Dopamine

Dopamine is a monoamine neurotransmitter (NT) with many important physiological functions. Despite being limited to only a small part of the brain, dopamine neurons project out to modulate the function of a large proportion of the central nervous system (CNS).[1] Dopamine is of particular importance in the nervous system as it is a key neurotransmitter in the mesolimbic reward pathway believed to be responsible for addiction. It is affected by many drugs including psychostimulants, psychedelics and monoamine oxidase inhibitors and some anti-depressants.[2]

Introduction to Dopamine

[​IMG]Despite its importance, only a small number of dopamine neurons are found in the brain. Of the 100 billion neurons in the human brain only 500,000 produce dopamine. Of these most have their cell bodies either in the substantia nigra pars compacta (SNc) or the ventral tegmental area (VTA)[1] dopamine is a ligand for the 5 dopamine receptors, all of which are G-Protein Coupled Receptors (GPCRs) which modulate the responses of neurons to excitatory and inhibitory amino acids through a multitude of different mechanisms.

Neurons from the VTA play a critical role in motivation, attention, reward-related behaviour and multiple forms of memory. Those found in the SNc play a critical role in learning and execution of motor programs.[1]

The death of dopamine neurons are the cause of Parkinson’s Disease (PD) which is an irreversible and progressive illness which primarily affects the elderly. Despite extensive research in this area it is still not known how or why these neurons die or how to prevent their death.

The Basics: What Do I Need To Know About Dopamine?

When using drugs which affect dopamine release it is important to understand the effects these have on reward pathways and the toxicity surrounding an excess of dopamine release. Despite the relatively simple mechanism of action behind stimulants such as methamphetamine and amphetamines which primarily act on neurons to cause the release of dopamine, this has profound implications in the central nervous system particularly with long periods of abuse. Despite years of intensive research in this field, much of how dopamine modulates the function of other neurotransmitters is still unknown.[3]

Dopamine Biosynthesis

Dopamine is produced from the amino acid L-Tyrosine and its production is required as a precursor for the synthesis of noradrenaline and adrenaline. [​IMG] The brains ability to produce 3 important NTs through the same biosynthetic pathway comes from the relative expression of the enzyme responsible for converting dopamine into noradrenaline (Dopamine-β-hydroxylase; DBH). This enzyme is expressed in NA and adrenaline cells but not in dopamine neurons so the production of these catecholamines is restricted. [1]

The rate-limiting enzyme (the enzyme which makes the least of the molecules along the biosynthetic pathway) is Tyrosine Hydroxylase (TH). In general an increase in catecholamine release will result in an increase in TH activity which is regulated at the transcription, translation, and post translational levels.

Rapid activation of TH occurs via the phosphorylation of 4 sites by a number of different protein kinases (proteins that phosphorylate other proteins). These phosphorylations are believed to induce a conformational change (change in shape) which results in a lower affinity of catecholamines involved in negative feedback (end product inhibition) and in a higher affinity for the cofactors involved in converting L-Tyrosine to L-Dopa. Long term changes in TH activity can be induced by extracellular factors, for example, chronic environmental stress is known to upregulate TH expression. [4]

Tyrosine cannot cross the blood brain barrier (BBB) without active transport. Therefore under normal physiological conditions the transport of Tyrosine across the BBB and subsequent conversion to L-Dopa by TH are fully saturated. This means that additional Tyrosine supplementation will not cause any significant increase in catecholamine levels within the CNS. The use of L-Dopa (administered peripherally) bypasses the rate limiting step and is able to cross the BBB so as long as its metabolism (either into dopamine or 3-OMD) in the periphery is inhibited. [1][5]

Dopamine Storage and Release and Re-uptake

Note: This section can be generalised for Dopamine, Noradrenaline, adrenaline and serotonin.

Storage: Dopamine is synthesised in the cytoplasm at nerve terminals (inside the cell next to where it will eventually be released). Following its synthesis it is packaged in vesicles (small bubbles where they are kept separate from the rest of the cell - proper definition coming soon), through the activity of the vesicular monoamine transporter protein (VMAT). Transporting dopamine into vesicles not only prepares it for release in an organised manner (small vesicles nearest to the cell membrane are released in response to a small stimulus, larger ones are released only after continuous stimulation) but also protects them from monoamine oxidases which are present within the cell. VMAT is non-selective for catecholamines, that is it transports dopamine, noradrenaline and adrenaline so drugs which have an effect on this protein disrupt the packaging of all three NTs.[1][6]

Release: In response to an action potential (large change in electrical potential between the inside and outside of a cell), vesicles are recruited to the cell membrane where they dock, fuse and release their contents into the synapse, (where the nerve terminals in the presynaptic neuron (the neuron which is releasing the NTs), are directly opposite the receptors which are activated by them located on the cell surface on the post synaptic neuron). Once in the synapse dopamine is able to bind to dopamine receptors causing a response in the post synaptic neuron.[6]

Reuptake: Along the membrane of pre-synaptic neurons are transporter proteins which transport released NTs back into the cell, where they will either be reloaded into vesicles by VMAT or degraded by MAOs within the cells cytoplasm. This process is the most significant mechanism by which the actions of released NTs are terminated and is particularly important as it fulfils a number of crucial roles including.[1][5]
  1. Limiting the duration of pre-synaptic and post-synaptic receptor activation (giving the cell further control over its communication with other cells).
  2. It allows for unmetabolised NTs to be recycled and reused.
  3. It limits the diffusion of NTs to other cell synapses to ensure that any signal transduction is limited to the local regions where they were released.
The Dopamine Transporter (DAT) has been implicated in a number of diseases including ADHD.[7] and Parkinson's disease. [8] Changes in the expression of DAT have been reported in a limited number of studies including dementia, Tourette's syndrome and schizophrenia,[7] however its importance in these diseases is not known.

DAT is also of key importance in psychostimulant and alcohol abuse (mentioned later on).

All these processes represent potential targets for drugs (in particular storage and re-uptake).

Dopamine Degradation

There are two main classes of enzymes which catabolize (degrade) dopamine (as well as NA and adrenaline). These include monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Once converted into aldehydes the aldehyde dehydrogenase converts them rapidly into carboxylic acids. [1]
[​IMG]

Monoamine Oxidase:
MAO breaks down all monoamines including dopamine, noradrenaline, adrenaline, serotonin and histamine. They are also present in both intracellular (within cells) and extracellular (outside of cells) regions. The intracellular MAOs primarily break down those NTs which have been transported into the cell via the reuptake proteins following release, whilst the extracellular MAOs are able to break down all remaining NTs which are present in the synapse. These enzymes are also responsible for metabolising psychoactive drugs (tryptamines and phenethylamines). [9]

Catechol-O-methyltransferase:
These enzymes, as the name suggests break down the catecholamines. Like MAO they exist in two forms. Peripherally the main form is soluble, however in the brain the major type is bound to the membranes in synapses where catecholamines are released. In the majority of the brain DAT plays a far greater role in the removal of dopamine from the synapse however in some areas where there is less DAT their role is more significant such as the prefrontal cortex. Mutations in COMT have been linked to schizophrenia, bipolar disorder and schizoaffective disorder. There is also evidence to suggest that they may play a role in attention deficit hyperactivity disorder (ADHD) and addictive disorders given its role in the prefrontal cortex although this has not yet been confirmed. Both these enzymes are also targets for a number of drugs. [1][9]

Drugs influencing these processes

COMT Inhibitors: Inhibit the breakdown of all catecholamines metabolised by COMT. There are few in use and their medicinal use is similar to MAO inhibitors. There are only a few drugs targeting COMT and used as antispasmodics (preventing muscle spasms) or as anti-parkinson drugs.

Monoamine Oxidase Inhibitors: See Monoamine Oxidase and Monoamine Oxidase Inhibitor for a comprehensive list.

Dopamine Reuptake (DAT) Inhibitors: There are a number of drugs currently used for medicinal purposes, which inhibit DAT including
Sibutramine - anti-depressant and anorexic[10] (Withdrawn from the US and Australia)
Mazindol - anorexic
Dexamphetamines, amphetamines, methylphenidate and methamphetamine - ADHD, narcolepsy and in some cases obesity. The abuse of amphetamine and methamphetamine is covered below.
A novel compound Amitifadine is currently in clinical trials for the treatment of major depressive disorder. [11]

Chemistry of Dopamine

Along with being a catecholamine and monoamine dopamine is also classified as a substituted phenethylamine which includes a wide variety of drug classes such as CNS stimulants and hallucinogens (25-B/C/I NBOME and the 2-C family). Its full chemical name is 3,4-dihydroxyphenethylamine (IUPAC Name: 4-(2-aminoethyl)benzene-1,2-diol) and its molecular formula is C8H11NO2.

Despite being present in many foods, dopamine itself cannot cross the blood brain barrier (BBB) so therefore its activity in the CNS is dependent on its production from the BBB permeable amino acid tyrosine. It biosynthesis from tyrosine occurs via two steps. The first is the addition of a hydroxyl group to the meta position on the phenyl ring of tyrosine via the activity of tyrosine hydroxylase to form 3,4 Dihydroxyphenylalanine (L-DOPA) which is also able to cross the BBB. The second step is the removal of the carboxyl group and subsequent addition of an amino group via aromatic L-amino acid decarboxylase (also called DOPA decarboxylase).

Dopamine Receptors

After being realeased from presynaptic nerve endings (or nerve terminals) dopamine binds to and activates members from the dopamine receptor family (of which there are 5 subtypes, D1-D5). These receptors are G-protein coupled receptors (GPCRs) meaning that they are bound (or coupled) to G-proteins which after dopamine binding become active and act as a second messenger. G-proteins relay signals from receptors on the cells surface to their targets within a cell.[12] Signalling pathways such as this often involve a number of molecules which also allow for signal amplification.

Briefly, this works as one second messenger will usually activate more than one of its target molecules whereby one dopamine molecule binding to one receptor can result in 10,000 target molecules being activated at the end of the signalling pathway.[1]

The physiological functions of dopamine are mediated by the 5 closely related yet functionally distinct dopamine receptors. Each of these dopamine receptors have different affinities (a measure of how tightly a molecule binds to its receptor) for dopamine which partially explains how one can have such a broad range of effects in the body.[5]

The five dopamine receptors are further divided into two classes of molecules based on their interactions with different subtypes of G proteins that have opposing effects on the enzyme adenylyl cyclase (AC) (which when stimulated catalyses the formation of another signalling molecule) resulting in opposing downstream effects. The D1-class of dopamine receptors include the D1 and D5 (The naming can be confusing) receptor subtypes, activate a G-protein which stimulates AC, whereas the D2-class dopamine receptors (D2, D3 and D4) activate a G-protein which inhibits AC.[5] The initially simple idea of dopamine binding to dopamine receptors with a single response is further complicated by the fact that these receptors are expressed in both different regions of the brain and on different regions of the neurons.[5] This is a common phenomena in the brain which explains why designing drugs for a specific therapeutic purpose is both very promising in being able to treat specific diseases but also extremely complex.

Dopamine Receptor Function and Dysfunction

Given that the primary role of dopamine receptors is in modulating other NTs actions, most research in establishing their functions has been done through studying the role dopamine plays in disease, as determining its physiological function is difficult. Dopamine receptors modulate the activity of other NTs and regulate the activity of several voltage-gated ion channels (which act to either enhance or inhibit a change in electrical potential as it gets to a specific voltage) and transcription factors which in turn regulate gene expression and are responsible for the long-lasting effects of dopamine.[13] For an in depth recent review behind the molecular aspects of dopamine receptor function see Beaulieu and Gainetdinoy (2011).[3]

D1 Receptors:

Note: Agonist - Activates receptors. Antagonist - Inhibits receptors.
  • D1 receptor modulation of both potentiation and depression of synapse strength occurs through its interactions with NMDA receptors via direct protein-protein interactions. This occurs by selectively coupling to one of two NMDA glutamate receptor subunits. One interaction inhibits NMDA receptor function whilst the other was involved in NMDA receptor-mediated excitotoxicity.[14] (damage and/or cell death in this case through over excitation from glutamate).
  • Drugs of abuse as well as food reinforcement learning impact upon neurons via a signalling cascade which involves D1 Receptors.[15]
  • Working memory depends on an optimal level of stimulation of D1 receptors[1], where mild dopaminergic stimulation enhances working memory whereas high levels of stimulation cause a profound disruption.[16] D1 receptor agonists have been studied as enhancers of working memory however given the role D1 receptors play in nausea and vomiting it has not been possible to generate compounds which are without intolerable side effects. Treatment with antipsychotics (D2 Receptor antagonists) has been shown to downregulate D1 receptors which impairs working memory which is reversed by short term use of the D1 agonist ABT431. This improvement lasted for more than a year after treatment.[17]
  • Genetic mutations in D1 receptors are associated with a strong susceptibility to the onset of schizophrenia.[18]
D2 Receptors:
  • D2 receptors have also been implicated in the onset of schizophrenia. Treatment with antipsychotics that act as D2 receptor antagonists is currently used to minimise symptoms associated with schizophrenia.[5]
  • Human evolution is characterised by a dramatic increase in brain size and complexity. A number of proteins including the D2 receptor have significantly higher rates of evolution compared to rats indicating that it is of importance in the development of the nervous system.[19]
  • D2 receptors are a key protein in facilitating movement. Patients with schizophrenia taking antipsychotics often experience difficulty in moving as a side effect.
  • Like the D1 receptor, the D2 receptor is involved in the reward-mediating pathways in the brain and has been associated with an increase in smoking and alcoholism.[20]
  • People with reduced numbers of D2 receptors respond less to negative feedback than those with normal levels which also potentially explains its contribution to an initial increased risk of developing addictive behaviours.[21]
  • It has also been shown that there is an increased susceptibility to addiction to cocaine in people who have dysfunctional D2 receptors.[22]
D3 Receptors:
  • The D3 receptor is expressed in the limbic areas of the brain which are associated with cognitive and emotional functions.[23]
  • Many of the functions carried out by the D2 receptors have been found to be mediated by the D3 receptor including impulsivity and propensity to cocaine addiction[22] and the response to anti-psychotic and anti-parkinson drugs.
  • Brain-derived neurotrophic factor (BDNF) is partially responsible for normal expression of the D3 receptor and this interaction may be an important determinant of drug addiction, schizophrenia and/or Parkinson disease where D3 receptor is abnormal.[24]
  • In comparison to the extensive research done on the D1 and D2 receptors very little is known about the exact functions of the D3, D4 and D5 receptors however its believed to be important in modulating responses from several other proteins.[3]
D4 Receptors:
  • Like the D1-D3 receptors, the D4 receptor has also been found to be linked to mental disorders.[25] There was six fold increase in the D4 receptor density found in the brains of patients with schizophrenia.[26]
  • The D4 receptor has also been shown to have an association with the development of ADHD. It has also been postulated that any change from the standard 4R (number of repeat sequences of amino acids in the receptor) receptor may define how the receptor is associated with ADHD.[27]
  • A recent review suggested that the D4 receptor shows promise for explaining significant variation in individual differences in behavioural and neuronal measures of inhibitory control.[28]
D5 Receptors
  • The D5 receptor selectively complexes (the two receptors join together and influence each other’s function) with the GABA-A ligand-gated ion channels. This enables mutual inhibitory functional interactions between these systems (GABA is an inhibitory neurotransmitter).[29]
  • Like the D4 receptor, mutations in the D5 receptor have been associated with ADHD in children.[30]
  • Like the D3 and D4 receptors relatively little research has been done on the D5 receptor so little of its true function is known.

Drugs influencing Dopamine Receptors

Non-selective drugs acting on dopamine receptors:
  • Levodopa (L-Dopa): Anti-parkinsonian agent. Levodopa is able to cross the blood brain barrier (which dopamine itself cannot) where it is converted into dopamine.
D1 Receptors:

D2 Receptors:
  • Bromocriptine (Brand: Parlodel, cycloset) – Treatment of type 2 diabetes[31] and off-label use to reduce symptoms of cocaine withdrawal.[32] Agonist of all dopamine receptor subtypes (only weakly at D1 and D5).
  • Cabergoline (Brand: Dostinex, Cabaser) – Treatment of hyperprolactinoma (too much prolactin in the blood caused by a tumour in the pituitary gland). D2 Agonist.[33]
Typical Antipsychotics (First generation antipsychotics): D2 Receptor antagonists
These drugs are primarily used in the treatment of schizophrenia and in some cases psychosis. Other uses include treatment of psychotic depression and mania.[5] These drugs are associated with profound side effects as they act on dopamine receptors in all regions of the brain (in particular parts of the brain which control movement). They are used to treat patients with behavioural emergencies (e.g psychosis, mania and delirium) chronic schizophrenia (mostly patients who were diagnosed and began treatment before the development of atypical antipsychotics).

Side effects: weight gain, dry mouth, blurred vision, constipation
Akathisia – sensation of inner restlessness which results in an inability to sit still. [5]
Acute dystonia – involuntary movements which are often accompanied by symptoms of Parkinson’s Disease. [5]
Tardive Dyskinesia – Involuntary and repetitive movements. Develops after months or years in 20-40% of patients. It is disabling and often irreversible condition which often gets worse if treatment with antipsychotics is stopped.[5]

Examples:
  • Phenothiazine Derivatives: chlorpromazine, triflupromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine.[3]
  • Thioxanthene Derivatives: clopenthixol, flupentixol, thiothixene.[3]
  • Butyrophenone Derivatives: haloperidol, droperidol, trifluperidol.[3]

Atypical Antipsychotics: D2 receptor antagonists
These drugs are newer antipsychotics which generally treat more symptoms than the typical antipsychotics with less side effects (particularly movement related).[5] Most atypical antipsychotics have a lower affinity for the D2 receptors and are either antagonists or inverse agonists (binding inactivates the usually active receptors) at the 5-HT(2a) receptors.[34]

Examples: clozapine (only used to treat patients who do not respond to other antipsychotics), olanzepine, risperidone, ariprizole

Antiemetics(prevents nausea and vomiting) D2 antagonists
  • Metoclopramide (Brand: Maxolon, Reglan) [5][35][36]
  • Domperidone (Brand: Motilium): Off-label use for promoting lactation. Also a D3 antagonist.[35]
  • Alizapride (Brand: Litican)[36][37]
  • Metopimazine[38]
D3 Receptors:
  • Sulpiride (Brand: Meresa) – Atypical antipsychotic (antagonist): Treatment of both productive and unproductive psychosis and depression. Also a D2 receptor antagonist.[39]
  • Piribedil (Brand: Trivastal) – Anti-parkinsonian Agent (agonist): Treatment of PD, cognitive defects and dizziness. Also a D2 receptor agonist.[40]
  • Pimozide[41] – antipsychotic (antagonist): Treatment of schizophrenia and chronic psychosis. Also a D2 receptor antagonist.
D4 Receptors:
  • Quetiapine[42] (Brand: Seroquel) – Atypical antipsychotic (antagonist): Treatment of schizophrenia and bipolar disorder. Also a D2 and D3 receptor antagonist.
  • Pramipexole[43] (Brand: Mirapex) – Anti-parkinsonian Agent (agonist): Treatment of early stage Parkinson’s Disease. Also a D2 and D3 receptor agonist.
  • Clozapine[44] (Brand: Many) – Atypical antipsychotic (antagonist): Treatment in patients who are unresponsive or intolerant to conventional antipsychotics (has potentially severe side effects). Also a D2 receptor antagonist, has some antagonistic activity on serotonin receptors.
  • Olanzapine[45] (Brand: Zyprexa) – Atypical antipsychotic (antagonist): Treatment of schizophrenia and bipolar disorder (mania). Also a D2 and D3 receptor antagonist.
D5 Receptors:None (except levodopa).

Mechanism of Psychostimulant Action on Dopamine Release by Methamphetamine and Amphetamines.

Methamphetamine is a powerful stimulant with a significant abuse potential and neurotoxicity primarily associated with the release of monoamines. [46] Dopamine release associated with methamphetamine use occurs via several different mechanisms, giving an indication as to the normal regulation of dopamine release. At low concentrations methamphetamine and amphetamine bind to the extracellular side of DAT (which can transport dopamine in both directions). This binding causes an exchange for methamphetamine going into the cell and dopamine going out. At higher concentrations whilst this still occurs DAT mediated transport is not necessary for methamphetamine to enter the cell as it is a highly lipophilic molecule which can diffuse across cell membranes.[47] At higher concentrations amphetamine and methamphetamine application stimulates protein kinase C (protein kinase: a protein which phosphorylates specific sites on other proteins ie it adds a phosphate (PO4- group)) activity increasing the phosphorylation of DAT which shifts the transporter into a position where it is in a more willing state for amphetamine induced dopamine efflux (transport out of the cell). Interestingly by investigating a model of DAT without the amino acids required for phosphorylation it was found that methamphetamine still caused a decrease on dopamine reuptake indicating that methamphetamine acts on DAT in both a phosphorylation-dependent and –independent mechanisms.[48]

The second main way amphetamines are able to cause dopamine release is through their effect on VMAT2. This is referred to as the weak base hypothesis.[47] Amphetamine and its derivatives are weak bases with a pKa of ~9.9[49] When amphetamine enters vesicles storing dopamine (vesicles are assumed to have a pH of ~5.5) they will accept protons thus changing the proton gradient required for vesicular dopamine sequestration and causes increased cytoplasmic dopamine. This increase in concentration means that dopamineinside the cell > dopamineoutside the cell so DAT which transports dopamine down its concentration gradient pumps dopamine out of the cell.[46]

These mechanisms when combined cause an uncontrolled flood of dopamine from dopaminergic neurons into the synapses where it acts on dopamine receptors at concentrations far above what is physiologically possible to promote feelings of alertness and euphoria.

The role of Dopamine in drug addiction

Despite the large variation in the mechanisms of action of addictive drugs, all of them have been found to either directly (e.g amphetamine and methamphetamine which both interact with dopamine transporters (DAT) causing it to reverse the direction of its transport pumping dopamine out of the cell) or indirectly (e.g opioids where opioids which interact with the mu-opioid receptor cause disinhibition ( i.e. they inhibit inhibitory neurons of dopamine signalling the result being an increase in signalling) increase dopamine release.[50] This comes from an evolutionary mechanism where dopamine release was increased upon important biological stimulus such as food or sex.[50]

At its simplest dopamine release prepares the brain to efficiently undergo synaptic plasticity (either the initiation/strengthening of new or existing neural connections in the brain called long term potentiation or the loos/weakening of new or existing neural connections called long term depression.) to learn how to obtain or avoid a specific stimulus via modulation of glutaminergic neurons and receptors (e.g AMPA and NMDA).[51] The mechanisms behind how these complex changes occur are far from fully understood, however, decades of intensive research has shown that it involves the expression and subsequent transport of proteins to specific regions within neurons (protein trafficking), alterations in the structure of the post synaptic neuron (postsynaptic morphology) and associations both within and between complex clusters of neurons (brain nuclei). Whilst in normal situations dopamine release diminishes with repeated exposure to the same stimulus so once a behaviour has been learnt and is associated with a certain stimuli dopamine is no longer needed for further learning. In contrast to this physiological process drugs of addiction cause a release in dopamine pharmacologically and this release does not (relative to normal function) diminish with repeated exposure. This facilitates further neuroplasticity and these behaviours in effect become overlearned.[52]


Whilst dopamine and psychostimulants affect hundreds of genes in brain circuits, the majority of research assesses the affects of expression of neuropeptide transmitters and immediate-early genes (IEGs). IEGs are of interest as they undergo rapid and transient induction by neuronal activity and drug use.[53] They are also directly involved with neuroplasticity and many IEGs regulate the expression of other genes. The cellular, molecular and epigenetic mechanisms by which addiction occurs is far too detailed for this review, however, some excellent reviews begin to explain these details. See [50][51][52].

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