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Wednesday, December 26, 2018

Phenylalanine

From Wikipedia, the free encyclopedia


Phenylalanine
Skeletal formula
L-Phenylalanine
1PhenylalanineAtPhysiologicalpH.svg
L-Phenylalanine at physiological pH
L-phenylalanine-3D-balls.png
3D phenylalanine model
Names
Pronunciation US: /ˌfɛnəlˈælənn/, UK: /ˌfnl-/
IUPAC name
(S)-2-Amino-3-phenylpropanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.517
KEGG
PubChem CID
UNII
Properties
C9H11NO2
Molar mass 165.19 g·mol−1
Acidity (pKa) 1.83 (carboxyl), 9.13 (amino)
Hazards
Safety data sheet See: data page
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oilHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroformReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
1
2
0
Supplementary data page
Refractive index (n),
Dielectric constantr), etc.
Thermodynamic
data
Phase behaviour
solid–liquid–gas
UV, IR, NMR, MS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula C
9
H
11
NO
2
. It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino acid is classified as neutral, and nonpolar because of the inert and hydrophobic nature of the benzyl side chain. The L-isomer is used to biochemically form proteins, coded for by DNA. Phenylalanine is a precursor for tyrosine, the monoamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), and the skin pigment melanin. It is encoded by the codons UUU and UUC.

Phenylalanine is found naturally in the breast milk of mammals. It is used in the manufacture of food and drink products and sold as a nutritional supplement for its reputed analgesic and antidepressant effects. It is a direct precursor to the neuromodulator phenethylamine, a commonly used dietary supplement. As an essential amino acid, phenylalanine is not synthesized de novo in humans and other animals, who must ingest phenylalanine or phenylalanine-containing proteins.

History

The first description of phenylalanine was made in 1879, when Schulze and Barbieri identified a compound with the empirical formula, C9H11NO2, in yellow lupine (Lupinus luteus) seedlings. In 1882, Erlenmeyer and Lipp first synthesized phenylalanine from phenylacetaldehyde, hydrogen cyanide, and ammonia.

The genetic codon for phenylalanine was first discovered by J. Heinrich Matthaei and Marshall W. Nirenberg in 1961. They showed that by using mRNA to insert multiple uracil repeats into the genome of the bacterium E. coli, they could cause the bacterium to produce a polypeptide consisting solely of repeated phenylalanine amino acids. This discovery helped to establish the nature of the coding relationship that links information stored in genomic nucleic acid with protein expression in the living cell.

Dietary sources

Good sources of phenylalanine are eggs, chicken, liver, beef, milk, and soybeans.

Dietary recommendations

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For phenylalanine plus tyrosine, for adults 19 years and older, 33 mg/kg body weight/day.

Other biological roles

L-Phenylalanine is biologically converted into L-tyrosine, another one of the DNA-encoded amino acids. L-tyrosine in turn is converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). The latter three are known as the catecholamines

Phenylalanine uses the same active transport channel as tryptophan to cross the blood–brain barrier. In excessive quantities, supplementation can interfere with the production of serotonin and other aromatic amino acids as well as nitric oxide due to the overuse (eventually, limited availability) of the associated cofactors, iron or tetrahydrobiopterin.

The corresponding enzymes in for those compounds are the aromatic amino acid hydroxylase family and nitric oxide synthase. Phenylalanine in humans may ultimately be metabolized into a range of different substances.

 Graphic of catecholamine and trace amine biosynthesis

In plants

Phenylalanine is the starting compound used in the synthesis of flavonoids. Lignan is derived from phenylalanine and from tyrosine. Phenylalanine is converted to cinnamic acid by the enzyme phenylalanine ammonia-lyase.

Phenylketonuria

The genetic disorder phenylketonuria (PKU) is the inability to metabolize phenylalanine because of a lack of the enzyme phenylalanine hydroxylase. Individuals with this disorder are known as "phenylketonurics" and must regulate their intake of phenylalanine. Phenylketonurics often use blood tests to monitor the amount of phenylalanine in their blood. Lab results may report phenylalanine levels using either mg/dL and μmol/L. One mg/dL of phenylalanine is approximately equivalent to 60 μmol/L. 

A (rare) "variant form" of phenylketonuria called hyperphenylalaninemia is caused by the inability to synthesize a cofactor called tetrahydrobiopterin, which can be supplemented. Pregnant women with hyperphenylalaninemia may show similar symptoms of the disorder (high levels of phenylalanine in blood) but these indicators will usually disappear at the end of gestation. Pregnant women with PKU must control their blood phenylalanine levels even if the fetus is heterozygous for the defective gene because the fetus could be adversely affected due to hepatic immaturity.

A non-food source of phenylalanine is the artificial sweetener aspartame. This compound is metabolized by the body into several chemical byproducts including phenylalanine. The breakdown problems phenylketonurics have with the buildup of phenylalanine in the body also occurs with the ingestion of aspartame, although to a lesser degree. Accordingly, all products in Australia, the U.S. and Canada that contain aspartame must be labeled: "Phenylketonurics: Contains phenylalanine." In the UK, foods containing aspartame must carry ingredient panels that refer to the presence of "aspartame or E951" and they must be labeled with a warning "Contains a source of phenylalanine." In Brazil, the label "Contém Fenilalanina" (Portuguese for "Contains Phenylalanine") is also mandatory in products which contain it. These warnings are placed to help individuals avoid such foods. 

Geneticists sequenced the genome of macaques in 2007. Their investigations found "some instances where the normal form of the macaque protein looked like the diseased human protein" including markers for PKU.

D-, L- and DL-phenylalanine

The stereoisomer D-phenylalanine (DPA) can be produced by conventional organic synthesis, either as a single enantiomer or as a component of the racemic mixture. It does not participate in protein biosynthesis although it is found in proteins in small amounts - particularly aged proteins and food proteins that have been processed. The biological functions of D-amino acids remain unclear, although D-phenylalanine has pharmacological activity at niacin receptor 2.

DL-Phenylalanine (DLPA) is marketed as a nutritional supplement for its purported analgesic and antidepressant activities. DL-Phenylalanine is a mixture of D-phenylalanine and L-phenylalanine. The reputed analgesic activity of DL-phenylalanine may be explained by the possible blockage by D-phenylalanine of enkephalin degradation by the enzyme carboxypeptidase A. The mechanism of DL-phenylalanine's supposed antidepressant activity may be accounted for by the precursor role of L-phenylalanine in the synthesis of the neurotransmitters norepinephrine and dopamine. Elevated brain levels of norepinephrine and dopamine are thought to have an antidepressant effect. D-Phenylalanine is absorbed from the small intestine and transported to the liver via the portal circulation. A small amount of D-phenylalanine appears to be converted to L-phenylalanine. D-Phenylalanine is distributed to the various tissues of the body via the systemic circulation. It appears to cross the blood–brain barrier less efficiently than L-phenylalanine, and so a small amount of an ingested dose of D-phenylalanine is excreted in the urine without penetrating the central nervous system.

L-Phenylalanine is an antagonist at α2δ Ca2+ calcium channels with a Ki of 980 nM.

In the brain, L-phenylalanine is a competitive antagonist at the glycine binding site of NMDA receptor and at the glutamate binding site of AMPA receptor. At the glycine binding site of NMDA receptor L-phenylalanine has an apparent equilibrium dissociation constant (KB) of 573 µM estimated by Schild regression which is considerably lower than brain L-phenylalanine concentration observed in untreated human phenylketonuria. L-Phenylalanine also inhibits neurotransmitter release at glutamatergic synapses in hippocampus and cortex with IC50 of 980 µM, a brain concentration seen in classical phenylketonuria, whereas D-phenylalanine has a significantly smaller effect.

Commercial synthesis

L-Phenylalanine is produced for medical, feed, and nutritional applications, such as aspartame, in large quantities by utilizing the bacterium Escherichia coli, which naturally produces aromatic amino acids like phenylalanine. The quantity of L-phenylalanine produced commercially has been increased by genetically engineering E. coli, such as by altering the regulatory promoters or amplifying the number of genes controlling enzymes responsible for the synthesis of the amino acid.

Derivatives

Boronophenylalanine (BPA) is a dihydroxyboryl derivative of phenylalanine, used in neutron capture therapy.

Ventral tegmental area

From Wikipedia, the free encyclopedia

Ventral tegmental area
Gray712.png
Transverse section of mid-brain at level of superior colliculi. (Tegmentum labeled at center right.)
Details
Part ofMidbrain
Identifiers
LatinArea tegmentalis ventralis
Acronym(s)VTA
MeSHD017557
NeuroNames521
NeuroLex IDbirnlex_1415

The ventral tegmental area (VTA) (tegmentum is Latin for covering), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including cognition, motivation, orgasm, and intense emotions relating to love, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.

Structure

Anatomical location of VTA in humans
 
Neurobiologists have often had great difficulty distinguishing the VTA in humans and other primate brains from the substantia nigra (SN) and surrounding nuclei. Originally, the ventral tegmental area was designated as a ‘nucleus’, but over time ‘area’ became the more appropriate term used because of the heterogeneous cytoarchitectonic features of the region and the lack of clear borders that separate it from adjacent regions. Because of the selective limbic-related afferents to the VTA, the cells of the VTA are given the designation A10 to differentiate them from surrounding cells.

Location

The ventral tegmental area is in the midbrain between several other major areas, some of which are described here. The mammillary bodies and the posterior hypothalamus, both included in the diencephalon, extend rostrally from the VTA. The red nucleus is situated laterally and oculomotor fibers are situated ventromedially to the VTA. The pons and the hindbrain lie caudally to the VTA. Finally, the substantia nigra is located laterally to the VTA.

Subdivisions

In 1987, Oades identified four primary nuclei in the VTA A10 group of cells: the nucleus paranigralis (Npn), the nucleus parabrachialis pigmentosus (Npbp), the nucleus interfascicularis (Nif), and the nucleus linearis (Nln) caudalis and rostralis. Presently, scientists divide the VTA up into four similar zones that are called the paranigral nucleus (PN), the parabrachial pigmented area (PBP), the parafasciculus retroflexus area (PFR), and the rostromedial tegmental nucleus (RMTg), which approximately adhere to the previous divisions. Some definitions of the VTA also include the midline nuclei (i.e. the interfascicular nucleus, rostral linear nucleus, and central linear nucleus).

The PN and PBP are rich in dopaminergic cells, whereas the other two regions have low densities of these neurons. The PFR and RMTg contain a low density of tyrosine hydroxylase (TH)-positive cell bodies that are small in size and lightly stain; the RMTg is composed mostly of GABAergic cells. On the other hand, the PN and PBP consist mainly of medium to large sized TH-positive cell bodies that stain moderately.

Inputs

Almost all areas receiving projections from the VTA project back to it. Thus, the ventral tegmental area is reciprocally connected with a wide range of structures throughout the brain suggesting that it has a role in the control of function in the phylogenetically newer and highly developed neocortex, as well as that of the phylogenetically older limbic areas.

The VTA is not a homogenous region, as it consists of a variety of neurons that are characterized by different neurochemical and neurophysiological properties. Therefore, glutaminergic and GABAergic inputs are not exclusively inhibitory nor exclusively excitatory. The VTA receives glutaminergic afferents from the prefrontal cortex, pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus, subthalamic nucleus, bed nucleus of the stria terminalis, superior colliculus, and lateral hypothalamic and preoptic areas.

GABAergic inputs to the VTA include the nucleus accumbens, ventral pallidum, and rostromedial tegmental nucleus (RMTg). The lateral habenula exerts an inhibitory effect on dopaminergic neurons in the VTA via exciting RMTg GABAergic neurons, which is thought to play an important role in reward prediction errors.

There are excitatory glutamatergic afferents that arise from most structures that project into the VTA. These glutamatergic afferents play a key role in regulating VTA cell firing. When the glutamatergic neurons are activated, the firing rates of the dopamine neurons increase in the VTA and induce burst firing. Studies have shown that these glutamatergic actions in the VTA are critical to the effects of drugs of abuse. In contrast, the tail of the ventral tegmental area (tVTA, a.k.a. the RMTg) projects to the VTA with GABAergic afferents, functioning as a "master brake" for the VTA dopamine pathways.

Subpallidal afferents into the VTA are mainly GABAergic and, thus, inhibitory. There is a substantial pathway from the subpallidal area to the VTA. When this pathway is disinhibited, an increase in the dopamine release in the mesolimbic pathway amplifies locomotor activity.

Outputs

The two primary efferent fiber projections of the VTA are the mesocortical and the mesolimbic pathways, which correspond to the prefrontal cortex and nucleus accumbens respectively. The full set of projections, all of which utilize dopamine as their primary neurotransmitter, is listed below.
  • Ventral tegmental area (VTA) projections

Development

Because they develop from common embryonic tissue and partly overlap in their projection fields, Dopaminergic cell groups lack clear anatomical boundaries. During the development of the mammalian brain, both substantia nigra (SN) and VTA neurons initially project to the dorsolateral and ventromedial striatum. However, at birth the SN dopaminergic neurons project exclusively into the dorsolateral striatum, and the VTA dopaminergic neurons project solely into the ventromedial striatum. This pruning of connections occurs through the elimination of the unnecessary collaterals.

Function

As stated above, the VTA, in particular the VTA dopamine neurons, serve several functions in the reward system, motivation, cognition, and drug addiction, and may be the focus of several psychiatric disorders. It has also been shown to process various types of emotion output from the amygdala, where it may also play a role in avoidance and fear-conditioning. Electrophysiological recordings have demonstrated that VTA neurons respond to novel stimuli, unexpected rewards, and reward-predictive sensory cues. The firing pattern of these cells is consistent with the encoding of a reward expectancy error. 

In 2006, MRI studies by Helen Fisher and her research team found and documented various emotional states relating to intense love correlated with activity in the VTA, which may help explain obsessive behaviors of rejected partners, since this is shared by the reward system. Nest sharing behavior is associated with increased V1aR expression in the VTA of newly paired zebra finches. However, V1aR expression was not related to female directed song rates, which may indicate a selective role of vasotocin in the VTA on pair maintenance versus courtship behavior.

Presence of gap junctions

The VTA has been shown to have a large network of GABAergic neurons that are interconnected via gap junctions. This network allows for electrical conduction, which is considerably faster than the chemical conduction of signals between synapses.

Neural composition

The VTA, like the substantia nigra, is populated with melanin-pigmented dopaminergic neurons. Recent studies have suggested that dopaminergic neurons comprise 50-60% of all neurons in the VTA, which is contrary to previous evidence that noted 77% of neurons within the VTA to be dopaminergic. In addition, there is a sizable population of GABAergic neurons in the rostromedial tegmental nucleus (RMTg), a functionally distinct brain structure. These GABAergic neurons regulate the firing of their dopaminergic counterparts that send projections throughout the brain to, but not limited to, the following regions: the prefrontal cortex, the nucleus accumbens, and the locus coeruleus. The VTA also contains a small percentage of excitatory glutamatergic neurons.

Limbic loop

The “limbic loop” is very similar to the direct pathway motor loop of the basal ganglia. In both systems, there are major excitatory inputs from the cortex to the striatum (accumbens nucleus), the midbrain project neuromodulatory dopamine neurons to the striatum, the striatum makes internuclear connections to the pallidum, and the pallidum has outputs to the thalamus, which projects to the cortex, thus completing the loop. The limbic loop is distinguished from the motor loop by the source and nature of the cortical input, the division of the striatum and pallidum that process the input, the source of the dopaminergic neurons form the midbrain, and the thalamic target of the pallidal output.

CA3 loop

Linking context to reward is important for reward seeking. In 2011, a group of researchers documented a VTA-CA3 loop that uses the lateral septum as an intermediary. They used a pseudo-rabies virus (PRV) as a transsynaptic tracer, and injected it into the VTA. They found that unilateral injection into the VTA resulted in bilateral PRV labeling in CA3 beginning 48 hours after injection. Lesions of the caudodorsal lateral septum (cd-LS) before VTA PRV injection resulted in significantly less PRV labeled neurons in CA3. Theta wave stimulation of CA3 resulted in increased firing rates for dopamine cells in the VTA, and decreased firing rates for GABA neurons in the VTA. The identity of VTA neurons was confirmed by neurobiotin™ labeling of the recording neuron, and then histological staining for tyrosine hydroxylase (TH). Temporary inactivation of CA3 via GABA agonists prevented context induced reinstatement of lever pressing for intravenous cocaine.

The authors propose a functional circuit loop where activation of glutamatergic cells in CA3 causes activation of GABAergic cells in cd-LS, which inhibits GABA interneurons in the VTA, releasing the dopamine cells from the tonic inhibition, and leading to an increased firing rate for the dopamine cells.

Reward system

The dopamine reward circuitry in the human brain involves two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. First, the posteromedial VTA and central linear raphe cells selectively project to the ventromedial striatum, which includes the medial olfactory tubercle and the medial NAC shell. Second, the lateral VTA projects largely to the ventrolateral striatum, which includes the NAC core, the medial NAC shell, and the lateral olfactory tubercle. These pathways are called the meso-ventromedial and the meso-ventrolateral striatal dopamine systems, respectively. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed behavior than the lateral projection system. Unlike the lateral part, the medial one is activated not by rewarding but by noxious stimuli. Therefore, the NAC shell and the posterior VTA are the primary areas involved in the reward system.

Clinical significance

Disorders

The dopaminergic neurons of the substantia nigra and the ventral tegmental area of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. The close proximity of these two pathways causes them to be grouped together under dopaminergic projections. Several disorders result from the disruption of these two pathways: schizophrenia, Parkinson's disease, and attention deficit hyperactivity disorder (ADHD). Current research is examining the subtle difference between the neurons that are involved in these conditions and trying to find a way to selectively treat a specific dopamine projection.

Drug addiction

The nucleus accumbens and the ventral tegmental area are the primary sites where addictive drugs act. The following are commonly considered to be addictive: heroin, cocaine, alcohol, opioids, nicotine, cannabinoids, amphetamine, and their analogs. These drugs alter the neuromodulatory influence of dopamine on the processing of reinforcement signals by prolonging the action of dopamine in the nucleus accumbens or by stimulating the activation of neurons there and also in the VTA. The most common drugs of abuse stimulate the release of dopamine, which creates both their rewarding and the psychomotor effects. Compulsive drug-taking behaviors are a result of the permanent functional changes in the mesolimbic dopamine system arising from repetitive dopamine stimulation. Molecular and cellular adaptations are responsible for a sensitized dopamine activity in the VTA and along the mesolimbic dopamine projection in response to drug abuse. In the VTA of addicted individuals, the activity of the dopamine-synthesizing enzyme tyrosine hydroxylase increases, as does the ability of these neurons to respond to excitatory inputs. The latter effect is secondary to increases in the activity of the transcription factor CREB and the up regulation of GluR1, an important subunit of AMPA receptors for glutamate. These alterations in neural processing could account for the waning influence of adaptive emotional signals in the operation of decision making faculties as drug-seeking and drug-taking behaviors become habitual and compulsive. 

Experiments in rats have shown that they learn to press a lever for the administration of stimulant drugs into the posterior VTA more readily than into the anterior VTA. Other studies have shown that microinjections of dopaminergic drugs into the nucleus accumbens shell increase locomotor activity and exploratory behaviors, conditioned approach responses, and anticipatory sexual behaviors.

The withdrawal phenomenon occurs because the deficit in reward functioning initiates a distress cycle wherein the drugs become necessary to restore the normal homeostatic state. Recent research has shown that even after the final stages of withdrawal have been passed, drug-seeking behavior can be restored if exposed to the drug or drug-related stimuli.

Comparative anatomy and evolution

All studies since 1964 have emphasized the impressive general similarity between the VTA of all mammals from rodents to humans. These studies have focused their efforts on rats, rabbits, dogs, cats, opossum, non-human primates, and humans. There have been slight differences noted, such as changes in the dorsal extent of the A10 cells. To be specific, the dorsal peak of A10 cells is more extensive in primates when compared to other mammals. Furthermore, the number of dopaminergic cells in the VTA increases with phylogenetic progression; for instance, the VTA of the mouse contains approximately 25,000 neurons, while the VTA of a 33-year-old man contains around 450,000 cell bodies. 

Romance (love)

From Wikipedia, the free encyclopedia

Romance is an emotional feeling of love for, or a strong attraction towards, another person, and the courtship behaviors undertaken by an individual to express those overall feelings and resultant emotions. 

Although the emotions and sensations of romantic love are widely associated with sexual attraction, romantic feelings can exist without expectation of physical consummation and be subsequently expressed. Historically, the term romance originates with the medieval ideal of chivalry as set out in the literature of chivalric romance.

General definitions

Romantic love is a relative term that distinguishes moments and situations within intimate relationships as contributing to a deepened relational connection.
  • The addition of "drama" to relationships of close, deep and strong love.
  • Anthropologist Charles Lindholm defined love as "an intense attraction that involves the idealization of the other, within an erotic context, with expectation of enduring sometime into the future".

Historical usage

The word "romance" comes from the French vernacular where initially it indicated a verse narrative. The word was originally an adverb of Latin origin, "romanicus," meaning "of the Roman style". European medieval vernacular tales, epics, and ballads generally dealt with chivalric adventure, not bringing in the concept of love until late into the seventeenth century. 

The word romance developed other meanings, such as the early nineteenth century Spanish and Italian definitions of "adventurous" and "passionate," which could intimate both "love affair" and "idealistic quality." 

Bernger von Horheim in the Codex Manesse (early 14th century)
 
Anthropologists such as Claude Lévi-Strauss show that there were complex forms of courtship in ancient as well as contemporary primitive societies. There may not be evidence, however, that members of such societies formed loving relationships distinct from their established customs in a way that would parallel modern romance.

Before the 18th century, many marriages were not arranged, but rather developed out of more or less spontaneous relationships. After the 18th century, illicit relationships took on a more independent role. In bourgeois marriage, illicitness may have become more formidable and likely to cause tension. In Ladies of the Leisure Class, Rutgers University professor Bonnie G. Smith depicts courtship and marriage rituals that may be viewed as oppressive to modern people. She writes "When the young women of the Nord married, they did so without illusions of love and romance. They acted within a framework of concern for the reproduction of bloodlines according to financial, professional, and sometimes political interests." Subsequent sexual revolution has lessened the conflicts arising out of liberalism, but not eliminated them.

Anthony Giddens, in The Transformation of Intimacy: Sexuality, Love and Eroticism in Modern Society, states that romantic love introduced the idea of a narrative to an individual's life, and telling a story is a root meaning of the term romance. According to Giddens, the rise of romantic love more or less coincided with the emergence of the novel. It was then that romantic love, associated with freedom and therefore the ideals of romantic love, created the ties between freedom and self-realization.

David R. Shumway states that "the discourse of intimacy" emerged in the last third of the 20th century, intended to explain how marriage and other relationships worked, and making the specific case that emotional closeness is much more important than passion, with intimacy and romance coexisting.

One example of the changes experienced in relationships in the early 21st century was explored by Giddens regarding homosexual relationships. According to Giddens, since homosexuals were not able to marry they were forced to pioneer more open and negotiated relationships. These kinds of relationships then permeated the heterosexual population.

La Belle Dame sans Merci 1893, by John William Waterhouse (1849-1917)

Popularization of love

The conception of romantic love was popularized in Western culture by the concept of courtly love. Chevaliers, or knights in the Middle Ages, engaged in what were usually non-physical and non-marital relationships with women of nobility whom they served. These relations were highly elaborate and ritualized in a complexity that was steeped in a framework of tradition, which stemmed from theories of etiquette derived out of chivalry as a moral code of conduct. 

Courtly love and the notion of domnei were often the subjects of troubadours, and could be typically found in artistic endeavors such as lyrical narratives and poetic prose of the time. Since marriage was commonly nothing more than a formal arrangement, courtly love sometimes permitted expressions of emotional closeness that may have been lacking from the union between husband and wife. In terms of courtly love, "lovers" did not necessarily refer to those engaging in sexual acts, but rather, to the act of caring and to emotional intimacy.

The bond between a knight and his Lady, or the woman of typically high stature of whom he served, may have escalated psychologically but seldom ever physically. For knighthood during the Middle Ages, the intrinsic importance of a code of conduct was in large part as a value system of rules codified as a guide to aid a knight in his capacity as champion of the downtrodden, but especially in his service to the Lord. 

In the context of dutiful service to a woman of high social standing, ethics designated as a code were effectively established as an institution to provide a firm moral foundation by which to combat the idea that unfit attentions and affections were to ever be tolerated as "a secret game of trysts" behind closed doors. Therefore, a knight trained in the substance of "chivalry" was instructed, with especial emphasis, to serve a lady most honorably, with purity of heart and mind. To that end, he committed himself to the welfare of both Lord and Lady with unwavering discipline and devotion, while at the same time, presuming to uphold core principles set forth in the code by the religion by which he followed.

Religious meditations upon the Virgin Mary were partially responsible for the development of chivalry as an ethic and lifestyle: the concept of the honor of a lady and knightly devotion to her, coupled with an obligatory respect for all women, factored prominently as central to the very identity of medieval knighthood. As knights were increasingly emulated, eventual changes were reflected in the inner-workings of feudal society. Members of the aristocracy were schooled in the principles of chivalry, which facilitated important changes in attitudes regarding the value of women.

Behaviorally, a knight was to regard himself towards a lady with a transcendence of premeditated thought—his virtue ingrained within his character. A chevalier was to conduct himself always graciously, bestowing upon her the utmost courtesy and attentiveness. He was to echo shades of this to all women, regardless of class, age, or status. Over time, the concept of chivalry and the notion of the courtly gentleman became synonymous with the ideal of how love and romance should exist between the sexes. Through the timeless popularization in art and literature of tales of knights and princesses, kings and queens, a formative and long standing (sub)consciousness helped to shape relationships between men and women. 

De amore or The Art of Courtly Love, as it is known in English, was written in the 12th century. The text is widely misread as permissive of extramarital affairs. However, it is useful to differentiate the physical from without: romantic love as separate and apart from courtly love when interpreting such topics as: "Marriage is no real excuse for not loving", "He who is not jealous cannot love", "No one can be bound by a double love", and "When made public love rarely endures".

Some believe that romantic love evolved independently in multiple cultures. For example, in an article presented by Henry Grunebaum, he argues "therapists mistakenly believe that romantic love is a phenomenon unique to Western cultures and first expressed by the troubadours of the Middle Ages."

The more current and Western traditional terminology meaning "court as lover" or the general idea of "romantic love" is believed to have originated in the late nineteenth and early twentieth centuries, primarily from that of the French culture. This idea is what has spurred the connection between the words "romantic" and "lover", thus coining English phrases for romantic love such as "loving like the Romans do". The precise origins of such a connection are unknown, however. Although the word "romance" or the equivalents thereof may not have the same connotation in other cultures, the general idea of "romantic love" appears to have crossed cultures and been accepted as a concept at one point in time or another.

Types

Romantic love is contrasted with platonic love, which in all usages, precludes sexual relations, yet only in the modern usage does it take on a fully nonsexual sense, rather than the classical sense, in which sexual drives are sublimated. Sublimation tends to be forgotten in casual thought about love aside from its emergence in psychoanalysis and Nietzsche.

Unrequited love can be romantic in different ways: comic, tragic, or in the sense that sublimation itself is comparable to romance, where the spirituality of both art and egalitarian ideals is combined with strong character and emotions. Unrequited love is typical of the period of romanticism, but the term is distinct from any romance that might arise within it.

Romantic love may also be classified according to two categories, "popular romance" and "divine or spiritual" romance:
Popular romance
may include but is not limited to the following types: idealistic, normal intense (such as the emotional aspect of "falling in love"), predictable as well as unpredictable, consuming (meaning consuming of time, energy and emotional withdrawals and bids), intense but out of control (such as the aspect of "falling out of love") material and commercial (such as societal gain mentioned in a later section of this article), physical and sexual, and finally grand and demonstrative.
Divine (or spiritual) romance
may include, but is not limited to these following types: realistic, as well as plausible unrealistic, optimistic as well as pessimistic (depending upon the particular beliefs held by each person within the relationship.), abiding (e.g. the theory that each person had a predetermined stance as an agent of choice; such as "choosing a husband" or "choosing a soul mate."), non-abiding (e.g. the theory that we do not choose our actions, and therefore our romantic love involvement has been drawn from sources outside of ourselves), predictable as well as unpredictable, self-control (such as obedience and sacrifice within the context of the relationship) or lack thereof (such as disobedience within the context of the relationship), emotional and personal, soulful (in the theory that the mind, soul, and body, are one connected entity), intimate, and infinite (such as the idea that love itself or the love of a god or God's "unconditional" love is or could be everlasting)

In philosophy

Plato

Roman copy of a Greek sculpture by Lysippus depicting Eros, the Greek personification of romantic love
 
Greek philosophers and authors have had many theories of love. Some of these theories are presented in Plato's Symposium. Six Athenian friends, including Socrates, drink wine and each give a speech praising the deity Eros. When his turn comes, Aristophanes says in his mythical speech that sexual partners seek each other because they are descended from beings with spherical torsos, two sets of human limbs, genitalia on each side, and two faces back to back. Their three forms included the three permutations of pairs of gender (i.e. one masculine and masculine, another feminine and feminine, and the third masculine and feminine) and they were split by the gods to thwart the creatures' assault on heaven, recapitulated, according to the comic playwright, in other myths such as the Aloadae.

This story is relevant to modern romance partly because of the image of reciprocity it shows between the sexes. In the final speech before Alcibiades arrives, Socrates gives his encomium of love and desire as a lack of being, namely, the being or form of beauty.

René Girard

Though there are many theories of romantic love—such as that of Robert Sternberg, in which it is merely a mean combining liking and sexual desire—the major theories involve far more insight. For most of the 20th century, Freud's theory of the family drama dominated theories of romance and sexual relationships. This gave rise to a few counter-theories. Theorists like Deleuze counter Freud and Jacques Lacan by attempting to return to a more naturalistic philosophy. René Girard argues that romantic attraction is a product of jealousy and rivalry—particularly in a triangular form

Girard, in any case, downplays romance's individuality in favor of jealousy and the love triangle, arguing that romantic attraction arises primarily in the observed attraction between two others. A natural objection is that this is circular reasoning, but Girard means that a small measure of attraction reaches a critical point insofar as it is caught up in mimesis. Shakespeare's A Midsummer Night's Dream, As You Like It, and The Winter's Tale are the best known examples of competitive-induced romance.

Girard's theory of mimetic desire is controversial because of its alleged sexism. This view has to some extent supplanted its predecessor, Freudian Oedipal theory. It may find some spurious support in the supposed attraction of women to aggressive men. As a technique of attraction, often combined with irony, it is sometimes advised that one feign toughness and disinterest, but it can be a trivial or crude idea to promulgate to men, and it is not given with much understanding of mimetic desire in mind. Instead, cultivating a spirit of self-sacrifice, coupled with an attitude of appreciation or contemplation, directed towards the other of one's attractions, constitutes the ideals of what we consider to be true romantic love. Mimesis is always the desire to possess, in renouncing it we offer ourselves as a sacrificial gift to the other.

Mimetic desire is often challenged by feminists, such as Toril Moi, who argue that it does not account for the woman as inherently desired. 

Though the centrality of rivalry is not itself a cynical view, it does emphasize the mechanical in love relations. In that sense, it does resonate with capitalism and cynicism native to post-modernity. Romance in this context leans more on fashion and irony, though these were important for it in less emancipated times. Sexual revolutions have brought change to these areas. Wit or irony therefore encompass an instability of romance that is not entirely new but has a more central social role, fine-tuned to certain modern peculiarities and subversion originating in various social revolutions, culminating mostly in the 1960s.

Arthur Schopenhauer

The process of courtship also contributed to Arthur Schopenhauer's pessimism, despite his own romantic success, and he argued that to be rid of the challenge of courtship would drive people to suicide with boredom. Schopenhauer theorized that individuals seek partners who share certain interests and tastes, while at the same time looking for a "complement" or completing of themselves in a partner, as in the cliché that "opposites attract", but with the added consideration that both partners manifest this attraction for the sake of the species:
But what ultimately draws two individuals of different sex exclusively to each other with such power is the will-to-live which manifests itself in the whole species, and here anticipates, in the individual that these two can produce, an objectification of its true nature corresponding to its aims. —World as Will and Representation, Volume 2, Chapter XLIV

Other philosophers

Later modern philosophers such as La Rochefoucauld, David Hume and Jean-Jacques Rousseau also focused on morality, but desire was central to French thought and Hume himself tended to adopt a French worldview and temperament. Desire in this milieu meant a very general idea termed "the passions", and this general interest was distinct from the contemporary idea of "passionate" now equated with "romantic". Love was a central topic again in the subsequent movement of Romanticism, which focused on such things as absorption in nature and the absolute, as well as platonic and unrequited love in German philosophy and literature. 

French philosopher Gilles Deleuze linked this idea of love as a lack mainly to Sigmund Freud, and Deleuze often criticized it.

In literature

Archetypal lovers Romeo and Juliet portrayed by Frank Dicksee
 
Shakespeare and Søren Kierkegaard share a similar viewpoint that marriage and romance are not harmoniously in tune with each other. In Shakespeare's Measure for Measure, for example, "...there has not been, nor is there at this point, any display of affection between Isabella and the Duke, if by affection we mean something concerned with sexual attraction. The two at the end of the play love each other as they love virtue." In Romeo and Juliet, in saying "all combined, save what thou must combine By holy marriage", Romeo implies that it is not marriage with Juliet that he seeks but simply to be joined with her romantically.

Kierkegaard addressed these ideas in works such as Either/Or and Stages on Life's Way:
In the first place, I find it comical that all men are in love and want to be in love, and yet one never can get any illumination upon the question what the lovable, i.e., the proper object of love, really is.
— Stages, p. 48
In How to Make Good Decisions and Be Right All the Time, British writer Iain King tried to establish rules for romance applicable across most cultures. He concluded on six rules, including:
  1. Do not flirt with someone unless you might mean it.
  2. Do not pursue people who you are not interested in, or who are not interested in you.
  3. In general, express your affection or uncertainty clearly, unless there is a special reason not to.

Tragedy and other social issues

The "tragic" contradiction between romance and society is most forcibly portrayed in literature, in Tolstoy's Anna Karenina, in Flaubert's Madame Bovary, and William Shakespeare's Romeo and Juliet. The female protagonists in such stories are driven to suicide as if dying for a cause of freedom from various oppressions of marriage. 

Even after sexual revolutions, on the other hand, to the extent that it does not lead to procreation (or child-rearing, as it also might exist in same-sex marriage), romance remains peripheral though it may have virtues in the relief of stress, as a source of inspiration or adventure, or in development and the strengthening of certain social relations. It is difficult to imagine the tragic heroines, however, as having such practical considerations in mind. 

Romance can also be tragic in its conflict with society. The Tolstoy family focuses on the romantic limitations of marriage, and Anna Karenina prefers death to being married to her fiancé, however this is because she is tired of waiting and being hidden away from public, when her fiance makes failed attempts to get his mother's approval of the marriage. Even being aristocrats did not make them both free, as the society was nevertheless equally binding for all. Furthermore, in the speech about marriage that is given in Kierkegaard's Either/Or, Kierkegaard attempts to show that it is because marriage is lacking in passion fundamentally, that the nature of marriage, unlike romance, is explainable by a man who has experience of neither marriage nor love. 

Reciprocity of the sexes appears in the ancient world primarily in myth where it is in fact often the subject of tragedy, for example in the myths of Theseus and Atalanta. Noteworthy female freedom or power was an exception rather than the rule, though this is a matter of speculation and debate.

Psychology

Many theorists attempt to analyze the process of romantic love.

Anthropologist Helen Fisher, in her book Why We Love, uses brain scans to show that love is the product of a chemical reaction in the brain. Norepinephrine and dopamine, among other brain chemicals, are responsible for excitement and bliss in humans as well as non-human animals. She is famous for the use of MRI to study the brain activity of a person "in love", discovering the importance of the ventral tegmental area and the caudate nucleus in this biological drive. Fisher concludes that these reactions have a genetic basis, and therefore love is a natural drive as powerful as hunger. 

In his book What Women Want, What Men Want, anthropologist John Townsend takes the genetic basis of love one step further by identifying how the sexes are different in their predispositions. Townsend's compilation of various research projects concludes that men are susceptible to youth and beauty, whereas women are susceptible to status and security. These differences are part of a natural selection process where males seek many healthy women of childbearing age to mother offspring, and women seek men who are willing and able to take care of them and their children.

Psychologist Karen Horney in her article "The Problem of the Monogamous Ideal", indicates that the overestimation of love leads to disillusionment; the desire to possess the partner results in the partner wanting to escape; and the friction against sex result in non-fulfillment. Disillusionment plus the desire to escape plus non-fulfillment result in a secret hostility, which causes the other partner to feel alienated. Secret hostility in one and secret alienation in the other cause the partners to secretly hate each other. This secret hate often leads one or the other or both to seek love objects outside the marriage or relationship. 

Psychologist Harold Bessell in his book The Love Test, reconciles the opposing forces noted by the above researchers and shows that there are two factors that determine the quality of a relationship. Bessell proposes that people are drawn together by a force he calls "romantic attraction", which is a combination of genetic and cultural factors. This force may be weak or strong and may be felt to different degrees by each of the two love partners. The other factor is "emotional maturity", which is the degree to which a person is capable of providing good treatment in a love relationship. It can thus be said that an immature person is more likely to overestimate love, become disillusioned, and have an affair whereas a mature person is more likely to see the relationship in realistic terms and act constructively to work out problems. 

Romantic love, in the abstract sense of the term, is traditionally considered to involve a mix of emotional and sexual desire for another as a person. However, Lisa M. Diamond, a University of Utah psychology professor, proposes that sexual desire and romantic love are functionally independent and that romantic love is not intrinsically oriented to same-gender or other-gender partners. She also proposes that the links between love and desire are bidirectional as opposed to unilateral. Furthermore, Diamond does not state that one's sex has priority over another sex (a male or female) in romantic love because her theory suggests it is as possible for someone who is homosexual to fall in love with someone of the other gender as for someone who is heterosexual to fall in love with someone of the same gender. In her 2012 review of this topic, Diamond emphasized that what is true for men may not be true for women. According to Diamond, in most men sexual orientation is fixed and most likely innate, but in many women sexual orientation may vary from 0 to 6 on the Kinsey scale and back again.

Martie Haselton, a psychologist at UCLA, considers romantic love a "commitment device" or mechanism that encourages two humans to form a lasting bond. She has explored the evolutionary rationale that has shaped modern romantic love and has concluded that long-lasting relationships are helpful to ensure that children reach reproductive age and are fed and cared for by two parents. Haselton and her colleagues have found evidence in their experiments that suggest love's adaptation. The first part of the experiments consists of having people think about how much they love someone and then suppress thoughts of other attractive people. In the second part of the experiment the same people are asked to think about how much they sexually desire those same partners and then try to suppress thoughts about others. The results showed that love is more efficient in pushing out those rivals than sex.

Research by the University of Pavia suggests that romantic love lasts for about a year (similar to limerence) before being replaced by a more stable, non-passionate "companionate love." In companionate love, changes occur from the early stage of love to when the relationship becomes more established and romantic feelings seem to end. However, research from Stony Brook University in New York suggests that some couples keep romantic feelings alive for much longer.

Attachment patterns

Attachment styles that people develop as children can influence the way that they interact with partners in adult relationships, with secure attachment styles being associated with healthier and more trusting relationships than avoidant or anxious attachment styles. Hazen and Shaver found that adult romantic attachment styles were similar to the categories of secure, avoidant, and anxious that had previously been studied in children’s attachments to their caregivers, demonstrating that attachment styles are stable across the lifespan. Later on, researchers distinguished between dismissive avoidant attachment and fearful avoidant attachment. Others have found that secure adult attachment, leading to the ability for intimacy and confidence in relationship stability, is characterized by low attachment-related anxiety and avoidance, while the fearful style is high on both dimensions, the dismissing style is low on anxiety and high on avoidance, and the preoccupied style is high on anxiety and low on avoidance.

Romantic love definition/operationalization

Singer (1984a, 1984b, 1987) first defined love based on four Greek terms: eros, meaning the search for beauty; philia, the feelings of affection in close friendships, nomos, the submission of and obedience to higher or divine powers, and agape, the bestowal of love and affection for the divine powers. While Singer did believe that love was important to world culture, he did not believe that romantic love played a major role (Singer, 1987). However, Susan Hendrick and Clyde Hendrick at Texas Tech University (1992, 2009) have theorized that romantic love will play an increasingly important cultural role in the future, as it is considered an important part of living a fulfilling life. They also theorized that love in long-term romantic relationships has only been the product of cultural forces that came to fruition within the past 300 years. By cultural forces, they mean the increasing prevalence of individualistic ideologies, which are the result of an inward shift of many cultural worldviews.

Passionate and companionate love

Researchers have determined that romantic love is a complex emotion that can be divided into either passionate or companionate forms. Berscheid and Walster (1978) and Hatfield (1988) found that these two forms can co-exist, either simultaneously or intermittently. Passionate love is an arousal-driven emotion that often gives people extreme feelings of happiness, and can also give people feelings of anguish. Companionate love is a form that creates a steadfast bond between two people, and gives people feelings of peace. Researchers have described the stage of passionate love as "being on cocaine", since during that stage the brain releases the same neurotransmitter, dopamine, as when cocaine is being used. It is also estimated that passionate love (as with limerence) lasts for about twelve to eighteen months.

Robert Firestone, a psychologist, has a theory of the fantasy bond, which is what is mostly created after the passionate love has faded. A couple may start to feel really comfortable with each other to the point that they see each other as simply companions or protectors, but yet think that they are still in love with each other. The results to the fantasy bond is the leading to companionate love. Hendrick and Hendrick (1995) studied college students who were in the early stages of a relationship and found that almost half reported that their significant other was their closest friend, providing evidence that both passionate and companionate love exist in new relationships. Conversely, in a study of long-term marriages, researchers (Contreras, Hendrick, and Hendrick, 1996) found that couples endorsed measures of both companionate love and passionate love and that passionate love was the strongest predictor of marital satisfaction, showing that both types of love can endure throughout the years.

The triangular theory of love

Psychologist Robert Sternberg (1986) developed the triangular theory of love. He theorized that love is a combination of three main components: passion (physical arousal); intimacy (psychological feelings of closeness); and commitment (the sustaining of a relationship). He also theorized that the different combinations of these three components could yield up to seven different forms of love. These include popularized forms such as romantic love (intimacy and passion) and consummate love (passion, intimacy, and commitment). The other forms are liking (intimacy), companionate love (intimacy and commitment), empty love (commitment), fatuous love (passion and commitment), and infatuation (passion). Studies on Sternberg’s theory love found that intimacy most strongly predicted marital satisfaction in married couples, with passion also being an important predictor (Silberman, 1995). On the other hand, Acker and Davis (1992) found that commitment was the strongest predictor of relationship satisfaction, especially for long-term relationships.

The self-expansion theory of romantic love

Researchers Arthur and Elaine Aron (1986) theorized that humans have a basic drive to expand their self-concepts. Further, their experience with Eastern concepts of love caused them to believe that positive emotions, cognitions, and relationships in romantic behaviors all drive the expansion of a person’s self-concept. A study following college students for 10 weeks showed that those students who fell in love over the course of the investigation reported higher feelings of self-esteem and self efficacy than those who did not (Aron, Paris, and Aron, 1995).

Mindful relationships

Gottman studies the components of a flourishing romantic relationship have been studied in the lab (1994; Gottman & Silver, 1999). He used physiological and behavioral measures during couples’ interactions to predict relationship success and found that five positive interactions to one negative interaction are needed to maintain a healthy relationship. He established a therapy intervention for couples that focused on civil forms of disapproval, a culture of appreciation, acceptance of responsibility for problems, and self-soothing (Gottman, Driver, & Tabares, 2002).

Relationship behaviors

Recent research suggests that romantic relationships impact daily behaviors and people are influenced by the eating habits of their romantic partners. Specifically, in the early stages of romantic relationships, women are more likely to be influenced by the eating patterns (i.e., healthiness/unhealthiness) of men. However, when romantic relationships are established, men are influenced by the eating patterns of women (Hasford, Kidwell, & Lopez-Kidwell).

Physiology

Researchers such as Feeney and Noller question the stability of attachment style across the life span since studies that measured attachment styles at time points ranging from 2 weeks to 8 months found that 1 out of 4 adults' attachment style changed. Furthermore, a study by Lopez and Gormley found that attachment styles could change during the first year of college and that changes to more secure attachment styles were associated with adjustments in self-confidence ratings and coping styles. On the other hand, attachment styles in childhood mirror the ones found in adult romantic relationships. In addition, research has shown that building interpersonal connections strengthens neural regulatory systems that are involved in emotions of empathy, enjoyment of positive social events, and stress management, providing evidence that early social interactions affect adult relationships.

Another topic of controversy in the field of romantic relationships is that of domestic abuse. Following the theory that romantic love evolved as a byproduct of survival, it can be said that in some instances, it has turned into a maladaptation. Oxytocin is a neurophysical hormone produced in the brain. It is known to cause a decrease in stress response. It also can cause an increase in feelings of attachment. In the beginning stages of a romantic relationship, OT levels surge and then remain relatively stable over the duration of the relationship. The higher the surge of OT, the greater the likelihood is of partners staying together. It plays an important role in increasing positive interpersonal behaviors such as trust, altruism, empathy, etc. This response is not universal and can in fact, cause the opposite to occur depending on environment and individual. Individuals ranked high in rejection sensitivity exhibited aggressive tendencies and decreased willingness for cooperation, indicating a link between oxytocin and relationship maintenance.

The feelings associated with romantic love function to ensure the greater reproductive fitness of individuals. The obligations of individuals in romantic relationships to preserve these bonds are based in kin selection theory, where by exhibiting aggressive behavior, a mate can use intimidation and dominance to ward off other potential predators, thus protecting the pair bond and their actual or potential offspring. This has however evolved to the point where it has become detrimental to the fitness of individuals; what is causing attachment to occur in a relationship, is now causing one partner to harm the other. 

In the search for the root of intimate partner violence, intranasal oxytocin was administered to a control group and a group of participants with aggressive tendencies. Participants were then surveyed on how willing they were to engage in 5 behaviors towards their romantic partner. What they found was that oxytocin increased IPV inclinations only among the participants with a predisposition towards aggressive tendencies. Oxytocin decreases trust and prosocial behavior in individuals with interpersonal difficulties. This, coupled with its role in relationship maintenance, illustrates that oxytocin serves to instill a sense of territoriality and protectiveness towards a mate.

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