Open Field Locomotion-Rats
Rotarod
Lever Pressing on Operant Schedules
FOOD REINFORCED
LEVER PRESSING: e.g. FR
SCHEDULE
How
many
times do I
have to do
this????
Elevated Plus Maze
Fig. 2.1
Radial Arm Maze
Morris Water Maze
Drug Self-administration
PHASES
Lipid (a triglyceride)
Water
Phospholipid
(a diglyceride):
Phosphatidyl
Choline
LECITHIN
Aqueous and Organic Phases
Fig. 3.1
ETHANOL MOLECULE
Lipophilic/Hydrophobic
H
H
H
C
C
H
H
O
CH3CH2OH
H
Lipophobic/
Hydrophilic
THC Molecule
(CH2)4CH3
HO
H3C
H
O
H
H3C CH3
Molecular Structure of THC
(delta-9-tetrahydrocannabinol)
THC: High hydrocarbon content, VERY
lipid soluble.
Routes of Administration
ICV: DRUG INJECTED
DIRECTLY INTO THE VENTRICLES
(fluid-filled spaces in the brain)
IC: DRUG INJECTED
DIRECTLY INTO BRAIN TISSUE
Response
(functional or behavioral units)
Typical Dose Response Curve
120
100
80
60
efficacy
40
20
ED50
0
0
2
4
6
8
Dose
(mg units, or mg/kg)
ED50: effective dose 50; dose that
gives 50% maximal effect; measure
of POTENCY of the drug
10
Structure of the Neuron
Chemical signals (i.e.,
neurotransmitters) are
released from terminals
Dendrites
Terminals
Nerve impulses (i.e.,
action potentials)
move along the
axon
Soma
(cell body)
AXON
Membrane Proteins and the Movement of Ions
Na+ pump
(Na+/K+ pump)
Actively pumps Na+
out of cell
Na+ Na+
Na+
Receptor
enzyme
Fig. 4.3
Second
Messenger
production
Chloride channels are open
K+
K+
EPSP, IPSP AND ACTION
POTENTIAL
60
VOLTAGE (mV)
40
ACTION
POTENTIAL
20
0
-20
-40
EPSP
threshold
Resting
Membrane
Potential
-60
-80
IPSP
-100
0
10
20
30
40
TIME ----->
50
60
70
TRANSMITTER BINDING TO A RECEPTOR
inside
RECEPTOR
Chemically Gated
Channel Opens:
Ions Move
Into Cell
(can be EPSP or
IPSP depending
on the channel)
membrane
outside
WHEN THE TRANSMITTER AND
RECEPTOR ARE BOUND TO
EACH OTHER, IT STIMULATES
BIOLOGICAL ACTIVITY
NEUROTRANSMITTER
Fig. 4.5
EXAMPLE OF GLUTAMATE-MEDIATED EXCITATION
inside
RECEPTOR
Cation Channel
Opens:
Positive Ions Move,
Na+ Ions Move
Into Cell
(EPSP)
membrane
outside
WHEN THE GLUTAMATE AND
RECEPTOR ARE BOUND TO
EACH OTHER, IT OPENS THE CHANNEL
GLUTAMATE
EXAMPLE OF GABA-MEDIATED INHIBITION
inside
RECEPTOR
Cl- Channel
Opens:
Cl- Ions Move
Into Cell
(IPSP)
membrane
outside
WHEN THE GABA AND
RECEPTOR ARE BOUND TO
EACH OTHER, IT OPENS THE CHANNEL
GABA
GENERATION OF THE ACTION
POTENTIAL
60
VOLTAGE (mV)
40
ACTION
POTENTIAL
20
0
DESCENDING
LIMB
ASCENDING
LIMB
-20
-40
EPSP
threshold
Resting
Membrane
Potential
-60
-80
-100
0
10
20
30
40
TIME ----->
50
60
70
Action Potential is Generated
K+
K+
Na+
Na+ moves inVoltage moves more positive
(ascending limb)
Na+ Na+
Na+
K+ moves outrestores resting
Potential (i.e.,
descending limb)
Towards
soma
AXON
Towards
terminals
INFORMATION PROCESSING BY
NEURONS
Each neuron is like a
tiny computer; it
receives many
inputs, both
excitatory and
inhibitory, and adds
them together (i.e.
summation) over
time and space.
If the summed excitatory
input at the initial part of the
axon exceeds the threshold,
an action potential is fired.
Chemical Transmission
Synthesis
Storage
Release
Cation
Channel
Calcium flowing into the
terminal, which is caused
by the action potential,
stimulates transmitter
release.
Postsynaptic Action (a) and Inactivation (b, c)
NEUROTRANSMITTERS AND
NEUROMODULATORS
Serotonin
Acetylcholine
SYNAPSE: Point of functional connection
DA terminal
Synaptic
cleft
SYNTHESIS:
Transmitter is
synthesized from a
precursor molecule by
enzymes in the
presynaptic cell
Postsynaptic cell
SYNAPSE: Point of functional connection
DA terminal
Synaptic
cleft
STORAGE:
Transmitter is stored
in presynaptic vesicles
Postsynaptic cell
Electrical
DA
impulse
“action potential”
terminal
Synaptic
cleft
Postsynaptic cell
DA terminal
Synaptic
cleft
Postsynaptic cell
DA terminal
Synaptic
cleft
Ca++
RELEASE: Action
Potential opens voltageGated Ca++ channels
Postsynaptic cell
DA terminal
Ca++
Ca++
Ca++
Synaptic
cleft
Ca++
RELEASE: There is an
influx of Ca++ into the
terminal
Postsynaptic cell
DA terminal
Synaptic
cleft
....
RELEASE:
Ca++ influx promotes
several processes that
lead the vesicles to go
from a pre-release state
into a fusion with release
sites on the membrane.
Transmitter is released
Postsynaptic cell
DA terminal
Synaptic
cleft
.. ..
.... .
Transmitter
diffuses across
synaptic cleft
Postsynaptic cell
DA terminal
Synaptic
cleft
. .
.
.
. ..
.
.
Transmitter
diffuses across
synaptic cleft
Postsynaptic cell
.
DA terminal
Synaptic
cleft
. .
.
.
.
.
.
POSTSYNAPTIC
ACTION:
a) Transmitter binds
to postsynaptic
receptors
.
DA Receptor proteins
Postsynaptic cell
.
DA terminal
Synaptic
cleft
..
.
POSTSYNAPTIC
ACTION:
b) Transmitter binding
induces intrinsic biological
activity (i.e. signal
transduction effects) in
postsynaptic cell.
Physiological and biochemical
effects (EPSPs or IPSPs)
Postsynaptic cell
BINDING
SPECIFIC
Response
OCCUPIED)
OF RECEPTORS
(NUMBER
(functional
or behavioral
units)
TYPICAL
BINDING
CURVE
Typical
Dose
Response
Curve
120
100
80
Maximum
Number of
receptors
60
40
20
Kd
0
0
2
4
6
Dose
8
10
Concentration of
(mg units, or mg/kg)
Drug Used
Kd or IC50: concentration that
gives 50% maximal binding; measure
of AFFINITY of the drug for the receptor
LIGAND BINDING TO A RECEPTOR
inside
outside
RECEPTOR
+-
WHEN THE LIGAND AND RECEPTOR
ARE BOUND TO EACH OTHER, IT
STIMULATES THE INTRINSIC
BIOLOGICAL ACTIVITY (i.e., signal
transduction)
-+
Signal
transduction
mechanism
membrane
LIGAND
IONOTROPIC SIGNAL TRANSDUCTION
inside
RECEPTOR
Chemically Gated
Channel Opens:
Ions Move
Into Cell
(can be EPSP or
IPSP depending
on the channel)
membrane
outside
WHEN THE TRANSMITTER AND
RECEPTOR ARE BOUND TO
EACH OTHER, IT STIMULATES
BIOLOGICAL ACTIVITY
NEUROTRANSMITTER
EXAMPLES: GLUTAMATE AND
GABA MECHANISMS THAT OPEN
CATION OR Cl- CHANNELS
METABOTROPIC SIGNAL
TRANSDUCTION
inside
RECEPTOR
G-proteins activated:
Regulates enzymes;
leads to production
of 2nd messengers
(e.g. c-AMP, IP3)
(can be EPSP or IPSP
depending on the processes
affected)
membrane
outside
WHEN THE TRANSMITTER AND
RECEPTOR ARE BOUND TO
EACH OTHER, IT STIMULATES
BIOLOGICAL ACTIVITY
NEUROTRANSMITTER
EXAMPLES: DA acting on D1
receptors increases c-AMP
production.
Fig. 5.5
Multiple Receptor Subtypes
• Each transmitter generally has more than
1 receptor
• These are called “subtypes”
D1
Family
D2
Family
Multiple Locations for Receptors
Presynaptic terminal
Synaptic
cleft
Fig. 4.7
Presynaptic
Receptors
Postsynaptic
Receptors
Postsynaptic cell
AGONISTS: BINDING AND SIGNAL TRANSDUCTION
inside
outside
RECEPTOR
+-+
Signal
transduction
mechanism
membrane
WHEN THE AGONIST AND RECEPTOR
ARE BOUND TO EACH OTHER, IT
STIMULATES THE SAME INTRINSIC
BIOLOGICAL ACTIVITY (i.e., signal
transduction) AS THE TRANSMITTER
ITSELF.
AGONIST
COMPETITIVE ANTAGONISTS:
BINDING AND SIGNAL TRANSDUCTION
inside
outside
ANTAGONIST AND RECEPTOR ARE IN THE
BOUND STATE
RECEPTOR
+-+
NEUROTRANSMITTER
IS DISPLACED FROM
THE RECEPTOR
ANTAGONIST OCCUPIES RECEPTOR;
THIS BLOCKS THE NEUROTRANSMITTER
OR AGONIST FROM BINDING
membrane
INVERSE AGONISTS:
BINDING AND SIGNAL TRANSDUCTION
inside
outside
RECEPTOR
+-+
Signal
transduction
mechanism
membrane
WHEN THE INVERSE AGONIST
AND RECEPTOR ARE BOUND TO EACH
OTHER, IT STIMULATES THE OPPOSITE
INTRINSIC BIOLOGICAL ACTIVITY (i.e.,
signal transduction effects opposite
from those produced by the
neurotransmitter)
LIGAND
DRUGS THAT AFFECT POSTSYNAPTIC
MECHANISMS BY ACTIONS ON SITES
OTHER THAN THE BINDING SITE
- NONCOMPETITIVE ANTAGONISTS
Competitive GABA
antagonists act here
Noncompetitive GABA
antagonist acts here;
block the channel
Fig. 10.3
DRUGS THAT AFFECT POSTSYNAPTIC
MECHANISMS BY ACTIONS ON SITES
OTHER THAN THE BINDING SITE
- POSITIVE ALLOSTERIC MODULATORS
Benzodiazepines like
Valium are positive
allosteric modulators
that act here
Fig. 10.3
POSTSYNAPTIC ACTION: AN
IMPORTANT SITE OF DRUG
INTERACTIONS
• There are interactions between agonists and
antagonists that act on the same receptor
Fig. 5.7
POSTSYNAPTIC ACTION: AN
IMPORTANT SITE OF DRUG
INTERACTIONS
• There are interactions between drugs
that act on different receptors, but
ultimately these actions converge on to
the same signal transduction mechanisms
STRIATAL NEURONS: Neurons originating
in brain area involved in PD symptoms
D2
DA D2 stimulation decreases c-AMP
DA D2 antagonism increases c-AMP
G
A
B
A
C-AMP
C-AMP
+
Adenosine A2A stimulation increases c-AMP
A2A
Adenosine A2A antagonism decreases c-AMP
STRIATUM
(in the forebrain)
Presynaptic terminal
Synaptic
cleft
.
.
Inactivation.
Transmitter is broken
down (i.e. “metabolized”)
by enzymes.
Postsynaptic cell
Presynaptic terminal
Synaptic
cleft
.
..
Inactivation.
Transmitter is transported
back into presynaptic
terminal by protein
transporter (i.e., uptake
or “reuptake”).
Postsynaptic cell
Neuromuscular Junction
a Motor
Neuron
Striated
(“voluntary”)
muscle
{
Nicotinic
ACh
Receptors on
Muscle Fibers
Neuromuscular Junction:
Acetylcholine (ACH) is the neurotransmitter.
ACh release makes muscle fibers contract.
NE
ACH
Autonomic
Nervous
System
Sympathetic and Parasympathetic
Divisions are shown.
Sympathetic: NE is
neurotransmitter. Promotes energy
expenditure, activated by emotion
and stress (e.g. increases heart
rate, blood pressure, decreases
lung secretions)
Parasympathetic: ACH is
neurotransmitter. Promotes
digestion and excretion (e.g.,
decreases heart rate & blood
pressure, stimulates salivation,
lung secretions, stomach and
intestinal activity)
Major Divisions of Brain
FOREBRAIN
MIDBRAIN
HINDBRAIN
anterior
posterior
Major Divisions of Brain
FOREBRAIN
MIDBRAIN
HINDBRAIN
Brain Anatomy
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus pons
hypothalamus
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum
medulla
Brain Anatomy: DA
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
see Fig. 5.10
Locus
ceruleus
Raphe
Substantia
Nigra
Ventral
(SNc)
Tegmental
Area
(VTA)
cerebellum
Brain Anatomy: ACh
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
see Fig. 5.10
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum
Brain Anatomy: NE
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
see Fig. 5.11
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum
Brain Anatomy: Serotonin (5-HT)
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
see Fig. 5.11
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum