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Neurotransmitters and Nicotine

Date: 14 Sep 1982 (est.)
Length: 11 pages
1000128400
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Abstract

Reviews the actions of nicotine in the peripheral, autonomic, and higher control nervous system and discusses the various mechanisms involved. Informs of the often opposing affects nicotine has on biological systems, stating that while low doses exite the autonomic ganglia, higher doses are inhibitory. Notes that nicotine's "mechanism of action in the brain" is cholinergic, but other noncholinergic mechanisms may also be involved. Includes a discussion of neurotransmitters and nicotine and how neurotransmitters operate in the autonomic nervous system. Attaches a chart of actions of nicotine in central nervous system, a chart documenting the peripheral actions of nicotine, and various diagrams. Includes a discussion of excitatory-inhibitory neurotransmitter control of superior cervical ganglion, and the effect of nicotine on the electrical activity of the medial vestibular nucleus.

Fields

Author
Abood, Leo G., Ph.D. (Biochemist, U of Rochester Med. Ctr.)
Outside research on nicotine analogs for PM. University of Rochester. Around 1980.
Keyword
Central nervous system (CNS)
Subject
CNS/Brain (Effects)
nicotine technology
nicotine analogues (Technology)
Pharmacology (Effects)

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~- . (.7 - l7-AGrc1W opposite to one another, thereby complicating its analysis. It excites and .then blocks both sympathetic and parasympathetic ganglia as well as the Nicotine produces a variety of pharmacologic- effects, many of which are cat echolam ine- secreting cells INTRODUCTION : f in the adrenal medulla. It also excites and blocks the myoneuro junctions in skeletal (voluntary) muscles, some sensory nerve endings, and sympathetic nerve endings, as well as multiple sites in the CNS. The problem is further complicated' by the fact that its pharmacologic spectrum is dose-dependent: lower doses tending to be excitatory to autonomic~ ganglia, while higher doses are inhibitory. This presentation will attempt to review the actions of nicotine in the peripheral, autonomic, and higher control nervous system and to discuss the possible mechanisms involved. The traditional view_ concerning nicotine's mechanism of action in the brain has been that it is cholinergic (nicotinic); but other mechanisms (noncholinergic) also appear to be involved. I
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' NELJROTRANSMITTERS AND NICOTINE The neuron is the functional unit of nervous tissue. It receives nerve impulses from the sensory systems and other neurons; and, after integration ; and modulation, it transmits impulses to other neurons as well as skeletal _ muscle and other end organs. The nerve impulse, which is generated by the movement of such ions as Na+., K+, Cl-, and Ca2+, initiates in the cell body, travels down the axon, and upon reaching the axon terminal (nerve ending), results in the release of a neurotransmitter (NT) which is stored in the synaptic vesicles. The NT acts upon the post-synaptic receptor (axonal, dendritic or somatic) to produce either a depolarizing (activating) or hyperpolarizing (inactivating) current which then travels to another cell body or end organ~. The list of known neurotransmitters continues to expand, and include the catecholamines (dopamine and noradrenalin), serotonin (5-hydroxy-tryptamine), acetylchline, 3. -amino- but yrat e, glutamate, glycine, and a number neuropeptides. Acetylcholine produces a depolarizing current at the synapse, while dopamine is an example of an inhibitory transmitter. The rate of firing a neuron is controlled by a variety of factors. The number of synapses terminating on its dendrites and cell body (as many as 100,000 on some cells); the factors regulating the rate of synthesis, biodegradation, storage, and release of neurotransmitters,, and the responsiveness of the neuron- being innervated. ~ Since nicotine is known to affect the release of a number of NT's, ~ . 0 . ~ including acetylcholine, dopamine, noradrenalin, and serotonin, its action in N the CNS is complex. The problem is further complicated by the integrated neural networks with their positive and negative feedback loops, designed to maintain homeostatic and adaptive behavior of the organism. ~ ~". . z
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SEGMENTAL POST- GANGLIONIC AD- RENERGIC FIBERS FROM,PARAVERTE- BRAL GANGUA TO BLOOD VESSELS AND HAIR FOLLICLES WI GRAY RAMI AND SPINAL:NERVES FiEure /-1, The antonomic senrous s,rutei S:henrrrric r.T.etenrution Oi.rrto- nwnic nertnr and rffeeror organf on the 6usir af the che/nicaf ntediotion x! nertte inywlses. Blue = cholinergics red = adrenergie: peen = v'esceral aRaAtt: ao6d lines = preganglionic; broken limea = pwef.wglionic. In the rectangle at the right iare shown the finer details of the nmitications of aJrcner{ic hben at anyy one segment of the spinal corJ. the path of the visceral aRercnt rservew the cholinergic nature of somatic motor nerves to skeletal muxle, and the presurna- bly cholinergic nature of the vasodilator lil-ers in the dorsal roots of spinal nerves. The asterisY (') indfcates that il is trot Laown whether these vasahlator 6tiers are motor or sensory or where their ceU bodies are situated. PRESSO- AND CHEMO- RECEPTORS OF CAROTID SINUS AND CAROTID BODY ~ ARCH OF AORTA VASOSENSITIVE AND CHEMORECEPTIVE ENDINGS _ ~ SUPERN)R, MIDDLE, AND ~ INFERIOR CERVICAL GANGLIA / / / \ ~Y a1rC/~1 YV~Vi nnu SPECIAUZED BLOOD VESSELS . OF LOWER LIMB SEGMENTAL POST: GANGUONIC CHOUN• ERGIC FIBERS FROM PARAVERTEBRAL GANG. LUi TO SWEAT GUUVOS AND CERTAIN BLOOD VESSELS VIA ' GRAY RAMI AND SPINAL NERVES
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, J-. v Effm{W -h s suG . /~ '1A ~ . ~ /`t~'1 ~ yVht~lS Ca~tr 1 ~'1t G . rp-&Yelm.- c (/} A-Cn (y.t co'{hv%tc Cblva~ s-;-rt.& w.~ C. AC1'-rc.Lat -MLCcLC-*- . . ~. AC4t Chcc.ofiAi c. ) tl;,-\ ~ A+ MA ~-X ( VLtit.t3f'ty1 tc. ~ .. -~ t.,/- - - - r ArC4%C hti"-S t:oL-Y 1 K t C) ..,~ ' NEUROTRANSMITTERS IN THE AUTONOMIC NERVOUS SYSTEK D, in the parasympathetic system acetylcholine is the neurotransmitter both at the ganglionic synapse (nicotinic action) and at the neuro-effector junction.(muscarinic action). Preganglionic nerves are indicated by solid lines and postganglionic by broken lines. nerves). .C, the chromaffin cells of the adrenal medulae are innervated by preganglionic sympathetic fibres releasing acetylcholine and acting upon nicotinic receptors. The chromaffin cells release a mixture of adrenaline (A) andnoradrenaline (NA) into the bloodstream. B, a small number of postganglionic sympathetic nerves release acetylcholine acting upon muscarinic receptors at the neuro-effector junction (cholinergic sympathetic nicotinic receptors in the ganglia. The majority of postganglionic sympathetic nerves release noradrenaline (NA) at the- neuro-effector junction (noradrenergic nerves) A, sympathetic preganglioriic nerves release acetylcholine (ACH) which acts upon C C C N ~. P O W C~Y~tC"l t•Ki~G~ ? ~tt f-i 1 ` ~ I rt 9 0.~9~ i o N i~~t ~w '~Sl'~art~
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Actions of Nicotine in Central Nervous System Brain area Effect Mechanism Comments Pituitary = LH and pro- ACh-DA . lactin secretion • ACh-NA = Hypothalamus -heart rate reflex from antidiuretic hormone -blood press. carotid NA-DA +neurosecretion chemoreceptors Medulla nausea vomitting ACh nicotine cholinergic + respiration Reticular arousal hippocampal - !followed by decreased -activating-- convulsions arousal activity-depression system (biphasic) : Superior retraction of release of followed by inhibition cervical nictating , NA of all 3 membrane mydrea- sis + BD Vestib ular Vertigo inhibition and possibly system -muscle tone activation noncholinergic - affect _ Cerebral Activation ACh release' indirect cortex convulsions motor cortex noncholinergic ' Hippocampus Arousal cholinergic + Action is convulsions noncholinergic indirect affect
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.. .. ._.. . .. __, . .. . ..... System Effect Mechanism ' ,. Neurotransmitter . . + Conduction Atrium ; ACh velocity A V node ~ -Contraction -cholinergic ACh +blood press. +chemoreceptors ;:. Heart . vasoconstrict. (aortic + ACh + heart rate carotid bodies) - heart rate -cholinergic ACh-NA Muscle Contraction 'ACh Bronchioles Glands Stimulation ACh Gastrointestinal ± motility + choliner ic t ACh-NA + sympathe ic Secretion +cholinergic Adrenal medulla + blood press. release of adren- . ACh-NA + heart rate alin and NA. ,.. Skeletal muscle + contraction + end plate ACh paralysis , - end plate direct-release . Respiratory augment or reflexively ACh-NA decrease (aorta-carotid) . I
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Ves+ai'idLr oS ystcm rnr-& 10~3 . . -~-~~ CA ca a.% C +h®ydLC-A- c- h ccn-J- I-A Pvtv% e ovis 3 r'c~t' cula~' : m.ct'a,ra ~Psi systcort ccooo~~erA ct.-1i oH o$ rccriiLtic'%) 39-we.,-1 oor' Yisccya.l fuxt-tisn ) Nl~ir C -mttsz.lc- ~a tic= c:A-k-4-e-la etm - -F-.
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G . w ~ C EU.. C--a S1Dw zPs? --~. NoYo.dn ' ;a I l A* re.leo-,Z.+-t d EXCITATORP-Iti'rIIEIT03Y VE'JROTRANSMITTER CONTROL OF SUPERIOR CERVICAL GANGLION ' The• release of noradrenalin from a superior cervical ganglion cell is controlled . by both excitatory (ace*_yicholine (ACh) ) inhibitory (dopamine) neurotransmitters. ACh acts at two receptor sites, a nicotinic site which results'in a fast excitatory (+) postsynaptic pote3tial (EPSt) and a muscasinic site which leads to a slow EPSP. The end result- is a rapid follow by a slow sustained~ release of noradrenalin (NA) in response to autonomic andl.central conmands by the nervous system to maintain homeostasis of the oroan_sm. In the evznt: that the excitatory input is excessive, an inhibitory interneuron is activated to rel easz dopamine which results in a slow inhi bitory (-) postsyr.aptic 'potential (IPSP). The*net result is an attenuation of the e.{citator1 input controlling the release of NA. Ftirther modulation of the oanglion cell is accomplished through an excitatory muscarinic cholinergic input on the interzeuron control the -releasz of the DA, the inhibitory transmitter. The fast EPS? which can be recorded with microelectrodes, can be blocked with atropine and the slow EPSP with d-tubocurarine; the net effect being an inhibition of NA release. Ch?orpronazine and related tranquilizers will block DA; thereby abolishing the modulatory controL of the interneuron. The ganglion cell: innervates heart, pharynx and carotid arteries resulting through (sti-nulatory) vasonotor, pilomotor and secratorf fibers. O . .
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Effect of ilicotine on the Electrical Activity of the ~' Medial Vestibular Nu l us . c e Nicotine (10 It 1 0:r 10-2 M), was injected iMto the lateral ventricle and electrical activity was recorded from the medial vestibular nucleus .from a chronically implanted electrode in free-moving, conscious rats. 1- Recordings taken during control period. .~: ventricle cannula. Animal becomes prostrated at this point. Injected 10 microliters of . 10-2M 1-Nicotine into the lateral 3 and 4-EleGtrical recordings taken during period when animal is showing .behavioral response to the drug. Recordings taken during recovery period.
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D03C AI, UPL':; ELrC'!':;OJE ILI7 LA'"3,h_AJ. VT::i'i"_zICT_k CA:rILlT,JA Illustration number: 1-Electricle recordini-s taken durinm the control period. 1 2-In,j'ected 10 microliters of 10-2'.4 1-;Iicotine into the lateral ventricle cannula. The aniMal becane prostrated at this point. ~ . . 3-Drug period. Animal shows ossilation of head in the verticle position. k-Animal is no longer prostrate. 4 5-Electricle recordin?s taken durinc*, the recovery period,(ap.- proxir.tatly twelve mir_utes after the injection),

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