introduÇÃo ao sistema nervoso central. sistema nervoso central sistema nervoso periférico nervos...
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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
ulat
ion
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
GLUTAMATEGABA 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)
GABA BZ
8-21 Stahl S M, Essential Psychopharmacology (2000)
GABABZ
BZ
GABA
8-23 Stahl S M, Essential Psychopharmacology (2000)
HIPERPOLARIZAÇÃO
GLU (Glutamate)
GlutamineGLUTAMATE IS PRODUCED
Glutaminase Glutamate
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 Receptor
Metabotrópico= 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 receptorM2 MX
N
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 forebrainCh1
Ch2Ch4
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
CATECOLAMINASE 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
TYRTOH
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 1Mood
Overactivity at the postsynaptic beta receptors increases anxietyNE deficiency = depressed mood
alpha 2 receptorFrontal 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-OH5HTP
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 5HT4
5HTX5HTY
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