Stimulus yang datang dari lingkungan, baik berupa cahaya, suara, tekanan, sentuhan, suhu, ataupun stimulus yang

lain, akan diterima oleh reseptor. Reseptor adalah bagian dari sel saraf yang terdapat pada organ pengindera. Di dalam reseptor, stimulus yg datang akan diubah dalam bentuk kode informasi. Kode informasi tersebut berupa perubahan elektrokimiawi pada neuron dan disebut sebagai impuls saraf. Impuls saraf inilah yang oleh neuron diteruskan ke otak untuk dipersepsi. Hasil persepsi otak kemudian akan dihantarkan kembali menuju efektor.

Efektor adalah sel atau organ yang menghasilkan tanggapan terhadap rangsangan/stimulus, seperti otot, kelenjar, atau sel target sehingga terjadi gerakan/aktivitas. Penghantaran impuls saraf tersebut terjadi melalui serabut akson dan sinapsis.

Penghantaran impuls, baik berupa rangsangan ataupun tanggapan melalui serabut akson, terjadi karena adanya perbedaan potensial listrik antara bagian luar dan bagian dalam sel. Pada waktu sel saraf beristirahat (polarized), kutub positif terdapat di bagian luar dan kutub negatif terdapat di bagian dalam sel saraf. Diperkirakan bahwa rangsangan (stimulus) pada indra menyebabkan terjadinya pembalikan perbedaan potensial listrik sesaat.

Extrasel lebih banyak mengandung ion natrium sehingga muatan lebih positif, sebaliknya intrasel lebih banyak mengandung ion kalium sehingga muatannya lebih negatif. Sifat membran sel saraf relatif impermeable terhadap kedua ion.

Stimulus yang datang menyebabkan terjadinya pembalikan potensial listrik. Ion natrium secara cepat berpindah ke bagian dalam sel saraf sehingga muatan bagian luar menjadi lebih negatif dibanding bagian dalam sel saraf. Dalam keadaan ini, sel saraf dikatakan mengalami depolarisasi.

Pada tempat perangsangan (datangnya stimulus) terbentuklah potensial aksi. Jika stimulus cukup kuat, potensial aksi akan dialirkan secara cepat ke sepanjang membran serabut akson.

Kecepatan perjalanan gelombang perbedaan potensial pada serabut akson bervariasi antara 1 - 120 m per detik, tergantung pada diameter akson dan ada atau tidaknya selubung mielin. Bila impuls telah lewat, maka untuk sementara serabut saraf tidak dilalui oleh impuls yang lain. Ini berarti bahwa serabut saraf mengalami perubahan potensial, kembali seperti semula (potensial istirahat).

Untuk dapat berfungsi kembali diperlukan waktu 1/500 sampai 1/1000 detik.

Stimulasi yang kurang kuat atau di bawah ambang (threshold) tidak akan menghasilkan impuls yang dapat merubah potensial listrik. Sebaliknya, bila kekuatan stimulus di atas ambang maka impuls akan dihantarkan sampai ke ujung akson. Stimulasi yang kuat dapat menimbulkan jumlah impuls yang lebih besar pada periode waktu tertentu daripada impuls yang lemah. Proses pengubahan stimulus menjadi impuls mengikuti hukum all or none (semua atau tidak sama sekali).

Muncul tidaknya suatu impuls, dapat terjadi karena dua kemungkinan, yaitu:
1. Penjumlahan temporal 2. Penjumlahan spasial

Jenis neuron berdasarkan kemampuannya menghantarkan impuls

1. Neuron eksitatoris 2. Neuron inhibitoris

Impuls yang telah sampai di bagian terujung dari serabut akson (terminal akson) akan disampaikan ke neuron berikutnya. Titik temu antara terminal akson salah satu neuron dengan neuron lain dinamakan sinapsis. Setiap terminal akson membengkak membentuk tonjolan sinapsis. Di dalam sitoplasma tonjolan sinapsis terdapat struktur kumpulan membran kecil berisi neurotransmitter; yang disebut vesikula sinapsis.

Neuron yang berakhir pada tonjolan sinapsis disebut neuron pra-sinapsis. Membran ujung dendrit dari sel berikutnya yang membentuk sinapsis disebut post-sinapsis. Bila impuls sampai pada ujung neuron, maka vesikula bergerak dan melebur dengan membran pra-sinapsis. Kemudian vesikula akan melepaskan neurotransmitter. Neurontransmitter adalah suatu zat kimia yang diproduksi oleh n pra-sinapsis dan dapat menyeberangkan impuls dari n pra-sinapsis menuju ke n post-sinapsis.

Neurotransmiter merupakan cara komunikasi antar neuron. Setiap neuron melepaskan satu transmitter. Zat zat kimia ini menyebabkan perubahan permeabilitas sel neuron, sehingga neuron menjadi lebih kurang dapat menyalurkan impuls. Neurotransmiter yang dilepaskan oleh n pra-sinapsis akan berdifusi melewati celah sinapsis dan menempel pada reseptor yang terdapat pada membran postsinapsis. Menempelnya neurotransmiter pada reseptor menyebabkan timbulnya impuls pada neuron postsinapsis. Bila neurotransmiter sudah melaksanakan tugasnya maka neurotransmiter akan diurai oleh enzim yang dihasilkan oleh membran post-sinapsis.

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Neurotransmitters found in the nervous system

EXCITATORY Acetylcholine Aspartate Dopamine Histamine Norepinephrine Epinephrine Glutamate Serotonin INHIBITORY GABA Glycine

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1.

2.

Asetilkolin yang terdapat di seluruh tubuh, kecuali otak. Dopamin yang terdapat di otak.
Dopamin berperan dalam mengendalikan fungsi gerakan, konsentrasi, dan proses kecanduan.

Kerusakan pada neuron dopaminergik menyebabkan:

1. Parkinson (akibat kekurangan dopamin) 2. Skizofrenia (akibat kelebihan dopamin)

3.

Seretonin yang terdapat di otak.

Seretonin dapat merangsang orang yang sedang tidur menjadi bermimpi.

In the cholinergic neurons acetylcholine is synthesized from choline. This reaction is activated by cholineacetyltransferase

As soon as acetylcholine is synthesized, it is stored within synaptic vesicles.

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Acetylcholin Synthese

 muscular movement faciliatory effect REM sleep learning memories

Cholinergic pathways in the brain - basal forebrain, dorsolateral pons, medial septum.

Glutamat Synthese

GABA and Glycin Synthese

Serotonin

Melatonin

-this is not for torture -understanding synthesis can be important for understanding drug action

Dopamine

Subtantia nigra and Parkinsons disease

Mesocorticolimbic system and schizophrenia

Receptor specificity

Histidin

Histidin Decarboxylase

Histamin

Tyrosin

Tyrosin Decarboxylase

Tyramin

Tyramin -Hyroxylase

Octopamin

Other Neurotransmitters:
Neurotransmitter Derived from Histidine Enzyme Histidine decarboxylase Glutamate decarboxylase Nitric Oxide Synthase
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Histamine

GABA (-Amino butyrate) Nitric Oxide

Glutamate

Arginine

Summary: Neurotransmitter Molecule

Acetylcholine

Derived From
Choline

Site of Synthesis
CNS, parasympathetic nerves

Serotonin 5-Hydroxytryptamine (5-HT)

Tryptophan

CNS, chromaffin cells of the gut, enteric cells

GABA

Glutamate

CNS

Histamine

Histidine

hypothalamus

Epinephrine synthesis pathway Norpinephrine synthesis pathway Dopamine synthesis pathway Nitric oxide, NO

Tyrosine

adrenal medulla, some CNS cells

Tyrosine

CNS, sympathetic nerves

Tyrosine

CNS

Arginine

CNS, gastrointestinal tract

Dopamines Normal Action

Based on Time, May 5, 1997

1. After being released into the synapse (the gap between nerve endings and receiver cells), dopamine binds to receptors on the next neuron 2. The dopamine is either quickly reabsorbed or broken down by the enzyme monoamine oxidase (MAO)

How Drug Affect Dopamine Levels

Based on Time, May 5, 1997

Cocaine blocks the normal absorption of dopamine. As a result, dopamine accumulates in the synapse, where is stimulates the receiver cell.

Amphetamines stimulate excess release of dopamine, overwhelming the processes of reuptake and enzyme breakdown.

Nicotine stimulates the release of dopamine, while another substance in cigarette smoke blocks the action of MAO.

Nucleus basalis of Meynert

Largely unknown -Downs syndrome link -but strongly inherited forms account for only small proportion -plaques seen in wide variety of disorders acquired by disease (encephalitis, CJD) and accident (punchdrunk syndrome)

1.

Cognitive enhancers -Acetylcholinesterase inhibitors to offset loss of cholinergic neurons NMDA antagonists -Memantine -idea here is that part of problem in AD is that chronic release of glutamate prevents NMDA receptors from working properly

2.

Methamphetamine

Nicotine
seattlepi.nwsource.com/ methamphetamines/

Alcohol

science.howstuffworks.com/ alcohol.htm

Methamphetamine alters Dopamine transmission in two ways:

1. Enters dopamine vesicles in axon terminal causing release of NT 2. Blocks dopamine transporters from pumping dopamine back into the transmitting neuron

QuickTime and a TIFF (LZW) decompressor are needed to see this picture.

seattlepi.nwsource.com/ methamphetamines/

NIH Publication No. 00-4871

This causes neurons to fire more often than normal resulting in a euphoric feeling.

1.

2.

3.

After the drug wears off, dopamine levels drop, and the user crashes. The euphoric feeling will not return until the user takes more methamphetamine Long-term use of methamphetamine causes dopamine axons to wither and die. Note that cocaine also blocks dopamine transporters, thus it works in a similar manner.

Similar to methamphetamine and cocaine, nicotine increases dopamine release in a synapse. However, the mechanism is slightly different. Nicotine binds to receptors on the presynaptic neuron.

Nicotine binds to the presynaptic receptors exciting the neuron to fire more action potentials causing an increase in dopamine release. Nicotine also affects neurons by increasing the number of synaptic vesicles released.

Alcohol has multiple effects on neurons. It alters neuron membranes, ion channels, enzymes, and receptors. It binds directly to receptors for acetylcholine, serotonin, and gamma aminobutyric acid (GABA), and glutamate. We will focus on GABA and its receptor.

GABA is a neurotransmitter that has an inhibitory effect on neurons. When GABA attaches to its receptor on the postsynaptic membrane, it allows Cl- ions to pass into the neuron. This hyperpolarizes the postsynaptic neuron to inhibit transmission of an impulse.

When alcohol enters the brain, it binds to GABA receptors and amplifies the hyperpolarization effect of GABA. The neuron activity is further diminished This accounts for some of the sedative affects of alcohol

science.howstuffworks.com/ alcohol.htm

From AMA pub 9416

The brain goes through dynamic change during adolescence, and alcohol can seriously damage long- and short-term growth processes. Frontal lobe development and the refinement of pathways and connections continue until age 16, and a high rate of energy is used as the brain matures until age 20. Damage from alcohol at this time can be longterm and irreversible.

In addition, short-term or moderate drinking impairs learning and memory far more in youth than adults. Adolescents need only drink half as much as adults to suffer the same negative effects.

Change in Neurotransmission increase the number of impulses release neurotransmitter from vesicles with or without impulses release more neurotransmitter in response to an impulse block reuptake produce less neurotransmitter prevent vesicles from releasing neurotransmitter block receptor with another molecule

Effect on Neurotransmitter release or availability increased neurotransmitter release increased neurotransmitter release increased neurotransmitter release more neurotransmitter present in synaptic cleft less neurotransmitter in synaptic cleft less neurotransmitter released no change in the amount of neurotransmitter released, or neurotransmitter cannot bind to its receptor on postsynaptic neuron

Drug that acts this way nicotine, alcohol, opiates amphetamines methamphetamines nicotine cocaine amphetamine probably does not work this way No drug example LSD caffeine

NIH Publication No. 00-4871

TERIMA KASIH

1)When the nerve impulse (Action potential) moves down the presynaptic axon to the terminal bulb the change in the membrane action potential causes the opening of voltage gated calcium channels open allowing Ca+2 ions to pass from the synaptic cleft into the axon bulb. 2) Within the bulb the increase in Ca+2 concentration causes the synaptic vesicles that contain acetylcholine to fuse with the axonal membrane and open spilling their contents into the synaptic cleft.
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The postsynaptic membrane of the receptor dendrite has specific cholinergic receptors toward which the neurotransmitter diffuses. Binding of acetylcholine trigger the opening of ion channels in the postsynaptic membrane initiating action potential that can pass in the next axon.
Acetylcholine receptors: Acetylcholine receptors are ion channels receptors made of many subunits arranged in the form [(2)()()()].

When Acetylcholine is not bounded to the receptors, the bulky hydrophobic leu side close the central channels preventing the diffusion of any ions. Binding of two acetylcholine molecules to the receptors will rotate the subunits in which the smaller polar residues will line the ion channel causing the influx of Na+ into the cell and efflux of K+ resulting in a depolarization of the postsynaptic neuron and the initiation of new action potential.

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In order to ready the synapse for another impulses: 1) The neurotransmitters, which are released from the synaptic vesicles, are hydrolyzed by enzyme present in the synaptic cleft Acetylcholinestrase giving choline, which poorly binds to acetylcholine receptors.

Acetylcholine + H2O

Acetylcholinestrase

Choline + H+ acetate

2) The empty synaptic vesicles, which are returned to the axonal terminal bulb by endocytosis, must be filled with acetylecholine.

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Acetylcholinesterase (AchE) is an enzyme, which hydrolyses the neurotransmitter acetylcholine. The active site of AChE is made up of two subsites, both of which are critical to the breakdown of ACh. The anionic site serves to bind a molecule of ACh to the enzyme. Once the ACh is bound, the hydrolytic reaction occurs at a second region of the active site called the esteratic subsite. Here, the ester bond of ACh is broken, releasing acetate and choline. Choline is then immediately taken up again by the high affinity choline uptake system on the presynaptic membrane.

Vertebraten
Acetylcholin GABA Glutamat Glycin

Invertebraten
Acetylcholin GABA Glutamat

Biogene Amine
Histamin
Serotonin Dopamin Noradrenalin

Histamin
Serotonin Dopamin (Noradrenalin)

Adrenalin

Tyramin/Octopamin

Neuropeptide

Neurotransmitter

Neuropeptide

1) First Step: Hydroxylation: In this step: the reaction involves the conversion of tyrosine, oxygen and tetrahydrobiopterin to dopa & dihydrobiopterin. This reaction is catalyzed by the enzyme tyrosine hydroxylase. It is irreversible reaction. 2) Second step: Decarboxylation: In this step: the dopa decaboxylase will catalyze the decaoxylation of dopa to produce dopamine. The deficiency of this enzyme can cause Parkinsons disease. It is irreversible reaction. The cofactor in this reaction is the PLP (pyridoxal phosphate). In the nerve cells that secrete dopamine as neurotransmitter the pathway ends at this step.
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Catecholamine Synthesis (Dopamine, Norepinephrine and Epinephrine).

3) Third step: Hydroxylation:

This reaction is catalyzed by the enzyme dopamine hydroxylase. The reactants include dopamine, O2 and ascorbate (vitamin C). The products are norepinephrine, water and dehydroascorbate. It is an irreversible reaction). The end product in noradrenergic cells is norepinephrine and the pathway ends her.
4) Forth step: Methylation:

This reaction is catalyzed by phenylethanolamine Nmethyltransferase. Norepinephrine and Sadenosylmethionin (ado-Met) form epinephrine and Sadenosyl homocysteine (ado-Hcy).
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