Neuromodulators and Cortical Arousal

Question 1

Survey the major molecule dopamine (DA) as a neurotransmitter/neuromodulator by the CNS

Answer 1

• Motor control
• motivated behavior and reward processing
• modulates impulsivity, aggression, and aspects of cognition

Synthesized by: tyrosine
Receptors: GPCR’s
— 5 receptor subtypes

Reuptake transporters

Vesicular transporters

Catabolitic enzymes: MAO & COMT

Question 2

Review the three major clusters of dopaminergic neurons, their pathways, and note the effects/side-effects of antipsychotic medications that target DA receptors in these pathways

Answer 2

1. Nigrostriatal pathway

     Extrapyramidal sx (dystonia, akathisia)
     Tardive dyskinesia

2. a) Mesolimbic and b) Mesocortical pathwaysa) inhibiting DA receptors in mesolimbic pathway
   decreases psychosisb) some anti-psychotics may worsen negative and
   cognitive sx d/t DA blockage
3. Tuberoinfundibular pathways

Has a stimulatory effect on prolactin secretion from
pituitary gland

antipsychotic - induced hyperprolactnemia

Question 3

Survey the major molecule serotonin (5-HT) as a neurotransmitter/neuromodulator by the CNS

Answer 3

• Neurons are clustered close to the midline of the brainstem and upper spinal cord

Synthesized by: tryptophan

Receptors: G-protein coupled receptors, 1 5HT3

Reuptake transporters: SERT; removes 5-HT from synapse…this process is inhibited by SSRI’s, TCA’s and ecstasy

Vesicular transporters

Catabolitic enzymes: MAO breaks it down into 5-HIAA

Question 4

What are the two major serotonin systems and components?

Answer 4

Ascending system (dorsal raphe)
Descending system (raphespinal)
     - raphe magnus
     - raphe pallidus (thermogenesis)
     - raphe obscurus

Question 5

Describe the ascending serotonin system and its general functions

Answer 5

dorsal raphe system

dorsal raphe projects to the following areas and helps them do what they do

cortex
amygdala
hippocampus
striatum
thalamus
hypothalamus

Question 6

Describe the descending serotonin system and its general functions

Answer 6

raphespinal system stimuli suppressants

• Axons terminate in all spinal laminae at all levels
• These projections suppress stimuli that would alter the major behavioral states

Pathways:

1. raphe to spinalthalamic neurons in dorsal horn of SC
   - endogenous analgesia system, driven by PAG
   - suppresses pain signaling from STT
2. raphe obscurus to motor neurons in SC
   - regulate the magnitude and timing of motor neuron activity in spinal cord central pattern generators

Question 7

How is pain modulated by the descending raphe magnus system for serotonin (5-HT)?

Answer 7

PAG activates the pathway and modulates pain transmission

PAG receives pain inputs from STT

PAG sends axons via raphe magnus tract in the lateral funiculus and terminates on interneurons in the dorsal horn

interneurons inhibit STT by binding to opiate receptors on 1st and 2nd order neurons in the STT pathway

Question 8

How are SSRI’s thought to relieve depression?

Answer 8

by acting with BDNF and potentially modulating glutamate

Effective tx but takes up to 2 weeks

Question 9

How is ketamine thought to relieve depression?

Answer 9

By blocking NMDAR-dependent Lateral habenula bursts, ketamine releases the brake on the VTA with rapid antidepressant effects

Alleviates depression in hours!

Question 10

Explain the concept of serotonin-dopamine opponency

Answer 10

Reciprocal connections b/t serotonin and dopamine thought to be activated in opposition

Projections from dorsal raphe 5-HT cells to DA areas oppose the actions of DA and mediate avoidance of threats

“Damned if you don’t?” - DA triggers reward seeking behavior in context of expected reward

“Damned if you do?” - 5-HT opposes DA in context of expected punishment, resulting in behavioral inhibition, especially in aversive contexts

Question 11

describe the anatomy and function of the locus coeruleus and its projections

Answer 11

deep blue place

largest cluster of NE producing neurons in the upper pons

Enhances cortical response to novel stimuli

inputs: Frontal cortex, CeA

Output: whole CNS

Part of direct arousal system

neurons are non-synaptically coupled, diffuse transmission

Question 12

Survey the major molecule norepinephrine (NE) as a neurotransmitter/neuromodulator by the CNS

Answer 12

Direct arousal system
modulates cortical plasticity, learning and memory

phasic release enhances cortical response to novel stimuli

Synthesis: Tyrosine

Receptors: G-Protein coupled receptors

Reuptake transporters

Vesicular transporters

Catabolitic enzymes

Question 13

Explain the role of NE in generating the acute stress response

Question 14

Differentiate between tonic and phasic activity in the locus coeruleus and explain why this is important

Question 15

Describe the organization, function, and distinctions between the mesopontine cholinergic system and cholinergic/GABAergic system of the substantia innominata

Question 16

Explain the function and basic mechanism of action of the endogenous cannabinoid system

Question 17

Distinguish between the direct and indirect components of the cortical arousal system, and explain their basic functions

Question 18

Explore how brainstem monoaminergic and cholinergic systems interact with hypothalamic systems for control of awake/sleep state stability