pamela project

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Abstract

This study was aimed at determining whether 3-iodo-L-tyrosine (mono-iodotyrosine, MIT), apotent but short-lived inhibitor of tyrosine hydroxylase, is able to release prolactin secretion from

dopamine inhibition. Administration of MIT (100 mg/kg, i.p.) to normal rats caused a highlysignificant elevation of serum prolactin levels within 30 min. This rise was not due to the initialmetabolites of MIT. The properties of MIT suggest its use in clinical studies of prolactinsecretion.

Copyright 1974 S. Karger AG, Basel

Author Contacts

J7ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:685-687

Serum prolactin response tometoclopramide

during status epilepticusUlla Lindbom, Torbjorn Tomson, BengtY Nilsson, Dan E H AnderssonAbstract

Transient elevation of serum prolactin

frequently follows generalised tonicclonic

and complex partial seizures. However,

the levels of prolactin during status

epilepticus are not increased above thenormal range. Exhaustion of central

prolactin supplies has been proposed as a

possible mechanism for the absence ofprolactin increase during status epilepticus.

To test this hypothesis we injected

intravenous metoclopramide (10 mg) ineight consecutive patients with status

epilepticus. One patient had generalised

tonic-clonic status epilepticus. Seven

patients had EEG-verified non-convulsive

status epilepticus, consisting of one typical

absence status, one atypical absencestatus and five complex partial status

epilepticus. Metoclopramide raised the

mean (SD) prolactin levels at least fivefold

in all patients, from 5-8 (8.0) .ugl to87-0 (39.0) ugIl, within 60 minutes afterthe injection. Thus the mechanism for low

prolactin values in status epilepticus is not
http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=122281&Ausgabe=234880&ProduktNr=223855#OLNhttp://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=122281&Ausgabe=234880&ProduktNr=223855#OLN


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cellular depletion of stored prolactin, but

more likely an altered regulation, presumably

induced by prolonged seizure

activity.(3 Neurol Neurosurg Psychiatry 1992;55:685-687)Karolinska Institute at

Sodersjukhuset,Stockholm, Sweden

Department of

Neurology

U LindbomT Tomson

Department ofClinical

NeurophysiologyBY Nilsson

Department ofInternal Medicine II

D E H AnderssonCorrespondence to:

Dr Lindbom, Department of

Neurology, Sodersjukhuset,S-100 64 Stockholm,Sweden.

Received 18 March 1991and in revised form

7 October 1991.

Accepted 20 November1991

Generalised tonic-clonic and complex partial

seizures are followed by a transient increase of

serum prolactin in about 70-90% of the

cases.`-9 Peak values are seen .15-20 minutesafter the seizures. Prolactin levels thereafter

decline to baseline values within 180 minutes.

Most simple partial seizures are not accompanied

by any significant increase of prolactin.

3 4 As for absence seizures, changes inserum prolactin from baseline values have not

been reported but the published cases are few

and the duration of siezures short.'10 Thereseems to be a lower limit of 30 seconds of

seizure activity necessary to cause elevation of

prolactin in serum.3 12 Prolactin levels in

status epilepticus do not seem to differ from

baseline values irrespective of the type ofstatus.'2-'4 Thus in the clinical situation a

normal prolactin value must be interpreted

with caution in the differentiation betweenepileptic and pseudoseizures.

The regulation of prolactin is not completelyknown but the predominant control mechanism

is inhibitory, mediated mainly by dopamine.'5 16 In relation to single epileptic

seizures the changes in prolactin levels may be

due to abnormal activity within the areas of the

central nervous system that regulate prolactin


3/27

release. Dana-Haeri et al3 have suggested that

spread of seizure activity from medial temporal

structures to the hypothalamic nuclei leads to

changes in prolactin output. This agrees with

the findings of Sperling et al9 that simple

partial seizures involving limbic structures isaccompanied by increased levels of prolactin.

Jackel et al'4 and Trimble'2 have proposed

depletion of stored prolactin as an explanation

for the absence of prolactin increase after

prolonged seizure activity. To test this hypothesis

we injected a dopamine receptor blocker,metoclopramide, in patients with status epilepticus.

Patients and methods

Eight consecutive patients (five male, three

female) with status epilepticus were studied.

Ages ranged from 55-74 years, median 67years. Nonconvulsive status epilepticus was

confirmed with ictal EEG recording. Patients

with focal ictal EEG seizure activity and

impaired consciousness without convulsions

were classified as having complex partial status

epilepticus'7 according to the criteria of

Mayeux and Lueders."6 Nonconvulsive statuswith generalised EEG seizure activity was

designated as absence status. If the generalised

discharges were rhythmic spike-wave at 3 Hz,

the status was classified as a typical absence

status. Patients with generalised seizure activity

other than 3 Hz spike waves were classified ashaving atypical absence status" in accordancewith the classification by Gastaut. Two patients

had absence status, one typical and one atypical.

Five patients were classified as having

complex partial status epilepticus and one

patient had generalised tonic-clonic status

epilepticus. This patient did not have ictal EEG

recording since this would have caused an

unacceptable delay in treatment of the status.

His clinical symptoms, observed at the hospital,

were, however, typical for the diagnosis.

Another criterion for inclusion was that intravenousinjection of diazepam in patients with

nonconvulsive status epilepticus should haveeffect on the seizure activity in EEG since the

clinical response to treatment in these patients

was not easily perceived. All patients with

nonconvulsive status epilepticus showed similar

clinical symptoms: fluctuating stupor, disorientation,

extreme latency for monosyllabic


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answers, if any, and a tendency to perseveration

in verbal communication. Verbal and

motor inactivity were striking even in patientswho seemed awake. Automatisms and685Downloaded fromjnnp.bmj.com on April 20, 2011 - Published by group.bmj.com

Lindbom, Tomson, Nilsson, AnderssonTable Clinical data on eight patients with status epilepticusAgelDuration Duration of status Drug therapy

Patient of epilepsy (years) Type of status (hours) (mg/day)

1 71/32 Typical absence 7 Carbamazepine (400)Ethosuximide (500)

Phenobarbital (15)

2 67/3 Atypical absence 4 Carbamazepine (200)

3 63/5 Complex partial 30 Phenytoin (300)

4 55/7 Complex partial 10 Carbamazepine (800)

5 69/0 x) Complex partial 5

69/0 Complex partial 7 Carbamazepine (400)

6 74/0 x) Complex partial 300

7 65/1 Complex partial 28 Phenytoin (250)

8 61/4 Generalised tonic-clonic 1 Phenytoin (?)

x) Status epilepticus was the first manifestation of epilepsy.

myoclonic jerks were often discrete. Six of thepatients had a previous history of epilepsyranging from a few months to 33 years, all of

whom were under continuous treatment with

anticonvulsant drugs (table). In two of thepatients, both with complex partial status

epilepticus, status was the first manifestation of

epilepsy.

Serum prolactin was determined before(ictal value) and after the administration of

metoclopramide. One or, when possible, twoictal blood samples were drawn from an antecubital

vein immediately before treatmnent ofstatus. Status was then terminated with

5-10 mg of intravenous diazepam. Ten mg of

intravenous metoclopramide was given during

status or within 15 minutes after its termination.

Further blood samples were obtained 15,30, 60, 90, 120 and 180 minutes after the

metoclopramide injection. One patient (5) was

admitted to the hospital with status epilepticus

twice within a few months. On the first

occasion metoclopramide was given immediately

after the termination of status and on

the second occasion during status, beforetreatment. A control experiment was conducted

in three patients, one with typicalabsence status and two with complex partial

status. In these patients the metoclopramide

injection and blood sampling were repeated atleast 5 days after the first injection and after at

least 24 seizure free hours. The second injection


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of metoclopramide was given at the same

time of the day as the first. Serum samples

were stored at - 20C until analysis by radioimmunoassay.'9 Normal serum prolactin levels

at our laboratory are less than 25,ug/l. Thestudy was approved by the local Ethical

Committee.

Results

Ictal levels of serum prolactin and responses to

metoclopramide injections are shown in fig 1.None of the patients had an ictal level above

the normal range. Six out of eight patients had

ictal levels below 5,ug/l. All eight patientsshowed at least a five-fold increase in prolactinconcentrations within 60 minutes after the

metoclopramide injection.

Mean (SD) ictal values were 5-8 (8 0) ,ug/l

and mean (SD) peak prolactin levels aftermetoclopramide were 87-0 (39 0) pg/l. Therewas no obvious difference between the various

types of status in the response to metoclopramide.

One patient was studied twice with two

separate episodes of status, on the first occasion

before, and on the other after treatment

with diazepam. The prolactin responses tometoclopramide were similar. In three patients

the effect of metoclopramide was studied also

under baseline conditions. The values obtained

after at least 24 hours without seizures did not

differ from the responses in connection withstatus. Two patients (5 and 6) were without

anticonvulsant medication at the time of the

status, but at the time the baseline values were

obtained they were under treatment with

carbamazepine in steady-state.

Discussion

Knowledge of the regulation of prolactin under

physiological conditions is incomplete. Two

major factors, prolactin-inhibiting factor andprolactin-releasing factor, regulate prolactin

secretion. The chemical identities of the prolactin-

inhibiting factor and to prolactin-releasingfactor still need to be clarified. In contrast

to other pituitary hormones, the neuroendocrine

control of prolactin is predominantly

inhibitory. The major physiologic inhibitor

appears to be dopamine, but gamma-aminobutyricacid has been suggested to be a part of

nondopamine prolactin-inhibiting factor."5 16Thyrotropin-releasing hormone and vasoactive


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intestinal polypeptide have been suggested as a

prolactin-releasing factor." The temporaryincrease in serum prolactin after single seizures

may be due to spread of abnormal electricalactivity to areas of the central nervous system

that regulate prolactin release.3 The seizure

activity is presumed either to suppress theprolactin-inhibiting factor or to stimulate the

prolactin-releasing factor.

It appears that seizure-induced prolactino typical absence

* atypical absenceo complex partial

* generalised

tonic-clonic

150100g a0.E200

Time after metoclopramide injection (min)Figure Prolactin response to metoclopramide in eight

patients with status epilepticus. Blood samples at time zero

were drawn before or within 15 minutes after the statuswas terminated.

686

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Serum prolactin response to metoclopramide during status epilepticus

release, apart from the localisation, is dependent

on the duration of seizure activity. A seizure

duration of at least 30 seconds appears to benecessary to induce an increased prolactin

concentration.3 12 However, with repeatedseizures there seems to be a reduction in

prolactin response.'4 In connection with seizure

activity of a more extreme duration, such

as status epilepticus, the prolactin levels are

similar to basal conditions.'3 We have presented

ictal prolactin values during 19 episodesof status epilepticus (this study and reference

13), four generalised tonic-clonic status, eight

complex partial status, one typical and six

atypical absence status epilepticus. None ofthese patients showed increased prolactin levelsduring status epilepticus.

The absence of increased levels of prolactin

after prolonged seizure activity may be due to

depletion of stored prolactin.'2"'We tested this

hypothesis by giving metoclopramide, a dopaminereceptor blocker, in status epilepticus.

The response to metoclopramide was prompt


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and the increase of prolactin at least five-fold in

all patients. Furthermore, the response tometoclopramide was, in three of our patients,

the same during status as during baseline

conditions. While five out of eight patients in

our study had complex partial status epilepticus,

typical and atypical absence status andgeneralised tonic-clonic status epilepticus were

only represented in one case each. Ictal levels

within the normal range (< 25,ug/1) and evidentresponse to metoclopramide were the

results in all patients independent of the type of

status. Hence, even though absence status and

generalised tonic-clonic status were representedby single cases only, our results indicate

that there is no cellular depletion of prolactin

in connection with status epilepticus.Treatment with diazepam might have influenced

the ictal prolactin levels as well as theresponse to metoclopramide. One patient was

given metoclopramide with two episodes of

status, the first time within 15 minutes afterthe status was terminated with diazepam and

the second time before diazepam was given.There was no difference in the prolactin

response to metoclopramide on these twooccasions. This agrees with the findings of

Wilson et alo2 who concluded that diazepamneither affects basal prolactin levels nor the

release of prolactin in response to metoclopramide.

The influence of other antiepileptic drugs onprolactin levels are somewhat controversial.

Effects of anticonvulsants on the hypothalamic-

pituitary axis have been reported but the

results deviate. Basal prolactin levels have been

reported to increase,223 to decrease24 25 or tobe unaltered26 27 during treatment with anticonvulsant

drugs. Monotherapy seemed to

have less effect than polytherapy.22 Six of our

eight patients were on monotherapy, and twopatients were without medication since status

epilepticus was their first manifestation ofepilepsy. However, when the latter were given

metoclopramide on a second occasion they

were both on medication with carbamazepine.Ictal and baseline responses to metoclopramide

did not differ in these two patients. Thus

medication with antiepileptic drugs did not

apparently influence our results.

The mechanisms behind the finding of

prolactin levels not different from baseline


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values in association with status epilepticusremain obscure. Our results suggest that mechanisms

other than cellular depletion of prolactin

must be involved.This study was supported by a grant from the Karolinska

Institute.

1 Trimble MR. Serum prolactin in epilepsy and hysteria. BMJ

1978;2: 1682.2 Abbot RJ, Browning MCK, Davidson DLW. Serum prolactin

and cortisol concentrations after grand mal seizures.

J Neurol Neurosurg Psychiatry 1980;43:163-7.

3 Dana-Haeri J, Trimble MR, Oxley J. Prolactin and gonadotrophin

changes following generalised and partial seizures.

J Neurol Neurosurg Psychiatry 1983;46:331-5.

4 Collins WCJ, Lanigan 0, Callaghan N. Plasma prolactin

concentrations following epileptic and pseudoseizures.

J Neurol Neurosurg Psychiatry 1983;46:505-8.5 Pritchard PB, Wannamaker BB, Sagel J, Nair R, DeVillier

C. Endocrine function following complex partial seizures.

Ann Neurol 1983;14:27-32.6 Laxer KD, Mullooly JP, Howell B. Prolactin changes after

seizures classified by EEG monitoring. Neurology

1985;35:31-5.

7 Bye AME, Nunn KP, Wilson J. Prolactin and seizureactivity. Arch Dis Child 1985;60:848-51.

8 Pritchard PB, Wannamaker BB, Sagel J, Daniel CM. Serum

prolactin and cortisol levels in evaluation of pseudoepileptic

seizure. Ann Neurol 1985;18:87-9.9 Sperling MR, Pritchard PB, Engel Jr J, Daniel C, Sagel J.

Prolactin in partial epilepsy: An indicator of limbic

seizures. Ann Neurol 1986;20:716-22.

10 Wroe SJ, Henley R, John R, Richens A. The clinical value of

serum prolactin measurement in the differential diagnosis

of complex partial seizures. Epilepsy Res 1989;3:248-52.

11 Bilo L, Meo R, Striano S. Serum prolactin evaluation after

"minor" generalised seizures monitored by EEG. JNeurol

Neurosurg Psychiatry 1988;51:308-9.12 Trimble MR. Hysteria, hystero-epilepsy and epilepsy. In:

Trimble MR, Reynolds EH, eds. What is epilepsy? The

clinical and scientific basis of epilepsy. Edinburgh: ChurchillLivingstone, 1986;192-205.13 Tomson T, Lindbom U, Nilsson BY, Svanborg E, Andersson

DHE. Serum prolactin during status epilepticus.

J Neurol Neurosurg Psychiatry 1989;52:1435-7.14 Jackel RA, Malkowicz D, Trivedi R, Sussman NM, Eskin

BA, Harner RN. Reduction of prolactin response with

repetitive seizures. Epilepsia 1987;28:588.15 Kato Y, Matsushita N, Ohta H, Tojo K, Shimatsu A, Imura

H. Regulation of prolactin secretion. In: Imura H, ed. Thepituitary gland. New York: Raven Press, 1985:261-78.

16 Leong DA, Frawley LS, Neill JD. Neuroendocrine control

of prolactin secretion. Ann Rev Physiol 1983;45: 109-27.17 Mayeux R, Lueders H. Complex partial status epilepticus:

case report and proposal for diagnostic criteria. Neurology

1978;28:957-61.

18 Gastaut H. Classification of status epilepticus. In: Delgado-

Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds.

Advances in neurology, Vol 34: Status epilepticus. NewYork:

Raven Press, 1983:15-35.

19 Rojdmark S, Andersson DEH, Sundblad L. Calcium andcalcium-antagonistic effects on prolactin and growth

hormone responses to thyrotropin-releasing hormone and

L-dopa in man. J Clin Endocrinol Metab 1981;53:594-8.

20 Wilson JD, King DJ, Sheridan B. Tranquillisers and plasma

prolactin. BMJ 1979;1:123-4.

21 London DR, Loizou LA, Butt WR, Rovei V, Bianchetti G,


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Morselli PL. The effect of anti-convulsant drugs (AED)

on hormonal responses in normal volunteers. In:

Johannessen SI, Morselli PL, Pippenger CE, et al, eds.

Antiepileptic Therapy: Advances in Drug Monitoring. NewYork: Raven Press, 1980;405-11.22 Franceschi M, Perego L, Cavagnini F, Cattaneo AG, Invitti

C, Caviezel F, Strambi LF, Smirne S. Effects of long-termantiepileptic therapy on the hypothalamic-pituitary axis in

man. Epilepsia 1984;25:46-52.23 Macphee GJA, Larkin JG, Butler E, Beastall GH, Brodie

MJ. Circulating hormones and pituitary responsiveness inyoung epileptic men receiving long-term antiepileptic

medication. Epilepsia 1988;29:468-75.

24 Isojarvi JIT, Myllyla W, Pakarinen AJ. Effects of carbamazepineon pituitary responsiveness to luteinizing hormone-

releasing hormone, thyrotropin-releasinghormone, and metoclopramide in epileptic patients.

Epilepsia 1989;30:50-6.

25 Rao ML, Stefan H, Bauer J. Epileptic but not psychogenicseizures are accompanied by simultaneous elevation of

serum pituitary hormones and cortisol levels. Neuroendocrinology

1989;49:33-9.

26 Dana-Haeri J, Oxley J, Richens A. Pituitary responsiveness

to gonadotrophin-releasing and thyrotrophin-releasing

hormones in epileptic patients receiving carbamazepine

or phenytoin. Clin Endocrinol 1984;20:163-8.27 Bonuccelli U, Murialdo G, Martino E, Lecchini S, Bonura

ML, Bambini G, Murri L. Effects of carbamazepine on

prolactin secretion in normal subjects and in epilepticsubjects. Clin Neuropharmacol 1985;8:165-74.

687Downloaded fromjnnp.bmj.com on April 20, 2011 - Published by group.bmj.com

doi: 10.1136/jnnp.55.8.685J Neurol Neurosurg Psychiatry1992 55: 685-687U Lindbom, T Tomson, B Y Nilsson, et al.

metoclopramide during status epilepticus.Serum prolactin response to

DownloadeDopamine

From Wikipedia, the free encyclopediaFor other uses, see Dopamine (disambiguation).

Dopamine
http://en.wikipedia.org/wiki/Dopamine_(disambiguation)http://en.wikipedia.org/wiki/Dopamine_(disambiguation)http://en.wikipedia.org/wiki/File:Dopamine-3d-CPK.pnghttp://en.wikipedia.org/wiki/File:Dopamine2.svghttp://en.wikipedia.org/wiki/Dopamine_(disambiguation)


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IUPAC name4-(2-aminoethyl)benzene-1,2-diol

Other names2-(3,4-dihydroxyphenyl)ethylamine;

3,4-dihydroxyphenethylamine;3-hydroxytyramine; DA; Intropin; Revivan; Oxytyramine

IdentifiersCAS number 51-61-6 , 62-31-7(hydrochloride)

PubChem 681ChemSpider 661

UNII VTD58H1Z2X

KEGG D07870

ChEMBL CHEMBL59

Jmol-3D images Image 1

SMILES c1cc(c(cc1CCN)O)O

InChI

InChI=1S/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2

Key: VYFYYTLLBUKUHU-UHFFFAOYSA-N

InChI=1/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2Key: VYFYYTLLBUKUHU-UHFFFAOYAA

Properties

Molecular formula C8H11NO2Molar mass 153.18 g/molDensity 1.26 g/cm3

Melting point 128 C, 401 K, 262 FBoiling point decomposesSolubilityin water 60.0 g/100 ml

Hazards

R-phrases R36/37/38S-phrases S26S36

(what is this?) (verify)Except where noted otherwise, data are given for materials in

theirstandard state (at 25 C, 100 kPa)Infobox references

Dopamine is a catecholamineneurotransmitterpresent in a wide variety of animals, includingboth vertebrates and invertebrates. In thebrain, this substituted phenethylamine functions as a

neurotransmitter, activating the five known types ofdopamine receptorsD1,D2, D3, D4, and D5and their variants. Dopamine is produced in several areas of the brain, including the substantianigra and the ventral tegmental area.[1] Dopamine is also a neurohormone released by thehypothalamus. Its main function as a hormone is to inhibit the release ofprolactin from theanterior lobe of thepituitary.

Dopamine is available as an intravenousmedication acting on the sympatheticnervous system,producing effects such as increased heart rate andblood pressure. However, because dopamine
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tp://en.wikipedia.org/wiki/Boiling_pointhttp://en.wikipedia.org/wiki/Solubilityhttp://en.wikipedia.org/wiki/Waterhttp://en.wikipedia.org/wiki/List_of_R-phraseshttp://en.wikipedia.org/wiki/R36/37/38:_Irritating_to_eyes,_respiratory_system_and_skinhttp://en.wikipedia.org/wiki/List_of_S-phraseshttp://en.wikipedia.org/wiki/S26:_In_case_of_contact_with_eyes,_rinse_immediately_with_plenty_of_water_and_seek_medical_advicehttp://en.wikipedia.org/wiki/S36:_Wear_suitable_protective_clothinghttp://en.wikipedia.org/wiki/Wikipedia:WikiProject_Chemicals/Chembox_validationhttp://en.wikipedia.org/w/index.php?title=Dopamine&diff=cur&oldid=407131742http://en.wikipedia.org/wiki/Standard_statehttp://en.wikipedia.org/wiki/Wikipedia:Chemical_infobox#Referenceshttp://en.wikipedia.org/wiki/Catecholaminehttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Human_brainhttp://en.wikipedia.org/wiki/Substituted_phenethylaminehttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Dopamine_receptorhttp://en.wikipedia.org/wiki/Dopamine_D1_receptorhttp://en.wikipedia.org/wiki/Dopamine_D2_receptorhttp://en.wikipedia.org/wiki/Dopamine_D3_receptorhttp://en.wikipedia.org/wiki/Dopamine_D4_receptorhttp://en.wikipedia.org/wiki/Dopamine_D5_receptorhttp://en.wikipedia.org/wiki/Substantia_nigrahttp://en.wikipedia.org/wiki/Substantia_nigrahttp://en.wikipedia.org/wiki/Ventral_tegmental_areahttp://en.wikipedia.org/wiki/Dopamine#cite_note-0http://en.wikipedia.org/wiki/Neurohormonehttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Prolactinhttp://en.wikipedia.org/wiki/Pituitaryhttp://en.wikipedia.org/wiki/Medicationhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Nervous_systemhttp://en.wikipedia.org/wiki/Heart_ratehttp://en.wikipedia.org/wiki/Blood_pressure


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cannot cross theblood-brain barrier, dopamine given as a drug does not directly affect thecentralnervous system. To increase the amount of dopamine in the brains of patients with diseases suchas Parkinson's disease and dopa-responsivedystonia, L-DOPA (the precursor of dopamine), isoften given because it crosses the blood-brain barrier relatively easily.

Contents

1 History 2 Chemistry 3 Biochemistry

o 3.1 Classificationo 3.2 Biosynthesiso 3.3 Inactivation and degradation

4 Functions in the braino 4.1 Anatomyo 4.2 Tonic and phasic activityo 4.3 Movemento 4.4 Cognition and frontal cortexo 4.5 Regulating prolactin secretiono 4.6 Motivation and pleasure

4.6.1 Reinforcement 4.6.2 Reuptake inhibition, expulsion 4.6.3 Incentive salience 4.6.4 Dopamine, learning, and reward-seeking behavior 4.6.5 Animal studies 4.6.6 The effects of drugs that reduce dopamine activity 4.6.7 Opioid and cannabinoid transmission 4.6.8 Sociability 4.6.9 Processing of pain 4.6.10 Salience 4.6.11 Behavior disorders

o 4.7 Latent inhibition and creative driveo 4.8 Chemoreceptor trigger zoneo 4.9 Dopaminergic mind hypothesis

5 Links to psychosis 6 Therapeutic use 7 Nonneural functions

o 7.1 Renal and cardiovascularo 7.2 Immunoregulatory

8 Fruit browning 9 See also 10 References

11 External links
http://en.wikipedia.org/wiki/Blood-brain_barrierhttp://en.wikipedia.org/wiki/Blood-brain_barrierhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Parkinson's_diseasehttp://en.wikipedia.org/wiki/Dystoniahttp://en.wikipedia.org/wiki/Dystoniahttp://en.wikipedia.org/wiki/L-DOPAhttp://en.wikipedia.org/wiki/Dopamine#Historyhttp://en.wikipedia.org/wiki/Dopamine#Chemistryhttp://en.wikipedia.org/wiki/Dopamine#Biochemistryhttp://en.wikipedia.org/wiki/Dopamine#Classificationhttp://en.wikipedia.org/wiki/Dopamine#Biosynthesishttp://en.wikipedia.org/wiki/Dopamine#Inactivation_and_degradationhttp://en.wikipedia.org/wiki/Dopamine#Functions_in_the_brainhttp://en.wikipedia.org/wiki/Dopamine#Anatomyhttp://en.wikipedia.org/wiki/Dopamine#Tonic_and_phasic_activityhttp://en.wikipedia.org/wiki/Dopamine#Movementhttp://en.wikipedia.org/wiki/Dopamine#Cognition_and_frontal_cortexhttp://en.wikipedia.org/wiki/Dopamine#Regulating_prolactin_secretionhttp://en.wikipedia.org/wiki/Dopamine#Motivation_and_pleasurehttp://en.wikipedia.org/wiki/Dopamine#Reinforcementhttp://en.wikipedia.org/wiki/Dopamine#Reuptake_inhibition.2C_expulsionhttp://en.wikipedia.org/wiki/Dopamine#Incentive_saliencehttp://en.wikipedia.org/wiki/Dopamine#Dopamine.2C_learning.2C_and_reward-seeking_behaviorhttp://en.wikipedia.org/wiki/Dopamine#Animal_studieshttp://en.wikipedia.org/wiki/Dopamine#The_effects_of_drugs_that_reduce_dopamine_activityhttp://en.wikipedia.org/wiki/Dopamine#Opioid_and_cannabinoid_transmissionhttp://en.wikipedia.org/wiki/Dopamine#Sociabilityhttp://en.wikipedia.org/wiki/Dopamine#Processing_of_painhttp://en.wikipedia.org/wiki/Dopamine#Saliencehttp://en.wikipedia.org/wiki/Dopamine#Behavior_disordershttp://en.wikipedia.org/wiki/Dopamine#Latent_inhibition_and_creative_drivehttp://en.wikipedia.org/wiki/Dopamine#Chemoreceptor_trigger_zonehttp://en.wikipedia.org/wiki/Dopamine#Dopaminergic_mind_hypothesishttp://en.wikipedia.org/wiki/Dopamine#Links_to_psychosishttp://en.wikipedia.org/wiki/Dopamine#Therapeutic_usehttp://en.wikipedia.org/wiki/Dopamine#Nonneural_functionshttp://en.wikipedia.org/wiki/Dopamine#Renal_and_cardiovascularhttp://en.wikipedia.org/wiki/Dopamine#Immunoregulatoryhttp://en.wikipedia.org/wiki/Dopamine#Fruit_browninghttp://en.wikipedia.org/wiki/Dopamine#See_alsohttp://en.wikipedia.org/wiki/Dopamine#Referenceshttp://en.wikipedia.org/wiki/Dopamine#External_linkshttp://en.wikipedia.org/wiki/Blood-brain_barrierhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Parkinson's_diseasehttp://en.wikipedia.org/wiki/Dystoniahttp://en.wikipedia.org/wiki/L-DOPAhttp://en.wikipedia.org/wiki/Dopamine#Historyhttp://en.wikipedia.org/wiki/Dopamine#Chemistryhttp://en.wikipedia.org/wiki/Dopamine#Biochemistryhttp://en.wikipedia.org/wiki/Dopamine#Classificationhttp://en.wikipedia.org/wiki/Dopamine#Biosynthesishttp://en.wikipedia.org/wiki/Dopamine#Inactivation_and_degradationhttp://en.wikipedia.org/wiki/Dopamine#Functions_in_the_brainhttp://en.wikipedia.org/wiki/Dopamine#Anatomyhttp://en.wikipedia.org/wiki/Dopamine#Tonic_and_phasic_activityhttp://en.wikipedia.org/wiki/Dopamine#Movementhttp://en.wikipedia.org/wiki/Dopamine#Cognition_and_frontal_cortexhttp://en.wikipedia.org/wiki/Dopamine#Regulating_prolactin_secretionhttp://en.wikipedia.org/wiki/Dopamine#Motivation_and_pleasurehttp://en.wikipedia.org/wiki/Dopamine#Reinforcementhttp://en.wikipedia.org/wiki/Dopamine#Reuptake_inhibition.2C_expulsionhttp://en.wikipedia.org/wiki/Dopamine#Incentive_saliencehttp://en.wikipedia.org/wiki/Dopamine#Dopamine.2C_learning.2C_and_reward-seeking_behaviorhttp://en.wikipedia.org/wiki/Dopamine#Animal_studieshttp://en.wikipedia.org/wiki/Dopamine#The_effects_of_drugs_that_reduce_dopamine_activityhttp://en.wikipedia.org/wiki/Dopamine#Opioid_and_cannabinoid_transmissionhttp://en.wikipedia.org/wiki/Dopamine#Sociabilityhttp://en.wikipedia.org/wiki/Dopamine#Processing_of_painhttp://en.wikipedia.org/wiki/Dopamine#Saliencehttp://en.wikipedia.org/wiki/Dopamine#Behavior_disordershttp://en.wikipedia.org/wiki/Dopamine#Latent_inhibition_and_creative_drivehttp://en.wikipedia.org/wiki/Dopamine#Chemoreceptor_trigger_zonehttp://en.wikipedia.org/wiki/Dopamine#Dopaminergic_mind_hypothesishttp://en.wikipedia.org/wiki/Dopamine#Links_to_psychosishttp://en.wikipedia.org/wiki/Dopamine#Therapeutic_usehttp://en.wikipedia.org/wiki/Dopamine#Nonneural_functionshttp://en.wikipedia.org/wiki/Dopamine#Renal_and_cardiovascularhttp://en.wikipedia.org/wiki/Dopamine#Immunoregulatoryhttp://en.wikipedia.org/wiki/Dopamine#Fruit_browninghttp://en.wikipedia.org/wiki/Dopamine#See_alsohttp://en.wikipedia.org/wiki/Dopamine#Referenceshttp://en.wikipedia.org/wiki/Dopamine#External_links


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[edit] History

Dopamine was first synthesized in 1910 by George Barger and James Ewens at WellcomeLaboratories in London, England.[2] It was named dopamine because it was a monoamine, and itssynthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). Dopamine's function as a

neurotransmitter was first recognized in 1958 by Arvid Carlssonand Nils-ke Hillarp at theLaboratory for Chemical Pharmacology of the National Heart Institute ofSweden.[3] Carlssonwas awarded the 2000Nobel Prize in Physiology or Medicine for showing that dopamine is notjust a precursor ofnorepinephrine (noradrenaline) and epinephrine (adrenaline), but aneurotransmitter as well.

[edit] Chemistry

Dopamine (right) has the chemical formula C6H3(OH)2-CH2-CH2-NH2. Its chemical name is "4-(2-aminoethyl)benzene-1,2-diol" and its abbreviation is "DA." As a medicinal agent, dopamine issynthesized by demethylation of 2-(3,4-dimethoxyphenyl)ethylamine (left) using hydrogenbromide.[4][5]

[edit] Biochemistry
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Biosynthesis of dopamine

[edit] Classification

As a member of the catecholamine family, dopamine is a precursor tonorepinephrine(noradrenaline) and then epinephrine (adrenaline) in the biosynthetic pathways for theseneurotransmitters.

[edit] Biosynthesis

Dopamine is biosynthesized in the body (mainly by nervous tissue and the medulla of the adrenalglands) first by the hydroxylation of the amino acid L-tyrosineto L-DOPA via the enzymetyrosine 3-monooxygenase, also known astyrosine hydroxylase, and then by thedecarboxylationofL-DOPA by aromatic L-amino acid decarboxylase (which is often referred to as dopadecarboxylase). In some neurons, dopamine is further processed into norepinephrine bydopamine beta-hydroxylase.
http://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=4http://en.wikipedia.org/wiki/Catecholaminehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=5http://en.wikipedia.org/wiki/Adrenal_medullahttp://en.wikipedia.org/wiki/Adrenal_glandhttp://en.wikipedia.org/wiki/Adrenal_glandhttp://en.wikipedia.org/wiki/L-tyrosinehttp://en.wikipedia.org/wiki/L-tyrosinehttp://en.wikipedia.org/wiki/Tyrosine_hydroxylasehttp://en.wikipedia.org/wiki/Tyrosine_hydroxylasehttp://en.wikipedia.org/wiki/Decarboxylationhttp://en.wikipedia.org/wiki/Decarboxylationhttp://en.wikipedia.org/wiki/L-DOPAhttp://en.wikipedia.org/wiki/Aromatic_L-amino_acid_decarboxylasehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Dopamine_beta-hydroxylasehttp://en.wikipedia.org/wiki/File:Catecholamines_biosynthesis.svghttp://en.wikipedia.org/wiki/File:Catecholamines_biosynthesis.svghttp://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=4http://en.wikipedia.org/wiki/Catecholaminehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=5http://en.wikipedia.org/wiki/Adrenal_medullahttp://en.wikipedia.org/wiki/Adrenal_glandhttp://en.wikipedia.org/wiki/Adrenal_glandhttp://en.wikipedia.org/wiki/L-tyrosinehttp://en.wikipedia.org/wiki/Tyrosine_hydroxylasehttp://en.wikipedia.org/wiki/Decarboxylationhttp://en.wikipedia.org/wiki/L-DOPAhttp://en.wikipedia.org/wiki/Aromatic_L-amino_acid_decarboxylasehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Dopamine_beta-hydroxylase


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In neurons, dopamine is packaged after synthesis into vesicles, which are then released into thesynapse in response to a presynaptic action potential.

Biodegradation of dopamine

[edit] Inactivation and degradation

Two major degradation pathways for dopamine exist. In most areas of the brain, including thestriatum andbasal ganglia, dopamine is inactivated byreuptake via the dopamine transporter(DAT1), then enzymatic breakdown by monoamine oxidase(MAOA and MAOB) into 3,4-dihydroxyphenylacetic acid. In the prefrontal cortex, however, there are very few dopaminetransporter proteins, and dopamine is instead inactivated by reuptake via thenorepinephrinetransporter(NET), presumably on neighboring norepinephrine neurons, then enzymaticbreakdown by catechol-O-methyl transferase (COMT) into3-methoxytyramine.[6]The DAT1pathway is roughly an order of magnitude faster than the NET pathway: in mice, dopamine

concentrations decay with a half-life of 200 ms in the caudate nucleus (which uses the DAT1pathway) versus 2,000 ms in the prefrontal cortex.[7] Dopamine that is not broken down byenzymes is repackaged into vesicles for reuse byVMAT2.

[edit] Functions in the brain

Dopamine has many functions in the brain, including important roles in behavior and cognition,voluntary movement, motivation,punishment and reward, inhibition ofprolactin production(involved in lactation and sexual gratification), sleep, mood,attention,working memory, andlearning. Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is dopamine) arepresent chiefly in the ventral tegmental area (VTA) of the midbrain, the substantia nigra pars

compacta, and the arcuate nucleusof the hypothalamus.

It has been hypothesized that dopamine transmits reward prediction error, although this has beenquestioned.[8] According to this hypothesis, the phasic responses of dopamine neurons areobserved when an unexpected reward is presented. These responses transfer to the onset of aconditioned stimulusafter repeated pairings with the reward. Further, dopamine neurons aredepressed when the expected reward is omitted. Thus, dopamine neurons seem to encode theprediction error of rewarding outcomes. In nature, we learn to repeat behaviors that lead to
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maximizing rewards. Dopamine is therefore believed to provide a teaching signal to parts of thebrain responsible for acquiring new behavior.Temporal difference learningprovides acomputational model describing how the prediction error of dopamine neurons is used as ateaching signal.

The reward system in insects uses octopamine, which is the presumed arthropod homolog ofnorepinephrine,[9] rather than dopamine. In insects, dopamine acts instead as a punishment signaland is necessary to form aversive memories.[10][11]

[edit] Anatomy

Main article: Dopaminergic pathways

Dopaminergic neurons form a neurotransmitter system which originates in substantia nigra parscompacta, ventral tegmental area (VTA), andhypothalamus. These project axons to large areasof the brain which are typically divided into four major pathways:

Mesocortical pathway connects the ventral tegmental area to the frontal lobe of thepre-frontal cortex. Neurons with somas in the ventral tegmental area project axons into thepre-frontal cortex.

Mesolimbic pathway carries dopamine from the ventral tegmental area to the nucleusaccumbensvia theamygdalaandhippocampus. The somas of the projecting neurons arein the ventral tegmental area.

Nigrostriatal pathway runs from the substantia nigra to theneostriatum. Somas in thesubstantia nigra project axons into the caudate nucleus andputamen. The pathway isinvolved in the basal ganglia motor loop.

Tuberoinfundibular pathway runs from the hypothalamus to the pituitary gland.

This innervation explains many of the effects of activating this dopamine system. For instance,the mesolimbic pathwayconnects the VTA and nucleus accumbens; both are central to the brainreward system.[12]

Whilst the distinction between pathways is widely used, and is regarded as a convenientheuristic when considering the dopamine system, it is not absolute, and there is some overlap inthe projection targets of each group of neurons.[13]

[edit] Tonic and phasic activity

The level of extracellular dopamine is modulated by two mechanisms, tonic and phasicdopamine transmission. Tonic dopamine transmission occurs when small amounts of dopamineare released independently of neuronal activity, and is regulated by the activity of other neuronsand neurotransmitter reuptake.[14] Phasic dopamine release results from the activity of thedopamine-containing cells themselves. This activity is characterized by irregularpacemakingactivity of single spikes, and rapid bursts of typically 2-6 spikes in quick succession.[15][16]

Concentrated bursts of activity result in a greater increase of extracellular dopamine levels thanwould be expected from the same number of spikes distributed over a longer period of time.[17]
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[edit] Movement

Dopamine reduces the influence of the indirect pathway while increasing the actions of the directpathway within thebasal ganglia.[citation needed] Insufficient dopaminebiosynthesisin thedopaminergic neurons can cause Parkinson's disease, a condition in which one loses the ability to

execute smooth, controlled movements.[citation needed]

[edit] Cognition and frontal cortex

In the frontal lobes, dopamine controls the flow of information from other areas of the brain.Dopamine disorders in this region of the brain can cause a decline in neurocognitivefunctions,especially memory, attention, andproblem-solving. Reduced dopamine concentrations in theprefrontal cortex are thought to contribute to attention deficit disorder. It has been found that D1receptors[18] as well as D4 receptors[19] are responsible for the cognitive-enhancing effects ofdopamine, whereas D2 receptors are more specific for motor actions.

[edit] Regulating prolactin secretion

Dopamine is the primary neuroendocrineinhibitor of the secretion ofprolactinfrom the anteriorpituitary gland.[20] Dopamine produced by neurons in thearcuate nucleus of the hypothalamus issecreted into the hypothalamo-hypophysial blood vessels of the median eminence, which supplythepituitary gland. The lactotrope cells that produceprolactin, in the absence of dopamine,secrete prolactin continuously; dopamine inhibits this secretion. Thus, in the context ofregulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor (PIF),prolactin-inhibiting hormone (PIH), or prolactostatin.

[edit] Motivation and pleasure

Dopamine Pathways. In the brain, dopamine plays an important role in the regulation of rewardand movement. As part of the reward pathway, dopamine is manufactured in nerve cell bodieslocated within the ventral tegmental area (VTA) and is released in the nucleus accumbens andthe prefrontal cortex. Its motor functions are linked to a separate pathway, with cell bodies in thesubstantia nigra that manufacture and release dopamine into the striatum.Further information:Motivation

[edit] Reinforcement
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Dopamine is commonly associated with thereward systemof the brain, providing feelings ofenjoyment and reinforcementto motivate a person proactively to perform certain activities.Dopamine is released (particularly in areas such as the nucleus accumbens andprefrontal cortex)by rewarding experiences such as food,sex,drugs, and neutral stimuli that become associatedwith them.[citation needed] Recent studies indicate that aggression may also stimulate the release of

dopamine in this way.[21]

This theory is often discussed[by whom?] in terms of drugs such as cocaine, nicotine, andamphetamines, which directly or indirectly lead to an increase of dopamine in themesolimbicreward pathway of the brain, and in relation to neurobiologicaltheories ofchemical addiction(not to be confused withpsychological dependence), arguing that this dopamine pathway ispathologically altered in addicted persons.[citation needed]

[edit] Reuptake inhibition, expulsion

Cocaine and amphetamines inhibit the re-uptakeof dopamine; however, they influence separate

mechanisms of action. Cocaine is a dopamine transporterand norepinephrine transporterblockerthat competitively inhibits dopamine uptake to increase the lifetime of dopamine and augmentsan overabundance of dopamine (an increase of up to 150 percent) within the parameters of thedopamine neurotransmitters. Like cocaine, amphetamines increase the concentration ofdopamine in the synapticgap, but by a different mechanism. Amphetamines andmethamphetamine are similar in structure to dopamine, and so can enter the terminal bouton ofthe presynaptic neuron via its dopamine transporters as well as by diffusing through the neuralmembrane directly.[citation needed] By entering the presynaptic neuron, amphetamines force dopaminemolecules out of their storagevesicles and expel them into the synaptic gap by making thedopamine transporters work in reverse.

[edit] Incentive salience

Main article: Incentive salience

Dopamine's role in experiencing pleasure has been questioned by several researchers. It has beenargued that dopamine is more associated with anticipatory desire and motivation (commonlyreferred to as "wanting") as opposed to actual consummatory pleasure (commonly referred to as"liking").

[edit] Dopamine, learning, and reward-seeking behavior

Dopaminergic neurons of the midbrain are the main source of dopamine in the brain.

[22]

Dopamine has been shown to be involved in the control of movements, the signaling of error inprediction of reward, motivation, and cognition. Cerebral dopamine depletion is the hallmark ofParkinson's disease.[22] Other pathological states have also been associated with dopaminedysfunction, such as schizophrenia, autism, and attention deficit hyperactivity disorder, as wellas drug abuse.
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Dopamine is closely associated with reward-seeking behaviors, such as approach, consumption,and addiction.[22] Recent researches suggest that the firing of dopaminergic neurons is amotivational substance as a consequence of reward-anticipation. This hypothesis is based on theevidence that, when a reward is greater than expected, the firing of certain dopaminergic neuronsincreases, which consequently increases desire or motivation towards the reward.[22] However,

recent research finds that while some dopaminergic neurons react in the way expected of rewardneurons, others do not and seem to respond in regard to unpredictability.[23] This research findsthe reward neurons predominate in the ventromedial region in the substantia nigra pars compactaas well as the ventral tegmental area. Neurons in these areas project mainly to the ventralstriatum and thus might transmit value-related information in regard to reward values.[23]Thenonreward neurons are predominate in the dorsolateral area of the substantia nigra pars compactawhich projects to the dorsal striatum and may relate to orienting behaviour.[23] It has beensuggested that the difference between these two types of dopaminergic neurons arises from theirinput: reward-linked ones have input from thebasal forebrainwhile the nonreward-related onesfrom the lateral habenula.[23]

[edit] Animal studies

Clues to dopamine's role in motivation, desire, and pleasure have come from studies performedon animals. In one such study, rats were depleted of dopamine by up to 99 percent in the nucleusaccumbensand neostriatumusing 6-hydroxydopamine.[22]With this large reduction in dopamine,the rats would no longer eat by their own volition. The researchers then force-fed the rats foodand noted whether they had the proper facial expressions indicating whether they liked ordisliked it. The researchers of this study concluded that the reduction in dopamine did not reducethe rat's consummatory pleasure, only the desire to actually eat. In another study, mutanthyperdopaminergic (increased dopamine) mice show higher "wanting" but not "liking" of sweetrewards.[24]

[edit] The effects of drugs that reduce dopamine activity

In humans, drugs that reduce dopamine activity (neuroleptics, e.g. antipsychotics) have beenshown to impair concentration, reduce motivation, cause anhedonia(inability to experiencepleasure), and long-term use has been associated with tardive dyskinesia, an irreversiblemovement disorder.[25] Antipsychotics have significant effects on gonadal hormones includingsignificantly lower levels of estradiol and progesterone in women whereas men displaysignificantly lower levels of testosterone and DHEAwhen undergoing antipsychotic drugtreatment compared to controls. Antipsychotics are known to cause hyperprolactinaemia leadingto amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism,false positive pregnancy tests, and long-term risk of osteoporosis in women. The effects ofhyperprolactinemia in men are gynaecomastia,lactation,impotence, loss oflibido, andhypospermatogenesis.[26] Furthermore, antipsychotic drugs are associated with weight gain,diabetes,drooling, dysphoria(abnormal depression and discontent),fatigue, sexual dysfunction,heart rhythm problems, stroke and heart attack. Selective D2/D3 agonistspramipexole andropinirole, used to treat restless legs syndrome (RLS), have limited anti-anhedonic properties asmeasured by the Snaith-Hamilton Pleasure Scale (SHAPS).[27]
http://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Substantia_nigra_pars_compactahttp://en.wikipedia.org/wiki/Ventral_tegmental_areahttp://en.wikipedia.org/wiki/Ventral_striatumhttp://en.wikipedia.org/wiki/Ventral_striatumhttp://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Dorsal_striatumhttp://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Basal_forebrainhttp://en.wikipedia.org/wiki/Basal_forebrainhttp://en.wikipedia.org/wiki/Basal_forebrainhttp://en.wikipedia.org/wiki/Habenula#Lateral_habenulahttp://en.wikipedia.org/wiki/Habenula#Lateral_habenulahttp://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=18http://en.wikipedia.org/wiki/Nucleus_accumbenshttp://en.wikipedia.org/wiki/Nucleus_accumbenshttp://en.wikipedia.org/wiki/Nucleus_accumbenshttp://en.wikipedia.org/wiki/Neostriatumhttp://en.wikipedia.org/wiki/Neostriatumhttp://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-fn1-23http://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=19http://en.wikipedia.org/wiki/Neuroleptichttp://en.wikipedia.org/wiki/Antipsychotichttp://en.wikipedia.org/wiki/Anhedoniahttp://en.wikipedia.org/wiki/Anhedoniahttp://en.wikipedia.org/wiki/Tardive_dyskinesiahttp://en.wikipedia.org/wiki/Dopamine#cite_note-fn2-24http://en.wikipedia.org/wiki/DHEAhttp://en.wikipedia.org/wiki/DHEAhttp://en.wikipedia.org/wiki/Hyperprolactinaemiahttp://en.wikipedia.org/wiki/Amenorrheahttp://en.wikipedia.org/wiki/Hirsutismhttp://en.wikipedia.org/wiki/Gynaecomastiahttp://en.wikipedia.org/wiki/Gynaecomastiahttp://en.wikipedia.org/wiki/Lactationhttp://en.wikipedia.org/wiki/Impotencehttp://en.wikipedia.org/wiki/Impotencehttp://en.wikipedia.org/wiki/Libidohttp://en.wikipedia.org/wiki/Libidohttp://en.wikipedia.org/wiki/Spermatogenesishttp://en.wikipedia.org/wiki/Spermatogenesishttp://en.wikipedia.org/wiki/Dopamine#cite_note-Raj-25http://en.wikipedia.org/wiki/Weight_gainhttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/Droolinghttp://en.wikipedia.org/wiki/Dysphoriahttp://en.wikipedia.org/wiki/Dysphoriahttp://en.wikipedia.org/wiki/Fatigue_(medical)http://en.wikipedia.org/wiki/Fatigue_(medical)http://en.wikipedia.org/wiki/Sexual_dysfunctionhttp://en.wikipedia.org/wiki/Sexual_dysfunctionhttp://en.wikipedia.org/wiki/Heart_rhythmhttp://en.wikipedia.org/wiki/Strokehttp://en.wikipedia.org/wiki/Heart_attackhttp://en.wikipedia.org/wiki/Pramipexolehttp://en.wikipedia.org/wiki/Pramipexolehttp://en.wikipedia.org/wiki/Ropinirolehttp://en.wikipedia.org/wiki/Restless_legs_syndromehttp://en.wikipedia.org/wiki/Dopamine#cite_note-fn3-26http://en.wikipedia.org/wiki/Dopamine#cite_note-fn3-26http://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Substantia_nigra_pars_compactahttp://en.wikipedia.org/wiki/Ventral_tegmental_areahttp://en.wikipedia.org/wiki/Ventral_striatumhttp://en.wikipedia.org/wiki/Ventral_striatumhttp://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Dorsal_striatumhttp://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/wiki/Basal_forebrainhttp://en.wikipedia.org/wiki/Habenula#Lateral_habenulahttp://en.wikipedia.org/wiki/Dopamine#cite_note-Matsumoto-22http://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=18http://en.wikipedia.org/wiki/Nucleus_accumbenshttp://en.wikipedia.org/wiki/Nucleus_accumbenshttp://en.wikipedia.org/wiki/Neostriatumhttp://en.wikipedia.org/wiki/Dopamine#cite_note-fn5-21http://en.wikipedia.org/wiki/Dopamine#cite_note-fn1-23http://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=19http://en.wikipedia.org/wiki/Neuroleptichttp://en.wikipedia.org/wiki/Antipsychotichttp://en.wikipedia.org/wiki/Anhedoniahttp://en.wikipedia.org/wiki/Tardive_dyskinesiahttp://en.wikipedia.org/wiki/Dopamine#cite_note-fn2-24http://en.wikipedia.org/wiki/DHEAhttp://en.wikipedia.org/wiki/Hyperprolactinaemiahttp://en.wikipedia.org/wiki/Amenorrheahttp://en.wikipedia.org/wiki/Hirsutismhttp://en.wikipedia.org/wiki/Gynaecomastiahttp://en.wikipedia.org/wiki/Lactationhttp://en.wikipedia.org/wiki/Impotencehttp://en.wikipedia.org/wiki/Libidohttp://en.wikipedia.org/wiki/Spermatogenesishttp://en.wikipedia.org/wiki/Dopamine#cite_note-Raj-25http://en.wikipedia.org/wiki/Weight_gainhttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/Droolinghttp://en.wikipedia.org/wiki/Dysphoriahttp://en.wikipedia.org/wiki/Fatigue_(medical)http://en.wikipedia.org/wiki/Sexual_dysfunctionhttp://en.wikipedia.org/wiki/Heart_rhythmhttp://en.wikipedia.org/wiki/Strokehttp://en.wikipedia.org/wiki/Heart_attackhttp://en.wikipedia.org/wiki/Pramipexolehttp://en.wikipedia.org/wiki/Ropinirolehttp://en.wikipedia.org/wiki/Restless_legs_syndromehttp://en.wikipedia.org/wiki/Dopamine#cite_note-fn3-26


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[edit] Opioid and cannabinoid transmission

Opioid and cannabinoid transmission instead of dopamine may modulate consummatory pleasureand food palatability (liking).[28] This could explain why animals' "liking" of food is independentof brain dopamine concentration. Other consummatory pleasures, however, may be more

associated with dopamine. One study found that both anticipatory and consummatory measuresof sexual behavior (male rats) were disrupted by DA receptor antagonists.[29] Libido can beincreased by drugs that affect dopamine, but not by drugs that affect opioid peptides or otherneurotransmitters.

[edit] Sociability

Sociability is also closely tied to dopamine neurotransmission. Low D2 receptor-binding is foundin people with social anxiety. Traits common to negative schizophrenia (social withdrawal,apathy, anhedonia) are thought to be related to a hypodopaminergic state in certain areas of thebrain. In instances ofbipolar disorder, manicsubjects can become hypersocial, as well as

hypersexual.[citation needed]

This is credited to an increase in dopamine, because mania can bereduced by dopamine-blocking antipsychotics.[30]

[edit] Processing of pain

Dopamine has been demonstrated to play a role inpainprocessing in multiple levels of thecentral nervous system including the spinal cord,[31]periaqueductal gray (PAG),[32]thalamus,[33]

basal ganglia,[34][35]insular cortex,[36][37] andcingulate cortex.[38] Accordingly, decreased levels ofdopamine have been associated with painful symptoms that frequently occur in Parkinson'sdisease.[39]Abnormalities in dopaminergic neurotransmission have also been demonstrated inpainful clinical conditions, includingburning mouth syndrome,[40]fibromyalgia,[41][42] and restless

legs syndrome.

[43]

In general, the analgesic capacity of dopamine occurs as a result of dopamineD2 receptor activation; however, exceptions to this exist in the PAG, in which dopamine D1receptor activation attenuates pain presumably via activation of neurons involved in descendinginhibition.[44]In addition, D1 receptor activation in the insular cortex appears to attenuatesubsequent pain-related behavior.

[edit] Salience

Dopamine may also have a role in thesalienceof potentially important stimuli, such as sourcesof reward or of danger.[45] This hypothesis argues that dopamine assists decision-making byinfluencing the priority, or level of desire, of such stimuli to the person concerned.

[edit] Behavior disorders

Deficient dopamine neurotransmission is implicated in attention-deficit hyperactivity disorder,and stimulant medications used to successfully treat the disorder increase dopamineneurotransmission, leading to decreased symptoms.[46] Consistent with this hypothesis,dopaminergic pathways have a role in inhibitory action control and the inhibition of the tendencyto make unwanted actions.[47]
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/Cingulate_cortexhttp://en.wikipedia.org/wiki/Dopamine#cite_note-37http://en.wikipedia.org/wiki/Parkinson's_diseasehttp://en.wikipedia.org/wiki/Parkinson's_diseasehttp://en.wikipedia.org/wiki/Dopamine#cite_note-38http://en.wikipedia.org/wiki/Burning_mouth_syndromehttp://en.wikipedia.org/wiki/Dopamine#cite_note-39http://en.wikipedia.org/wiki/Fibromyalgiahttp://en.wikipedia.org/wiki/Dopamine#cite_note-40http://en.wikipedia.org/wiki/Dopamine#cite_note-41http://en.wikipedia.org/wiki/Restless_legs_syndromehttp://en.wikipedia.org/wiki/Restless_legs_syndromehttp://en.wikipedia.org/wiki/Dopamine#cite_note-42http://en.wikipedia.org/wiki/Dopamine#cite_note-43http://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=23http://en.wikipedia.org/wiki/Salience_(neuroscience)http://en.wikipedia.org/wiki/Dopamine#cite_note-44http://en.wikipedia.org/w/index.php?title=Dopamine&action=edit&section=24http://en.wikipedia.org/wiki/Attention-deficit_hyperactivity_disorderhttp://en.wikipedia.org/wiki/Dopamine#cite_note-45http://en.wikipedia.org/wiki/Dopamine#cite_note-46


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The long term use oflevodopa in Parkinson's disease has been linked to dopamine dysregulationsyndrome.[48]

[edit] Latent inhibition and creative drive

Dopamine in the mesolimbic pathway increases general arousal and goal directed behaviors anddecreases latent inhibition; all three effects increase the creative drive of idea generation. Thishas led to a three-factor model ofcreativity involving the frontal lobes, the temporal lobes, andmesolimbic dopamine.[49]

[edit] Chemoreceptor trigger zone

Dopamine is one of the neurotransmitters implicated in the control ofnauseaandvomiting viainteractions in the chemoreceptor trigger zone. Metoclopramideis a D2-receptor antagonist thatfunctions as aprokinetic/antiemetic.

[edit] Dopaminergic mind hypothesis

The dopaminergic mind hypothesis seeks to explain the differences between modern humans andtheir hominid relatives by focusing on changes in dopam

pamela project

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