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Dopamine and Depression
Dopamine)and)Depression)
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Acknowledgements
I would like to thank my tutor, Prof. Giuseppe Di Giovanni for the time, the patience, and the
insight on the subject that were crucial in helping me write this paper.
In addition, I extend my thanks to Prof. Richard Muscat who also helped me in setting up this
research paper.
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Abstract
This report treats the nature of dopamine as chemical, followed by a discussion regarding the
correlation between its anatomical territories within neurologic terms, its neurophysiology,
the roles it satisfies in everyday behaviour, and how, within this poorly understood
complexity, depressive symptoms evolve to render the condition one of the most disabling in
the modern world accounting for morbidity of many patients, as well as mortality, not as a
direct cause, but through suicidal attempts as a result of the concomitant perception of self-
worthlessness and guilt that comes with depression.
Keywords: dopamine, ventral tegmental area, substantia nigra, depression, antidepressants,
dopamine transporter
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Contents
Acknowledgements 1
Abstract 2
Figures 4
Abbreviations 5
1 Dopamine 7
2 Dopaminergic Functions 7
3 Dopaminergic Nuclei 8
4 Receptor Physiology 11
5 Dopamine Signalling 14
6 Dopaminergic mechanisms of behaviour 15
7 Aetiology of Depression 17
8 Therapeutic Drugs 19
9 Conclusion 23
10 Bibliography 24
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Figures
Figure 1: Distribution of DA neuron in 9 cell groups in the adult rodent brain
Figure 2: The dopaminergic synapse
Figure 3: Pharmacologic modulation of monoamine neurons
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Abbreviations
1-PP 1-(2-pyramidal)-piperazine
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-hydroxytryptamine
5-HT1A: 5-hydroxytryptamine receptor type 1A
5-HT1B: 5-hydroxytryptamine receptor type 1B
5-HT2C: 5-hydroxytryptamine receptor type 2C
5-HT4: 5-hydroxytryptamine receptor type 4
5-HT6: 5-hydroxytryptamine receptor type 6
5H-T7: 5-hydroxytryptamine receptor type 7
ADHD: attention deficit hyperactivity disorder
BDNF: brain-derived neurotrophic factor
BP: blood pressure
COMT: catechol-methyltransferase
CREB: cyclic-AMP-response-element-binding protein
DAT: dopamine transporter
DAT-1: dopamine transporter type 1
DAT-2: dopamine transporter type 2
DOPA: dopamine
GABA: gamma-aminobutyric acid
GSAD: generalized social anxiety disorder
HR: heart rate
L-DOPA: Levo-Dopa
LTD: long-term depression
LTP: long-term potentiation
MAO: monoamine oxidase
MAOA: monoamine oxidase A
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MAOB: monoamine oxidase B
NAc: nucleus accumbens
NMDA : N-methyl-D-aspartate
OCD: obsessive compulsive disorder
PFC: prefrontal cortex
SGZ: subgranular zone (of hippocampus)
SN: substantia nigra
SSRI: selective serotonin reuptake inhibitor
THC: tetra-hydrocannibol
VAT: ventral tegmental area
VEGF: vascular endothelial growth factor
VGF: vascular growth factor
VMAT: vesicular monoamine transporter
VMAT: vesicular monoamine transporter
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1 Dopamine
Dopamine is a catecholamine present in the substantia nigra pars compacta (SNc) and ventral
tegumental area (VTA) of the brain acting also as a neurohormone on release from the
arcuate nucleus in the hypothalamus. As a hormone, it inhibits prolactin release by the
anterior lobe of the pituitary gland. Its chemical formula is C6H3(OH)2-CH2-CH2-NH2
(Costanzo, 2009).
2 Dopaminergic functions
Dopamine is a biogenic amine, being present in several regions of the brain but to a major
extent in the corpus striatum which receives input from the substantia nigra , having a vital
role in body movement (dopaminergic neurons in substantia nigra degenerate in Parkinson’s
resulting in the motor dysfunction characteristic of the disease) (Purves et al., 2008).
Besides being a neurotransmitter, dopamine is a neurohormone released by hypothalamus to
inhibit the release of prolactin by the anterior lobe of pituitary (Costanzo, 2009).
Dopamine has a role in cognition and behaviour .Fluoro-L-m-tyrosine (FMT), a substrate of
the enzyme that catalyses DA production, in higher than normal amounts, indicates disrupted
dopaminergic function during development and aging. It is these dopamine system deficits
both in striatum and the connected frontal cortex that cause cognitive impairment (Braskie et
al., 2008).
It is involved in motivation reward and reinforcement. It is a product of tyrosine metabolism,
being produced from dihydroxyphenylalanine dopamine(DOPA) by DOPA decarboxylase in
cytoplasm of presynaptic terminals. It is loaded into synaptic vesicles by a vesicular
monoamine transporter(VMAT) . Its action in the synaptic cleft ends on its reuptake into
nerve terminals or glia by a sodium- dependent dopamine transporter, the action of which is
blocked by cocaine. Within the neurons or glia, dopamine is degraded via the action of
monoamine oxidase (MOA) or catecholamine methyltransferase (COMT). These enzymes
are the targets of some antidepressants (Purves et al., 2008).
Dopamine drives goal-directed learning and potentiation of memory. Dopamine modifies
excitatory synapses in dopamine terminal fields, including the prefrontal cortex within
circuits controlled tightly by GABAergic inhibitory tone. Through both D1and D2-class
receptors, dopamine enables the induction of long-term potentiation within a 30ms window
during which inhibitory transmission is suppressed (Tai-Xiang and Wei-Dong, 2010).
Background dopamine signalling enables the induction of long-term potentiation (LTP) in the
prefrontal cortex (PFC). A pathological conversion of LTP to Long-term depression (LTD)
may occur in the prefrontal cortex (PFC) when the basal level of stimulation of dopamine and
NMDA receptors is low, resulting in cognitive impairment and disruption of goal-directed
behaviour. (Yoshiki et al., 2006).
Motivation of actions related to the gain of rewards is entailed through dopamine release
during rewarding experiences, thereby inducing learning. Most dopamine (DA) neurons, in
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fact, are strongly activated by unexpected primary rewards as are food and water, very often
interpreted through the phasic ‘bursts’ of activity (phasic excitations including multiple
spikes (Bromberg et al., 2010).
It is the interactions between the neocortex, amygdale and related subcortical circuits that
bring about what we know as feelings or emotions. Neuronal DA release , presynaptic sites
for DA uptake, enzymatic machinery for DA synthesis and catabolism have been
demonstrated in the amygdale (Kilts et al.,1987). The amygdala projects to the ventral
portions of the basal ganglia where cortico-striatal projections are received from prefrontal
cortex regions associated with emotion processing. Abnormal cerebral blood flow was found
in these circuits in depressed patients (through functional imaging studies) (Purves et al.,
2008).!!
Dopamine influence in the striatum is essential to motor behaviour (Liang et al., 2008).
Dopamine effects in the striatum are mediated through D1 and D2 dopamine receptor
subtypes, which subserve the direct and indirect striatal projection neurons respectively
(Gerfen et al., 2002)
These ventral regions of the basal ganglia that are neuromodulated by dopamine influence,
affecting the processing of reinforcement signals which leads to potenitation of addiction in
the limbic regions (due to recreational drug consumption). Thus, the area which is
responsible for the physiological process of depression, is related to the “high” experienced
with recreational drugs and the concomitant compulsive behaviour towards drug consumption
in search for the correlated rewards (Purves et al., 2008).
3 Dopaminergic Nuclei
The substantia nigra is a black area in the midbrain (due to its high melanin content) which is
highly involved in modulating movement (Ikemoto, 2007). The ventral tegmental area
projects towards the striatum and the nucleus accumbens, an area concerned with motivation
and rewarding stimuli, whereby dopamine levels increase on eating, having sex, or taking
recreational drugs. Dopamine travels also to the prefrontal cortex, where it is believed to have
a role in schizophrenia, attention deficit hyperactive disorder (ADHD), and obsessive
compulsive disorder (OCD) (Ikemoto, 2007).
Research shows dopaminergic neurons to be localized in the posteromedial VTA and central
linear nucleus raphe from where they project to the ventromedial striatum (medial olfactory
tubercle and medial nucleus accumbens shell). The lateral VTA projects mainly to the
ventrolateral striatum. Anteromedial VTA has insignificant projection towards the ventral
striatum. This is in line with behavioural research which suggests that cocaine and
amphetamine would be much more rewarding on administration into the ventromedial
striatum than into the ventrolateral striatum. Opiates and nicotine tend to have more of their
euphoric effect when administered into the posterior VTA or the central linear nucleus
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(compared with administration into anterior VTA). The medial projection system is crucial in
arousal regulation (Ikemoto, 2007).
Cell bodies of dopaminergic neurons projecting to the nucleus accumbens and olfactory
tubercle spread at a 45° angle (to the anteroposterior axis) from the posteromedial to
anterolateral VTA. Medial olfactory tubercle and medial accumbens shell (areas of striatum
triggering drug-related arousal) receive strong dopaminergic innervation from the
posteromedial VTA and central linear nucleus (areas of ventral midbrain triggering drug-
related arousal), in contrast with such innervation from anteromedial or lateral VTA being
insignificant. Three different nuclei of dopaminergic neurons exist in the ventral midbrain:
A8, A9, A10, the latter having limbic-related afferents to the VTA area (Ikemoto, 2007). A8
is located in the retrorubral area, A9 in the SN, and A10 in the VTA. A12 is present in the
hypothalamus and is responsible for the inhibitory projections upon the anterior pituitary (Di
Giovanni et al., 2009).
The ventral midbrain consists of the ventral and dorsal tiers. The dorsal tier contains the
ventral striatal, limbic and cortical areas, as well as the matrix of the dorsal striatum. The
ventral tier consists of the patch area and is the area associated with pathophysiology of
Parkinson’s disease (Di Giovanni et al., 2009).
VTA projects to the limbic and hippocampal areas (Di Giovanni et al., 2009). The meso-
limbic dopamine system controls part of drug-reward mediation (Ikemoto, 2007). The A10
dopamine nucleus in the VTA projects primarily to the ventral striatum (nucleus accumbens
and olfactory tubercle). A10 dopaminergic dysfunction has been associated with the
pathology of schizophrenia. The nigro-striatal dopamine system projects from the A9 nucleus
to the dorsal striatum. It is involved with the pathology of Parkinson’s disease. A10 nuclei
project also to the septum, hippocampus, amygdala and prefrontal cortex (latter two centres
receive inputs from substantia nigra) (Ikemoto, 2007).
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Figure 1 : Distribution of DA neuron in 9 cell groups in the adult rodent brain
(Di Giovanni et al, 2009)
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4 Receptor Physiology
Dopamine, on release acts on 7-transmembrane G-protein coupled receptors (GPCRs) which
act either by activating or else by inhibiting adenyl cyclase, the second messenger (Purves et
al., 2008; Di Giovanni et al., 2009).
In a study involving generalized social anxiety disorder and obsessive compulsive disorder
patients (with a group of healthy subjects being the control), it was found that general social
anxiety disorder (GSAD) comorbid with OCD may be correlated to a decrease in D2 receptor
density in the striatum (Schneier et al., 2008).
Such a decrease was previously reported in non-comorbid GSAD patients (Schneier et al.,
2000). However, this decrease was not found in OCD patients (non-comorbid) which
contradicts the result of a similar study (Denys et al., 2004 ) whereby quantitatively, the latter
study is more representative and concluded that striatal D2 density is decreased. Also in 10
OCD subjects (mostly female and having been on medical treatment prior to experiment
washout period), a lower blood pressure (BP) was recorded in the left caudate, but not in the
right caudate or left or right putamen (Denys et al., 2004). Schneier et al., (2000) found a
22% decrease in overall striatal BP of OCD patients, however, this finding being within the
limit of the relatively small number of subjects involved in the experiment.
Low striatal D2 receptor availability in OCD comorbid with GSAD could function by several
means at the receptor level such as the possibility of higher levels of endogenous dopamine
competing with the radio-ligand used in the experiment with the possible result of down-
regulation postsynaptic striatal D2 receptors. Also affinity of striatal D2 receptors for the
ligands could have changed. Also D2 receptor function could have been diminished by a
deficit in the receptor density brought about as a repercussion of decreased dopaminergic
neurotransmission within the striatum (Schneier et al., 2000).
Jonnson et al. in a study whereby subjects were examined for D2 receptor density and then
made to answer a personality questionnaire noticed a correlation between receptor density
and trait detachment.
Dopamine transporters DAT-1 clean up dopamine from the cleft in the stratum and basal
ganglia, followed by enzymatic breakdown by monoamine oxygenase MAOA or MAOB into
3,4-dihydroxyphenylacetic acid. In the prefrontal cortex, it is however collected by
norepinephrine transporters on neighbouring norepinephrine neurons, then broken down
bycatecholamine-O-methyl transferase(COMT) into 3-methoxytyramine. Dopamine receptors
are five: D-1, being D-2,D-3,D-4,D-5.
D1 and D5 are stimulatory meaning they stimulate the cell they are on, on being contacted by
dopamine (the cell propagates action potential). D2, D3 D4 are inhibitory receptors thus
inhibiting the neuron by reducing the depolarisation further away from the threshold that has
to be reached in order for n action potential to be propagated (Ikemoto, 2007). These
receptors are all G-protein coupled metabotropic receptors with seven transmembrane
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regions. They modulate the release of dopamine, acetylcholine and glutamate (Di Giovanni et
al., 2009).
The D1 receptor family is positively coupled to adenylate cyclase via a stimulatory G-protein.
D1 is found in the caudate and putamen (striatum) and in the ventral part of the striatum
(NAc). D5 is present in hippocampus, hypothalamus and midbrain, and is more selective for
agonists (Di Giovanni et al., 2009).
The D2 receptor family is negatively coupled to adenylate cyclase via and inhibitory G-
protein. D2 is found in the caudate and putamen, nucleus accumbens and midbrain amygdale.
D3 is found in nucleus accumbens and midbrain. D4 is found in thalamus, hypothalamus and
olfactory bulb.
DAergic neurons bear D2 and D3 autoreceptors at axon terminal(for modulation of terminal
excitability and the release of DA from the nerve terminals and /or its synthesis) and
somatodendritic regions(modulation of the excitability of local dendritic regions) (Tepper et
al.,1997)
Two transporters exist for reuptake (DAT-1, DAT-2), but drugs do not seem to discriminate.
Cocaine, as an example, blocks both receptors rendering dopamine effects to last longer
stimulating over and over again the adjacent neurones leading to feelings of high, focus, and
euphoria (Ikemoto, 2007).
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Figure 2
The dopaminergic synapse (Di Giovanni et al., 2009).
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5 Dopamine Signalling
DA neurons function in distinct tonic and phasic timescales to distinguish on the physiogical
level behaviourally relevant and distinct information. The DA neuron fires tonically at a low
frequency that consists of individual action potentials. Episodes of DA neuron phasic burst
firing of near 20Hz do occur. Phasic or burst firing effects a greater extracellular DA release
than that with tonic, single-spike firing activity. These two various modes of signal arise from
midbrain DA neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area
(VTA) which project to the whole striatum.
Phasic changes are induced via a Ca2+-dependent process (Di Giovanni et al., 2009) They are
deemed to play crucial roles in learning, because in most cases associative learning depends
on temporal contiguity (referring to the relatively short time span between response and
reinforce or between conditioned stimulus and unconditioned stimulus). Tonic changes may
play a critical role in motivation and affect. Tonic signals in the ventral striatum actually do
correlate with hyper-activity effects on being examined by microdialysis (Ikemoto, 2007).
Regulation of DA release is done via the following: spontaneous discharge of DA neurons;
auto-inhibitory processes regulating synthesis, release and neural firing rate; and excitatory
and inhibitory inputs made by a heteroreceptor population of DA neurons (Di Giovanni et al.,
2009).
50% of DA neurons are active at any one time. Reward and some neurotransmitters increase
the number of active neurons. They have a high threshold membrane potential of -30mV and
a resting potential of -50mV.
Ca2+-dependent K+-channels hyperpolarize the potential to -60mV after AP. Depolarization is
via a Ca2+-dependent pacemaker-like slow depolarization. Firing rate changes according to
motivation and attention. Unpredictability of reward results in DA neuron activation.
Absence of expected reward results in a decrease in DA neuron firing. DA neurons produce a
broad AP (>2ms), having a pacemaker-like firing pattern in one modality which is the single
spike mode (tonic release). The other modality is the burst mode whereby spikes are related
close to each other in time. An intermediate mode exists which is in compromise between the
single spike and burst modes.
Voltage dependent calcium channels exist in three forms. One is long-lasting (in its effect),
known as CaV1 (L-type), another is CaV2 (with different types being P/Q-type, N-type, and
R-type), and a transient (short-lasting effect) CaV3 (T-type).
L- and P/Q type channels are involved with the depolarizing phase of the pacemaker
potential. The T-type channels are probably involved in both the depolarizing and
repolarising phases of the potential (Di Giovanni et al., 2009).
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6 Dopaminergic mechanisms of behaviour
The meso-ventromedial striatal dopamine system does seem to play a major role in regulating
arousal and situations entailing reciprocal interaction between the mind and the body.
Elevation to heightened states of mind/body interaction allows animal/environment active
interaction as well as fight or flight modes. Activation of the system leads to positive affect, a
state resulting in approach learning (reward notion within the mind)Inhibition of the meso-
ventromedial striatal dopamine system, on the other hand, appears to lead to negative affect
and avoidance learning (Ikemoto, 2007).
The meso-ventromedial striatal dopamine system functions as Hebb defined, as a general
drive state being “an engine, but not a steering gear” The meso-ventromedial striatal
dopamine system enables conduction of signals from the limbic system, which in turn detects
vital changes in the environment relating to self-preservation and procreation. Sensation of
this system is brought about by regulatory imbalances, incentive stimuli and especially when
the reward is uncertain of being reachable (Ikemoto, 2007).
Behavioural variation, a process that generates unconditioned responding, is normally
triggered by the perception of novelty, opportunity, danger or uncertainty. The induction of
this process appears to be mimicked by the activation of the meso-ventromedial striatal
dopamine system. Administration of drugs into the posteromedial VTA or the central linear
nucleus, which activates dopaminergic projections to the ventromedial striatum, elicits
heightened locomotion and rearing, behaviours that enable organisms to interact with the
environment. Locomotor activity is elicited by rewarding treatments such as microinjections
of the cholinergic receptor agonists carbachol or cytisine, NMDA receptor agonists µ-opiate
receptor agonists; or the cannabinoid receptor agonist delta-9 tetrahydrocannibol(THC) into
the posteromedial VTA, or the GABA receptor agonist muscimol into the central linear
nucleus. Thus, these observations are consistent with the role of the meso-ventromedial
striatal dopamine system in action-arousal and behavioral variation. The significance of these
findings is that the activation of the meso-ventromedial striatal dopamine system elicits
unconditioned responses (Ikemoto, 2007)
Ikemoto and Panksepp (1999) proposed dopamine in the nucleus accumbens to effect
incentive learning. During a consummatory phase, increased dopaminergic activity in the
accumbens increases the perceived motivational value of the incoming stimulus, while
dopaminergic inactivity during the consummatory phase decreases the same value. Fast-scan
cyclic voltammetry data suggests that dopaminergic signals in the accumbens occurring just
after lever-pressing (the consummatory phase) becomes smaller and smaller during the
extinction phase, while response intervals increase more and more (Stuber et al., 2005). On
execution of an action and receival of a concomitant reward, ventral striatal dopaminergic
projections participate in the potentiation of incentive memory. Disturbing of normal
dopaminergic activity in this striatal area during consummatory behaviour followed by
appetitive behaviour will lead to re-organization of a stimulus-outcome and stimulus-action
association, such that the presentation of conditioned stimuli in the next trial will be
ineffective in eliciting conditioned responding (Ikemoto, 2007).
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Following a study, dopamine receptor agonist bromocriptine was found to improve set
switching by stimulating dopamine D2 receptors. In the studied cases, bromocriptine reduced
the error switch cost in individuals with genetically-based low dopamine levels, This
beneficial effect of bromocriptine on set switching was ablated by pretreatment with the
selective dopamine D2 receptor antagonist sulpiride. This finding surely suggests a role for
dopamine D2 receptor signalling in set switching, a role set outside of the areas of working
memory and learning in humans. According to a theory by Durstewitz and Seamans (2008)
and Seamans and Yang (2004), dopamine D2 receptor stimulation enables rapid switching
between various tasks (multitasking of the brain), by allowing multiple stimuli to input
simultaneously on the prefrontal cortex (Van Holstein et al., 2011).
7 Aetiology of Depression
Aetiology of depression is very poorly defined, most cases being idiopathic, with associations
being made to other conditions as are cancer, as a side-effect of isotretinoin treatment, genetic
susceptibility and stressful life events. Genetic predisposition is not believed to be a main
determinant, however in conjunction with environmental risk factors, some depressive genes
may in fact precipitate depressive episodes in patients, keeping in mind that environmental
factors (stressful situations) may also be hereditary in some individuals (Krishnan and
Nestler, 2008).
In a Vietnam Head Injury Study patient sample, Vietnam veterans with bilateral ventromedial
PFC damage reported a significant lowering in depression severity than did fellow veterans
sustaining damage to other areas of the brain or veterans with no brain damage, in particular
regard to the cognitive/affective symptoms of depression. This is mainly due to the vmPFC
being home to the processes of self-awareness and reflection (Koenigs et al.,2008)
Dysfunctional changes within some highly interconnected ‘limbic’ regions have been labelled
as the sites for pathophysiology of depression and antidepressant action. Post-mortem and
neuroimaging studies of depressed patients have been known to report reductions in grey-
matter volume and glial density in the prefrontal cortex and the hippocampus, regions
believed to mediate depressive cognition, such as feelings of worthlessness and guilt. Activity
within the amygdale and subgenual cingulated cortex is correlated with dysphoric emotions,
being transiently increased with transient sadness in normal subjects, and chronically
increased in depressed individuals, then improving with treatment. The nucleus accumbens is
a striatal subregion associated with reward pathways (Krishnan and Nestler, 2008).
The mentioned forebrain regions are under modulation by monoamine projections from
midbrain and brainstem nuclei, entailing the release of dopamine by VTA projections,
serotonin from the dorsal raphe located in the periaqueductal grey area surrounding the
cerebral aqueduct, and noradrenaline from the locus coeruleus located in the tegmentum of
midbrain and pons. These neurotransmitters have a role in alertness, awareness, and arousal.
They also act as modulators of the salience of emotional stimuli. Depressive symptoms are
probably mediated by dysfunction in a diffuse series of neural networks, however, its
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aetiology goes far beyond what we understand today as a simplistic tagging of compartments
with specific functions. The amygdale, for example, is associated with fear and anxiety
pathways (Krishnan and Nestler, 2008).
A role for neurotrophins has been proposed, with studies being focused on one in particular;
brain-derived neurotrophic factor(BDNF). BDNF signalling decreases in the hippocampus of
depressed patients who post-mortem also present with volumetric decreases in the
hippocampus and other relevant forebrain regions, which also underline the deficiency of
neurotrophins in depressed patients. This theory however is controversial, as in some
experiments, the theory was disproved and BDNF actually is depressive in the VTA and
NaC. BDNF-mediated signalling effects neuroplasticity in response to stress and
antidepressants, these effects being both region-specific and antidepressant-specific, taking
place in conjunction with other potent genetic and environmental factors (Krishnan and
Nestler, 2008).
Antidepressant treatments tend to bring about adult hippocampal neurogenesis whereby
neural progenitors of the subgranular zone (SGZ) in the hippocampus divide by mitosis
producing new neurons which differentiate to be integrated into the dentate gyrus. Studies in
rodent models reveal that blockade of hippocampal neurogenesis prevents the therapeutic
effects of most antidepressant treatments. Antidepressants, increases the quantity of growth
factors in the hippocampus that influence neurogenesis. These include BDNF (which
promotes neuronal survival), as well as vascular endothelial growth factor (VEGF) and nerve
growth factor (VGF), being themselves intrinsically of an antidepressant and pro-neurogenic
nature (at least being so in rodents). Certain activities do stimulate increases in hippocampal
neurogenesis which increases neuronal propagation and signalling through hippocampal
subfields allowing for hippocampal networks to adapt and learn from these new experiences.
This has its repercussion as the same process of intact neurogenesis during stressful episodes
acts to promote maladaptive learning thereby promoting depressive sequelae. Stress in many
forms does reduce subgranular zone (SGZ) cell proliferation, however it is not the decreased
neurogenesis itself that does produce depression (as studies in rodents with destroyed
neurogenesis have shown). Mechanisms that are potential actors in the promotion of
depressive symptoms in a physiological response to stress are various from one neural circuit
to the next. Also, they can be distinct from the alterations in brain physiology that are
responsible for endogenous depression (one that is present in absence of a major external
factor). Neuroplastic events that follow antidepressant therapy do not always function in a
manner totally counteractive to the plasticity induced by stress. They do so, however in
separate, and sometimes somehow paradoxically, parallel manners (Krishnan and Nestler
2008).
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8 Therapeutic Drugs
Dopamine does have its use on infusion into the bloodstream, whereas it is used to divert
blood to vital organs (brain, heart) as well as increasing blood pressure. However, it cannot
cross the blood/brain barrier and therefore is ineffective in the treatment of diseases
characterised by dopamine deficiency such as Parkinson’s and depression (Di Giovanni et al.,
2009).
Stress does reduce SGZ cell proliferation, however decreased neurogenesis does not itself
produce depression (Krishnan and Nestler, 2008). Many antidepressants induce adult
hippocampal neurogenesis — whereby neural progenitors of the SGZ divide by mitosis to
form new neurons regenerating the dentate gyrus. This is brought by an increase in
hippocampal growth factors; BDNF (enhances neuron survival) and VEGF, as well as VGF,
all having antidepressant effects in the subject.
There is no correlation between age and hippocampal volume in medically healthy subjects
while smaller hippocampal volumes are found in subjects with a history of depression
(Sheline et al., 1999). A decrease in hippocampal volume, arguably attributed to
hypercortisolism (which is not addressed by many modern-day antidepressants) is recorded in
the remission period in depressed subjects (Sapolski, 2001).
Antidepressants are designed to effect an acute monoamine augmentation, through
inhibiting neuronal reuptake (for example, selective serotonin reuptake inhibitors(SSRIs)
such as fluoxetine) or by inhibiting degradation (for example, monoamine oxidase inhibitors
such as tranylcypromine). Although these monoamine-based agents are potent
antidepressants, the chemical cause of depression is far more elaborated than a simple
deficiency of central monoamines. Monoamine oxidase inhibitors and SSRIs produce
immediate acute increases in monoamine transmission, however mood-enhancement takes
place over weeks of treatment, with mood generally becoming worse before becoming better.
Experiments show that decreasing monoamines worsens mood in unmedicated depressed
patients, the same test having no effect whatsoever on mood in healthy controls. Studying on
rodent stress models have shown that enhancements in dopamine and noradrenaline
transmission can have adverse effects in stress-related disorders by strengthening memories
of past aversive events thereby affecting recovery (Krishnan and Nestler, 2008).
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Figure 3
The drug a-methyltyrosine inhibits tyrosine hydroxylase (one step in the DA production
pathway). Amphetamine increases cytosolic DA concentration in the presynaptic neuron, as
well as inducing reverse transport of DA from the transporter DAT back into the synaptic
cleft. Cocaine binds the reuptake dopamine receptor resulting in a rise in synaptic cleft
neurotransmitter (Di Giovanni et al., 2009).
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The first antidepressants used in therapy were nonselective, irreversible inhibitors of both
MAO-A and MAO-B (e.g., phenelzine and tranylcypromine) (Murphy et al., 2000).
Following the discovery that antidepressant efficacy needed only MAO-A (not MAO-B
inhibition) and that the dangerous potentiation of pressor responses to ingested tyramine
while on MAO-A inhibition (due to increased production of cathecolamines leading to
hypertension) could be well decreased by reversible inhibitors of MAO-A led to the
development of more efficient and safe drugs (Murphy et al., 2000).
Moclobemide is one of the most studied reversible selective MAO-A–inhibiting
antidepressant now available in most of the global market.
The drug elicits good tolerance within subject with no anticholinergic or cardiovascular side
effects. Nausea was the only apparent side effect. Restriction of tyramine in the diet along
with drug intake in between meals diminishes chances of potential interactions with tyramine
in food. Although a weak MAO inhibitor in vitro, in the body it is rapidly metabolised to
potent MAO-A selective metabolite(s). It has relatively little effect on rapid-eye-movement
sleep suppression and on catecholamine metabolite changes (Murphy et al., 2000).
It has been proved that acute increases synaptic monoamine concentration brought by
antidepressants produce secondary neuroplastic changes in the long run mediating molecular
and cellular plasticity by translation and transcription of certain genes. Chronically
administered antidepressants have also been shown to upregulate the transcription factor
cyclic-AMP-response-element-binding protein (CREB), which is downstream of several
serotonin and other stimulatory GPCRs, in the hippocampus; this effect has been validated in
human post-mortem tissue and directly linked to antidepressant-like responses in animal
models. The same factor is activated by stress in NAc resulting in depression-like responses,
emphasizing the reality of region-specific actions of neurotransmitters and their downstream
effectors (Krishnan and Nestler, 2008).
Monoamine-based antidepressants remain the first line of therapy for depression, but this
does not necessarily mean they are the only, or the best, way of treatment. Downsides to
these drugs are long therapeutic delays and low (about 30%) remission rates. More effective
agents were thus researched. The serotonin receptors involved in the action of SSRIs remain
unknown as are the exact biochemical pathways of SSRIs (Krishnan and Nestler 2008).
Medifoxamine is a monoamine reuptake inhibitor that preferentially inhibits dopamine
uptake. It is poorly studied and on use in France showed limitations in its efficacy.
GBR12909 (not yet evaluated in humans), GBR12783 and GBR13069, which are piperazine
compounds are effective potent highly selective dopamine uptake blockers, also stimulating
locomotion in subjects (Murphy et al., 2000).
Lisuride is a dopaminergic antidepressant acting centrally as a dopamine and serotonin
agonist being currently commercialized in the European market as an antidepressant. In
animal screening studies, lisuride showed some potential in having clinical antidepressant
properties. To this day, however there are no published controlled clinical studies to ensure
Dopamine)and)Depression)
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21!
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its possible antidepressant activity. Lisuride has a very high affinity for the 5-HT6 and 5-HT7
receptor sites, a site which is very much compatible with a number of antidepressant and
antipsychotic agents (Murphy et al., 2000).
Azaperones are antipsychotics, which are metabolized to 1-(2-pyramidal)-piperazine(1-PP)
resulting in the latter component (the metabolite) rising to brain concentrations tenfold higher
than the parent component. 1-PP is an alpha 2-adrenergic antagonist, belonging to a class of
drugs argued to have antidepressant potential. In a particular clinical study, 1-PP plasma
levels were found to be hugely correlated with improvement in in depressed patients on
buspirone treatment (Murphy et al., 2000).
Amineptine is an atyipical tricyclic anitdepressant, having an 7-aminoheptanoic acid side
chain. Amineptine antagonized reserpine-induced ptosis and hypothermia in animal screening
models, increase mobility in a behavioral despair test, and improved impaired social behavior
in monkeys, having also direct locomotor stimulatory effects in mice. Amineptine also
selectively inhibited the reuptake of dopamine into rat striatal synaptosomes, even causing a
release of dopamine, norepinephrine, and serotonin at higher concentrations. A microdialysis
study found dose-dependent elevations of dopamine in the striatum, nucleus accumbens, and
frontal cortex. Chronic administration of amineptine develops a kind of resistance manifest in
a reduction in the number of striatal dopamine binding sites (Murphy et al., 2000).
Amisulpride and clozapine, are reported to have antidepressant properties, initially being
atypical antipsychotics used to block D2 and/or D1 receptors. In a double-blind comparison,
Amisulpride has been reported to have equivalent antidepressant properties to amitriptyline
while clozapine's combination of properties has been indicated to be of therapeutic benefit in
schizoaffective disorder. Therapeutic effects of clozapine could be correlated either to its 5-
HT2 or α2-adrenergic antagonistic properties. No controlled trials of clozapine in any form
of depression are at hand (Murphy et al., 2000).
Dopamine)and)Depression)
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9 Conclusions
According to our limited knowledge, depression boils down to little more than abnormal
fluctuations in the brain monoamine DA, with 5-HT playing a vital role as its receptors
modulate dopaminergic function. This explains why depression essentially tampers with all
aspects of bodily dynamics and behaviour, as are voluntary movements, cognition, attention,
emotion, mood, learning, memorizing and sleeping patterns.
Depression is still a stigmatic disease even in today’s culture. People need to realize the
gravity of such a condition, realise its repercussions, and act to promote awareness of this
problem and encourage affected individuals to seek professional help without any shame
whatsoever, the roots of such a condition being, after all, physiological in origin, as are many
other common but not tabooed diseases.
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