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4 Textbook: NTs and Neuropharmacology

2/9/23 1:46 PM

Ionotropic receptors: NT binds to it and changes its shape to open an ion

channel (fast)
Metabotropic receptor: altering chemical reactions within the target cell (slow)
Ex: G protein coupled receptor

Inverse Agonist: compound that binds to a receptor and causes it to have an

opposite effect from the normal endogenous compound

Noncompetitive ligands: bind to a modulatory site

Endogenous vs Exogenic sources

Criteria for Classic NT:

1. Exist in presynaptic axon terminals
2. The presyn cell has enzymes for synthesizing the substance
3. The substance is released in significant quantities when APs reach the
terminals
4. There are postsyn receptors for the NT
5. Experimental application of the substance produces changes in postsyn
cells
6. Blocking the release of the substance will induce changes in activity on
the postsyn cell

Modulators do not constitute one of the four major categories of NT

Co-localization (Co-release): more than one NT can be released from the same
neuron

The most abundant excitatory and inhibitory NTs in the brain are amino
acids:
- Glutamate and Aspartate
○ Both are excitatory
○ Glutamatergic transmission:
§ AMPA
§ Kainate
§ NMDA receptors (ionotropic)
§ mGluR's (metabotropic)
○ NMDA receptors have been associated with memory and learning
○ Excitotoxicity: Event wherein neural injury caused by stroke or
trauma triggers excessive release of glutamate which will
overexcites neurons and kills them

- GABA (Gama-Aminobutyric Acid) and Glycine

○ Both are typically Inhibitory
○ Classes of GABA receptors
§ GABAA:
□ Ionotropic; ligand gated
□ Inhibitory potentials due to localized Cl- influx
§ GABAB:
□ Metabotropic
□ Slow ISPS due to changes in K+ ion conductance
§ GABAc:
□ Ionotropic with a chloride channel
○ Drugs that activate GABAA
§ Have sedative effects, reduce anxiety and panic attacks,
block epileptic seizures
○ Some GABA-ergic neurons also co-release Glutamate
§ Balancing out the inhibitory and executory influence on
postsyn

ACh was the first NT to be identified:

- Otto Loewi
- Cholinergic (ACh-using) neurons
- Clusters of Cholinergic Neurons in the basal forebrain
○ Medial septal nucleus
○ Nucleus of diagonal band
○ Nucleus basalis
§ These clusters will project into the hippocampus, amygdala
and thru out the cerebral cortex
- Damage to Cholinergic Neurons have been linked to Alzheimer's
○ ***Linking ACh systems to learning and memory ***
- Two Families of ACh receptors
○ Nicotinic (nACh)
§ Most are ionotropic with excitatory effect
§ Muscles use nACh receptors

○ Muscarinic (mACh)
§ Metabotropic GPCRs and can be excitatory or inhibitory

5 monoamines act as NTs

- Catecholamine NTs
○ Derived by tyrosine
○ Include:
§ Dopamine
§ Epinephrine
§ Norepinephrine

- Indoleamine NTs
○ Derived from tryptophan
○ Include:
§ Dopamine
§ Serotonin
§ Norepinephrine

Pathways for NT Synthesis:

ChAT: choline acetyltransferase

AChE: acetylcholinesterase
- Breakdown of ACh

Where AChE is more readily available than

ChAT

Neurons must have Tyrosine hydroxylase

in order to synthesize any Catecholamine
NT

L-Dopa is a precursor to all three

Neuropeptides synthesized through gene transcription and translation of

mRNA
- Therefore we can find neurons making these NTs by looking for the
appropriate mRNA transcript

Dopamine (DA)
- D1, D2, D3, D4 and D5 receptors
- Dopaminergic neuron projections in the:
○ Mesostriatal pathway:
§ Substantia nigra (midbrain) --medial forebrain bundle-->
striatum (caudate and putamen)
§ important in motor control
□ Damage can lead to parkinson's

○ Mesolimbocortical pathway
§ Ventral tegmental area (VTA-midbrain) ---> amygdala,
nucleus accumbens, hippocampus and cortex
§ Important in reward and reinforcement
□ Esp thru D2 receptor
□ Damage can lead to SZ

Serotonin (5-HT)
- Small concentration of 5-HT neurons in the brain
○ Found in the raphe nuclei midline (midbrain and brainstem)
○ Small concentration but able to innervate large areas of the brain
- Important for:
○ Sleep
○ Mood
○ Sexual behavior
○ Anxiety
- 14 types of receptors, all but one are metabotropic

Norepinephrine (aka: noradrenaline)

- Two clusters in the brain
○ Locus coeruleus
§ Blue spot in pons
○ Lateral tegmental area of the midbrain
- "noradrenergic" cells
- Sympathetic fibers that innervate the body are also noradrenergic
- 4 types of receptors all of which are metabotropic
- Important for:
○ Mood
○ Overall arousal
○ Sexual behavior

Many peptides function as NTs

- Opioid peptides
○ Actions that resemble opiate drugs (ie: morphine)
- Non-opioid peptides
○ Synthesized by neurons in the spinal cord and work in the
periphery
- Peptide hormones
○ Ie: oxytocin, vasopressin

Some NTs are soluble gases

- Nitric Oxide (NO)
○ How does it differ from classical NTs:
§ Not synthesized in the axon terminal
□ Typically in dendrites instead
§ Are not contained in vesicles
§ Does not bind onto receptors, diffuses into the cell instead
and stimulates second messengers
§ Can serve as retrograde transmitters, able to diffuse back
into the presynaptic neuron

Effects of a Drug Depend on Its Site of Action and Dose

- The Agonistic and Antagonistic Actions of Drugs

○ Antagonists block

Lock and Key Model

- Receptors have gone through more changes evolutionarily than NTs

Drug- Receptor interactions vary in specificity and activity:

- Binding affinity: chemical attraction between a ligand and receptor

- Efficacy (intrinsic activity): likelihood of activating the receptor after binding

○ Agonists have high efficacy, antagonists have low
- Partial Agonists
- Efficacy + Affinity = overall action of drug

Dose-Response Relationships reflect the potency and safety of drugs:

- Dose-Response Curve (DRC)
- Pharmacodynamics

Drug Administration and Elimination:

- Bioavailable routes
○ In this form of administration, the drug is free to act on the target tissue, it is not bound to other
proteins and therefore forgoes the longer process of being metabolized or excreted
§ Smoking
§ Intravenous injection
- Build up route
○ Slower
§ Oral injection
§
- Pharmacokinetics: how the drug moves through the body
- Biotransformation of Drugs: breaking drugs down into their components or metabolites
- Drugs can collect in deposits

Tolerance:
- Metabolic tolerance
○ The body has gotten efficient at metabolizing and eliminating the drug before it can take affect

- Functional tolerance
○ Altered sensitivity
○ Plasticity of receptors available on the membrane
○ Overexposure to an AGONIST drug/substance --> cell responds by down regulating the number of
receptors on the membrane in hopes of curtailing the effects
§ Therefore becoming less sensitive to the substance
○ Overexposure to an ANTAGONIST substance --> upregulation of receptors
§ More sensitive

- Cross-tolerance: tolerance to one drug may lead to tolerance to other drugs under its family
- Withdrawal symptoms
- Sensitization: wherein drug responses become stronger with repeated treatments
○ "craving"
○ Associated with dysfunction to the reward regulating mesolimbocortical DA Pathway

Local Anesthetics: block Na+ channels

- Therefore blocking APs and pain signal

Drug Effects on Presynaptic Mechanisms

(autoreceptor interference)

- Botox: disenables SNAREs and therefore halting Ca2+ dependent release of NT

- Caffeine: blocks adenosine (a neuromodulator) on the autoreceptors

○ Therefore, catecholamine release is not stopped --> arousal

- Interfering with transmitter reuptake thru blockage of transporters

○ Antidepressants inhibiting the reuptake of serotonin
○ Considered a presynaptic effect bcos the transporters are on the presyn neuron

Drug Effect on Postsyn Mechanism

- The future of drug research:

○ Inducing genomic changes (through DNA alternation) that will produce long term changes in the
structure of targeted neurons

- DREADDs: Designer receptor exclusively activated by designer drugs

○ Having them only expressed in drugs of interest
○ Used for selectively activating or inhibiting target cells

Antipsychotics (neuroleptics)--> SZ
- First Gen:
○ Included:
§ Chlorpromazine (Thorazine)
§ Haldol
§ Loxitane
○ Acting as antagonists for D2 receptors
§ Lead to dopaminergic model of SZ
§ Solved the positive symptoms

- Second Gen:
○ Drugs that blocked 5-HT receptors in addition to DA receptors
○ Solving the negative symptoms

Antidepressants -> affective (mood) disorders

- First Gen:
○ MAO inhibitors
§ Therefore they down breakdown the monoamine NTs in the synapses and allow them to
accumulate

- Second Gen:
○ Tricyclics: blocking the reuptake of 5-HT and NE therefore allowing them to accumulate in the
synapses
○ SSRIs: selectively allowing 5-HT to accumulate by inhibiting reuptake
○ SNRIs: allows NE to accumulate by inhibiting reuptake

Anxiolytics -> anxiety

- Considered depressants: drugs that relax the NS
○ Reducing Anxiety, promoting sleep, and preventing epileptic seizures

- Examples:
○ Barbiturate: first gen
§ Dangerously easy to OD

○ Benzodiazepine agonists
§ Bind to specific orphan receptor sites on the GABAa receptor
§ Since GABAa receptors are inhibitory, the agonist drug binding to this site will help to amplify
the ISPS (compared to GABA binding alone)

○ Allopregnanolone
§ Steroid derivative of Progesterone
□ Binds to a different site on GABAa
§ Released during stress to calm down
§ Increases during alcohol ingestion

- Other vocab:
○ Orphan receptor site: site that is different/far away from the main site for endogenous NT and it
has been very difficult to find/identify the NT that binds to this orphan site
○ Neurosteroids: steroids that are produced in the brain

Opiates --> Alleviate Pain

- Active substance --> morphine = analgesic (painkiller)
- Heroin, fentanyl
- Bind to opioid receptors found in the limbic and hypothalamic areas (esp: locus coeruleus and in the
periaqueductal gray [gray mater that surrounds the cerebral aqueduct in the brainstem])

○ What are the endogenous substances?

§ Enkephalins
§ Endorphins
§ Dynorphins

○ Types of opioid receptors: all are metabotropic

§ Delta
§ Kappa
§ Mu

Cannabinoids:
- Cannabis
- THC and CBD
- Cannabinoid receptors in the substantia nigra, hippocampus, cerebral and cerebellar cortex

○ Types of receptors: both are GPCR

§ CB1: found in NS
□ Damage to this receptor means that the individual will no longer be able to experience
the high from cannabis
§ CB2: found in immune system

○ What are the endogenous substances?

§ Endocannabinoids
□ Retrograde messengers (postsyn to presyn cell) that modulate the NT release by the
presyn cell
® Anandamide (subtype of Endocannabinoid)
◊ Important in altering memory formation, appetite stimulation, reduced
sensitivity to pain, protection from excitotoxic brain damage
□ Can modulate GABA release

Stimulants
- Tipping the balance between ISPS and ESPS
○ Either through increasing ESPS or blocking inhibitory responses (breakdown, reuptake,
autoregulation)
- However, there are some stimulants (ie: Ritalin used in ADHD) that have a calming effect

- Examples:
○ Nicotine
§ Lungs --> bloodstream
§ Impairment to glutamatergic synapses in the prefrontal cortex (cognitive decline)
§ Bind to nicotinic ACh receptors
□ Leading to contraction of muscles
□ Acting on the ventral tegmental area --> rewarding/addicting effect

○ Cocaine
§ Loss of gray matter
§ Blocking Monoamine transporters therefore blocking reuptake and promoting DA buildup in
synapses and perpetuating reward effect
§ Dual dependence: using a drug together with another drug can create metabolites that
further cause addiction

○ Amphetamine
§ Has a molecular structure that closely resembles DA, Epinephrine and NE
§ Methamphetamine
§ Amplifies the effects of monoamines (4 ways)
1) Stimulating the release of the monoamines from presyn cells even without AP
2) If there is an AP, the drug can increase the power/magnitude of NT release into the
synapse
3) Blocking the reuptake of NT
4) Providing alternative target for MAO (enzyme that usually breaks down Monoamine
NTs) and therefore inhibits the metabolic breakdown of these NTs
§ Overall effect: Monoaminergic synapses are too strong resulting in neurotoxic damage
§ Cathinone, khat, bath salts

Alcohol as a stimulant and depressant

- Biphasic: two phases (initial stim, secondary prolonged stage)
- Alcohol activates the GABAa receptor-coupled Cl channel
○ Contributing to social disinhibition, impaired motor coordination and sensory disturbances
(drunkenness)
- Low doses stimulate the DA pathways
- Chronic usage:
○ Damage to superior frontal cortex, purkinje cells (cerebellum), hippocampal pyramidal cells
○ Thiamine deficiency leading to neural degeneration and Korsakoff's syndrome
○ White matter degeneration
○ Cortical region atrophy
§ Frontal and cingulate cortices
§ Hippocampus
§ Medial temporal lobes
§ Olfactory bulbs
§ Diencephalon and cerebellum
- Damage may be reduced with abstinence
○ Up-regulation of a specific form of NMDA receptors in the nucleus accumbens
- Alcoholism is hereditary

Hallucinogenic and Dissociative Drugs

- Psychedelics
- Hallucinogenic is a misnomer bcos these drugs alter existing sensory stim whereas hallucinations are
perceptions without the stimulus (hearing voices that are not there)
- Different types drugs affect different systems
○ Opioid kappa receptors
○ ACh receptor
- Most act as agonists or partial agonists to these receptors
- Acting on receptors on the visual cortex leading to alternations in visual perception
- Reducing the activity in medial prefrontal cortex and anterior cingulate cortex
○ Uninhibited limbic system

- Ketamine
○ Dissociative effects at low doses
○ Blocks NMDA receptors
○ Increasing activity in prefrontal cortex
○ Administered in clinical settings as rapid antidepressant

- Ecstasy: MDMA
○ Increasing release of Serotonin, increased stimulation of receptors
○ Stimulating prolactin and oxytocin, greater social receptiveness

Models of Substance Abuse

1. Moral Model
a. Blaming drug abuse on the failure of moral character and lack of self control in the user
b. Religious aspect that only a divine being can help
c. Little evidence that these types of interventions actually help

2. Disease Model
a. Abusers need to be medically treated instead of social/moral exhortation
b. That abusers have turned to drugs as a form of self medication

3. Physical Dependence
a. Aka: Withdrawal Avoidance Model
b. Dysphoria

4. Positive Reward Model

a. Addictive behavior due to positive reinforcement
b. Cocaine- highest rates of lever pressing in rats
c. Reward pathways
i. DA release in nucleus accumbens
ii. DA mesolimbocorital pathway
iii. Endocannabinoid reward circuit
d. Downregulation of D2 and D3 receptors, inhibiting DA receptors
i. Altogether decreasing dopaminergic activity and increasing drug hunger

Uncovering the Insula

- Found in the frontal cortex
- Important in addiction
- Ppl who have damage to their left insula will lose their addiction to smoking
- Has interconnections with prefrontal and sensory cortex and the VTA
- Social pressure

Different vulnerability to Drug Abuse

- Biological factors
○ Sex
○ Genetic predisposition
- Family situation
- Personal characteristics
- Environmental factors
○ Cue-induced Drug use: being in an environment where they had previously used drugs can trigger
craving
§ Controlled by nucleus accumbens and central nucleus of the amygdala (emotional cue)

Treatments
- Lessening the discomfort of withdrawal
○ rTMS
○ Benzodiazepines

- Providing alternatives
○ Agonists or partial agonists that weakly activate the same mechanisms that the drugs do (ie vaping)

- Directly blocking the actions of addictive drug

○ Using antagonists

- Altering the metabolism of the abused drug

○ Altering its breakdown and changing its metabolites may change its effect on the receptors

- Blocking the Brain's reward system

○ DA receptor blockers
§ Reduce the activity of mesolimbocortical pathway
□ Problem: generalized and lose pleasure in more things other than the drug

- Immunization to render the drug ineffective

○ "Vaccinations" to produce antibodies to rapidly metabolize and remove the drug before it can
reach the brain