Chapter 5

Catecholamines
• Parkinson's intimately involves Dopamine(DA).
• Catecholamines= Dopamine, Norepinephrine, Epinephrine.
• Catecholamine = A core catechol structure & a nitrogen containing group called Amine.
• Monoamines: containing 1 amine gr.
• Biogenic Amines: produced by living organisms.
• EPI- Adrenaline (Adrenergic)
• NE-Noradrenaline (Noradrenergic)
• Location of Dopaminergic Neurons: CNS, PNS, Adrenal Medulla.
• Adrenal Medulla secretes EPI & NE in the blood stream, where they act as hormones.

Catecholamine synthesis, Release, & Inactivation

• The biochemical pathway begins w/ AA Tyrosine
• Tyrosine – dietary proteins, transported from the blood into the brain.
• Only first 2 enzymes present in neurons that use DA: Tyrosine Hydroxylase, AADC.
• Neurons that synthesize NE possess DBH(Dopamine B-Hydroxylase)
• Tyrosine Hydroxylase: Rate limiting step for all catecholamines.
• High levels of catecholamines tend to inhibit TH – negative feedback mechanism.
• When neurons are activated and firing @ a high rate – like in stress, TH is stimulated & Catecholamine
synthesis accelerates to keep up w/ the +sed demand.
• Agonist: L-DOPA – A biochemical precursor that +ses catecholamine formation. Used for Parkinson's
treatment
• Antagonist: AMPT( - methyl-para-tyrosine) – blocks TH, preventing catecholamine synthesis &
causing depletion.
• AMPT caused return of depressive symptoms to patients who have been treated previously w/ drugs that
act on noradrenergic system.

Storage of Catecholamines
• Once synthesized, they are transported into synaptic vesicles for later use.
• VMAT: vesicular memb protein responsible for vesicular catecholamine uptake.
• 2 types of VMATs: VMAT1 – in Adrenal Medulla; VMAT2 – in the Brain.
• Reserpine blocks both the vesicular transporters.
• DA & NE can easily breakdown by the enzymes w/in the nerve terminal and levels drop temporarily.
• Symptoms of Reserpine: Sedation in Animals, Depression in Humans.
• The effects of Reserpine can be counteracted by restoring catecholamines w/ DOPA.
• Catecholamine Release normally occurs when a nerve impulse enters the terminal & triggers one or
more synaptic vesicles to release their contents into the synaptic cleft by exocytosis.
• Drugs can also release them independently of nerve cell firing.
• Ex: Amphetamine & Methamphetamine
 • Catecholamine depletion – behavioral sedation, depression
• Catecholamine activation – behavioral activation
• In animals this activation can mean +sed locomotor activity. @ high doses, it could mean stereotyped
behaviors.( sniffing, head & limb movements, licking, biting, etc
• these behaviors are a result of +sing stimulation of DA receptors in the Nucleus Accumbens & striatum.
• Amphetamines & methamphetamines in humans cause +sed alertness, heightened energy, euphoria,
insomnia, etc.
• Catec. Release inhibited by Ars on cell bodies, terminals, & dendrits of dopaminergic & noradrenergic
neurons by reducing the amt of Ca that enters the terminal in response to a nerve impulse.
• D2 – DA AR
• A2(Alpha2) – NE AR
• AR agonist: inhibit catec release
• AR antagonist: enhance catec release.
• Noradrenergic system activated by w/drawal from opiates which leads to +sed heart rate, elevated blood
pressure, diarrhea.
• Clonidine – A2 agonist used to treat opioid w/drawal b/c they stimulate the AR & inhibit NA cell firing.
• Yohimbine – A2 antagonist blocks AR & +ses NA cell firing and NE release which provokes w/d
symptoms & drug cravings in opioid dependent patients.
• NE – may be involved in anxiety in patients w/ panic disorder.
• Yohimbine triggers anxiety and can even cause a panic attack.

Catecholamine inactivation = reuptake + metabolism

• DA & NE released synaptically is taken up again in the Nerve terminal by specific transporters like
DAT and NET respectively on the nerve cell memb.
• After the return to the terminal, some Nts are re-packaged into vesicles for re-release while the
remainder are broken down & eliminated.
• Transporter blocking drugs enhance the synaptic transmission of DA or NE by +sing the amount of NT
in the synaptic cleft.
• Ex: Tricyclic Antidepressants – inhibit the reuptake of both NE and non catecholamine 5-HT
• Reboxetine – selectively inhibits NE reuptake by blocking only the NET.
• Cocaine – blocks NET, DAT, and 5-HT transporters VMAT2
• The break down of catecs – COMT(Catechol – O – methyltransferase) & MAO(Monoamine
Oxidase).
• 2 types of MAO – MAO-A & MAO-B
• COMT & MAO together or individually give rise to metabolites – break down products.
• Homovanillic Acid – DA metabolite in humans.
• MHPG & VMA – NE metabolites
• MHPG – primary metabolite of NE in brain
• VMA – primary metabolite of NE in PNS
• HVA & MHPG – brain metabolites that make their way into the CSF for clearance from brain into blood
stream and alongw/ VMA excreted in the urine.
• HVA, MHPG, VMA – rough indication of catecholaminergic activity in NS.
• MAO Inhibitors like phenelzine/ tranylcypromine – used to treat clinical depression.
• COMTinhibitors like entacapone(Comtan) & tolcapone(Tasmar) – used to enhance effectiveness of
L-DOPA in treating Parkinson's.
• Volume Transmission: When some DA-gic or NA-gic nerve terminals do not seem to form traditional
synaptic arrangements, the neurotransmitter molecules released from these terminals might reach
multiple target cells after diffusing a short distance through the extracellular space.
Organization & F/n of DA-gic system
• A1-A7 nerve cells in brain – Noradrenergic
• A8-A16 – Dopaminergic
• A9 – imp dA-gic cell bodies associated w/ substantia Nigra
• A10 – imp DA-gic cell bodies associated w/ VTA(Ventral Tegmental Area
• A9 axons ascend to a forebrain structure called caudate putamen/striatum.
• Nigrostriatal Tract – the pathway from the substantia nigra to the striatum. This tract severely damaged
in Parkinson's disease.
• Symptoms of Parkinson's – deficits in motor f/n, tremors, postural disturbances, difficulty initiating
voluntary movements, etc.
• NS tract plays a crucial role in the control of movement.
• 2 imp ascending DA-gic sys arise from cells of VTA : Mesolimbic DA pathway & Mesocortic DA
pathway.
• Mesolimbic DA pathway: the axons from these neurons travel to nucleus accumbens, septum,
amygdala, & hippocampus in the limbic system
• Mesocortic DA pathway: the axons go from VTA to the cerebral cortex in the prefrontal area.
• Both pathways imp b/c implicate neural mechanisms underlying drug abuse & schizophrenia.
• Tuberohypophyseal DA pathway: starts from hypothalamus and imp in controling the secretion of
hormone prolactin by the pituitary.
• 6-OHDA(6-hydroxydopamine) – A neurotoxin ; catecholamine pathways that use DA can be lesioned
by 6-OHDA.
• 6-OHDA must be injected directly in brain to produce lesions b/c doesn't cross BBB.
• Taken up by Cat-gic neurons. Leads to behavioral dysfunction in animals, exhibit sensory neglect,
motivational deficits, motor impairment.

Subtypes of DA receptors
• 5 sub receptors – D1-D5
• All metabotropic
• D1 & D2 → both found in the striatum and nucleus accumbens → major termination sites of the NS &
ML pathways respectively.
• D2 – Autoreceptors & normal postsynaptic receptors.
• Location: cells in the pituitary gland that make prolactin.
• D2 activation by DA from the hypothalamus – inhibition of prolactin secretion; blockade stimulates
prolactin release.
• D2 antagonist: antischizophrenic drugs.
• D1 → stimulate Adenylyl cyclase responsible for cAMP synthesis. cAMP formation +ses.
• D2 → inhibits adenylyl cyclase.cAMP formation -ses.
• D2 → regulation of memb ion channels for K+.
• Opening such channels causes hyperpolarization of the cell memb thus -sing the cell's excitability &
rate of firing.

DA agonists & antagonists affect locomotor activity

• Apomorphine: D1 &D2 agonist.
• Causes beh activation similar to amphetamines & cocaine.
• Also used to treat ED in men.
• +se penil blood flow by acting through DA receptors in the brain.
• Taken sublingually(under the tongue) to bypass digestive system and enter straight into blood stream.
• EX: Viagra, Uprima, etc.
• Viagra – involves inhibiting the breakdown of cGMP in the penis.
 • Receptor selective agonists & antagonists are extremely imp in understanding which behaviors are
under the control of a particular subtype.
• SKF 38393 – D1 agonist.
• Elicits self grooming behaviors.
• Quinpirole – D2 & D3 agonist. +se locomotion & sniffing behavior.
• Quinpirole not as powerful as amphetamine or apomorphine.
• DA receptor antagonist : suppress spontaneous exploratory & locomotor behavior.
• Catelepsy- higher doses of agonists leads to this.
• Catelepsy is a lack of spontaneous movement.
• Usually associated w/ D2 receptor blockers such as haloperidol
• D1 blocker – SCH 23390 also elicits catelepsy.
• Catelepsy is particularly related to the inhibition of DA receptors in the striatum.
• D2 antagonists used to treat schizophrenia.
• Produce inhibition of movement & other troublesome motor side effects b/c of the simulatenous
interference w/ DA-gic transmission in the striatum.
• Behavioral supersensitivity – when the haloperidol treatment is stopped & subjects are given DA
agonist like apomorphine, they respond more strongly than control subjects not pretreated w/
haloperidol.
• Both 6-OHDA & Haloperidol treatments persistently reduce the amt of DA stimulation of D2 receptors.
• Haloperidol blocks the receptors
• 6-OHDA causes a long lasting depletion of DA.
• Supersensitivity related to haloperidol and 6-OHDA is partly due to an +se in the density of the D2
receptors on the postsynaptic cells in the striatum.
• Receptor up-regulation – adaptive response whereby the lack of normal NT (DA) input causes the
neurons to +se their sensitivity by making more receptors.

Organization & Function of the Noradrenergic System

• NE neurons location: parts of brain stem – pons & medulla.
• Locus Coeruleus(LC) – a small area of pons that contains a dense collection NA-gic neurons
corresponding roughly to the A6 cell group.
• LC send fibers into almost all areas of the forebrain – providing NE in the cortex, limbic system,
thalamus, hypothalamus.
• LC provides NA-gic input to the cerebellum & spinal cord.
• NE plays an imp role in the PNS.
• Neurons that have cell bodies in the ganglia of sympathetic branch of the ANS use NE as their
transmitter.
• NE & EPI f/n as a hormone secreted by the adrenal glands directly in the blood stream.
• 2 ways NE reaches heart or such organs – 1) it can be released from symp NA-gic neurons @ synapse
like contacts w/ cardiac cell, 2) it can be released from the adrenal glands & travel to the heart through
the circulatory sys.
• Blood borne NE does not reach the brain b/c it is effectively excluded by the blood brain barrier.
• NA-gic neurons of the LC play an imp role in vigilance – being alert to imp stimuli in the envt.

Effects of A &B adrenergic receptors

• The receptors for NE & EPI are called adrenergic receptors or adrenoceptors.
• Metabotropic Receptors
• serve a broad role by having to mediate both NT-s mainly NE & hormonal mainly EPI actions of the
catecholamines.
 • 2 adrenoceptors subtypes – A & B (Alpha & Beta)
• A & B represent 2 families.
• a – a1 & a2
• b – b1 & b2
• Location: cerebral cortex, thalamus, hypothalamus, cerebellum, various limbic structures like
hippocampus & amygdala.
• A2 AR-s are located on NA-gic nerve terminals & cell bodies of NA-gic neurons in the LC.
• Cause an inhibition of NA-gic cell firing & a reduction in NE release from the terminals.
• B1 & b2 both stimulate adenylyl cyclase like D1 receptors & enhance the formation of cAMP.
• A2 Rs reduce the rate of cAMP synthesis by inhibiting adenylyl cyclase & also cause a hyper
polarization of the cell memb by +sing K channel opening.
• A1 Rs operate through the phosphoinositide 2nd mssngr system that leads to an +sed conc of free Ca++
ions w/in the postsynaptic cell.

Adrenergic agonists stimulate arousal & eating behavior

• NE involved in hunger & eating behavior, sexual beh, fear, anxiety, pain, sleep, arousal.
• Firing of NA-gic neurons of the LC is correlated w/ arousal & vigilance.
• A1 agonist- phenylephrine
• B- agonist – isoproterenol
• both agonists in the medial septum imp for NE's arousing effect
• A1 & B – receptors are involved in NE-mediated arousal.
• Dexmedetomidine (precedex) – a2 agonist w/ combined sedative, anxiolytic & analgesic (pain reducing
) effects.
• The sedative & anxiolytic effects of demedetomidine are believed to mediated by a2-ARs in the LC,
analgesic effects occur in the spinal cord.
• Neural mechanisms underlying eating behavior – hypothalamus.
• PVN (paraventricular nucleus) – key area in hypothalamus – a small paired structure that lies on
either side of the 3rd ventricle.
• PVN receives NA-gic input from the LC, & when NE injected directly in PVN – elicits a robust eating
response even if animals not food deprived.
• The PVN a2 Rs responsible for triggering eating beh thought to lie on postsynaptic neurons that receive
NA-gic synapses.

Drugs that stimulate or inhibit peripheral adrenergic receptors

• A-gic agonists that activate both a & b receptors – sometimes used to treat bronchial asthma.
• Stimulating a-Rs causes constriction of the blood vessels in the bronchial lining, reducing congestion &
edema(swelling of the tissue) by restricting blood flow to the tissue.
• B-receptor stimulation – relaxation of the bronchial muscles.
• Asthma treated w/ a selective b-adrenoceptor agonist albuterol.
• B2receptors in airways, b1- heart
• Albuterol effective in alleviating the bronchial congestion of asthamatics w/out producing undesirable
CV side effects.
• OTC cold meds based on peripheral A-gic receptors.
• A1 agonist phenylephrine – key ingredient in Neosynephrine – used a nasal spray to constrict blood
vessels & reduce inflammed & swollen nasal memb resulting from colds & allergies.
• Also used in eye drops to stimulate a-receptors of the iris to dilate the pupils during eye exams or before
eye surgery.
• A2-receptor agonist – clonidine – commonly used in the treatment of hypertension (high blood pressure)
• A2 agonists – tye typical side effects of clonidine are sedaiton & feelings of sleepiness.
• A2 antagonist Yohimbine – helps treatment of some male impotence.
• Yohimbine +ses parasymp & -ses symp activity, that stimulates blood inflow and/or inhibit blood
outflow.
• A1 antagonist – prazosin
• B agonist(B1 & B2) – propanolol
• Both used clinically in the treatment of hypertension
• Prozasin causes a dilation by blocking the a1-Rs responsible for constricting blood vessels.
• The main f/n of propanolol – block the B-Rs in the heart, reducing the heart's conractile force.
• B1 – major adrenoceptor in the heart that led to the B1 selective antagonists such as metoprolol.
• B-Rs agonists like propanolol and metoprolol- treatment of cardiac arrhythmia & angina
pectoris(feelins of pain & constriction around the heart caused by deficient blood flow & oxygen
delivery to the heart)
• propranolol & other B-agonists – used for general anxiety disorder.
• Symptoms of general anxiety disorder- palpitations, flushing, tachycardia(racing heart)
• Beta blockers – help patient feel better by reducing some of these distressing physical symptoms