Dopamine antagonist

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Dopamine_antagonist 

 

Dopamine receptor antagonist Dopaminergic blockers
Drug class
Skeletal structor formula of Haloperidol, a typical antipsychotic
Class identifiers
Use	Schizophrenia, bipolar disorder, nausea and vomiting, etc.
ATC code	N05A
Biological target	Dopamine receptors
External links
MeSH	D012559

Not to be confused with dopamine reuptake inhibitor.

A dopamine antagonist (anti-dopaminergic) is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

Receptor Pharmacology

Dopamine Receptor Flow Chart

All dopamine receptors are G-protein coupled and are divided into 2 classes based on which G-protein they are coupled to. The D₁-like class of dopamine receptors is coupled to Gα_s/olf and stimulates adenylate cyclase production, whereas the D₂-like class is coupled to Gα_i/o and thus inhibits adenylate cyclase production.

D₁-like receptors: D₁ and D₅

These receptors are always found post-synaptically. The genes coding these receptors lack introns, so there are no splice variants.

D₁ receptors

• Found mainly on neurons in the nucleus accumbens as well as substantia nigra, striatum, amygdala, frontal cortex and olfactory bulb and retina
• Also found (in lower levels) in the hypothalamus, thalamus, cerebellum and hippocampus
• Peripherally, these receptors have been found in the renal artery, mesenteric artery, and splenic artery where activation leads to vasodilation. In addition, D₁ receptors have been found in the kidney

D₅ receptors

• Low levels of D₅ receptors have been found in the hypothalamus, prefontal cortex and cingulate cortex; as well as memory areas such as hippocampus, dentate gyrus and entorhinal cortex.
• In addition, D₅ receptors have been found in the kidney

D₂-like receptors: D₂, D₃ and D₄

Unlike the D₁-like class, these receptors are found pre and post-synaptically. The genes that code these receptors have introns, leading to many alternately spliced variants.

D₂ receptors

• D₂ receptors are found in the striatum, substantia nigra, ventral tegmental area, hypothalamus, cortex, septum, amygdala, hippocampus, and olfactory tuburcle.
• These receptors have also been found in the retina and pituitary gland.
• Peripherally, these receptors have been found in the renal, mesenteric, and splenic arteries as well as on the adrenal cortex and medulla and within the kidney

D₃ receptors

• These receptors are highly expressed on neurons in islands of Calleja and nucleus accumbens shell and lowly expressed in areas such as the substantia nigra pars compacta, hippocampus, septal area, and ventral tegmental area.
• Additional studies have found these receptors periperally in the kidney

D₄ receptors

• These receptors are found in amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, the thalamus, the retina and the kidney 

Implications in disease

The dopaminergic system has been implicated in a variety of disorders. Parkinson's disease results from loss of dopaminergic neurons in the striatum. Furthermore, most effective antipsychotics block D₂ receptors, suggesting a role for dopamine in schizophrenia. Additional studies hypothesize dopamine dysregulation is involved in Huntington's disease, ADHD, Tourette's syndrome, major depression, manic depression, addiction, hypertension and kidney dysfunction. Dopamine receptor antagonists are used for some diseases such as schizophrenia, bipolar disorder, nausea and vomiting.

• Melatonin suppresses dopamine activity as part of normal circadian rhythm functions, although pathological imbalances have been implicated in Parkinson's disease

Side effects

They may include one or more of the following and last indefinitely even after cessation of the dopamine antagonist, especially after long-term or high-dosage use:

• Cardiovascular disease
  

• Extrapyramidal symptoms (EPS) associated with typical antipsychotics:
  • Early stage – occurs at onset of treatment or following increased dose, patients recover when dose is decreased
    • Acute dystonias – muscle spasms and sustained abnormal postures and onset occurs within a few days; can be treated with anticholinergics
      • risk factors include age, gender and family history
    • Akathisia - pacing and restlessness and onset occurs within the first few months; can be treated with beta blockers and benzodiazepines
    • Parkinsonism due to effects on the nigrostriatal pathway - includes tremors, bradykinesia and muscle rigidity
      • risk factors include age and gender
  • Late stage – occurs after prolonged (months-years) treatment, symptoms persist even after dose is decreased
    • Tardive dyskinesia  - includes involuntary and repetitive facial movements
      • risk factors include age, race and gender
  • It is hypothesized that these effects are due to chronic blockade of the D₂ receptor
• Hyperprolactinaemia due to blockade of the D₂ receptors in the anterior pituitary leading to increased prolactin release
• Increased appetite including increased craving and binge eating that lead to weight gain
• Increased risk for insulin resistance
• Sexual dysfunction
• Metabolic changes with increased risk of obesity and diabetes mellitus type 2
• Sedation

Examples

First-generation antipsychotics (typical)

First generation antipsychotics are used to treat schizophrenia and are often accompanied by extrapyramidal side effects.

• Benperidol binds D₂ and some serotonin receptors. It's absorbed very easily and has a high first pass effect.
• Chlorpromazine binds D₃ with the highest affinity, but also binds D₁, D₂, D₄ and D₅

Chemical Structure of typical antipsychotic chlorpromazine

• Clopenthixol
• Droperidol is used as an antipsychotic and antiemetic.
• Haloperidol binds D₂, D₃ and D₄ with the highest affinity, but also binds D₁ and D₅
• Fluphenazine binds D₂ and D₃ with the highest affinity but D₁ and D₅ as well
• Flupenthixol binds D₁, D₂, D₃, and D₅ and is also used as an antidepressant.
• Fluspirilene
• Penfluridol
• Perazine

• Perphenazine
• Pimozide binds D₂ and D₃ with high affinity, also binds D₄ receptors

• Spiperone binds D₂, D₃ and D₄ with high affinity; can also bind D₁

• Sulpiride binds D₂ and D₃ and is also used as an antidepressant.
• Thioridazine binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅ at higher concentrations

Second-generation antipsychotics (atypical)

These drugs are not only dopamine antagonists at the receptor specified, but also act on serotonin receptor 5HT_2A. These drugs have less extrapyramidal side effects and are less likely to affect prolactin levels when compared to typical antipsychotics. 

• Amisulpride binds D₂ and D₃ and is used as an antipsychotic, antidepressant and also treats bipolar disorder. It treats both the positive and negative symptoms of schizophrenia. 
• Asenapine binds D₂, D₃ and D₄ and is used to treat bipolar disorder and schizophrenia. Its side effects include weight gain but there is lower risk for orthostatic hypotension, hyperprolactinemia
• Aripiprazole binds D₂ as a partial agonist but antagonizes D_3. In addition, aripiprazole treats schizophrenia, bipolar disorder (mania), depression, and tic disorders.

Clozapine

• Clozapine binds D₁ and D₄ with the highest affinity but still binds D₂ and D₃. Clozapine is unique because it is only prescribed when treatment with at least two other antipsychotics has failed due to its very harsh side effects. It also requires weekly white blood cell counts to monitor potential neutropenia.

• Loxapine binds D₂, D₃ and D₄ with high affinity; can also bind D_1. Loxapine is often used to treat agitated and violent patients with neuropsychiatric disorders such as bipolar disorder and schizophrenia. 
• Nemonapride binds D₃, D₄ and D_5. 
• Olanzapine binds all receptors and is used to treat the positive and negative symptoms of schizophrenia as well as bipolar disorder and depression. It has been associated with significant weight gain.

• Quetiapine binds D₁, D₂ and D₃ and can bind D₄ at high concentrations. It is used to treat the positive symptoms of schizophrenia, bipolar disorder and depression.
• Paliperidone binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅.

• Remoxipridebinds D₂ receptors with relatively low affinity.
• Risperidone binds D₂, D₃ and D₄ receptors. Risperidone not only treats the positive and negative symptoms of schizophrenia but also treats bipolar disorder.

• Tiapride blocks D₂ and D₃ and is used as an antipsychotic. It is also often used to treat dyskinesias, psychomotor agitations, tics, Huntington's chorea and alcohol dependence.
• Ziprasidone blocks the D₂ receptor  and is used to treat schizophrenia, depression and bipolar disorder. There is controversy on whether Ziprasidone treats negative symptoms and it has well documented gastrointestinal side effects. 

Dopamine antagonists used to treat nausea and vomiting

• Domperidone is a peripherally selective dopamine D2 receptor antagonist used as an antiemetic, gastroprokinetic agent and galactagogue.
• Bromopride binds enteric D₂ receptors and also treats gastroparesis.
• Metoclopramide also treats gastroparesis

Antagonists used only in research settings

• Eticlopride binds D₂ and D₃ with high affinity but also binds D4
• Nafadotride binds D₂ and D₃
• Raclopride binds D₂ and D₃ and can be radiolabeled and used in PET imaging to identify disease progression in Huntington's Disease

Dopamine agonist

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Dopamine_agonist 

 

Dopamine agonist
Drug class
The skeletal structure of dopamine
Class identifiers
Use	Parkinson's disease, clinical depression, hyperprolactinemia, restless legs syndrome, low sex drive
ATC code	N04BC
Biological target	Dopamine receptors
External links
MeSH	D010300

A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D₂-like and D₁-like, and they are all G protein-coupled receptors. D₁- and D₅-receptors belong to the D₁-like family and the D₂-like family includes D₂, D₃ and D₄ receptors. Dopamine agonists are used in Parkinson’s disease and, to a lesser extent, to treat depression, hyperprolactinemia and restless legs syndrome.

Medical uses

Parkinson's disease

Dopamine agonists are mainly used in the treatment of Parkinson's disease.  The cause of Parkinson's is not fully known but genetic factors, for example specific genetic mutations, and environmental triggers have been linked to the disease. In Parkinson's disease dopaminergic neurons that produce the neurotransmitter dopamine in the brain slowly break down and can eventually die. With decreasing levels of dopamine the brain can't function properly and causes abnormal brain activity, which ultimately leads to the symptoms of Parkinson's disease.

There are two fundamental ways of treating Parkinson's disease, either by replacing dopamine or mimicking its effect.

Dopamine agonists act directly on the dopamine receptors and mimick dopamine's effect. Dopamine agonists have two subclasses: ergoline and non ergoline agonists. Both subclasses target dopamine D₂-type receptors. Types of ergoline agonists are cabergoline and bromocriptine and examples of non-ergoline agonists are pramipexole, ropinirole and rotigotine. Ergoline agonists are much less used nowadays because of the risk of cartilage formation in heart valves.^[5]

Treatment of depression in Parkinson's patients

Depressive symptoms and disorders are common in patients with Parkinson's disease and can affect their quality of life. Increased anxiety can accentuate the symptoms of Parkinson's and is therefore essential to treat. Instead of conventional antidepressant medication in treating depression, treatment with dopamine agonists has been suggested. It is mainly thought that dopamine agonists help with treating depressive symptoms and disorders by alleviating motor complications, which is one of the main symptoms of Parkinson's disease.  Although preliminary evidence of clinical trials has shown interesting results, further research is crucial to establish the anti-depressive effects of dopamine agonists in treating depressive symptoms and disorders in those with Parkinson's.

Hyperprolactinemia

Dopamine is a prolactin-inhibiting factor (PIFs) since it lowers the prolactin-releasing factors (PRFs) synthesis and secretion through DD₂-like receptors. That is why dopamine agonists are the first-line treatment in hyperprolactinemia. Ergoline-derived agents, bromocriptine and cabergoline are mostly used in treatment. Research shows that these agents reduce the size of prolactinomas by suppressing the hypersecretion of prolactin resulting in normal gonadal function.

Restless leg syndrome

Numerous clinical trials have been performed to assess the use of dopamine agonists for the treatment of restless leg syndrome (RLS). RLS is identified by the strong urge to move and is a dopamine-dependent disorder. RLS symptoms decrease with the use of drugs that stimulate dopamine receptors and increase dopamine levels, such as dopamine agonists.

Adverse effects

Side effects

Dopamine agonists are mainly used to treat Parkinson’s disease but are also used to treat hyperprolactinemia and restless legs syndrome. The side effects are mainly recorded in treatment for Parkinson’s disease where dopamine agonists are commonly used, especially as first-line treatment with levodopa.

Dopamine agonists are divided into two subgroups or drug classes, first-generation and newer agents. Ergoline derived agonists are the first generation and are not used as much as the newer generation the non-ergoline derived agonists. Ergoline derived agonists are said to be dirtier drugs because of their interaction with other receptors than dopamine receptors, therefore they cause more side effects. Ergoline derived agonists are for example bromocriptine, cabergoline, pergolide and lisuride. Non-ergoline agonists are pramipexole, ropinirole, rotigotine, piribedil and apomorphine.

The most common adverse effects are constipation, nausea and headaches. Other serious side effects are hallucinations, peripheral edema, gastrointestinal ulcers, pulmonary fibrosis and psychosis.

Dopamine agonists have been linked to cardiac problems. Side effects such as hypotension, myocardial infarction, congestive heart failure, cardiac fibrosis, pericardial effusion and tachycardia. A high risk for valvular heart disease has been established in association with ergot-derived agonists especially in elderly patients with hypertension.

Somnolence and sleep attacks have been reported as an adverse effect that happen to almost 30% of patients using dopamine agonists. Daytime sleepiness, insomnia and other sleep disturbances have been reported as well.

Impulse control disorder that is described as gambling, hypersexuality, compulsive shopping and binge eating is one serious adverse effect of dopamine agonists.

After long-term use of dopamine agonist a withdrawal syndrome may occur when discontinuing or during dose reduction. The following side effects are possible: anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalised pain, and drug cravings. For some individuals, these withdrawal symptoms are short-lived and make a full recovery, for others a protracted withdrawal syndrome may occur with withdrawal symptoms persisting for months or years.

Interactions

Dopamine agonists interact with a number of drugs but there is little evidence that they interact with other Parkinson’s drugs. In most cases there is no reason not to co-administer Parkinson's drugs. Although there has been an indication that the use of dopamine agonists with L-DOPA can cause psychosis therefore it is recommended that either the use of dopamine agonists be discontinued or the dose of L-DOPA reduced. Since ergot-dopamine agonist have antihypertensive qualities it is wise to monitor blood pressure when using dopamine agonists with antihypertensive drugs to insure that the patient does not get hypotension. That includes the drug sildenafil which is commonly used to treat erectile dysfunction but also used for pulmonary hypertension.

There is evidence that suggests that since ergot dopamine agonists are metabolized by CYP3A4 enzyme concentration rises with the use of CYP3A4 inhibitors. For example, in one study bromocriptine was given with a CYP3A4 inhibitor and the AUC (e. Area under the curve) increased 268%. Ropinirole is a non-ergot derived dopamine agonist and concomitant use with a CYP1A2 inhibitor can result in a higher concentration of ropinirole. When discontinuing the CYP1A2 inhibitor, if using both drugs, there is a change that a dose adjustment for ropinirole is needed. There is also evidence the dopamine agonists inhibit various CYP enzymes and therefore they may inhibit the metabolism of certain drugs.

Pharmacology

Ergoline class

Pharmacokinetics of Bromocriptine

The absorption of the oral dose is approximately 28% however, only 6% reaches the systemic circulation unchanged, due to a substantial first-pass effect. Bromocriptine reaches mean peak plasma levels in about 1–1.5 hours after a single oral dose. The drug has high protein binding, ranging from 90-96% bound to serum albumin. Bromocriptine is metabolized by CYP3A4 and excreted primarily in the feces via biliary secretion. Metabolites and parent drugs are mostly excreted via the liver, but also 6% via the kidney. It has a half-life of 2–8 hours.

Pharmacokinetics of Pergolide

Pergolide has a long half-life of about 27 hours and reaches a mean peak plasma level in about 2–3 hours after a single oral dose. The protein binding is 90% and the drug is mainly metabolized in the liver by CYP3A4 and CYP2D6. The major route of excretion is through the kidneys.

Drug	Maintenance	Half-life	Protein binding	Peak plasma	Metabolism	Excretion
Bromocriptine	Oral, 2.5–40 mg/day	2–8 hours	90-96%	1-1,5 hours	Hepatic, via CYP3A4, 93% first-pass metabolism	Bile, 94-98% Renal, 2-6%
Pergolide	Oral, 0.05 mg/day Usual response up to 0.1 mg per day	27 hours	90%	2–3 hours	Extensively hepatic	Renal, 50% Fecal 50%

Non-Ergoline class

Pharmacokinetics of Pramipexole

Pramipexole reaches maximum plasma concentration 1–3 hours post-dose. It is about 15% bound to plasma proteins and the metabolism is minimal. Pramipexole has a long half-life, around 27 hours. The drug is mostly excreted in the urine, around 90%, but also in feces.

Pharmacokinetics of Ropinirole

Ropinirole is rapidly absorbed after a single oral dose, reaching plasma concentration in approximately 1–2 hours. The half-life is around 5–6 hours. Ropinirole is heavily metabolized by the liver and in vitro studies show that the enzyme involved in the metabolism of ropinirole is CYP1A2.

Pharmacokinetics of Rotigotine

Since rotigotine is a transdermal patch it provides continuous drug delivery over 24 hours. It has a half-life of 3 hours and the protein binding is around 92% in vitro and 89.5% in vivo. Rotigotine is extensively and rapidly metabolized in the liver and by the CYP enzymes. The drug is mostly excreted in urine (71%), but also in feces (23%).

Drug	Maintenance	Half-life	Protein binding	Peak plasma	Metabolism	Excretion
Pramipexole	Oral, 0.125 mg 3x/day (IR) Oral, 0.375 mg/day (ER)	8–12 hours	15%	1–3 hours	Minimal < 10%	Urine 90% Fecal 2%
Ropinirole	Oral, 0.25 mg 3x/day (IR) Oral, 2 mg/day (ER)	5–6 hours	10-40%	1–2 hours	Hepatic, via P450 CYP1A2 — can increase ↑ INR	Renal > 88%
Rotigotine	Transdermal, 2 – 4 mg/day	3 hours	92%	24 hours	Hepatic (CYP-mediated).	Urine 71% Fecal 23%

Mechanism of action

The dopamine receptors are 7-transmembrane domains and are members of the G protein-coupled receptors (GPCR) superfamily. Dopamine receptors have five subtypes, D₁ through D₅, the subtypes can be divided into two subclasses due to their mechanism of action on adenylate cyclase enzyme, D₁-like receptors (D₁ and D₅) and D₂-like receptors (D₂, D₃ and D₄). D₁-like receptors are primarily coupled to Gα_s/olf proteins and activates adenylate cyclase which increases intracellular levels of cAMP, they also activate the G_βγ complex and the N-type Ca²⁺ channel. D₂-like receptors decrease intracellular levels of the second messenger cAMP by inhibiting adenylate cyclase.

Bromocriptine

Bromocriptine is an ergot derivative, semi-synthetic. Bromocriptine is a D₂ receptor agonist and D₁ receptor antagonist with a binding affinity to D₂ receptors of anterior pituitary cells, exclusively on lactotrophs. Bromocriptine stimulates Na⁺, K⁺-ATPase activity and/or cytosolic Ca²⁺ elevation and therefore reduction of prolactin which leads to no production of cAMP.

Pramipexol

Pramipexol is a highly active non-ergot D₂-like receptor agonist with a higher binding affinity to D₃ receptors rather than D₂ or D₄ receptors. The mechanism of action of pramipexole is mostly unknown, it is thought to be involved in the activation of dopamine receptors in the area of the brain was the striatum and the substantia nigra is located. This stimulation of dopamine receptors in the striatum may lead to the better movement performance.

Structure–activity relationship

When dealing with agonists it can be extremely complex to confirm relationships between structure and biological activity. Agonists generate responses from living tissues. Therefore, their activity depends both on their efficacy to activate receptors and their affinity to bind to receptors.

Crossing the blood brain barrier

Many molecules are unable to cross the blood brain barrier (BBB). Molecules must be small, non-polar and lipophilic to cross over. If compounds do not possess these qualities they must have a specific transporter that can transport them over the BBB. Dopamine cannot diffuse across the BBB because of the catechol group, it is too polar and therefore unable to enter the brain. The catechol group is a dihydroxy benzene ring. 

The synthesis of dopamine consists of three stages. The synthesis process starts with an amino acid, called L-Tyrosine. In the second stage Levodopa (L-dopa) is formed by adding a phenol group to the benzene ring of L-Tyrosine. The formation of L-dopa from L-tyrosine is catalyzed by the enzyme tyrosine hydroxylase. The third stage is the formation of dopamine by removing the carboxylic acid group from L-dopa, catalysed by the enzyme dopa decarboxylase.

Levodopa is also too polar to cross the blood brain barrier but it happens to be an amino acid so it has a specialized transporter called L-type amino acid transporter or LAT-1 that helps it diffuse through the barrier.

Dopamine

When dopamine interacts with ATP, which is a component of some dopamine receptors, it has a significant preference for a trans-conformation of the dopamine molecule. The dopamine-ATP complex is stabilised by hydrogen bonding between catechol hydroxyls and purine nitrogens and by electrostatic interactions between the protonated ammonium group of dopamine and a negative phosphate group. Two conformers of dopamine have been identified as alpha- and beta-conformers in which the catechol ring is coplanar with the plane of the ethylamine side chain. They are substantial in agonist-receptor interactions.

Ergoline derivatives

Central dopaminergic agonist properties of semisynthetic ergoline derivatives lergotrile, pergolide, bromocriptine and lisuride have been established. Some studies suggest that ergot alkaloids have the properties of mixed agonist-antagonist with regards to certain presynaptic and postsynaptic receptors. N-n-Propyl groups (chemical formula: –CH₂CH₂CH₃) frequently enhance dopamine agonist effects in the ergoline derivatives.

Bromocriptine

The (+)-enantiomer displays notably diminished activity whereas the (-)-enantiomer possess potent dopamine agonist properties.

Bromocriptine

Bromocriptine has an ergot alkaloid structure. Ergot alkaloids are divided into 2 groups; amino acid ergot alkaloids and amine ergot alkaloids, bromocriptine is part of the former group. It contains a bromine halogen on the ergot structure which increases the affinity for the D₂-receptor but often reduces the efficacy. The similarity between the dopamine structure and the ergoline ring in bromocriptine is likely the cause for its action on the dopamine receptors. It has shown to have equal affinity for D₂- and D₃-receptor and much lower affinity for D₁-receptor.

Apomorphine

Non-ergoline derivatives

Non-ergoline dopamine receptor agonists have higher binding affinity to dopamine D₃-receptors than dopamine D₂-receptors. This binding affinity is related to D₂ and D₃ receptor homology, the homology between them has a high degree of sequence and is closest in their transmembrane domains, were they share around 75% of the amino acid.

Rotigotine

Apomorphine

Apomorphine has a catechol element and belongs to a class called β-phenylethylamines and its main components are similar to the dopamine structure. The effect that apomorphine has on the dopamine receptors can also be linked to the similarities between its structure and dopamine. It is a chiral molecule and thus can be acquired in both the R and S form, the R form is the one that is used in therapy. When apomorphine interacts with the dopamine receptor, or the ATP on the receptor, the catechol and nitrogen are important to stabilize the structure with hydrogen bonding. The position of the hydroxyl groups is also important and monohydroxy derivatives have been found to be less potent than the dihydroxy groups. There are a number of stability concerns with apomorphine such as oxidation and racemization.

Rotigotine

Rotigotine is a phenolic amine and thus has poor oral bioavailability and fast clearance from the body. Therefore, it has been formulated as a transdermal patch, first and foremost to prevent first pass metabolism in the liver.

Members

Examples of dopamine agonists include:

Partial agonist

• Aripiprazole (Partial agonist of the D₂ family receptors - Trade name "Abilify" in the United States; atypical antipsychotic)
• Phencyclidine (a.k.a. PCP; partial agonist. Psychoactivity mainly due to NMDA antagonism)
• Quinpirole (Partial agonist of the D₂ and D₃ family of receptors)
• Salvinorin A (chief active constituent of the psychedelic herb salvia divinorum, the psychoactivity of which is mainly due to Kappa-opioid receptor agonism; partial agonist at the D₂ with an Intrinsic activity of 40-60%, binding affinity of K_i=5-10nM and EC₅₀=50-90nM)

Agonists of full/unknown efficacy

• Apomorphine (Apokyn – used to treat Parkinson's disease & Restless leg syndrome) – biased at the D1 receptor.
• Bromocriptine (Parlodel – used to treat PD/RLS)
• Cabergoline (Dostinex – used to treat PD/RLS)
• Ciladopa (used to treat PD/RLS)
• Dihydrexidine (used to treat PD/RLS)
• Dinapsoline (used to treat PD/RLS)
• Doxanthrine (used to treat PD/RLS)
• Epicriptine (used to treat PD/RLS)
• Lisuride (used to treat PD/RLS)
• Pergolide (used to treat PD/RLS) – previously available as Permax, but removed from the market in the USA on March 29, 2007.
• Piribedil (Pronoran and Trivastal – used to treat PD/RLS)
• Pramipexole (Mirapex and Sifrol – used to treat PD/RLS)
• Propylnorapomorphine (used to treat PD/RLS)
• Quinagolide (Norprolac – used to treat PD/RLS)
• Ropinirole (Requip – used to treat PD/RLS)
• Rotigotine (Neupro – used to treat PD/RLS)
• Roxindole (used to treat PD/RLS)
• Sumanirole (used to treat PD/RLS)

Some, such as fenoldopam, are selective for dopamine receptor D1.

Indirect agonists

There are two classes of drugs that act as indirect agonists of dopamine receptors: dopamine reuptake inhibitors and dopamine releasing agents.

The most commonly prescribed indirect agonists of dopamine receptors include:

• Amphetamine and/or dextroamphetamine (used to treat ADHD, narcolepsy, and obesity)
• Bupropion (used to facilitate smoking cessation and treat nicotine addiction and clinical depression)
• Lisdexamfetamine (used to treat ADHD and binge eating disorder)
• Methylphenidate or dexmethylphenidate (used to treat ADHD and narcolepsy)

Other examples include:

• Cathinone
• Cocaine (anesthetic with no medical uses as a central nervous system stimulant)
• Methamphetamine (used in rare circumstances to treat ADHD and obesity)
• Phenethylamine (endogenous trace amine)
• p-Tyramine (endogenous trace amine)

History

Since the late 1960 Levodopa (L-DOPA) has been used to treat Parkinson’s disease but there has always been a debate whether the treatment is worth the side effects. Around 1970 clinicians started using the dopamine agonist apomorphine alongside L-DOPA to minimize the side effects caused by L-DOPA, the dopamine agonists bind to the dopamine receptor in the absence of dopamine. Apomorphine had limited use since it had considerable side effects and difficulty with administration. In 1974 bromocriptine was use widely after clinicians discovered its benefits in treating Parkinsons. When using the two drug classes together there is a possibility to reduce the amount of L-DOPA by 20-30% and thus keeping the fluctuating motor responses to a minimum. Dopamine agonists are often used in younger people as monotherapy and as initial therapy instead of L-DOPA. Although it is important to know that there is a correlation between the two drugs, if l-DOPA doesn't work dopamine agonists are also ineffective.

The early dopamine agonists, such as bromocriptine, were ergot derived and activated the D₂-receptor. They induced major side effects such as fibrosis of cardiac valves. It is considered that the reason they induced such side effects is that they activate many types of receptors.

Because of the major adverse effects of ergot derived dopamine agonists they are generally not used anymore and were mostly abandoned in favor of non-ergot agonists such as pramipexole, ropinirole and rotigotine. They do not induce as serious side effects although common side effects are nausea, edema and hypotension. Patients have also shown impaired impulse control such as overspending, hypersexuality and gambling.

Glutamate hypothesis of schizophrenia

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Glutamate_hypothesis_of_schizophrenia 

 

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

Like the dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, NMDA antagonists mimic some positive and negative symptoms with less brain harm, when combined with a GABA_A activating drug. Likely, both dopaminergic and glutaminergic abnormalities are implicated in schizophrenia, from a profound alteration in the function of the chemical synapses, as well as electrical synaptic irregularities. These form a portion of the complex constellation of factors, neurochemically, psychologically, psychosocially, and structurally, which result in schizophrenia.

The role of heteromer formation

Alteration in the expression, distribution, autoregulation, and prevalence of specific glutamate heterodimers alters relative levels of paired G proteins to the heterodimer-forming glutamate receptor in question. 

Namely: 5HT2A and mGlu2 form a dimer which mediates psychotomimetic and entheogenic effects of psychedelics; as such this receptor is of interest in schizophrenia. Agonists at either constituent receptor may modulate the other receptor allosterically; e.g. glutamate-dependent signaling via mGlu2 may modulate 5HT2A-ergic activity. Equilibrium between mGlu2/5HT2A is altered against tendency towards of psychosis by neuroleptic-pattern 5HT2A antagonists and mGlu2 agonists; both display antipsychotic activity. AMPA, the most widely distributed receptor in the brain, is a tetrameric ionotropic receptor; alterations in equilibrium between constituent subunits are seen in mGlu2/5HT2A antagonist (antipsychotic) administration GluR2 is seen to be upregulated in the PFC while GluR1 downregulates in response to antipsychotic administration. 

Reelin abnormalities may also be involved in the pathogenesis of schizophrenia via a glutamate-dependent mechanism. Reelin expression deficits are seen in schizophrenia, and reelin enhances expression of AMPA and NMDA alike. As such deficits in these two ionotropic glutamate receptors may be partially explained by altered reelin cascades. Neuregulin 1 deficits may also be involved in glutaminergic hypofunction as NRG1 hypofunction leads to schizophrenia-pattern behavior in mice; likely due in part to reduced NMDA signaling via Src suppression.

The role of synaptic pruning

Various neurotrophic factors dysregulate in schizophrenia and other mental illnesses, namely BDNF; expression of which is lowered in schizophrenia as well as in major depression and bipolar disorder. BDNF regulates in an AMPA-dependent mechanism - AMPA and BDNF alike are critical mediators of growth cone survival. NGF, another neurotrophin involved in maintenance of synaptic plasticity is similarly seen in deficit.

Dopaminergic excess, classically understood to result in schizophrenia, puts oxidative load on neurons; leading to inflammatory response and microglia activation. Similarly, toxoplasmosis infection in the CNS (positively correlated to schizophrenia) activates inflammatory cascades, also leading to microglion activation. The lipoxygenase-5 inhibitor minocycline has been seen to be marginally effective in halting schizophrenia progression. One of such inflammatory cascades' downstream transcriptional target, NF-κB, is observed to have altered expression in schizophrenia.

In addition, CB2 is one of the most widely distributed glial cell-expressed receptors, downregulation of this inhibitory receptor may increase global synaptic pruning activity. While difference in expression or distribution is observed, when the CB2 receptor is knocked out in mice, schizophreniform behaviors manifest. This may deregulate synaptic pruning processes in a tachyphlaxis mechanism wherein immediate excess CB2 activity leads to phosphorylation of the receptor via GIRK, resultant in b-arrestin-dependent internalization and subsequent trafficking to the proteasome for degradation.

The role of endogenous antagonists

Alterations in production of endogenous NMDA antagonists such as agmatine and kyenurenic acid have been shown in schizophrenia. Deficit in NMDA activity produces psychotomimetic effects, though it remains to be seen if the blockade of NMDA via these agents is causative or actually mimetic of patterns resultant from monoaminergic disruption.

AMPA, the most widely distributed receptor in the brain, mediates long term potentiation via activity-dependent modulation of AMPA density. GluR1 subunit-containing AMPA receptors are Ca2+ permeable while GluR2/3 subunit-positive receptors are nearly impermeable to calcium ions. In the regulated pathway, GluR1 dimers populate the synapse at a rate proportional to NMDA-ergic Ca2+ influx. In the constitutative pathway, GluR2/3 dimers populate the synapse at a steady state.

This forms a positive feedback loop, where a small trigger impulse degating NMDA from Mg2+ pore blockade results in calcium influx, this calcium influx then triggers trafficking of GluR1-containing(Ca2+ permeable) subunits to the PSD, such trafficking of GluR1-positive AMPA to the postsynaptic neuron allows for upmodulation of the postsynaptic neuron's calcium influx in response to presynaptic calcium influx. Robust negative feedback at NMDA from kyenurenic acid, magnesium, zinc, and agmatine prevents runaway feedback.

Misregulation of this pathway would sympathetically dysregulate LTP via disruption of NMDA. Such alteration in LTP may play a role, specifically in negative symptoms of schizophrenia, in creation of more broad disruptions such as loss of brain volume; an effect of the disease which antidopaminergics actually worsen, rather than treat.

The role of a7 nicotinic

Anandamide, an endocannabinoid, is an a7 nicotinic antagonist. Cigarettes, consumed far out of proportion by schizophrenics, contain nornitrosonicotine; a potent a7 antagonist. This may indicate a7 pentameter excess as a causative factor, or possibly as a method of self-medication to combat antipsychotic side effects. Cannabidiol, a FAAH inhibitor, increases levels in anandamide and may have antipsychotic effect; though results are mixed here as anandamide also is a cannabinoid and as such displays some psychotomimetic effect. However, a7 nicotinic agonists have been indicated as potential treatments for schizophrenia, though evidence is somewhat contradictory there is indication a7 nAChR is somehow involved in the pathogenesis of schizophrenia.

The role of 5-HT

This deficit in activation also results in a decrease in activity of 5-HT1A receptors in the raphe nucleus. This serves to increase global serotonin levels, as 5-HT1A serves as an autoreceptor. The 5-HT1B receptor, also acting as an autoreceptor, specifically within the striatum, but also parts of basal ganglia then will inhibit serotonin release. This disinhibits frontal dopamine release. The local deficit of 5-HT within the striatum, basal ganglia, and prefrontal cortex causes a deficit of excitatory 5-HT6 signalling. This could possibly be the reason antipsychotics sometimes are reported to aggravate negative symptoms as antipsychotics are 5HT6 antagonists This receptor is primarily GABAergic, as such, it causes an excess of glutamatergic, noradrenergic, dopaminergic, and cholinergic activity within the prefrontal cortex and the striatum. An excess of 5-HT7 signaling within the thalamus also creates too much excitatory transmission to the prefrontal cortex. Combined with another critical abnormality observed in schizoid patients: 5-HT2A dysfunction, this altered signalling cascade creates cortical, thus cognitive abnormalities. 5-HT2A allows a link between cortical, thus conscious, and the basal ganglia, unconscious. Axons from 5-HT2A neurons in layer V of the cerebral cortex reach the basal ganglia, forming a feedback loop. Signalling from layer V of the cerebral cortex to the basal ganglia alters 5-HT2C signalling. This feedback loop with 5-HT2A/5-HT2C is how the outer cortex layers can exert some control over our neuropeptides, specifically opioid peptides, oxytocin and vasopressin. This alteration in this limbic-layer V axis may create the profound change in social cognition (and sometimes cognition as a whole) that is observed in schizoid patients. However, genesis of the actual alterations is a much more complex phenomena.

The role of inhibitory transmission

The cortico-basal ganglia-thalamo-cortical loop is the source of the ordered input necessary for a higher level upper cortical loop. Feedback is controlled by the inhibitory potential of the cortices via the striatum. Through 5-HT2A efferents from layer V of the cortex transmission proceeds through the striatum into the globulus pallidus internal and substantia nigra pars compacta. This core input to the basal ganglia is combined with input from the subthalamic nucleus. The only primarily dopaminergic pathway in this loop is a reciprocal connection from the substantia nigra pars reticulata to the striatum. 

Dopaminergic drugs such as dopamine releasing agents and direct dopamine receptor agonists create alterations in this primarily GABAergic pathway via increased dopaminergic feedback from the substantia nigra pars compacta to the striatum. However, dopamine also modulates other cortical areas, namely the VTA; with efferents to the amygdala and locus coeruleus, likely modulating anxiety and paranoid aspects of psychotic experience. As such, the glutamate hypothesis is probably not an explanation of primary causative factors in positive psychosis, but rather might possibly be an explanation for negative symptoms. 

Dopamine hypothesis of schizophrenia elaborates upon the nature of abnormal lateral structures found in someone with a high risk for psychosis.

Altered signalling cascades

Again, thalamic input from layer V is a crucial factor in the functionality of the human brain. It allows the two sides to receive similar inputs, thus be able to perceive the same world. In psychosis, thalamic input loses much of its integrated character: hyperactive core feedback loops overwhelm the ordered output. This is due to excessive D2 and 5-HT2A activity. This alteration in input to the top and bottom of the cortex. The altered 5-HT signal cascade enhances the strength of excitatory thalamic input from layer V. This abnormality, enhancing the thalamic-cortical transmission cascade versus the corticostriatal control, creates a feedback loop, resulting in abnormally strong basal ganglia output.

The root of psychosis (experiences that cannot be explained, even within their own mind) is when basal ganglia input to layer V overwhelms the inhibitory potential of the higher cortexies resulting from striatal transmission. When combined with the excess prefrontal, specifically orbitofrontal transmission, from the hippocampus, this creates a brain prone to falling into self reinforcing belief.

However, given a specific environment, a person with this kind of brain (a human) can create a self-reinforcing pattern of maladaptive behavior, from the altered the layer II/III and III/I axises, from the disinhibited thalamic output. Rationality is impaired, primarily as response to the deficit of oxytocin and excess of vasopressin from the abnormal 5HT2C activity.

Frontal cortex activity will be impaired, when combined with excess DA activity: the basis for the advancement of schizophrenia, but it is also the neurologic mechanism behind many other psychotic diseases as well.. Heredation of schizophrenia may even be a result of conspecific "refrigerator parenting" techniques passed on though generations. However, the genetic component is the primary source of the neurological abnormalities which leave one prone to psychological disorders. Specifically, there is much overlap between bipolar disorder and schizophrenia, and other psychotic disorders.

Psychotic disorder is linked to excessive drug use, specifically dissociatives, psychedelics, stimulants, and marijuana.

Current state of schizophrenia treatment

Alterations in serine racemase indicate that the endogenous NDMA agonist D-serine may be produced abnormally in schizophrenia and that d-serine may be an effective treatment for schizophrenia. 

Schizophrenia is now treated by medications known as antipsychotics (or neuroleptics) that typically reduce dopaminergic activity because too much activity has been most strongly linked to positive symptoms, specifically persecutory delusions. Dopaminergic drugs do not induce the characteristic auditory hallucinations of schizophrenia. Dopaminergic drug abuse such as abuse of methamphetamine may result in a short lasting psychosis or provokation of a longer psychotic episode that may include symptoms of auditory hallucinations. The typical antipsychotics are known to have significant risks of side effects that can increase over time, and only show clinical effectiveness in reducing positive symptoms. Additionally, although newer atypical antipsychotics can have less affinity for dopamine receptors and still reduce positive symptoms, do not significantly reduce negative symptoms. A 2006 systematic review investigated the efficacy of glutamatergic drugs as add-on: 

Adding glutamatergic drug to antipsychotics compared to the same antipsychotic plus a placebo for schizophrenia

Summary
In general, all glutamatergic drugs appeared to be ineffective in further reducing 'positive symptoms' of the illness when added to the existing antipsychotic treatment. Glycine and D-serine may somewhat improve 'negative symptoms' when added to regular antipsychotic medication, but the results were not fully consistent and data are too few to allow any firm conclusions.

Outcome	Findings in words	Findings in numbers	Quality of evidence
Global outcome
Relapse (add-on glycine)	At present it is not possible to be confident about the effect of adding the glutamatergic drug to standard antipsychotic treatment. Data supporting this finding are very limited.	RR 0.39 (0.02 to 8.73)	Very low
Service outcome
Hospital admission (add-on glycine)	There is no clarity about the benefits or otherwise of adding a glutamatergic drug to antipsychotics for outcomes about how much hospital/community care is used. Data supporting this finding are based on low quality evidence.	RR 2.63 (0.12 to 59.40)	Low
Mental state
No clinically significant improvement (add-on glycine)	There is no evidence of clear advantage of using add-on glutamatergic to standard antipsychotic medication. These findings are based on data of low quality.	RR 0.92 (0.79 to 1.08)	Low
Adverse effects
Constipation (add-on glycine or D-serine)	There is no clarity from very limited data. Additional glutamatergic could cause constipation or help avoid it. Data are very limited.	RR 0.61 (0.06 to 6.02)	Very low
Insomnia (add-on glycine or D-serine)	Additional glutamatergic may help or cause insomnia - it is not clear from the very limited data.	RR 0.61 (0.13 to 2.84)	Very low
Missing outcomes
Quality of life	This outcome was not reported in any studies

Psychotomimetic glutamate antagonists

Ketamine and PCP were observed to produce significant similarities to schizophrenia. Ketamine produces more similar symptoms (hallucinations, withdrawal) without observed permanent effects (other than ketamine tolerance). Both arylcyclohexamines have some(uM) affinity to D2 and as triple reuptake inhibitors. PCP is representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia. Although unconfirmed, Dizocilpine discovered by a team at Merck seems to model both the positive and negative effects in a manner very similar to schizophreniform disorders.

Possible glutamate based treatment

An early clinical trial by Eli Lilly of the drug LY2140023 has shown potential for treating schizophrenia without the weight gain and other side-effects associated with conventional anti-psychotics. A trial in 2009 failed to prove superiority over placebo or Olanzapine, but Lilly explained this as being due to an exceptionally high placebo response. However, Eli Lilly terminated further development of the compound in 2012 after it failed in phase III clinical trials. This drug acts as a selective agonist at metabotropic mGluR2 and mGluR3 glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia.).

Studies of glycine (and related co-agonists at the NMDA receptor) added to conventional anti-psychotics have also found some evidence that these may improve symptoms in schizophrenia.

Animal models

Research done on mice in early 2009 has shown that when the neuregulin-1\ErbB post-synaptic receptor genes are deleted, the dendritic spines of glutamate neurons initially grow, but break down during later development. This led to symptoms (such as disturbed social function, inability to adapt to predictable future stressors) that overlap with schizophrenia. This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.

Disrupted in schizophrenia 1 is a gene that is disrupted in schizophrenia.