolarizes postsynaptic cell; increases

-ve charge within cell, move it further from threshold, decrease probability of AP

Inhibitory Postsynaptic Potential (IPSP): temporary hyperpolarization of a membrane; resemebles EPSP; occurs when synaptic input selectively opens gates for K+ ions to leave cell or Cl- ions to enter cell

Relationship Among EPSP, IPSP and Action Potentials

NS full of complex patterns of connections, produce variety of responses
Synapses vary in duration of effects
Effect of two synapses at same time can be more than double effect of either one, or less than double
Spontaneous firing rate: periodic production of APs without synaptic input.

EPSPs increase frequency of APs above spontaneous rate, IPSPs decrease it

CHEMICAL EVEiTS AT THE SYiAPSE The Discovery of Chemical Transmission at Synapses

Sympathetic NS (set of nerves) accelerates heart beat, relax stomach muscles, dilate pupils, regulate organs; sympathetic nerves stimulate muscles by releasing adrenaline (or a similar chemical)

Nerves send messages by releasing chemicals
Chemical transmission predominates over electrical synapses in the nervous system

The Sequence of Chemical Events at a Synapse  Major Events:

Neuron synthesizes chemicals that serve as neurotransmitters (synthesizes smaller neurotransmitters in axon terminal and neuropeptides in cell body)
AP travel down axon. At presynaptic terminal, AP allows Ca to enter cell; Ca releases neurotransmitters from terminals into synaptic cleft (space between pre and postsynaptic neuron)
Released molecules diffuse across cleft  attach to receptors  alter activity of postsynaptic neuron
Neurotransmitter molecules separate from receptors
Neurotransmitter molecules taken back into presynaptic neuron for recycling or may diffuse away
Some postsynaptic cells send reverse messages to control further release of neurotransmitter by presynaptic cells Types of ieurotransmitters

Neurotransmitters: neuron releases chemicals that affect another neuron
Amino acids: contain amine group (NH₂)
Monoamines: chemicals formed by change in amino acids
Acetylcholine: chemical similar to amino acid, but contains a N(CH₃)₃
ieuropeptides: chains of amino acids
Purines: category includes: adenosine and several of its derivatives
Gases: nitric oxide and others
iitric oxide: (NO) gas released by small local neurons; many neurons have enzyme that allows them to make if efficiently. When brain area active, blood flow to area increases; neurons release nitric oxide when stimulated, acts as signal, dilates nearby blood vessels, increasing blood flow to that area Synthesis of Transmitters
Neurons synthesize all neurotransmitters from amino acids, from proteins Catecholamine: contain a catechol and amine group (epinephrine, norepinephrine, and dopamine)
Tryptophan (precursor to serotonin) cross blood-brain barrier by special transport system (compete with larger/abundant amino acids)  amount of tryptophan in diet controls amount of serotonin in brain Storage of Transmitters
Most neurotransmitters synthesized in presynaptic terminal (near point of release); stores high concentrations of neurotransmitters in vesicles and many outside vesicles
Neuron can have excess neurotransmitters (ex: neurons that release serotonin, dopamine or norepinephrine contain MAO (monoamine oxidase): breaks down transmitters into inactive form

Release and Diffusion of Transmitters

At end of axon, AP doesn’t release neurotransmitter; depolarization opens voltage-dependent Ca gates in presynaptic terminal  causes exocytosis (release of neurotransmitter in bursts from presynaptic neuron into synaptic cleft; separates one neuron from another). AP often fails to release any neurotransmitter  amount can vary
Neurotransmitter diffuses across synaptic cleft to postsynaptic membrane; attaches to receptor
Most neurons release a combo of 2 or more transmitters
Motor neurons in spinal cord have one branch to muscles  release acetylcholine and another branch to other spinal cord neurons  release Ach and glutamate
Combo makes neuron’s message complex (brief excitation  prolong inhibition)
A neuron can receive and respond to many neurotransmitters at different synapses

Activating Receptors of the Postsynaptic Cell

Sherrington’s concept: input produced excitation/inhibition (on/off)
Effect of neurotransmitter depends on receptor on postsynaptic cell Ionotropic Effects
Brief on/off effects. When neurotransmitter binds to ionotropic receptor, twists receptor enough to open central channel; shape lets certain ion pass through
Transmitter/ligand-gated channels: controlled by neurotransmitter; when it attaches, the gate opens (ligand binds to other chemicals)

Used to convey visual/auditory info and anything that needs to be updated quickly

Glutamate: most abundant (excitation)
GABA: (inhibitory) opens chloride gates so Cl- ions enter membrane fast
Glycine: (inhibitory) found mostly in spinal cord
Acetylcholine: (excitatory) outer portion embedded in neuron’s membrane, inner portion surrounds Na+ channel. When receptor at rest, inner portion coils together to block Na passage. When Ach attached, receptor folds outwards, opening the Na+ channel

Metabolic Effects and 2^nd Messenger Systems

Initiate sequence of metabolic reactions; slower/longer lasting than ionotropic effects
Many neurotransmitters (dopamine, norepinephrine, serotonin, glutamate, GABA)
When neurotransmitter attaches to metabotropic receptor, bends receptor protein that goes through membrane of cell. Other side of receptor attached to G protein (protein coupled to GTP, energy-storing molecule)
Bending detaches G protein (take energy elsewhere)  increased conc. of 2^nd messenger (communicates to many cell areas; 1^st messenger: carry info to postsynaptic cell)  open/close ion channels in membrane or activate part of chromosome.
Influences activity in much/all of the cell over a long time
Better suited for enduring effects (ex: taste, smell, pain, arousal, attention, pleasure, emotion)
Receptors differ in chemical properties, responses to drugs, and roles in behaviour

Neuropeptides

ieuromodulators  synthesizes neuropeptides in cell body, slowly transports to other parts of cell; released by dendrites, cell body and sides of axon

(neurotransmitter synthesized in the presynaptic terminal)

Neuropeptide release requires repeated stimulation; after a few dendrites release, primes other dendrites to release same neuropeptides
Don’t release often, but when released  in large amounts
Diffuse widely, affect many neurons in brain area
Involved in hunger, thirst, pain, LT changes in behaviour and experience ieurogliaform cell: release GABA, form “cloud”, spreads to neurons in area  widespread inhibition Hormones
Secreted by cells in 1 part of body, conveyed by blood to influence other cells

(neuropeptides intermediate, diffuse only within brain)

Endocrine glands (hormone-producing)
Useful to coordinate long-lasting change in many parts of body
Protein hormones/Peptide hormones: chains of amino acids (proteins longer; peptide shorter) attach to membrane receptors, activate a 2^nd messenger within cell
Hormones secreted by brain control secretion of many other hormones
Pituitary gland: attached to hypothalamus, consists of 2 glands
1. Anterior pituitary: made of glandular tissue; synthesizes 6 hormones (hypothalamus controls release); hypothalamus secretes releasing hormones (flow through blood to the anterior pituitary)  stimulate/inhibit release of many hormones
2. Posterior pituitary: made of neural tissue, extension of hypothalamus; neurons in hypothalamus synthesize oxytocin and vasopressin

(antidiuretic hormone) migrate down axons to posterior pituitary  then released to blood

Hypothalamus maintains constant circulating levels of certain hormones through negative feedback system.

Inactivation and Reuptake of ieurotransmitters

After Ach activates receptor, broken down by acetyl-cholinesterase (acetate and choline); choline diffuses back to presynaptic neuron, takes it up, reconnects it with acetate already in cell to form Ach again (rapid series of APs can deplete neurotransmitter faster than presynaptic cell can replenish it
Serotonin and catecholamine don’t break down into inactive fragments at postsynaptic membrane; just detach from receptor
Reuptake: In some brain areas, presynaptic neuron takes up most of released neurotransmitter intact and reuses them; occurs through membrane proteins, transporters (differ in function, abundance)
Dopamine: some areas transporters efficient, in others, slower: if dopamine released fast into areas, COMT breaks down excess to inactive chemicals that can’t stimulate dopamine receptors; products wash away in blood/urine; neurons diminish supply of dopamine, can’t release dopamine rapidly for long Neuropeptides diffuse away; because resynthesized slowly, neuron can temporarily use up supply iegative Feedback from the Postsynaptic Cell
Presynaptic terminals have receptors sensitive to same transmitter released (auto-receptors  respond to released transmitter by sending chemicals that travel back to presynaptic terminal and inhibit further synthesis/release) Electrical Synapses
Some synapses operate electrically; faster than chemical transmission in cases where need exact synchrony between 2 cells
Gap junction: At electrical synapse, membrane of 1 neuron comes into direct contact with membrane of another (contact)
Large pores of membrane of 1 neuron line up with pores in membrane of other cell (large enough so ions pass through); always open. When 1 neuron depolarized, Na+ ions from cell pass quickly into other neuron and depolarize it too

SYiAPSES, DRUGS AiD ADDICTIOiS

Nearly every drug with psychological effects acts at synapses
Most of the commonly abused drugs derive from plants
Nearly all neurotransmitters/hormones same in humans and other species Drug Mechanisms
Antagonist: blocks neurotransmitter (inhibit transmission)
Agonist: mimics/increase effects, can be mixed agonist- antagonist
Drug can: increase/decrease synthesis of neurotransmitter, leak from vesicles, increase release, decrease reuptake, block breakdown into inactive chemicals, act on postsynaptic receptors
Affinity: drug will bind to the receptor (key in lock)
Efficacy: tendency to activate the receptor (drug that binds to receptor but fails to stimulate has high affinity but low efficacy
Effectiveness/side effects of drugs vary between people, drugs affect many receptors and people vary in # of each kind of receptor

A Survey of Abused Drugs

What Abused Drugs have in common

iucleus Accumbens: areas with axons that directly/indirectly increase release of dopamine/norepinephrine; central to reinforcing experiences (ex: sexual excitement, sugar, imagine something pleasant)
Reinforcement involves wanting (motivation; more brain) and liking (pleasure) Addictive drugs activate nucleus accumbens by releasing dopamine or norepinephrine; show drive to obtain drug even if it doesn’t provide pleasure

(liking-wanting)

Stimulant Drugs

Increase excitement, alertness, activity while elevating mood and decreasing fatigue
Amphetamine/cocaine stimulate dopamine synapses in nucleus accumbens by increasing the presence of dopamine in presynaptic terminal
Presynaptic terminal usually reabsorbs released dopamine through dopamine transporter; drugs inhibit transporter, decreasing reuptake, prolonging effects of dopamine
Amphetamines have similar effects on serotonin/norepinephrine receptors, methamphetamines have similar effects but stronger
Stimulant drugs increase accumulation of dopamine in synaptic cleft; excess dopamine in synapse washes away faster, presynaptic cell makes more to replace it. After use, deficit of neurotransmitters  withdrawal (reduced energy, motivation and depression)
Varied behavioural affects; low doses: increase attention (treat ADHD); high doses: impair attention and learning, alters blood flow thereby increase risk of stroke and epilepsy
Methylphenidate (Ritalin)  (stimulant) prescribed for ADHD  block reuptake of dopamine; same affect as cocaine, but cocaine produces a rush effect on brain when sniffed, Ritalin has gradual increase in concentration then slow decline.
Those with ADHD more likely to abuse tobacco, alcohol, other drugs iicotine
Compound in tobacco, stimulates Ach receptors (nicotine receptors); many exist on neurons that release dopamine in nucleus accumbens; decreased dopamine release; Nicotine increases dopamine release in same cells cocaine stimulates (Nicotine enhances reward)
Repeated exposure to nicotine  receptors in nucleus accumbens become more sensitive to nicotine; less responsive to other kinds of reinforcement Opiates
Derived from opium poppy (morphine, methadone, heroin) heroin enters brain faster than morphine  bigger rush of effect/more addictive
Relax people, decrease attention, decrease pain sensitivity

Used as painkillers

Opiates attach to specific receptors in brain meant for certain neuropeptides called endorphins (relieve pain by acting on receptors)
Endorphins indirectly activate dopamine release; synapses inhibit neurons that release GABA (inhibit dopamine)  increase dopamine release
Endorphins have rewarding effects too, and also depend on dopamine Marijuana
Contain THC and cannaboids (used to relieve nausea, combat glaucoma)
Psychological effects: intense sensory experience, illusion time slowed down, impaired memory and cognition
Cannaboids receptors abundant (not in medulla; controls breathing/heart)
2 chemicals that bind to cannaboids receptors: anandamide, and 2-AG
Cannaboid receptors located on presynaptic neuron: when certain neurons depolarized, release chemicals as retrograde transmitters that travel back to incoming axons, inhibit further release of glutamate or GABA. Tell presynaptic cell that message received, even though nothing released; chemicals in marijuana decrease excitatory/inhibitory messages
Cannaboids increase release of dopamine indirectly; inhibit GABA in midbrain (major source of axons that release dopamine in nucleus accumbens); increases activity of neurons that release dopamine
Relieve nausea, stimulate receptors that increases rewarding value of a meal Hallucinogenic Drugs
Distort perception (ex: LSD resemble serotonin and provide stimulation at inappropriate times/longer duration)
MDMA (ecstasy): stimulant at low doses  increase dopamine release; higher doses –> releases serotonin, alters perception and cognition; side-effects: lethargy, depression, increased body temperature
Repeated users: long-term loss of serotonin receptors  depression, anxiety, impaired learning/memory

Alcohol and Alcoholism

Habitual use of alcohol despite medical/social harm (most common of abused drugs)
Moderate amounts: relaxes people, decrease anxiety; larger amounts: causes health problems, impairs judgement

Affect on neurons: response at GABA receptor (inhibitory: risky behaviors), blocks glutamate receptors (excitatory: increase stimulation of dopamine receptors)  decreased brain activity. Genetics

Type I (A): develop alcohol problems gradually, 25+, may/may not have relatives with history of alcohol abuse
Type II (B): rapid onset, before 25, close relatives with alcohol problems
Genes influences chance of alcoholism in many ways (ex: dopamine type 4 receptor has 2 forms, long form less sensitive  craves more alcohol)
Gene controls COMT (enzyme breaks down dopamine after release); active form

 breaks down more dopamine  decrease reinforcement  more impulsiveness

Genes influence alcohol: effects on risky behaviour, responses to stress, reactions to anxiety-provoking situations
Prenatal environment contributes to risk of alcoholism: if mother drinks alcohol during pregnancy  increase chance child will be an alcoholic
Biological forces interact with stressful experiences, opportunities for alcohol use and other environmental factors Risk Factors
People at risk: impulsive, risk-taking, easily bored, sensation seeking, outgoing
Sons of alcoholics often alcoholics themselves: less intoxication after drinking, decreases stress more (in sons of alcoholics), smaller amygdala in right hemisphere (predisposition to alcohol abuse) Addiction
Habit does more harm than good, pleasure becomes weaker while risks increases; still difficult to quit

Tolerance and Withdrawal

Tolerance: As addiction develops, many effects decrease; learned response
Withdrawal: As body expects a drug, reacts strongly when absent
Effect of drug cessation (anxiety, sweating, diarrhea, irritability, fatigue, convulsions, insomnia, headache, distress)
Addiction is seen as an attempt to avoid withdrawal symptoms
Someone with an addiction learns to use substance to cope with stress
Receiving a drug in withdrawal period is powerful; user learns drug relieves distress caused by withdrawal  generalizes to other situations  learn to crave the drug during all types of distress

Cravings in Response to Cues

User learns to associate cues with a drug; after abstinence, exposure to cues triggers renewed craving; drug-related cue increases activity in nucleus accumbens and several related areas, but after instruction to inhibit craving, people can decrease arousal Brain Reorganization
Addiction hijacks person’s motivation  changes brain so reinforcing experiences become less powerful and less able to compete with the drug
Events change expression of genes
Cocaine increases certain genes that control changes in dendrites within nucleus accumbens  drug stimulates more dendrites, other events stimulate fewer, sexual stimulation less rewarding, induce changes that impair extinction (drug-seeking response of reinforcement ceases, even if drug less enforcing, responding persists)

Medications to Combat Substance Abuse

 Overcome substance abuse: AA, NA, psychotherapy, medication available

Medications to Combat Alcohol Abuse

After someone drinks ethyl alcohol, enzymes in liver metabolize it to acetaldehyde (poison); acetaldehyde dehydrogenase, converts acetaldehyde to acetic acid (chemical body uses for energy)
People with weaker gene for acetaldehyde dehydrogenase, metabolize acetaldehyde slower  accumulate enzyme  flushed face, increased heart rate, impaired breathing, tissue damage
Disulfiram (Antabuse): antagonize effects on acetaldehyde dehydrogenase, binding it to copper ion  lead to illness/vomiting; works when supplements alcoholic’s commitment to stop drinking (take daily pill)
Drink alcohol then take a drug that produces nausea  learned aversion to the taste of alcohol. Effective, but not for long-term
Naloxone: blocks opiate receptors, decrease pleasure from alcohol; works with people motivated to quit; more with Type II then I Medications to Combat Opiate Abuse
Switch to methadone: taken orally, gradually enters blood stream and brain, effects slowly, withdrawal symptoms more gradual, avoid use of injection
LAAM (similar to methadone) used to treat opiate addiction; produce long-term effect  visit clinic 3x/week (not daily)  live healthier and longer, easier to hold a job
These drugs don’t end addiction, just satisfy craving in a safer way

