introduÇÃo ao sistema nervoso central

INTRODUÇÃO AO SISTEMA NERVOSO

CENTRAL

Sistema

Nervoso

Central

SistemaNervosoPeriféric

o

Nervos

Encéfalo

Cérebro

Cerebelo

TroncoEncefálico

Mesencéfalo

Ponte

Bulbo

Medulaespinhal

GângliosTerminações nervosas

Espinhais

Cranianos

SN

Anatomia macroscópica

Basal ganglia

terminal axonfibers

dendrites

axon

cell body

1-1 Stahl S M, Essential Psychopharmacology (2000)

ANATOMIA MICROSCÓPICA - NEURÔNIO

1-2 Stahl S M, Essential Psychopharmacology (2000)

dendritic spines

cell body

dendrites

synaptic vesicles

spine

dendrite

postsynaptic density

axon

presynapticneuron

postsynapticneuron

mitochondrion

vesicles

synaptic cleft1-3 Stahl S M, Essential

Psychopharmacology (2000)

neurotransmitter(first messenger)

bound neurotransmitterreceptor

second messenger

cellular actions1-10 Stahl S M, Essential

Psychopharmacology (2000)

Regulação dos genes por NT ou psicofármacos

2--35 Stahl S M, Essential Psychopharmacology (2000)

first messenger neurotransmitter

receptor second messenger

neuronal membrane

inactive protein kinase

activation active protein kinase

inactive transcription

factor

activated “early” transcription factor

mRNA

FOS

2-42 Stahl S M, Essential Psychopharmacology (2000)

mRNA

mRNA

mRNA

Late gene products

Regulação do número de receptores:

“Down-regulation” e “Up-regulation”

2-43 Stahl S M, Essential Psychopharmacology (2000)

DOWN REGULATIONDOWN REGULATION

2-44 Stahl S M, Essential Psychopharmacology (2000)

UP REGULATIONUP REGULATION

2-45 Stahl S M, Essential Psychopharmacology (2000)

Down Regulation

Up

Reg

ula

tio

n

TIPOS DE RECEPTORES MAIS TIPOS DE RECEPTORES MAIS FREQUENTES EM SNCFREQUENTES EM SNC

side view of receptor with seven transmembrane regions

extracellular

intracellular

membrane transmembrane

2-2 Stahl S M, Essential Psychopharmacology (2000)

5 copies of the ligand gated ion channels receptors make a functioning channel

2-6 Stahl S M, Essential Psychopharmacology (2000)

channel

=

Four transmembrane regions

2-7 Stahl S M, Essential Psychopharmacology (2000)

12 transmembrane regions

7 transmembrane region G protein

linked

4 transmembrane ligand gated ion

channel

12 transmembrane region transporter

2-13 Stahl S M, Essential Psychopharmacology (2000)

INTERAÇÃO FÁRMACO-RECEPTOR

Haloperidol

X

GABA site

BZ site

picrotoxin site

alcohol site

barbiturate site

8-20 Stahl S M, Essential Psychopharmacology (2000)

2-20 2-21 2-22

Stahl S M, Essential Psychopharmacology (2000)

= fluoxetine (Prozac)

= serotonin

= sodium

2-24 Stahl S M, Essential Psychopharmacology (2000)

= fluoxetine

NEUROTRANSMISSORES

Critérios para identificação dos NT

• Síntese no local de liberação

• Armazenagem

• Presença no espaço sináptico e ação pós-sináptica

• Ativação de Receptores

• Presença de enzimas inativadoras

AMINOÁCIDOS

GLUTAMATE

GABA IS PRODUCED

Glu-AD

GABA

GABA8-16 Stahl S M, Essential

Psychopharmacology (2000)

GABA IS DESTROYED

GABA T destroys

GABA

GABA transporter

8-17 Stahl S M, Essential Psychopharmacology (2000)

Metabólito = semi-aldeído succínico

GABA RECEPTORS

GABA transporter

GABA A

receptor

GABA B receptor

8-18 Stahl S M, Essential Psychopharmacology (2000)

Baclofen

muscimol

GABA site

BZ site

picrotoxin site

alcohol site

barbiturate site

8-20 Stahl S M, Essential Psychopharmacology (2000)

GABABZ

8-21 Stahl S M, Essential Psychopharmacology (2000)

GABABZ

BZ

GABA

8-23 Stahl S M, Essential Psychopharmacology (2000)

HIPERPOLARIZAÇÃO

GLU (Glutamate)

Glutamine

GLUTAMATE IS PRODUCED

GlutaminaseGlutamate

Glutamate

Glutamine synthase

Glutamine

Glial cell

10-21 Stahl S M, Essential Psychopharmacology (2000)

Transportadores (ASCT2, GlnT, SN1)

GLUTAMATE IS REMOVED

10-22 Stahl S M, Essential Psychopharmacology (2000)

Glial cell

GLUTAMATE RECEPTORS

NMDA receptor

AMPA receptor

kainate receptor

metabotropic receptor

10-23 Stahl S M, Essential Psychopharmacology (2000)

GLUTAMATE RECEPTORS

ReceptorNMDA

ReceptorAMPA

Cainato ReceptorMetabotrópico= 8

LTP

PCP

Calcium channel

glycine site

zinc site

polyamine site

Mg site (in the ion channel)

PCP site (in the ion channel)

10-24 Stahl S M, Essential Psychopharmacology (2000)

ACETILCOLINA

Glucose

ACETYLCHOLINE IS PRODUCED

CAT

Choline

ACh

ACh12-8 Stahl S M, Essential

Psychopharmacology (2000)

AcCoA

AChE

ACETYLCHOLINE IS DESTROYED

AChE

12-9 Stahl S M, Essential Psychopharmacology (2000)

ACETYLCHOLINE RECEPTORS

presynaptic M2 receptor

M1 receptor

M2 MXN

12-10 Stahl S M, Essential Psychopharmacology (2000)

hippocampus

frontal

neocortex

amygdala

Nucleus basalis of Meynert

Acetylcholine Pathways

Ch1=medial septal nucleusCh2=vertical nucleus of the diagonal bandCh3=horizontal nucleus of the diagonal bandCh4=n basalis de Meynert

Basal forebrain

Ch1Ch2

Ch4

Ch3

(Mediate memory, learning, problem solving, judgement)

Loss in NB-Ch4 Alzheimer’s disease

striatum

lateral tegmental area

12-12 Stahl S M, Essential Psychopharmacology (2000)

Upper pons/mesencephalon

Medullary Ach neurons

thalamus

Interneurons involved in regulating motor movements

Arousal, attention, sleep

Parkinson

CATECOLAMINAS

E INDOLAMINAS

tyrosine transporter

TOH

TYR

DOPA

DDC

DA (Dopamine)

DOPAMINE IS PRODUCED

5--31 Stahl S M, Essential Psychopharmacology (2000)

dihydroxyphenylalanine)

COMTdopamine transporter

MAO

DOPAMINE IS DESTROYED

5--32 Stahl S M, Essential Psychopharmacology (2000)

(DOPAC - Ácido diidroxifenilacético)

Ácido homovanílico

DOPAC,HVA

DOPAMINE RECEPTORS

presynaptic autorecptor

D1 D2 D3 D4 D5

dopamine transporter

hypothalamus

d

c

Nucleus accumbens

Tegmentum

bSubstantia nigra

Basal Ganglia

a

DOPAMINE PATHWAYS

10-7 Stahl S M, Essential Psychopharmacology (2000)

mesolimbic pathway

Part of limbic system – involved in pleasurable sensations, motivation, delusions and hallucinations of psychosis

Midbrain VTA

Nucleus accumbens

mesolimbic overactivity = positive symptoms of psychosis

10-9 Stahl S M, Essential Psychopharmacology (2000)

meso-cortical pathway

VTA

Limbic Cortex

Memory, attention, problem solving

nigrostriatal pathway

SN

Basal ganglia

Part of the extrapyramidal nervous systemControls movements

EPSs

Stahl S M, Essential Psychopharmacology (2000)

Nigrostriatal pathway

When DA is deficient, it can cause parkinsonism with tremor, rigidity.When DA is in excess, it can cause hyperkinetic movements such as tics and dyskinesias.

tubero infundibular pathway

10-13 Stahl S M, Essential Psychopharmacology (2000)

hypothalamus

Pituitary gland

Controls prolactin secretion

Prolactin levels rise

11-6 Stahl S M, Essential Psychopharmacology (2000)

Tuberoinfundibular pathway

D2 receptors are blocked

NE (norepinephrine)

tyrosine transporter

TYR

TOH

DOPA

DDC DA

DBH

NOREPINEPHRINE IS PRODUCED

5-17 Stahl S M, Essential Psychopharmacology (2000)

NOREPINEPHRINE IS DESTROYED

COMT destroys NEnorepinephrine

transporter

MAO

5-18 Stahl S M, Essential Psychopharmacology (2000)

MHPG3-metoxi-4-hidroxifenilglicol

NOREPINEPHRINE RECEPTORS

presynaptic alpha 2 autoreceptor

postsynaptic alpha 2

receptorpostsynaptic beta 1 receptor

alpha 1 receptor

5-19 Stahl S M, Essential Psychopharmacology (2000)

Norepinephrine Pathways

Locus Coeruleus

5-23 Stahl S M, Essential Psychopharmacology (2000)

PFC

PFC

Limbiccortex

Cerebellum

Brainstem

beta 1 receptor

5-24 Stahl S M, Essential Psychopharmacology (2000)

Depression/AnxietyFrontal 1

Mood

Overactivity at the postsynaptic beta receptors increases anxietyNE deficiency = depressed mood

alpha 2 receptor

Frontal 2 Attention

5-25 Stahl S M, Essential Psychopharmacology (2000)

Alpha 2 receptor = regulates attention, concentration, working memory, speed of informationNE deficiency = impaired attention, problems concentrating, deficiencies in working memory

5-26 Stahl S M, Essential Psychopharmacology (2000)

Limbic

EmotionsAgitationEnergy Level

5-27 Stahl S M, Essential Psychopharmacology (2000)

Cerebellum Tremor

Motor movements

5HT (Serotonin)

SEROTONIN IS PRODUCEDtryptophan transporter

TRY-OH

5HTP

AAADC

Tryptophan

5--34 Stahl S M, Essential Psychopharmacology (2000)

serotonin transporter

MAO

SEROTONIN IS DESTROYED

5--35 Stahl S M, Essential Psychopharmacology (2000)

5-HIAAÁc. 5-hidroxi-indol-acético

SEROTONIN RECEPTORS

alpha 2 hetero receptor

5HT1D autoreceptor

5HT1A

serotonin transporter

5HT2A5HT2C

5HT3 5HT45HTX

5HTY

5HTZ

5--36 Stahl S M, Essential Psychopharmacology (2000)

Serotonin Pathways

Raphe Nucleus

5--51 Stahl S M, Essential Psychopharmacology (2000)

PFC

Basalganglia

Limbic

Hypothalamus

Sleep center

5--52 Stahl S M, Essential Psychopharmacology (2000)

Frontal Cortex Mood

5--53 Stahl S M, Essential Psychopharmacology (2000)

Basal Ganglia OCDAkathisia/Agitation

5-HT control movements as well as obsessions and compulsions

5--54 Stahl S M, Essential Psychopharmacology (2000)

Limbic Anxiety/ Panic

5--55 Stahl S M, Essential Psychopharmacology (2000)

Hypothalamus Appetite/bulimia

5--56 Stahl S M, Essential Psychopharmacology (2000)

Brainstem Sleep Centers Insomnia

5--57 Stahl S M, Essential Psychopharmacology (2000)

Spinal Cord Sexual Dysfunction

5--58 Stahl S M, Essential Psychopharmacology (2000)

Brainstem Vomiting Center

Nausea and vomiting

5-HT3

Ações de Fármacos no SNC

• Ação específica vs inespecífica

• Ações gerais ou inespecíficas:– Depressores gerais do SNC – anestésicos gerais

inalatórios– Estimulantes gerais do SNC – PTZ

• Ações específicas: atuam seletivamente no SNC, deprimindo ou estimulando as funções do SNC (anticonvulsivantes, antidepressivos, sedativos, hipnóticos, psicoestimulantes…)

Alvos das ações de fármacosAlvos das ações de fármacos

N

PRECURSOR

1

N

N

N

2

3

4

N

4

N

5

6

7

1 – Síntese2 – Armazenamento3 – Liberação4 – Interação com receptores5 – Recaptação6 – Catabolismo extra-neuronal7 – Catabolismo intra-neuronal

DOPAMINA

phenylalaninePA-OHase

Tir-OHase

Estimula adenilato-ciclase

Inibe a adenilato-ciclase

Classificação dos fármacos de ação Classificação dos fármacos de ação centralcentral

• Psicolépticos: a atividade psíquica normal ou alterada. – Antipsicóticos (neurolépticos). Ex: haloperidol– Ansiolíticos. Ex: diazepam, CDZ– Hipnóticos. Ex: flurazepam, barbitúricos

• Psicoanalépticos: ↑ a atividade psíquica normal ou alterada.– Antidepressivos. Ex: imipramina, tranilcipromina– Psicoestimulantes. Ex: anfetamina

Psicodislépticos: promovem alterações de sensopercepção (alucinações, delírios, euforia)

- Psicotogênicos ou alucinógenos. Ex: LSD, mescalina- Euforizantes e desinibidores. Ex: cocaína, etanol, heroína

Normalizadores psíquicos: corrigem estados psíquicos anormais

Eutímicos. Ex: sais de lítioEnergizantes ou nootrópicos. Ex: piracetam, piritinol