GABA and dopamine

2. Introduction:
• Gamma-Amino Butyric acid (GABA) is an amino acid which acts as a
neurotransmitter in the central nervous system.
• It inhibits nerve transmission in the brain, calming nervous activity.
• Chemical formula: 𝐶4 𝐻9 𝑁𝑂2
• GABA is a zwitter ion with deprotonated carboxyl group and protonated
amino group.

3. Discovery:
• • In 19th century – was known as metabolite of plant and microorganisms.
• • In 20th century – was isolated as amino acid in the brain of mouse through
paper chromatography.
• • In 1950 Robert and Frankel discovered that GABA act as inhibitory
neurotransmitter in human brain.
•

4. Synthesis
•Synthesized from amino acid L-glutamic acid in present of GAD.
•Glutamic acid decarboxylase (GAD) present in neurons, pancreatic cells and in body fluid.
GAD acts as a catalyst that removes carboxyl group from glutamate and produce GABA

5. Classes of GABA receptor:(2 types)
𝑮𝑨𝑩𝑨 𝑨Receptor:
•It has pentameric structure.
•It has structural & functional similarity with Ligand-gated ion.
•Each GABA-A receptor contain two alpha ,two beta, and one
gamma subunit
.

7. • 𝑮𝑨𝑩𝑨 𝑩Receptor:
• They are hetro dimers.
• GABA-B has been cloned to b1 & b2 subunits.
• B1 subunit has GABA binding site while B2 subunit interact with G-protein.
• Two biological action:
• -Decrease 𝐶𝑎2+ conductance
• -Increase 𝐾+ conductance

9. GABAC receptor
• • The GABAC receptor is less widely distributed than the A and B subtypes.
• modulators (e.g., benzodiazepines and barbiturates) seem not to interact
with GABAC receptors.
• • GABAC receptors are found in the retina, spinal cord, superior colliculus,
and pituitary.

10. How it works?
• Most of the sedative and hypnotic drug(Barbiturate & Bzds) either binds
with α, β or γ subunits that activated GABA receptor thus opening of
chloride channel that causes hyperpolarization of cells and finally depression
of CNS.

12. Example of some drug that act on GABA
receptor

13. STORAGE, RELEASE
• Newly synthesized GABA is stored in synaptic vesicle by means of vesicular
transporter.
• These are stored at postsynaptic terminal untill action potential release.
Stored GABA releases into synaptic cleft stimulated by depolarisation of
presynaptic neurons.
• GABA diffuses across the cleft to target receptors on postsynaptic
surfaceThe action of GABA is terminated by reuptake of GABA by
presynaptic nerve terminals & glial cells

14. Function of GABA :
• Relieving anxiety .
• Relieving pain.
• Regulating the release of sex hormones.
• Treating ADHD(Attention deficit hyperactivity disorder).
• Burning fat.
• Stabilizing blood pressure.
• Decrease blood sugar level in diabetics.

15. Dopamine
• Dopamine neurons are more widely distributed than those of other
monamines, residing in the midbrain substantia nigra and ventral
tegmental area and in the periaqueductal gray, hypothalamus, olfactory
bulb, and retina.
• In the periphery, dopamine is found in the kidney where it functions to
produce renal vasodilation, diuresis, and natriuresis.
• Three dopamine systems are highly relevant to psychiatry: The nigrostriatal,
mesocorticolimbic, and tuberohypophyseal system.

16. Tyrosine, a precursor to dopamine, is taken up into
dopamine nerve terminals via a tyrosine transporter
and converted into DOPA by the enzyme tyrosine
hydroxylase (TOH). DOPA is then converted into
dopamine (DA) by the enzyme DOPA decarboxylase
(DDC). After synthesis, dopamine is packaged into
synaptic vesicles via the vesicular monoamine
transporter (VMAT2) and stored there until its
release into the synapse during neurotransmission.

17. Degradation
• Two enzymes that play major roles in the degradation of dopamine are monoamine oxidase and catechol O-
methyltransferase (COMT).
• MAO is located on the outer membrane of mitochondria.
• Two MAO isozymes
• MAO-A : Which preferentially deaminates serotonin and norepinephrine.
• MAO-B : Which deaminates dopamine, histamine, and a broad spectrum of phenylethylamines.
• COMT is located in the cytoplasm and is widely distributed throughout the brain and peripheral tissues.
• It has a wide substrate specificity, catalyzing the transfer of methyl groups from S-adenosyl methionine to the m-
hydroxyl group of most catechol compounds.
• The predominant metabolites of dopamine is Homovanillic acid (HVA)
•

19. Storage
• Dopamine synthesized within neurons from common amino acid precursors (step 1) and taken
up into synaptic vesicles via a vesicular monoamine transporter (step 2).
• Upon stimulation, vesicles within nerve terminals fuse with the presynaptic terminal and release
the neurotransmitter into the synaptic cleft (step 3).
• Once released, the monoamines interact with postsynaptic receptors to alter the function of
postsynaptic cells (step 4), and they may also act on presynaptic autoreceptors on the nerve
terminal to suppress further release (step 5).
• In addition, released dopamine may be taken back up from the synaptic cleft into the nerve
terminal by DAT Dopamine Transpoter(step 6), a process known as reuptake.
• Once monoamines are taken up, they may be subject to enzymatic degradation (step 7), or they
may be protected from degradation by uptake into vesicles.

20. • DRUGS AFFECTING DOPAMINERGIC SYSTEM…
• Dopamine Agonist:
• Levodopa
• Carbidopa
• Ropinirole —Antidepressent:
• Bupuropion —Antipsychotics:
• Typical antipsychotic like halopoperidol, pimozide,
• Atypical antipsychotics like olanzapine, quetiapine, resperidone etc —Stimulants:
• Methylphenidate
• Modafinil
• Armodafinil

21. • Tracts in brain…
• The Mesolimbic Dopamine Pathway : midbrain ventral tegmental area to the nucleus
accumbens .a part of the limbic system of the brain thought to be involved in many behaviors
such as pleasurable sensations, the powerful euphoria of drugs of abuse, as well as delusions and
hallucinations of psychosis.
• The Mesocortical Dopamine Pathway : It also projects from the midbrain ventral tegmental
area but sends its axons to areas of the prefrontal cortex, where they may have a role in
mediating cognitive symptoms (dorsolateral prefrontal cortex) and affective symptoms
(ventromedial prefrontal cortex) of schizophrenia.
• The Nigrostriatal Dopamine Pathway : which projects from the substantia nigra to the basal
ganglia or striatum, is part of the extrapyramidal nervous system and controls motor function
and movement.
• Tuberoinfundibular Dopamine Pathway : projects from the hypothalamus to the anterior
pituitary gland and controls prolactin secretion.
• The fifth dopamine pathway arises from multiple sites, including the periaqueductal
gray, ventral mesencephalon, hypothalamic nuclei, and lateral parabrachial nucleus, and
it projects to the thalamus. Its function is not currently well known.

23. • Dopamine transporter (DAT) exists presynaptically and is responsible
for clearing excess dopamine out of the synapse. The vesicular
monoamine transporter (VMAT2) takes dopamine up into synaptic
vesicles for future neurotransmission.
• There is also a presynaptic dopamine-2 autoreceptor, which regulates
release of dopamine from the presynaptic neuron. In addition, there
are several postsynaptic receptors
•

24. • These include dopamine-1, dopamine-2, dopamine-3, dopamine-4,
and dopamine-5 receptors. The functions of the dopamine-2 receptors
are best understood, because this is the primary binding site for
virtually all antipsychotic agents as well as for dopamine agonists used
to treat Parkinson's disease.

25. • Presynaptic dopamine-2 autoreceptors are "gatekeepers" for
dopamine. That is, when these gatekeeping receptors are not bound
by dopamine, they open a molecular gate, allowing dopamine release.
• However, when dopamine binds to the gatekeeping receptors, they
close the molecular gate and prevent dopamine from being released.

26. DRUGS AFFECTING DOPAMINERGIC
SYSTEM…
• Dopamine Agonist: Levodopa, Carbidopa Ropinirole
• —Antidepressent:Bupuropion
• —Antipsychotics:
• Typical antipsychotic like halopoperidol, pimozide,
• Atypical antipsychotics like olanzapine, quetiapine, resperidone etc —Stimulants:
• Methylphenidate
• Modafinil
• Armodafinil

27. Disorders associated with dopaminergic
system…
• Parkinsonism : Decrease Dopamine. It occurs in substantia nigra Leading to symptoms like rigidity ,
bradykinesia
• Substance Abuse :
• Nucleus Accumbens is a center for reward.
• Occurs due to increased release of dopamine caused by the psychotropic substances like
• morphin
• heroin
• Cannabis
• cocaine
• nicotine

28. • Schizophrenia
• Increase And Decrease Of Dopamine —In Different Region Of Brain.
• Mesolimbic pathways
• Mesocortical pathways

29. • ADHD :
• Decrease In Dopamine Level in anterior frontal cortex
• An area associated with cognitive function such as
• Ø attention
• Øconcentration.
• Impulse Control Disorder :
• Decrease In Dopamine Level.