MEMBRANE POTENTIALS AND PSYCHOACTIVE DRUGS

Membrane Potential and Action Potential

Signal Transduction Mechanisms:
Electrical Signals in Nerve Cells  Every cell in the body is electrically active: to a greater or lesser degree,
Most animals have nervous system that : they all pump ions across the cell membranes to maintain an electrical
1) collects information, 2) processes information and  potential difference across the membrane.
3) elicits responses to the information.  This difference in electrical charge between the inside and outside of the
Neurons are specially adapted for the transmission of electrical signals.  membrane is the basis for many types of physiological processes,
The cell body bears the nucleus and organelles.  including transport of particles across the membrane and signalling
The dendrites receive (and combine) signals. 
among cells.
The axons conduct signals. 
The myelin sheath surrounds the axon in a discontinuous manner (form the  In some cells up to 40% of energy is used to power active transport, a
nodes of Ranvier).  process that maintains or restores membrane potentials.
Nerve cells can be long (e.g., a motor neuron's cell body in the spinal cord and the  Membrane potential is a property of all cells and reflects a difference in
axon ends in your toes).  charge on either side of the cell membrane. Normally, cells are net
An axon ends with terminal bulbs or synaptic knobs that transmit the signal negative inside the cell which results in the resting membrane potential
through a specialized junction: the synapse.  or Vm (a negative resting membrane potential). 

 The resting membrane potential depends on differing concentrations of

ions inside (cytoplasm) and outside the membrane (extracellular fluid). 
 Large negatively charged molecules (proteins, RNA) do not pass through  In nerve cells, a neurotransmitter can affect the activity of
the membrane to set up the negative resting membrane potential.  a postsynaptic cell via 2 different types of receptor proteins: ionitropic
or ligand-gated ion channels, and metabotropic receptors.
1. Ligand-gated ion channels combine receptor and channel
functions in a single protein complex.
2. Metabotropic receptors usually activate G-proteins, which
modulate ion channels directly or indirectly through intracellular
effector enzymes and 2nd messengers.

 If the cell membranes were simply permeable to these ions, they would
approach an equilibrium with equal concentrations on each side of the
membrane, and no voltage difference. But there is a voltage difference, so
the processes which produce the membrane potential are not simply
diffusion and osmosis.
 Electrical excitability depends upon “ion channels” acting like gates for
the movement of ions through the membrane to produce an action 3. Voltage-gated ion channels respond to differences in voltage across the
potential.  membrane (ligand-gated ion channels respond to ligands). 
 In passive channels, ions may freely move diffusively through the  Specific domains of voltage-gated channels act as sensors and
channel. Leakage channels are the simplest type, since their permeability inactivators. 
is more or less constant.  A specific transmembrane stretch of amino acids act as voltage sensor. 
 Chemically gated channels pump Na+ (and some Ca+2) out of the cell,  Based upon the conformation of the voltage-gated sodium channel, the
while pumping in K+ in the ratio of 2 K+ for every 3 Na+ pumped out. channel can be closed but sensitive to a depolarizing signal  (channel
 The flow of oppositely charged ions towards each other is the potential or gating) or completely desensitized to the signal (channel inactivation) by
voltage.  When the ions move, this is current.  the inactivating particle, a stopper-like part of the channel protein itself.
 Eventually electrochemical equilibrium (chemical versus electrical) is  Recovery from an action potential is partly dependent on a type of
established and the equilibrium membrane potential is reached. voltage-gated K+ channel which is closed at the resting voltage level but
opens as a consequence of the large voltage change produced during the
action potential.
  Steady-state movement of ions define the membrane potential and is
maintained by the Na+-K+ pump.
 In the resting state of a neuron, the inside of the nerve cell membrane is
negative with respect to the outside. The voltage arises from differences
in concentration of the K+  and Na+ ions.
Depolarization (or a lowering of the membrane potential) results from flow of
positive sodium ions into the cell. 

 Nerve, muscles and some glands share electrical excitability which, in

response to stimuli, causes rapid changes in membrane potential (action
potential) to occur. 
 Within a millisecond, the membrane potential changes from negative to
positive and back. 
 In neurons, the action potential moves down the axon as a nerve
impulse.

Sodium-Potassium Pump
 The resting potential of a neuron is -70 to -80 mV.
 The action potential results from the rapid movement of ions through axonal
 Action potentials propagate electrical signals along an axon. Initially, a
membrane channels
resting neuron is made ready for electrical activity through the balance of
and the increased sodium current results in a positive feedback loop
ion gradients and membrane permeabilities. 
known as the Hodgkin cycle. 
 A small amount of depolarization (<+20mV) will normally result in
 Sub-threshold depolarization results in no action potential generated,
recovery without effect. 
which is at least partially due to the outward movement of K + ions. If the
 More depolarization causes the membrane to reach the threshold
K+ ion exit cannot compensate for the influx of Na + ions, the membrane
potential at which the nerve cell membrane rapidly changes electrical
reaches the threshold of depolarization. 
properties and ion permeability to initiate an action potential. 
 When the voltage-dependent Na+ channels open, Na+ flows in during the
 The action potential is a brief depolarization/ repolarization that
depolarizing phase. 
propagates from the site of origin.
 Once the membrane potential peaks, the repolarizing phase begins with
 Graded potentials are short lived
the inactivation of the Na+ channels (blocking the Hodgkin cycle) and the
depolarizations or
opening of the voltage-gated K+ channels. 
hyperpolarizations of an
 The recovery is due to the passive movement of ions- not the action of
area of membrane.
the Na+/K+  pumps. 
 These changes cause local flows of current
 During the absolute refractory period (~few milliseconds), Na + channels
that decrease with
cannot be opened by depolarization and no action potential can be
distance.
generated. 
 The more intense the
 During the hyperpolarizing phase, the Na + channels are reactivated but
stimulus, the more ion
Na+ flow is opposed by K+ currents which produces a relative refractory
channels that are opened,
period.
and the greater the voltage
change.
 4. depolarization to induce the membrane potential in adjacent parts of the
axon to reach the threshold potential which then triggers the intake of Na +
ions and continuation of the cycle. 
 The hyperpolarizing phase results from the increased permeability of K +
due to the open voltage-gated K+ channels.  For example, signals move from the dendrites through the cell body to the base
 The membrane potential returns to resting state with the closing of the of the axon (the axon hillock) where Na + channels are concentrated. 
voltage-gated K+ channels.  At the axon hillock, a great influx of Na+ ions can occur which specify that action
 Hyperpolarization prevents the neuron from receiving another stimulus potentials initiated here are propagated down the axon. The propagated action
during this time, or at least raises the threshold for any new stimulus. potential is the nerve impulse. 
 Hyperpolarization also prevents any stimulus already sent up an axon 4. The rate of impulse transmission depends on electrical properties of the
from triggering another action potential in the opposite direction. It axon such as the electrical resistance of the cytosol and the ability to
assures that the signal is proceeding in one direction. retain electric charge (capacitance) of the plasma membrane.
After hyperpolarization, the Na+/K+ pump eventually brings the membrane back to
its resting state of -70 mV

 The discontinuous myelin sheath acts like

an electrical insulator surrounding the
axon. 
 The neurons of the CNS have myelin
Action potentials are propagated along the axon without losing strength by active sheath composed of oligodendrocytes and
propagation: in the PNS the myelin sheath is composed
of Schwann cells. In each case, the myelin
1. The passive spread of depolarization causes cells wrap several layers of their plasma
cations (mostly K+) to spread to membranes around the axon. 
adjacent regions of the  Each Schwann cell surrounds a stretch of 1
axon's cytoplasm.  mm of axon, with many Schwann cells
2. As the depolarization acting to insulate each axon. 
spreads, it loses its
magnitude and MUST be  Myelination permits a
actively propagated to move far.  depolarization of events to spread
3. Propagation depends upon farther and faster than without
the passive spread of because of saltatory propagation. 
 This process depends upon the
gathering of voltage-gated sodium
channels at the nodes of Ranvier. 
 Action potentials jump from node
 Synapses are specialized junctions through which NS cells signal to one another
and to effectors (muscles or glands). They provide the means through which the
NS connects to and controls the other systems of the body.

Nerve cells communicate with muscles, glands and other nerve cells via synaptic
transmission. In an electrical synapse, the axon of the presynaptic neuron
connects to the dendrite of postsynaptic neuron by gap junctions. 

In a chemical synapse, the presynaptic and postsynaptic neurons are

separated by a gap, the synaptic cleft. 
SYNAPSE
An excitatory neuro-transmitter causes depolari-zation

A NE
UROT
RANS
MITT
ER is a small molecule that, through the interaction with a specific receptor,
relays a signal across nerve synapses. Neurotransmitter molecules that are kept in
the terminal bulbs or synaptic knobs are secreted into the synaptic cleft and then
bind to receptors in the postsynaptic neuron. This generates an electrical signal to
stimulate or inhibit a new action potential.

A neurotransmitter must:
1) cause a response when 
injected into the synaptic
cleft, 2) occur naturally in
the presynaptic neurons
and 3) be released when
the presynaptic neurons
are stimulated.
An inhibitory neuro-transmitter causes hyperpola-rization in the post-synaptic  The enkephalins are neuropeptides that are produced in the brain to
neuron.  inhibit pain reception. 
 The neuropeptide endocrine hormones (prolactin, growth hormones and
 Neurons can integrate both excitatory and inhibitory signals from other leutinizing hormone) act on tissues other than the brain.
neurons.   Elevated calcium levels stimulate
 The summation of synaptic inputs leads to whether or not an action potential secretion of neurotransmitters from the
is formed in the postsynaptic neuron. presynaptic neurons. 
 The neurotransmitters are stored
in neurosecretory vesicles in the terminal
bulbs. 
 The release of calcium within the
terminal bulb mobilizes neurosecretory
vesicles rapidly (by the phosphorylation of
synapsin and release from the cytoskeleton)
and causes the fusion of the vesicles to the
plasma membrane and neurotransmitters
release. 
 Exocytosis of neurotransmitters
requires the docking and fusion of vesicles
with the plasma membrane
This requires ATP and voltage-gated calcium
 Acetylcholine is the most common vertebrate neurotransmitter outside channels. 
of the CNS to form cholinergic synapses between  PNS neurons and at
neuromuscular junctions.   W h e n t h e a
 The catecholamines (dopamine, norepinephrine, epinephrine: all tyrosine calcium channels open and calcium flood in. 
derivatives) are found in adrenergic synapses at junctions between 
nerves and smooth muscles and nerve-nerve junctions in the brain.   This initiates the docking of the
 Other neurotransmitters are other amino acids and derivatives  vesicles at the presynaptic neuron's
(histamine, serotonin, gamma-aminobutyric acid [GABA], glycine, membrane in an active zone through the
glutamate). Serotonin functions as an excitatory neurotransmitter in the action of docking proteins
CNS by indirectly closing the K+ channels.  (synaptotagamin, synaptobrevin, syntaxin). 
 The neuropeptides are short chains of amino acids formed by cleavage of
precursor proteins and stored in secretory vesicles. 
  The docking process is blocked by neurotoxins such as tetanus toxin (in
the spinal cord) and botulinum toxin (in the motor neurons).
Neurotransmitters are detected by specific receptors on postsynatic neurons such
as ligand-gated channels.The acetylcholine receptor is a ligand-gated sodium
channel that binds two molecules of acetylcholine to open. This receptor is
specifically bound by snake venom components (alpha-bungarotoxin and
cobratoxin).  
 The GABA  (gamma-aminobutyric acid) receptor is a ligand-gated Cl-
channel which produces an influx of Cl- ions in the postsynaptic neuron. 
 The entry of Cl- ions neutralize the effect of Na + influx on the membrane
potential which reduces depolarization and may prevent  initiation of an
action potential in the postsynaptic neuron. 
 Benzodiazeprine drugs (Valium and Librium) enhance the effects of GABA
on the receptor to produce a tranquilizing effect.
 For neurotransmitters to work effectively and not overstimulate or
inhibit, they must be neutralized shortly after their release by either
degradation or recovery by the presynaptic neuron. 
 Acetylcholine is hydrolyzed by acetylcholinesterase. 
Some neurotransmitters are returned to the presynaptic axon terminal
bulbs by specific transporter proteins (endocytosis).
Serotonin is involved in the regulation of sleep. Insufficiency of neurons that
release serotonin can result in depression. Prozac blocks the reabsorption of
serotonin into the neurons, and thus, prolongs serotonin's effects.

Alcohol bind important receptors on the brain- repeated

binding causes the neurons to die, but can be repaired after
abstinence

Receptors are
blocked by alcohol
and slows down
transmission
Brain images showing decreased dopamine (D 2) receptors in the brain of a person
addicted to cocaine versus a nondrug user. The dopamine system is important for
conditioning and motivation, and alterations such as this are likely responsible, in
part, for the diminished sensitivity to natural rewards that develops with
addiction.