Dopamine receptor

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Dopamine Dopamin - Dopamine.svg
Dopamine

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein (dopamine receptor-interacting proteins) interactions. [1] The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

Contents

Dopamine receptors are implicated in many neurological processes, including motivational and incentive salience, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders. [2] Thus, dopamine receptors are common neurologic drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors.

Subtypes

The existence of multiple types of receptors for dopamine was first proposed in 1976. [3] [4] There are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. The D1 and D5 receptors are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 receptors are members of the D2-like family . There is also some evidence that suggests the existence of possible D6 and D7 dopamine receptors, but such receptors have not been conclusively identified. [5]

At a global level, D1 receptors have widespread expression throughout the brain. The relative amount of DA receptors is in the following order: D1 > D2 > D3 > D5 > D4. [6] D1-2 receptor subtypes are found at 10–100 times the levels of the D3-5 subtypes. [7]

D1-like family

The D1-like family receptors are coupled to the G protein Gsα. D1 is also coupled to Golf.

Gsα subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP). [8]

D2-like family

The D2-like family receptors are coupled to the G protein Giα, which directly inhibits the formation of cAMP by inhibiting the enzyme adenylyl cyclase. [9]

Receptor heteromers

Dopamine receptors have been shown to heteromerize with a number of other G protein-coupled receptors. [16] Especially the D2 receptor is considered a major hub within the GPCR heteromer network. [17] Protomers consist of

Isoreceptors [18]

Non-isoreceptors

Signaling mechanism

Dopamine receptor D1 and Dopamine receptor D5 are Gs coupled receptors that stimulate adenylyl cyclase to produce cAMP, which in turn increases intracellular calcium and mediates a number of other functions. The D2 class of receptors produce the opposite effect, as they are Gαi and/or Gαo coupled receptors, which blocks the activity of adenylyl cyclase. cAMP mediated protein kinase A activity also results in the phosphorylation of DARPP-32, an inhibitor of protein phosphatase 1. Sustained D1 receptor activity is kept in check by Cyclin-dependent kinase 5. Dopamine receptor activation of Ca2+/calmodulin-dependent protein kinase II can be cAMP dependent or independent. [19]

The cAMP mediated pathway results in amplification of PKA phosphorylation activity, which is normally kept in equilibrium by PP1. The DARPP-32 mediated PP1 inhibition amplifies PKA phosphorylation of AMPA, NMDA, and inward rectifying potassium channels, increasing AMPA and NMDA currents while decreasing potassium conductance. [8]

cAMP independent

D1 receptor agonism and D2 receptor blockade also increases mRNA translation by phosphorylating ribosomal protein s6, resulting in activation of mTOR. The behavioral implications are unknown. Dopamine receptors may also regulate ion channels and BDNF independent of cAMP, possibly through direct interactions. There is evidence that D1 receptor agonism regulates phospholipase C independent of cAMP, however implications and mechanisms remain poorly understood. D2 receptor signaling may mediate protein kinase B, arrestin beta 2, and GSK-3 activity, and inhibition of these proteins results in stunting of the hyperlocomotion in amphetamine treated rats. Dopamine receptors can also transactivate Receptor tyrosine kinases. [19]

Beta Arrestin recruitment is mediated by G-protein kinases that phosphorylate and inactivate dopamine receptors after stimulation. While beta arrestin plays a role in receptor desensitization, it may also be critical in mediating downstream effects of dopamine receptors. Beta arrestin has been shown to form complexes with MAP kinase, leading to activation of extracellular signal-regulated kinases. Furthermore, this pathway has been demonstrated to be involved in the locomotor response mediated by dopamine receptor D1. Dopamine receptor D2 stimulation results in the formation of an Akt/Beta-arrestin/PP2A protein complex that inhibits Akt through PP2A phosphorylation, therefore disinhibiting GSK-3. [20]

Role in the central nervous system

Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory. [21] Dopamine also plays an important role in the reward system, incentive salience, cognition, prolactin release, emesis and motor function. [22]

Non-CNS dopamine receptors

Cardio-pulmonary system

In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasodilatory effects of dopamine in the blood. [23] Such receptor subtypes have also been discovered in the epicardium, myocardium, and endocardium of the heart. [24] In rats, D1-like receptors are present on the smooth muscle of the blood vessels in most major organs. [25]

D4 receptors have been identified in the atria of rat and human hearts. [26] Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors. [5]

Renal system

Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density. [25] In rats, D1-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D2-like receptors are present on the glomeruli, zona glomerulosa cells of the adrenal cortex, renal tubules, and postganglionic sympathetic nerve terminals. [25] Dopamine signaling affects diuresis and natriuresis. [5]

The Pancreas

The role of the pancreas [27] is to secrete digestive enzymes via exocrine glands and hormones via endocrine glands. Pancreatic endocrine glands, composed of dense clusters of cells called the Islets of Langerhans, secrete insulin, glucagon, and other hormones essential for metabolism and glycemic control. Insulin secreting beta cells have been intensely researched due to their role in diabetes. [28]

Recent studies have found that beta cells, as well as other endocrine and exocrine pancreatic cells, express D2 receptors [29] and that beta cells co-secrete dopamine along with insulin. [30] Dopamine has been purported to be a negative regulator of insulin, [31] [32] meaning that bound D2 receptors inhibit insulin secretion. The connection between dopamine and beta cells was discovered, in part, due to the metabolic side-effects of certain antipsychotic medications. [33] [34] Traditional/typical antipsychotic medications function by altering the dopamine pathway in the brain, such as blocking D2 receptors. [35] Common side effects of these medications include rapid weight gain and glycemic dysregulation, among others. [36] The effects of these medications are not limited to the brain, so off-target effects in other organs such as the pancreas have been proposed as a possible mechanism. [37]

In disease

Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including social phobia, [38] Tourette's syndrome, [39] Parkinson's disease, [40] schizophrenia, [39] neuroleptic malignant syndrome, [41] attention-deficit hyperactivity disorder (ADHD), [42] and drug and alcohol dependence. [39] [43]

Attention-deficit hyperactivity disorder

Dopamine receptors have been recognized as important components in the mechanism of ADHD for many years. Drugs used to treat ADHD, including methylphenidate and amphetamine, have significant effects on neuronal dopamine signaling. Studies of gene association have implicated several genes within dopamine signaling pathways; in particular, the D4.7 variant of D4 has been consistently shown to be more frequent in ADHD patients. [44] ADHD patients with the 4.7 allele also tend to have better cognitive performance and long-term outcomes compared to ADHD patients without the 4.7 allele, suggesting that the allele is associated with a more benign form of ADHD. [44]

The D4.7 allele has suppressed gene expression compared to other variants. [45]

Addictive drugs

Dopamine is the primary neurotransmitter involved in the reward and reinforcement (mesolimbic) pathway in the brain. Although it was a long-held belief that dopamine was the cause of pleasurable sensations such as euphoria, many studies and experiments on the subject have demonstrated that this is not the case; rather, dopamine in the mesolimbic pathway is responsible for behaviour reinforcement ("wanting") without producing any "liking" sensation on its own. [46] [47] [48] [49] Mesolimbic dopamine and its related receptors are a primary mechanism through which drug-seeking behaviour develops (Incentive Salience), and many recreational drugs, such as cocaine and substituted amphetamines, inhibit the dopamine transporter (DAT), the protein responsible for removing dopamine from the neural synapse. When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signaling. When this occurs, particularly in the nucleus accumbens, [50] increased D1 [43] and decreased D2 [50] receptor signaling mediates the "incentive salience" factor and can significantly increase positive associations with the drug in the brain. [49]

Pathological gambling

Pathological gambling is classified as a mental health disorder that has been linked to obsessive-compulsive spectrum disorder and behavioral addiction. Dopamine has been associated with reward and reinforcement in relation to behaviors and drug addiction. [51] The role between dopamine and pathological gambling may be a link between cerebrospinal fluid measures of dopamine and dopamine metabolites in pathological gambling. [52] Molecular genetic study shows that pathological gambling is associated with the TaqA1 allele of the Dopamine Receptor D2 (DRD2) dopamine receptor. Furthermore, TaqA1 allele is associated with other reward and reinforcement disorders, such as substance abuse and other psychiatric disorders. Reviews of these studies suggest that pathological gambling and dopamine are linked; however, the studies that succeed in controlling for race or ethnicity, and obtain DSM-IV diagnoses do not show a relationship between TaqA1 allelic frequencies and the diagnostic of pathological gambling. [51]

Schizophrenia

While there is evidence that the dopamine system is involved in schizophrenia, the theory that hyperactive dopaminergic signal transduction induces the disease is controversial. Psychostimulants, such as amphetamine and cocaine, indirectly increase dopamine signaling; large doses and prolonged use can induce symptoms that resemble schizophrenia. Additionally, many antipsychotic drugs target dopamine receptors, especially D2 receptors.

Genetic hypertension

Dopamine receptor mutations can cause genetic hypertension in humans. [53] This can occur in animal models and humans with defective dopamine receptor activity, particularly D1. [25]

Parkinson's disease

Parkinson's disease is associated with the loss of cells responsible for dopamine synthesis and other neurodegenerative events. [51] Parkinson's disease patients are treated with medications which help to replenish dopamine availability, allowing relatively normal brain function and neurotransmission. [54] Research shows that Parkinson's disease is linked to the class of dopamine agonists instead of specific agents. Reviews touch upon the need to control and regulate dopamine doses for Parkinson's patients with a history of addiction, and those with variable tolerance or sensitivity to dopamine. [55]

Dopamine regulation

Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels can downregulate (reduce the numbers of) or upregulate (increase the numbers of) dopamine receptors. [56]

Haloperidol, and some other antipsychotics, have been shown to increase the binding capacity of the D2 receptor when used over long periods of time (i.e. increasing the number of such receptors). [57] Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.

Addictive stimuli have variable effects on dopamine receptors, depending on the particular stimulus. [58] According to one study, [59] cocaine, opioids like heroin, amphetamine, alcohol, and nicotine cause decreases in D2 receptor quantity. A similar association has been linked to food addiction, with a low availability of dopamine receptors present in people with greater food intake. [60] [61] A recent news article [62] summarized a U.S. DOE Brookhaven National Laboratory study showing that increasing dopamine receptors with genetic therapy temporarily decreased cocaine consumption by up to 75%. The treatment was effective for 6 days. Cocaine upregulates D3 receptors in the nucleus accumbens, further reinforcing drug seeking behavior. [63] and Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain, [64] Caffeine, or other more selective adenosine A2A receptor antagonists, causes significantly less motor stimulation in dopamine D2 receptor. [65]

Certain stimulants will enhance cognition in the general population (e.g., direct or indirect mesocortical DRD1 agonists as a class), but only when used at low (therapeutic) concentrations. [66] [67] [68] Relatively high doses of dopaminergic stimulants will result in cognitive deficits. [67] [68]

Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity 		Type of reinforcer Sources
OpiatesPsychostimulantsHigh fat or sugar food Sexual intercourse Physical exercise
(aerobic) 		Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs Tooltip medium spiny neurons		↑↑↑↑↑↑ [58]
Behavioral plasticity
Escalation of intakeYesYesYes [58]
Psychostimulant
cross-sensitization 		YesNot applicableYesYesAttenuatedAttenuated [58]
Psychostimulant
self-administration 		↑↑↓↓↓ [58]
Psychostimulant
conditioned place preference 		↑↑↓↑↓↑ [58]
Reinstatement of drug-seeking behavior ↑↑↓↓ [58]
Neurochemical plasticity
CREB Tooltip cAMP response element-binding protein phosphorylation
in the nucleus accumbens		↓↓↓↓↓ [58]
Sensitized dopamine response
in the nucleus accumbens		NoYesNoYes [58]
Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [58]
Altered striatal opioid signaling No change or
↑μ-opioid receptors 		↑μ-opioid receptors
↑κ-opioid receptors 		↑μ-opioid receptors ↑μ-opioid receptors No changeNo change [58]
Changes in striatal opioid peptides ↑dynorphin
No change: enkephalin 		↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [58]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens↓↑↑ [58]
Dendritic spine density in
the nucleus accumbens		↓↑↑ [58]

See also

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Aripiprazole</span> Atypical antipsychotic

Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder; other uses include as an add-on treatment in major depressive disorder and obsessive–compulsive disorder (OCD), tic disorders, and irritability associated with autism. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.

The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder.

<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.

<span class="mw-page-title-main">Dopaminergic pathways</span> Projection neurons in the brain that synthesize and release dopamine

Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

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Dopamine receptor D<sub>4</sub> Protein-coding gene in the species Homo sapiens

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Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never used before.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. 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 primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

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Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

Dopamine receptor D<sub>5</sub> Protein-coding gene in humans

Dopamine receptor D5, also known as D1BR, is a protein that in humans is encoded by the DRD5 gene. It belongs to the D1-like receptor family along with the D1 receptor subtype.

Dopamine receptor D<sub>3</sub> Subtype of Dopamine Receptor

Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">L-741,626</span> Chemical compound

L-741,626 is a drug which acts as a potent and selective antagonist for the dopamine receptor D2. It has good selectivity over the related D3 and D4 subtypes and other receptors. L-741,626 is used for laboratory research into brain function and has proved particularly useful for distinguishing D2 mediated responses from those produced by the closely related D3 subtype, and for studying the roles of these subtypes in the action of cocaine and amphetamines in the brain.

Disorders of diminished motivation (DDM) are a group of disorders involving diminished motivation and associated emotions. Many different terms have been used to refer to diminished motivation. Often however, a spectrum is defined encompassing apathy, abulia, and akinetic mutism, with apathy the least severe and akinetic mutism the most extreme.

<span class="mw-page-title-main">Motivation-enhancing drug</span> Drug increasing motivation in humans

A motivation-enhancing drug, also known as a pro-motivational drug, is a drug which increases motivation. Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). They can also be used in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, disorders that can be caused by conditions like stroke, traumatic brain injury (TBI), and neurodegenerative diseases. Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts.

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  58. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC   3139704 . PMID   21459101. Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)." Table 1"
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  65. ↑ Voiculescu M, Ghiță I, Segărceanu A, Fulga I, Coman O (2014). "Molecular and pharmacodynamic interactions between caffeine and dopaminergic system". Journal of Medicine and Life. 7 (Spec Iss 4): 30–38. ISSN   1844-122X. PMC   4813614 . PMID   27057246.
  66. ↑ Ilieva IP, Hook CJ, Farah MJ (January 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J. Cogn. Neurosci. 27 (6): 1069–1089. doi:10.1162/jocn_a_00776. PMID   25591060. S2CID   15788121. The present meta-analysis was conducted to estimate the magnitude of the effects of methylphenidate and amphetamine on cognitive functions central to academic and occupational functioning, including inhibitory control, working memory, short-term episodic memory, and delayed episodic memory. In addition, we examined the evidence for publication bias. Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches. Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition. ... Earlier research has failed to distinguish whether stimulants' effects are small or whether they are nonexistent (Ilieva et al., 2013; Smith & Farah, 2011). The present findings supported generally small effects of amphetamine and methylphenidate on executive function and memory. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ...

    The results of this meta-analysis cannot address the important issues of individual differences in stimulant effects or the role of motivational enhancement in helping perform academic or occupational tasks. However, they do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
  67. 1 2 Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 318. ISBN   978-0-07-148127-4. Mild dopaminergic stimulation of the prefrontal cortex enhances working memory. ...
    Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spatial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.
  68. 1 2 Wood S, Sage JR, Shuman T, Anagnostaras SG (January 2014). "Psychostimulants and cognition: a continuum of behavioral and cognitive activation". Pharmacol. Rev. 66 (1): 193–221. doi:10.1124/pr.112.007054. PMC   3880463 . PMID   24344115.
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