Chapter 5Catecholamines

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