Complete Notes on Dopamine including the receptors and diseases.

1. Dopaminergic Neurotransmission
Prepared By: Sidbi Mani Prakash
M.Pharmacy (Pharmacology)
First Semester-2020-21
Submitted To: Dr.Bhupesh Sharma

2. Contents
TOPICS SLIDESNO.
Introduction 4
Chemistry and metabolism of da 5-13
MAO (A&B),COMT and their Inhibitors 14- 16
HISTORICAL CLASSIFICATION AND
MOLECULAR PROPERTIES OF DA
RECEPTORS
17-18
G PROTEIN COUPLED RECEPTOR(GPCR) 19-21
Dopamine Receptors 22-38
DA RECEPTORSAS SIGNALTRANSDUCERS 39-43

3. Contents
TOPICS SLIDESNO.
CLASSIFICATIONOF DOPAMINERGICDRUGS
ACCORDING TO TREATMENT CATEGORY
44-56
Dopaminergic Pathways 57
Dopamine agonist &antagonist with major
clinical implications
58
REFERENCES 60

4. Introduction
 Dopamine (DA) is a neurotransmitter in the central and peripheral nervous systems
where it regulates numerous physiological processes.
 Belongs to catecholamine's.
 In CNS system, it regulates the emotion, reward, cognition, memory, endocrine
functions, motor control.
 Alterations in dopaminergic transmission are known to be involved in the etiology
and/or therapy of a number of neurological and psychiatric disorders, including
Parkinson’s disease, Tourette’s syndrome, attention-deficit hyperactivity disorder
(ADHD), schizophrenia, and substance use.
 It is a member of the general chemical class of compounds known as
phenylethylamines, monoamines, and biogenic amines.

5. Chemistry and metabolism of da
Catechol Ethyl Amine
HO 3 NH2
4
HO
Phenylethylamine
 The International Union of Pure and
Applied Chemistry (IUPAC) and
common chemical name for dopamine
is 2-(3,4-dihydroxyphenyl)ethylamine.
 Its chemical structure is comprised of
a catechol ring (3,4-dihydroxyphenyl)
linked by an ethyl to a primary amine.
 Dopamine has a catecholamine
pharmacophore.
 High water solubility- due to presence of
ionizable hydroxyl group at
physiological pH and smaller
molecular size of DA, which restricts
its passive transport across the blood-
gut and blood brain barrier (BBB).

6. Contd…
 Good substrate for the Norepinephrine transporter and this transporter localized in
capillary endothelial cells at the BBB.
 DA precursor L-DOPA (Dihydrophenylalanine) actively
transported by the neutral bulky amino acid transport complex 4F2hc/LAT1(situated
in cellular membranes comprising the BBB).
 Catechol moiety of DA Makes it susceptible to oxidation
 Oxidative Conditions - Catechol converted to highly reactive Quinone (3,4-
diketophenyl) series of reactions Water-insoluble conjugated diene polymer
(absorbs light and gives deep brown colored precipitates observed in solutions of
oxidized dopamine).
 Lower plasma levels of orally administered L-DOPA are observed following a high-
protein meal due to delayed or erratic gastric emptying and competition between
levodopa and large neutral amino acids for gut mucosal carrier systems may impair
levodopa absorption.
* Erratic gastric emptying- means motility disorder in which the stomach doesn’t
empty food as quickly as it should. Or (not even or regular in pattern or movement)

7. CONTD..
 precursors tyrosine and L-DOPA are responsible for the formation of melanin's and
related products which serve as biological pigments and account for such biological
phenomena as the browning of bananas and the tanning of skin and cuticles.
 It also serves as a signaling molecule.
 Dopamine is considered a neurotransmitter when it is released from neuronal synapses and
acts locally on presynaptic or postsynaptic DA receptors or
 A neurohormone when its release is humoral, meaning that it is transported to a distant DA
receptor site through blood circulation.
 Both synaptic and humoral responses to DA are observed in the periphery and the CNS.
 An example: A humoral response in the CNS is the tonic, pulsatile release of DA from the
arcuate nucleus(shaped like a bow; curved) of the hypothalamus that regulates prolactin
secretion from the anterior pituitary.
*Tonic, pulsatile – means persistently, or regulates the intensity of the phasic dopamine
response through its effect on extracellular level. Or we can say, secretion of chemical products
in a regular pattern.
 A humoral-type response in the periphery is the nausea induced by high plasma levels
of peripheral DA via stimulation of DA receptors in the chemoreceptor trigger zone.

8. Rate Limiting Step
Metabolic Pathways for DA

9. Metabolic Pathways for DA

10. CONTD..
 To reduce such a side effect, L-DOPA is co-administered with peripheral inhibitors of
the enzyme aromatic amino acid decarboxylase (AAAD), such as carbidopa, which
prevent the peripheral conversion of L-DOPA to DA.
 It is a derivative of the aromatic amino acids phenylalanine and tyrosine and a
precursor of the neurotransmitters norepinephrine and epinephrine.
 Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of DA, and
consequently, in situ intracellular localization of this enzyme is a popular marker for
dopaminergic (and noradrenergic) cells.
 Key role in DA anabolism, tyrosine hydroxylase is under heavy regulation at both the
transcriptional and posttranslational levels.
• DA anabolism- MEANS building-up aspect of metabolism i.e. is the synthesis of
complex molecules from simpler ones. These chemical reactions require energy.
 One protein isoform of tyrosine hydroxylase is present in rats, while, due to differential
splicing, two are present in nonhuman primates and four in humans.

12. Contd..
 L-DOPA is converted to dopamine by AAADs associated with biogenic amine-containing
neurons.
 Once formed, DA can be converted by the enzyme dopamine-b-hydroxylase, which is
present in noradrenergic neurons, or it can undergo catabolism or be taken back up
following release.
 Reuptake is the process by which the released transmitter is brought back into presynaptic
nerve terminals or is internalized by surrounding glial cells.
 Reuptake of dopamine is mediated by two classes of transporters:
dopamine transporter DAT, which transports dopamine from the extracellular to the
intracellular space, and VMAT, which reloads dopamine into the vesicles.
 Two most reliable measures of DA turnover are 3,4-dihydroxyphenyl acetic acid (DOPAC)–
DA and homovanillic acid (HVA)–DA ratios.
 HVA–DA ratios in cerebral spinal fluid (CSF), in particular, serve as an accurate measure of
brain dopaminergic activity.

13. Contd..
 The main enzymes responsible for the
metabolism of dopamine are shown in the
figure:
1) Monoamine oxidase (MAO)
2) Catechol-O-methyl transferase (COMT)
 Catabolism is one of the effective
mechanisms for dopamine inactivation.
 This involves multiple pathways that
include oxidative deamination by
monoamine oxidase (MAO), O-methylation
by catechol-O-methyl transferase (COMT),
and conjugation by sulfotransferases or
glucoronidases.
 The preferred metabolic pathway at a given
site depends on the compartmentalization
of the metabolic enzymes.
 For example, MAO is located in the
external membrane of the mitochondria
and acts intracellularly, whereas COMT is
associated with the external cell membrane
and acts only extracellularly.


14. Contd..
 In the phase II catabolism of DA in rats, the major excreted metabolites are
glucuronidated, while in humans they are sulfonated.
 Monoamineoxidase(MAO):
o Exists as two isoenzymes, A and B, with an apparent molecular mass of 60–63 kDa
each.
o The two MAO genes, each comprised of 15 exons, are located on the X-chromosome
and appear to have been derived from the same ancestral gene.
o They differ in substrate specificity as well as selectivity for inhibitors.
o MAO-A is more highly expressed in catecholaminergic neurons, whereas MAO-B is
more abundant in serotonergic and histaminergic neurons and in glial cells.
o Deamination of dopamine by MAO produces dihydroxyphenylacetic acid (DOPAC).
o Determination of the ratio of DOPAC/dopamine concentrations serves as a good
method for estimating rapid changes in neuronal activity.

15. MAO (A&B),COMT and their Inhibitors
o Inhibitors of the catabolic enzyme
monoamine oxidase (MAO) B extend the
actions of DA by slowing its degradation.
o MAOB-selective inhibitors like selegiline
are effective in preventing 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine
(MPTP) neuro- toxicity, because they
block the enzymatic conversion of
protoxin MPTP to its toxic metabolite 1-
methyl-4-phenylpyridine (MPP).
o MAOB is generally associated with the
metabolism of DA and tyramine, while
MAOA is primarily responsible for
norepinephrine and serotonin
metabolism.
o New MAO inhibitors that are reversible and
highly selective for the A or B isoforms are
becoming available (e.g., moclobemide and
lazabemide, respectively) and should prove
to be much safer alternatives.
 Catechol-O-methyltransferase (COMT):
 O-Methylation by COMT is primarily
responsible for inactivation of circulating
catecholamines.
 Consecutive conversion of dopamine
by MAO and COMT yields homovanillic
acid.
 The enzyme introduces a methyl group to the
catecholamine, which is donated by S-
adenosyl methionine (SAM).
 COMT is an intracellular enzyme located
in the postsynaptic neuron. Any compound
having a catechol structure, like
catecholestrogens and catechol-containing
flavonoids, are substrates of COMT.

16. CONTD..
 Catechol-O-methyl transferase (COMT) inhibitors are commonly coadministered to those
receiving L-DOPA to counter the observed up regulation of this enzyme that results from
chronic treatment.
 This prevents the peripheral conversion of L-DOPA to its 3-methoxy derivative that competes
for active transport but that cannot then be converted to DA once inside the brain.

17. HISTORICAL CLASSIFICATION AND MOLECULAR PROPERTIES
OF DA RECEPTORS
 DA exert its actions through the binding and activation of specific cell surface
receptors which are members of the G-protein-coupled receptor (GPCR) super gene
family.
 Metabotropic G protein coupled receptors
 Linked to heterotrimeric GTP-binding (G) proteins.
 Before the establishment that multiple subtypes of DA receptors exist, the stimulatory
effect of dopamine on adenylyl cyclase activity in neostriatum was demonstrated.
 Subsequent testing of dopaminergic agonists revealed that few promote inhibition, and
this discrepancy led to the classification.
 Through the application of molecular biological techniques, we now know that there
are D1 and D2 subfamilies of receptors rather than singular receptor subtypes.

19. G PROTEIN COUPLED RECEPTOR(GPCR)
 G proteins, also known as Guaninie nucleotide-binding proteins, involved in
transmitting signals and function as molecular switches.
 G-protein-coupled receptors (GPCRs), also known as seven-transmembrane domain
receptors, 7 T receptors, serpentine receptors, G protein-linked receptors(GPLR).
 It constitutes a large protein family of receptors that sense molecules outside the cell
and activate inside signal transduction pathways and ultimately, cellular responses.
 They are called as seven-transmembrane receptors because they pass through the cell
membrane seven times.
 Humans express over 800 GPCRs.
 Approx. 45% of all the pharmaceutical drugs are known to target GPCRs.
 GPCRs are responsible for every aspect of human biology from vision, taste, sense of
smell, sympathetic and parasympathetic nervous functions, metabolism and immune
regulation to reproduction.

20. STRUCTURE OF G PROTEIN
 The structure of a GPCR can be divided into three parts:
1) The extra-cellular region, consisting of the N Terminus and three extracellular loops
(ECL1-ECL3);
2) The Transmembrane region, consisting of seven a-helices (TM1-TM7)
3) The intracellular region, consisting of three intracellular loops (ICL1-ICL3), an
intracellular amphipathic helix (H8), and the C terminus.
 G protein complexes are made up:
 23 alpha (α)
 7 beta (β)
 12 gamma (γ) subunits
 Beta and gamma subunits can form a stable dimeric complex referred to as the beta-
gamma complex.

21. Contd..
 In a broad sense, the extracellular region modulates ligand access; the TM region forms
the structural core, binds ligands and transduces this information to the intracellular
region through conformational changes, and the intracellular region interfaces with
cytosolic signaling proteins.
 The α - subunits fall into 04 families (Gs, Gi, Gq, and G12/13 ) which are responsible
for coupling GPCRs to relatively distinct effectors.

23. Dopamine Receptors
 There are five types of Dopamine receptors: D1,D2,D3,D4,D5.
 We can categorize dopamine receptors in two main subtypes:
 D1 RECEPTOR SUBFAMILY: the Gs protein is involved and adenylyl cyclase
would be activated. The action of the enzyme causes the conversion of adenosine
triphosphate to cyclic adenosine monophosphate (cAMP).
 D2 RECEPTOR SUBFAMILY: which is the receptor combining with the Gi
protein and its activated alpha-subunit then inhibits adenylyl cyclase so that
the concentration of cAMP is reduced.
 Five subtypes of dopamine receptor have been cloned.
 The D1 and D5 receptors are closely related, and couple to Gs alpha and stimulate
adenylyl cyclase activity. In contrast, the D2, D3 and D4 receptors couple to Gi alpha
and inhibit the formation of cAMP.

24. Distribution of Dopamine receptors

26. D1 RECEPTOR Subfamily
 The D1 receptor, was independently cloned by four separate groups using either the
polymerase chain reaction with degenerate primers derived from previously cloned
GPCR sequences or homology screening with a D2 receptor probe.
 It enables the isolation of complementary deoxyribo- nucleic acids (cDNAs) or genes
from either human or rat DNA libraries.
 Both D1 receptor genes encode a 446-amino-acid protein.
 Both are 91% homologous at the amino acid level.
 structure of the D1 receptor deduced by hydropathy analysis.
 The amino acids in these domains are thought to be in the alpha-helical configuration.
 Asparagine-linked glycosylation sites are found on the amino terminal domain and the
second extracellular loop, small third cytoplasmic loop which are coupled to the
stimulatory guanyl nucleotide binding protein Gs.

27. Fig: Diagram of the structure of dopamine receptor-1 (D1R) and D2R and classification
by their effects on cAMP. D1-like have a longer C terminal tail and a smaller third
intracellular loop that links to G-protein than D2-like

28. D1 RECEPTOR
 In the third cytoplasmic loop are found several serine and threonine residues as well as a
consensus recognition sequence for the cAMP-dependent protein kinase, which are potential
sites of phosphorylation.
 postranslational modification include a cysteine residue in the carboxyl terminal domain,
which is palmitoylated, and numerous serine and threonine residues also in the carboxyl
terminus which serve as sites of G-protein-coupled receptor kinase (GRK)–mediated
phosphorylation.
Palmitoylation- It is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (S-
palmitoylation) and less frequently to serine and threonine(O- palmitoylation) residues of
proteins, which are typically membrane proteins.
 Mapped to Chromosome 5.
 While the coding region is intronless, D1 receptor genes contain a small intron in the 50
noncoding region.
 The D1-like receptors are found throughout the brain and in blood vessels and smooth
muscle.
 Expression of D1 receptor mRNA is highest in the caudate putamen, nucleus accumbens,
and olfactory tubercle. Lower levels found in the basolateral amygdala, cerebral cortex,
septum, thalamus, and hypothalamus.
 D1 receptors are localized largely on neuronal cell bodies rather than nerve terminals in
these nuclei.

29. D5 RECEPTOR
 isolated from human genomic libraries in 1991.
 477 Amino acids protein.
 50 and 80% homology with the human D1 receptor in their coding regions and
transmembrane-spanning domains, respectively.
 Rat homolog of this receptor was initially termed the D1B receptor.
 The rat D1B receptor encodes a 475-amino-acid protein which is 83% homologous
with its human homolog, the D5 receptor.
 D1B and D5 receptors have asparagine-linked glycosylation sites in the amino
terminus and the second extracellular loop, a small third cytoplasmic loop with
putative phosphorylation sites, and a cysteine residue in the carboxyl terminus.
 The coding region is intronless.
 In the human genome, two pseudo genes related to the D5 receptor have been isolated
and termed D5c1 and D5c2.
 The nucleotide sequences of these pseudo genes are 95% conserved with the human D5
sequence.

30. D5 receptors
 D5c1 and D5c2 genes have shown to be transcriptionally active.
 D5 receptor gene has been mapped to chromosome 4.
 The D5c1 and D5c2 to chromosomes 1 and 2, respectively.
 Both the rat and human D5 receptor homologs stimulate adenylyl cyclase activity and bind
D1-selective ligands with similar affinities as the D1 receptor.
 Dopamine binds with a 5- to 10- fold higher affinity to the D5 receptor than to the D1
receptor. The reason for this high degree of pharmacological similarity is probably due to
high structural homology that these receptors show in the transmembrane-
spanning/ligand binding domains.
 Another notable distinction between the two D1-like receptors is that the D5 receptor has
been suggested to be constitutively active when expressed in HEK-293 cells(Human
Embryonic Kidney cells).
 D5 receptor mRNA expression has not been observed in the striatum suggesting that this
receptor may not play as large a role in motor control as the D1 receptor.
 In the rat, regions where D5 receptor mRNA expression is observed to be high include the
olfactory tubercles, hippocampus, hypothalamus, and mammillary bodies.

31. D2 receptor subfamily
 D2 receptor was the first DA receptor to be cloned, its isolation was dependent on
homology to a similar GPCR.
 The human D2 receptor homolog was subsequently cloned and found to be 96%
identical with the rat receptor with one amino acid deletion.
 Mapped to chromosome 11. While the coding region have 07 introns.
 D2 receptor contains a large third cytoplasmic loop, a short carboxyl terminal tail and
three asparagine-linked glycosylation sites in the amino terminal region.
 The main structural difference between the D2 and the D1 receptor subfamilies is that
the D2-like receptors have large third cytoplasmic loops and short carboxyl termini,
structural motifs that are characteristic of Gi/o-coupled receptors.
 When transfected into mammalian cells, cloned D2 receptors have been shown to
activate a variety of signal transduction pathways.
 In addition to adenylyl cyclase inhibition , these include stimulation of arachidonic
acid release, phosphatidylinositol hydrolysis and mobilization of calcium, regulation
of K+ channels, and suppression of prolactin release.

32. D2 receptor
 The areas of highest expression in the brain include the caudate putamen, nucleus accumbens, and
olfactory tubercle. Also found in dopaminergic cell bodies within the substantia nigra pars
compacta and ventral tegmental areas, suggesting an additional presynaptic role for the D2
receptor.
 Cellular localization in the striatum, where about 50–75% of the medium-sized cells appear to
express receptor mRNA.
 D2 receptor mRNA in high abundance are enkephalinergic neurons.
 also been observed in large-diameter cells in the striatum, the majority of which appear to be
cholinergic interneurons.
 two isoforms with different-sized coding regions have been isolated.
 D2 long (D2L) receptor contains a 29-amino-acid sequence which is absent from the D2 short (D2S)
receptor. This sequence is encoded by one of the eight exons of the D2 receptor gene.
 Both isoforms are found in human, rat, bovine, and murine tissue.
 Similar profiles in terms of affinity but different in regulation.
 Zhang et al. found that agonist pretreatment of D2L receptor–expressing cells resulted in up
regulation of receptor expression whereas a similar treatment of D2S receptor–expressing cells
resulted in receptor down regulation.

33. D3 receptor
 Cloned in 1990.
 52% overall homology and 75% transmembrane homology with the D2 receptor.
 The rat D3 receptor is 446 amino acids long and contains asparagine-linked glycosylation sites in
the amino terminus, a cAMP-dependent protein kinase recognition sequence in the third
cytoplasmic loop, and a cysteine residue in the carboxyl terminal domain. The human D3
receptor gene, which encodes a 400-amino-acid protein, has been cloned.
 Mapped to chromosome 3.
 The pharmacological profile of the D3 receptor is similar to that of the D2 receptor.
 D3 receptor is the only cloned DA receptor which is guanine nucleotide insensitive and
relatively ineffective in regulating adenylyl cyclase activity.
 Regulation of DA release, stimulation of neurite extension and branching, and activation of c-
fos (proto oncogene) and mitogenesis(A mitogen is a peptide or small protein that induces a cell
to begin cell division: mitosis. Mitogenesis is the induction of mitosis, typically via a mitogen)
have all been identified as D3 receptor–mediated events.

34. D3 receptor
 Seabrook et al. have also shown that the D3 receptor can depress Ca2+ currents in transfected
NG108-15 cells.
 Liu et al. also working with NG108-15 cells, have found that the D3 receptor can directly couple to
the modulation of K+ currents.
 In brain, localization is greater in hypothalamic and limbic nuclei such as the olfactory tubercle,
islands of Calleja, hippocampus, nucleus accumbens, and bed nucleus of the stria terminalis than in
the basal ganglia.
 Minimal expression is observed in the caudate and putamen.
 limited ligand specificity between D2 and D3 receptors.
 D3 receptor gene contains 05 introns.
 A functional variant has been identified in mice which lacks a 63-base pair sequence in the third
cytoplasmic loop.

35. D4 receptor
 A partial-length human D4 receptor cDNA was isolated by homology screening of a neuroblastoma
cell library with a D2 receptor probe.
 A full-length, correctly spliced D4 receptor cDNA clone was subsequently isolated from a library
constructed from COS cells which had been transfected with the D4 receptor genomic DNA.
 COS cells- are fibroblast-like cell lines derived from monkey kidney tissue. COS cells are obtained
by immortalizing CV-1 cells with a version of the SV40 virus that can produce large T antigen but has
a defect in genomic replication.
 The human D4 receptor is 387 amino acids long.
 41 and 56% homology with the D2 receptor coding and transmembrane regions, respectively.
 Its large third cytoplasmic loop contains a cAMP-dependent protein kinase recognition site and its
amino terminus contains one asparagine-linked glycosylation site.
 Mapped to chromosome 11.
 As with D2 receptors, agonist binding to D4 receptor is guanine nucleotide sensitive. D4 receptors are
coupled to inhibition of adenylyl cyclase when transfected into a variety of mammalian cell lines.

36. D4 receptor
 In rodents, the highest expression of D4 receptor mRNA is found in the heart.
 In rodent brain, expression is about 10-fold lower than in heart, with the highest levels observed in the
frontal cortex, amygdala, olfactory bulb, and hypothalamus. Very low levels of expression are detected
in the olfactory tubercles and striatum.

39. DA RECEPTORS AS SIGNAL TRANSDUCERS
 Dopamine transmits signals across cellular membranes by interacting with membrane-bound signal-
transducing receptors that induce changes in the level of intracellular second messengers.
 DA receptors couple to intracellular guanosine triphosphate (GTP)–sensitive heterotrimeric G-
protein complexes, although D3 receptors may be an exception to this.
 The G-protein subtype coupling preference of the receptor determines the type of intracellular second-
messenger response. This selectivity of G-protein coupling is controlled primarily by the subtype of the
alpha subunit and is secondarily modulated by the subtype of beta and gamma subunits.
 It is becoming apparent that heterooligomerization of DA receptors with other non-DA GPCRs can
dramatically affect G-protein coupling preferences.
Hetrooligomerization- The formation of a heterooligomer. Any oligomer composed of two or more
different monomers.
 For instance, D2 receptors are known to prefer to couple with Gi/o over Gs, but when coexpressed with
cannabinoid CB1 receptors, this D2 receptor–mediated coupling preference is reversed.
 The strength of coupling to G-protein subfamilies and subtypes (isoforms) is known to vary among the
DA receptor subtypes, the extent of intracellular signaling can depend in large part upon the presence
of the appropriate isoforms of the enzymes activated by the G proteins.
 For example, D3 receptor stimulation only leads to a robust increase in cAMP when the adenylyl
cyclase isoform V is present.

40. DA RECEPTORS AS SIGNAL TRANSDUCERS
 D1-like DA receptors prefer to couple to Gas proteins which stimulate the enzyme adenylyl cyclase,
while all the D2-like DA receptors couple to Gai/o proteins that inhibit this enzyme and the pertussis
toxin–insensitive Gaz .
 D2, D3, and D4 receptors have been shown to induce mitogenesis in serum-sensitive cell lines via a G-
protein-dependent mechanism.
 D2 receptors have also been shown to couple to Gaq, and thereby stimulate the enzyme phospholipase
C.
 The D4 receptor is among the growing number of known nonopsin receptors that couple to transducin
(Gat), which is in line with the localization of D4 receptors in the retina.
 TheGPCRcycle begins when an agonist binds to the receptor and converts it from the inactive low-
affinity state to the active high-affinity state.
 This induces a conformational change in the receptor that allows the inactive form of the heterotrimer
G-protein complex to bind.
 This in turn promotes the exchange of guanosine diphosphate (GDP) for GTP from the α-subunit of
the G-protein in the presence of magnesium ions and activates the G-protein complex.

41. DA RECEPTORS AS SIGNAL TRANSDUCERS
 The activated GTP α -bound subunit of the G-protein complex undergoes a conformational change, which
promotes the dissociation of its G-protein beta and gamma subunits as well as its own dissociation from
the receptor.
 Once the receptor is no longer bound by G protein, it converts back to the low-affinity state, which
promotes the dissociation of agonist.
 In some cases the free b and g subunits may associate with ion channels or other proteins and modulate
their activity.

42. DA RECEPTORS AS SIGNAL TRANSDUCERS
 The activated GTP-bound alpha-subunit associates with effector enzymes and either potentiates or
inhibits their activity until the bound GTP is auto hydrolyzed to GDP by the G protein.
 This results in a change in the conformation of the inactivated GDP-bound alpha subunit, which
favors dissociation from the enzyme and reassociation with its b and g subunits, and the cycle begins
a new.

44. CLASSIFICATION OF DOPAMINERGIC DRUGS ACCORDING TO
TREATMENT CATEGORY
 Dopaminergic systems regulate a variety of cognitive and motor behaviors, drugs that target DA
receptors, transporters, and metabolic enzymes are vital to the pharmacotherapeutic management of
neurological and psychiatric conditions through the palliative relief of selected symptom modalities.
 While drugs are typically classified on the basis of their molecular mechanisms of action, such as
agonist, partial agonist, inverse agonist, or antagonist, it is often useful to group them according to
their clinical applications.
 Parkinson’s Disease :
 It is a slowly progressive neurodegenerative disease characterized by rigidity, tremor, hypokinesia
with secondary manifestation like defective posture and gait.
 Dopamine receptor agonists provide relief to Parkinson’s disease patients by replenishing the lost
dopaminergic activity in the striatum that results from the death of DA-producing neurons
projecting from the substantia nigra.
 Antiparkinsonian drugs are the DA precursor L-DOPA; apomorphine, pramipexole, ropinirole, and
the ergolines bromocriptine and pergolide.
 Pergolide and apomorphine are sparingly selective for D2-like over D1-like DA receptors, and
pramipexole and ropinirole are moderately selective for D3 over D2.

45. Parkinson’s Disease
 Pramipexole has other properties that would be beneficial for slowing the progression of
neurodegeneration.
 It is an effective antioxidant at high concentrations and can block the mitochondria transition pore
at low concentrations.
 Chronic stimulation of D2 DA receptors is associated with potentially severe extrapyramidal side
effects, like tardive dyskinesia, efforts have focused on developing D1-selective agonists.
 Most D1-selective agonists are not highly selective over D2 or that many have low efficacy.
 Most D1- selective agonists have low oral bioavailability or they rapidly desensitize D1 receptors,
producing tolerance.
 An exception- Dinapsoline sparingly D1-selective (approximately six-fold selective over D2) agonist,
but it remains to be seen.

47. Schizophrenia
 Abnormally high dopaminergic transmission has been linked to psychosis.
 Increased dopaminergic functional activity, specifically in the mesolimbic pathway, is found in
schizophrenic individuals. However, decreased activity in the mesocortical pathway, may also be
involved.
 The treatment of psychosis has been closely correlated with the blockade of D2 DA receptors.
 The D2-selective partial agonist ARIPIPRAZOLE has been shown to not only be effective in
treating psychosis but also be free of the extrapyramidal and neuroendocrine side effects
common of typical antipsychotics (e.g., fluphenazine and haloperidol), which are due to excessive
D2 receptor blockade.
 Aripiprazole appears to be that it reduces dopaminergic activity without completely blocking it.
 Atypical antipsychotics have reduced extrapyramidal and neuroendocrine side-effect liability and, in
general, have lower affinity for the D2 receptors than typical antipsychotics, but acts on D1,D3,D4
receptors.
 Newer atypical antipsychotics (i.e., Clozapine, Olanzapine, Quetiapine, Risperidone, and
Ziprasidone) as it lacks the cardiovascular and blood dyscrasia liability and has a reduced
obesity/diabetes liability.

49. Bipolar Mania, Autism, Alzheimer’s Disease, and Tourette’s
Syndrome
 Some of the second-generation atypical antipsychotics are also used to treat psychosis and/or agitation
and aggression of the Alzheimer’s type as well as a range of symptom modalities related to other
psychiatric or neurological disorders.
 Risperidone has been shown in double-blind placebo-controlled studies to effectively treat autism
spectrum disorders.
 Atypical antipsychotics have also proved effective in treating bipolar mania.
 While typical antipsychotics (e.g., pimozide and haloperidol) are approved for the treatment of the tic
component of Gilles de la Tourette’s syndrome, atypical antipsychotics appear to be promising
alternatives.

50. Attention-Deficit Hyperactivity Disorder(ADHD)

51. Attention-Deficit Hyperactivity Disorder(ADHD)
 The psychostimulants (amphetamine and methylphenidate) are used to treat ADHD.
 These are indirect dopaminergic (and norepinephrine) agonists, meaning that they increase levels of
synaptic DA (and norepinephrine) by altering the activity of synaptic transporters and/or the activity
and distribution of vesicular monoamine transporter-2.
 Animal studies suggest that selective DA D4 antagonists may have potential as non-psychostimulant
anti-ADHD drugs.
 Neonatal rodents injected intracisternally with 6-hydroxydopamine (and a norepinephrine transport
blocker to spare noradrenergic neurons) develop a temporary juvenile hyperactive phenotype, which
has been used as a model for hyperactivity in ADHD. This hyperactivity is reversed by some D4-
selective antagonists.

52. Attention-Deficit Hyperactivity Disorder(ADHD)

53. Substance Use

54. Substance Use
 Dopamine is the primary neurotransmitter involved in the reward pathway in the brain. Thus, drugs
that increase dopamine signaling may produce euphoric effects.
 Many recreational drugs, such as cocaine and substituted amphetamines, inhibit the dopamine
transporter(DAT), the protein responsible for removing dopamine from the neuronal synapse.
 When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signaling.
 When this occurs, particularly in the nucleus accumbens, increased D1 and decreased D2 receptor
signaling mediates the “rewarding” stimulus of drug intake.
 Targets for the potential treatment of substance use, this goal has yet to be fully realized and the
findings in this field tend to be controversial.
 For example, systemically administered D1-selective agonists (e.g., ABT-431) reduce cocaine-seeking
behavior in rats and human.

56. Other uses
 Agonists with high selectivity for the D4 DA receptor have been shown recently to
induce penile erection in male rats and they continue to be evaluated for possible use
in erectile dysfunction.
 double-blind and placebo-controlled clinical trials with the moderately D3-selective
agonist Ropinirole have demonstrated that it is effective in treating restless-leg
syndrome.
 Dopamine receptor antagonists that do not cross the blood–brain-barrier, such as
domperidone, are effective antiemetics as they block the D2 receptors residing on the
peripheral portion of the chemoreceptor trigger zone.

57. Dopaminergic Pathways

60. references
 http://flipper.diff.org/app/pathways/info/1597
 http://plantbiotech.metu.edu.tr/plantbiotech/bio417/dopamine_receptors.pdf
 http://slideshare.net/
 JOHN A. S, DAVID R. SIBLEY, “Dopaminergic Neurotransmission”; Handbook of
Contemporary Neuropharmacology, Edited by David R. Sibley, Israel Hanin, Michael
Kuhar, and Phil Skolnick. Copyright r 2007 John Wiley & Sons, Inc. page no.221-239.