Norepinephrine, dopamine and GABA are removed via reuptake

Acetylcholine and peptide Y removed via metabolism

Glutamate removed via reuptake via glial cells.

Describe the ligand-gated ion channels (ionotropic receptors)

Ligand-gated ion channel (ionotropic) receptors

G-protein coupled (metabotropic) receptors

Receptor tyrosine kinase

Nuclear hormone receptor

Synthesized in the neurons by glial cells and metabolized to glutamate in presynaptic terminals (and transamination of alpha-ketoglutarate)

Does not cross blood-brain barrier

trivia: glutamate is found in chinese food and was used by the Romans to sweeten food. Can cause  hypotension

_____ receptors are target for antagonist drugs in development for anxiety, schizophrenia, pain, epilepsy

gamma-aminobutyric acid (GABA)

- oMay be responsible for mediation of presynaptic inhibition in spinal cord

Give the 3 GABA receptors.

a. which is one is metabotropic (GPCR)?

b. Which is ones have allosteric modulators?

c. which one is expressed mostly in brain and retina?

d. name the one that uses inotropic (ligand-gated Cl- channel) receptors

Metabotropic (GPCR) = GABA-B receptor

GABA-A = allosteric modulators ex. barbiturates, BZD

Expressed in brain and retina = GABA-C

GABA-A and GABA- C receptor = ionotropic ligand-gated Cl- channel) receptors

Metabotropic acts via secondary messengers.

Ionotropic receptors form an ion channel pore. In contrast, metabotropic receptors are indirectly linked with ion channels on the plasma membrane of the cell through signal transduction mechanisms, oftenG proteins. Hence, G protein-coupled receptors are inherently metabotropic. Other examples of metabotropic receptors include tyrosine kinases orguanylyl cyclase receptors

GABA-A = Flumazenil

GABA-B = Baclofen

 GABA-C = none

Give examples of GABA-A receptor agents. Which are agonist, antagonists or positive allosteric modulators?

Agonist - Muscimol

Antagonists - Picrotoxin & Flumazenil

Positive allosteric modulators - Benzodiazepines, barbiturates, general anesthetics, neurosteroids, & alcohol.

ACh can have excitatory or inhibitory action

Nicotinic receptors (ionotropic) - Excitatory action --> 2 types (muscle and neuronal)

Muscarinic receptor (metabotropic) --> Excitatory (M1, M3, & M5) and inhibitory (M2 & M4) => found in autonomic nervous system (parasympathetic), smooth muscle, heart, CNS, and eye.

1. Nicotinic receptors are excitatory, while muscarinic receptors are both excitatory and inhibitory.
2. Nicotinic cholinergic receptor is found in skeletal muscles at neuromuscular junctions, autonomic ganglia and CNS, while muscarinic receptors are found in smooth muscles, autonomic nervous system (parasymp), heart, CNS, and eye.

Alzheimers = cholinesterase inhibitors (pro-cholinergic)

Parkinson's = anti-cholinergic agent (anti-muscarinic agents)

Note: Never give a Parkinson's patient a cholinesterase inhibitor or vice-versa.

Dopamine

Norepinephrine

Epinephrine

Location: most brain regions especially hypothalamus and some parts of limbic system.

Actions: inhibitory effects via beta receptors and sometime excitatory via alpha or beta receptors

Action of NE is terminated by ____ and _____ inside the cells 

re-uptake into noradrenergic nerve ending

and

circulating NE is degraded enzymatically by
COMT and MAO

alpha 1 - neurons - vasoconstriction, relaxation of GI muscles, and contraction of genitourinary smooth muscles.

alpha 2 - glial and vascular cell ==> controls release of NE; activates platelet aggregation, inhibition of NT release, and contraction of muscle.

beta - beta 1, 2, 3

beta-1 => increase cardiac rate and force

beta-2 => bronchodilation and smooth muscle dilation; insulin release

beta-3 => lipolysis

 Salmeterol and albuterol - β2-selective agents are used in the treatment of asthma.

Carbidopa, methyldopa (used occasionally for phaeochromocytoma)

Which dopaminergic pathway is the most important for motor control?

excitatory - D1& D5 like receptors => activates adenyl cyclase

Inhibitory - D2, D3 & D4 receptors => inhibits adenyl cyclase  suppress Ca2+ and activates K+ channels

____ disease is associated with dopamine deficit in the nigrostriatal pathway

What is the endocrine effects of dopamine.

DI receptor:

Most serotonin receptors are ____, only 5-HT3 is a ____

G-protein coupled

ligand-gated ion channel

5HT1 B/D agonists are used for _____

5HT2 antagonists are used for _____

Selective serotonin reuptake inhibitors (SSRIs) are used for _____

5HT3 antagonists are used for _____

Central Nervous System (CNS);  Brain and spinal cord

Peripheral Nervous System (PNS):  Sensory neurons, Voluntary motor systems, Autonomic systems

Enteric Nervous System (ENS): Neuroendocrine cells in the GI tract and related viscera that regulate their function.

Metabolic demands are higher in ____matter than in ___matter.  This is reflected in increase (~4-fold) density of capillaries in ___matter.

gray > white matter

gray 

Neurons may be classified according to 6 factors : t

1.  Neurotransmitter they release

2. Morphology of neuron (size & shape- examples pyramidal, stellate, bipolar, chandelier cells

3. Location in the brain

4. Function 

There are a few neuronal populations that are constantly produced; most important are __and ___.

These are a type of glial cell that supports the function of neurons. They help maintain the ionic composition of the brain ECF, supply metabolites to neurons and enhance blood-brain barrier function of blood vessels. During neuronal degeneration, they become reactive and are involved in clearing cellular debris and sealing off damaged regions by creating a glial scar.  There are approximately 10x as many them in human brain as there are neurons. 

Myelination of axons in the PNS is accomplished by ____.

These are bone marrow derived cells that invade the CNS early in development. They are the “macrophages of the CNS”. They phagocytize debris and cellular content released during normal activity. They are also critical for synaptogenesis in that they help remodel tissue structure to allow for expansion of synapses or alternatively elimination of unnecessary synapses. During tissue damage they also become reactive and contribute clearing dead and damaged tissue.

These cells form a layer that lines the ventricles and the surface of the brain. They contain cilia that help propel the movement of CSF.

They are responsible for CSF production and along with BBB capillaries help determine the composition of brain ECF. Found in choroid plexus.

Which of these are elevated in plasma and which are negligible?

K+

Ca2+

Creatinine

Mg2+

Cholesterol

Proteins

glucose

Elevated in CSF = Mg2+ anmd creatinine

Neglible = protein and cholesterol

So where does the Glu in brain come from? 

Afferent (posterior) = processing signals

efferent (anterior) = producing response 

T/F:

Na+ = depolarization (-40mV)

K+ = repolarization

The rate at which an action potential propagates down an axon is due to two factors:

1.     The diameter of the axon: current spreads faster due to lower electrical resistance.

     2. Myelination: Action potentials are conducted in a saltatory fashion where they skip myelinated sections of axon. Na⁺ channels are concentrated in unmyelinated membrane, the Nodes of Ranvier, where the action potentials are executed.

cation = influx of Na+ = depolarization = excitatory

Anions = influx of Cl - = hyperpolarization = inhibitory

Excitatory Postsynaptic Potentials (EPSPs); 

 Inhibitory Postsynaptic Potentials (IPSPs) 

A single EPSP (typically only a few mV) is insufficient to trigger an action potential. So neuronal firing requires multiple EPSPs to reach threshold. The EPSPs may arise on different dendrites (termed spatial summation) from synapses formed by different upstream neurons. This is one mechanism by which neurons integrate incoming activity. 

Spatial summation: EPSP arises from different dendrites from synapses formed by different upstream neurons.

Temporal summations: EPSP received rapidly before membrane potential has been restored.

There are numerous other small metabolites that function as neurotransmitters. These include ___,___,__and ___ 

The Dale Hypothesis (one neuron-one transmitter) is no longer accepted. Many neurons are capable of releasing multiple transmitters, although this is usually a major transmitter along with a peptide. Often a vesicle will contain both transmitters. I’ve never heard of Glu and GABA released by the same neuron or Norepi and 5HT released together.

The _____also contains the location of the cell bodies for the catecholamines and serotonin.

substantia nigra and the ventral tegmentum

substantia nigra = stratium = motor function

 ventral tegmentum = frontal cortex & limbic structures = motivation and behavior reinforcement

 locus coeruleus

 Axons from LC project diffusely throughout nearly the entire brain.  NE fibers typically do not make classical synaptic structures but rather appear to release NE in a more hormonal or paracrine fashion from so-called "varicose" (beaded) structures in the axons.  NE appears to play a role in attention, arousal and vigilance.  The activity of LC neurons varies with the sleep-wake cycle.

    This region at the base of the brain functions to maintain the homeostatic environment of an organism. (For example, body temperature, appetite, reproductive hormones, emotional display)

frontal = efferent

parieto-temporal-occipto = afferent

The motor cortex located on the precentral gyrus contains the neurons that synapse with motor neurons in the ventral horn of the ____

____cortex is where primary information is processed and is involved in higher (intellectual) functions. 

visual information is broken down into where the object is and whether it’s moving in the magnocellular visual association cortical pathway in the _____cortex. 

Information regarding color and fine detail are analyzed in the parvocellular visual association pathwayin the _____cortex. 

parietal ;

temporal 

• The ____ association cortex is involved in interpreting the sensory information obtained from the surrounding primary cortical regions.

hippocampus ;

cerebral cortex

1) electrophysiology

2) lesion studies

____ is an imaging tool for structural analysis, rather than functional analysis of brain activity.

___imaging technique is used to identify o    different phosphorylated intermediates, such as ATP and phosphocreatine, based on their chemical shift and thereby measure localized concentrations of these compounds.

Functional MRI

This technique relies on the ability of the instrument to distinguish between oxy- and deoxyhemoglobin and goes by the acronym BOLD. 

Neurological disorders may be precipitated by all the usual suspects

·        Nutritional/Metabolic:  e.g, Thiamin deficiency- Wernicke-Korsakoff’s syndrome

·        Toxicity: e.g., heavy metal poisoning

·        Infectious: meningitis, neurosyphilis, AIDS-associated myopathy, dementia

·        Genetic: Gaucher’s disease, Adrenoleukodystrophy

·        Immunological:  Lambert-Eaton, Myasthenia gravis, Multiple sclerosis

·        Malignancy

·        Developmental

·        Trauma

·        Iatrogenic/drug-induced

What does each disease occur (selective vulnerability):
 ALS

Parkinson's disease

Alzheimer's disease 

ALS - motor neurons

Parkinson's disease - dopaminergic neurons in substantia nigra

Alzheimer's disease - Association cortex (large pyramidal neurons)

• Glutamate elicits toxicity when it binds to NMDA receptors on neurons. These receptors allow the influx of Ca⁺⁺, which with sufficient time and concentration induces apoptotic pathways in sensitive neurons.

• Glutamate opens AMPA channels that pass way too much Na⁺. The influx of Na⁺ results in increased osmotic pressure, influx of water, cell swelling and bursting. This type of cell death is rapid and will also induce neuroinflammation- activation of reactive astrocytes and microglia.

Partition coefficient P (usually expressed as log10P orlogP) is defined as:

P is a measure of the relative affinity of a molecule for the lipid and aqueous phases in the _____.

High P value =  

Low p value =  

High P value = lipophilic

Low p value = water soluble

1. Increases potency

2. Increase BBB penetration 

3. increase oral absorption

Dopamine is produced from ____.

Remember that dopamine cannot pass the BBB but ____ can.

T/F: Selective inhibition of one isoform of MAO

 increases dopamine levels