Neurotransmitter Pathways & Reboxetine

• Catecholamines include dopamine and norepinephrine.

Learning Objectives

• Distinguish between monoamine neurotransmitters of the catecholamine and indolamine families.
• Describe and identify dopamine and norepinephrine as catecholamine neurotransmitters.
• Identify features of dopaminergic and noradrenergic neurons, including synthesis, storage, release, breakdown, and reuptake mechanisms.
• Describe the receptors responsible for transmission at dopaminergic and noradrenergic synapses.
• Identify the systems (central and peripheral) using dopaminergic and noradrenergic neurotransmission.
• Describe the application of pharmacological agents to dopaminergic and noradrenergic neurotransmission and the resulting effects on the brain and body.

Monoamines

• Monoamines, also known as biogenic amines, share a single amine functional group and include neurotransmitters and hormones

Catecholamine Neurotransmitters

• They share a common structure with individual variations
• Consist of a catechol nucleus and an amine group

Synthesis

• L-tyrosine (dietary) is converted to L-dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase (TH)
• L-DOPA is converted to dopamine by DOPA decarboxylase.
• Dopamine is converted to norepinephrine by dopamine-β-hydroxylase (DBH).
• Norepinephrine is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT).

Vesicular Transport

• VMAT is the transporter that loads the vesicles with monoamines into synaptic vesicles.
• Reserpine inhibits VMAT, depleting dopamine and norepinephrine as cytosolic catecholamines that are rapidly degraded.
• Reserpine treatment leads to sedation in animals and depression in humans.

Dopamine Transporter (DAT)

• Cocaine and amphetamines inhibits DAT, preventing dopamine reuptake.
• Leads to increased dopamine in the synapse.
• Prolongs dopamine signaling and hyperactivity of dopaminergic circuits.

Catecholamine Metabolism

• Dopamine is metabolized through intracellular and extracellular pathways.
• In the intracellular pathway, dopamine is broken down by monoamine oxidase (MAO) and aldehyde dehydrogenase into 3,4-dihydroxyphenylacetic acid (DOPAC).
• DOPAC is converted to homovanillic acid (HVA) by catechol-O-methyl-transferase (COMT).
• In the extracellular pathway, dopamine is converted by catechol-O-methyl-transferase (COMT) into 3-methoxytyramine (3-MT).
• 3-MT is broken down by monoamine oxidase (MAO) and aldehyde dehydrogenase into homovanillic acid (HVA).
• Vanillin gives vanilla its flavor.

Dopaminergic Synapse

• Presynaptic cells are rich in anabolic enzymes (TH, DOPA decarboxylase).
• VMAT is expressed on vesicles to load dopamine.
• Dopamine receptors in postsynaptic membrane.
• Autoreceptors in the presynaptic membrane allows for feedback inhibition
• The DAT is responsible for dopamine reuptake.

Dopamine Receptors

• D1 family [D1, D5] are G-protein coupled receptors using Gsα for signaling that increases cAMP and is excitatory.
• D2 family [D2, D3, D4] are coupled receptors signalling through Giα to decrease cAMP and are inhibitory

Dopaminergic Terminals

• Dopamine often synapses onto the neck of dendritic spines, which allows dopamine to modulate the activity of the synapse.
• Dopamine gates the signals at dendritic spines, increasing or decreasing signal transmission

Dopaminergic pathways

• Dopamine accounts for 90% of catecholamine neurotransmission in the CNS.
• Main pathways:
  • Nigrostriatal system: involved in motor control and projects from the substantia nigra and ventral tegmental area to the striatum (caudate and putamen).
  • Tuberoinfundibular system: projects from the hypothalamus to the medial eminence to stimulate the pituitary, resulting in prolactin secretion.
  • Mesolimbic/mesocortical system: Projects from the ventral tegmental area to the limbic system (nucleus accumbens, mesial frontal, anterior cingulate, and entorhinal cortex) and generates emotional states.

Dopaminergic Lesions

• 6-hydroxydopamine (6-OHDA) is a selective neurotoxin taken up by catecholaminergic neurons after injection using a stereotactic apparatus.
• Bilateral nigrostriatal lesion results in sensory neglect, motivational deficits, and motor impairment.
• Unilateral lesion of the nigrostriatal pathway results in postural asymmetry and turning.
• Degradation in Parkinson's leads to motor symptoms
• Treatment includes L-DOPA, a precursor to dopamine.
• MPTP is a neurotoxin that degrades dopaminergic neurons in the substantia nigra, producing Parkinson's symptoms, and is resistant to L-DOPA treatment.

Nigrostriatal Dopaminergic Pathways

• Degeneration of dopaminergic neurons in the nigrostriatal system leads to Parkinson's disease.
• Symptoms: tremors, rigidity, forward-flexed posture and shuffling steps, and bradykinesia (slowed movement).
• Targets are enriched are D1 and D2 receptors in the basal ganglia, leads to decreased dopamine.

Nigrostriatal Dopamine

• Genetic modification of dopamine function induces locomotor effects.
• DAT knockout causes hyperactivity.
• Decreased re-uptake prolongs dopamine signalling at the synapse, leading to increased dopamine in the synapse and increased locomotion.

Cocaine

• Cocaine inhibiting DAT activity has comparable effects on locomotion to DAT knockout.
• D1 receptor knockout ablates cocaine's hyperlocomotion.

Mesolimbic Dopaminergic Pathways

• Targets are enriched in D1 and D2 family receptors.
• Limbic connections are proposed to mediate memory, learning, and affect.
• The nucleus accumbens modifies salience of information flow.
• Implicated in motivational salience which impacts motivation and addictions, and sensory salience which distinguishes reality from not-reality and impacts psychosis.

Schizophrenia and Psychotic Disorders

• Exists along a spectrum of differing severity and combinations of symptoms: – Delusions, hallucinations and disorganized speech. – Grossly disorganized or catatonic motor behavior. – Avolition, social and cognitive deficits as well as flattened affect.
• Altered dopaminergic signaling may cause psychosis.
• Hyperactivity in the mesolimbic system can cause positive symptoms.

Nucleus Accumbens

• Mesolimbic dopamine (DA) proposed to mediate salience, motivational salience relating to addiction and sensory salience relating to hallucinatory gating
• Excess dopamine activity leads patients to perceive voices/sounds/imagery as inappropriately salient
• False recognition of internal/external signally leads to delusions/hallucinations

Antipsychotics & Adverse Effects

• Typical antipsychotics inhibit dopamine receptors in the D1 and D2 families with the goal of modulating pathological effects

• Haloperidol is still used as a front line antipsychotic

• Antipsychotic efficacy correlates with D2 binding potential

• Dopaminergic stimulants (esp. amphetamine) can induce psychosis at sufficient dosage

• Side effects include: Extrapyramidal side effects Tardive dyskinesia (delayed involuntary movements) Hyperprolactinemia

Mesolimbic Dopamine and Addictions

• Mesolimbic dopamine is connected to areas in the brain relating to reward
• Nicotine interacts with DA neurons
• Opiods interact with GABA neurons

Dopamine and Addictions

• Addictive behavior is linked to impulsive behavior
• Impulse control is a manifestation of executive function involving structures such as the anterior cingulate, dorsolateral prefrontal cortex, lateral orbital prefrontal cortex, and motor cortex
• Inhibitory control can be considered a gating event.

Key points: Dopamine

• Synthesized from tyrosine that signals only to metabotropic receptors, plays a role in gating
• DA projections in nigrostriatal system from the substantia niagra to the striatum
• VTA connects it to cortex and limbic structures, dysfunctional in reward/addiction/psychosis
• L-DOPA is a dopamine precursor used in Parkinsons
• Reserpine and Cocaine influence depression
• Amphetamine and 6-OHDA are associated with efflux

Norepinephrine (NE)

• Is also known as Noradrenaline (UK)
• Neurons secreting norepinephrine that are noradrenergic or adrenergic

Norepinephrine Synthesis

• L-tyrosine (dietary) is converted to L-dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase (TH)
• L-DOPA converted to dopamine by DOPA decarboxylase.
• Dopamine converted to norepinephrine by dopamine-ß-hydroxylase (DBH).

Noradrenergic Synapse

• NE is synthesized in vesicles from dopamine by the enzyme dopamine-β-hydroxylase (DBH).
• After release, NE is recycled into the cell by the NE transporter (NET).
• NE is degraded by MAO and COMT or recycled into vesicles through the vesicular monoamine transporter (VMAT).

Adrenergic Receptors

• Norepinephrine and epinephrine activate adrenergic metabotropic receptors, which are G-protein coupled.
• Responsible for both CNS (neurotransmitters) and peripheral (autonomic/hormones) functions.

Adrenergic Receptors Cont

• Agonists of the adrenergic system are sympathomimetic
• Antagonists of the adrenergic system are sympatholytic such as Betablockers

Adrenergic Receptors

• Alpha: Vasoconstriction, Lower BP
• Beta: Vasodilation, Muscle relaxation, Increase HR+ contractility

Key Points: Cholinergic System

• Extensive NE projections emanate from the locus coeruleus (pons), influencing everything
• NE affects Eating, Arosual, and depression
• Alertness and Consciousness is associated with activity

Specific Role of NE in depression

• NE and MAIO system is implicated
• Can act of adrenergic receptors (predominately a₁) Often target norepinephine reuptake and its breakdown

The Monoamine Hypothesis

• Depression is causes by the lack of key monoamine transmitters
• First Antidepressant a MAOI IPRONIAZIAD the antibacteria

Tricyclic Antidepressants

• Developed in the 1950
• Antidepressants like imipramine help aid depression -Side effects include but not limited to Parasympatholytic effects (dry mouth), poor safety margin.

Targeted Drug Design

• SNRI -Seritonin and N-E reuptake inhibiors replace TCI -Fewer side effect of of TCI improved safety margin

Selective NE reuptake inhibitors

• 20 x more potent for NAT
• Same spesificicy of SRI’s
• Not currently marketet

Keypoints: Norepinephine

• Breakdown by MAO and COMT to to MHPG.
• High level NE in locus
• Medial Septum - Vigilance, Limbic Corext for emotion and depression
• Hypopthalamus controls eating behavior
• Resertpine Inhibits VMAT
• Cocaine and amphetamine inhiting NE
• Clondidine and iproniazad

Questions about neurotransmitter pathways such as the nigrostriatal, tuberoinfundibular, mesolimbic/mesocortical systems, and selective neurotoxins. Also covers the reboxetine.