General anaesthesia

From Wikipedia, the free encyclopedia

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

 

General anaesthesia
Equipment used for anaesthesia in the operating theatre
MeSH	D000768
MedlinePlus	007410

General anaesthesia or general anesthesia (see spelling differences) is a medically induced coma with loss of protective reflexes, resulting from the administration of one or more general anaesthetic agents. It is carried out to allow medical procedures that would otherwise be intolerably painful for the patient; or where the nature of the procedure itself precludes the patient being awake.

A variety of drugs may be administered, with the overall aim of ensuring unconsciousness, amnesia, analgesia, loss of reflexes of the autonomic nervous system, and in some cases paralysis of skeletal muscles. The optimal combination of drugs for any given patient and procedure is typically selected by an anaesthetist, or another provider such as an operating department practitioner, anaesthetist practitioner, physician assistant or nurse anaesthetist (depending on local practice), in consultation with the patient and the surgeon, dentist, or other practitioner performing the operative procedure.

History

Attempts at producing a state of general anaesthesia can be traced throughout recorded history in the writings of the ancient Sumerians, Babylonians, Assyrians, Egyptians, Greeks, Romans, Indians, and Chinese. During the Middle Ages, scientists and other scholars made significant advances in the Eastern world, while their European counterparts also made important advances.

The Renaissance saw significant advances in anatomy and surgical technique. However, despite all this progress, surgery remained a treatment of last resort. Largely because of the associated pain, many patients chose certain death rather than undergo surgery. Although there has been a great deal of debate as to who deserves the most credit for the discovery of general anaesthesia, several scientific discoveries in the late 18th and early 19th centuries were critical to the eventual introduction and development of modern anaesthetic techniques.

Two enormous leaps occurred in the late 19th century, which together allowed the transition to modern surgery. An appreciation of the germ theory of disease led rapidly to the development and application of antiseptic techniques in surgery. Antisepsis, which soon gave way to asepsis, reduced the overall morbidity and mortality of surgery to a far more acceptable rate than in previous eras. Concurrent with these developments were the significant advances in pharmacology and physiology which led to the development of general anaesthesia and the control of pain. On 14 November 1804, Hanaoka Seishū, a Japanese doctor, became the first person to successfully perform surgery using general anaesthesia.

In the 20th century, the safety and efficacy of general anaesthesia was improved by the routine use of tracheal intubation and other advanced airway management techniques. Significant advances in monitoring and new anaesthetic agents with improved pharmacokinetic and pharmacodynamic characteristics also contributed to this trend. Finally, standardized training programs for anaesthesiologists and nurse anaesthetists emerged during this period.

Purpose

General anaesthesia has many purposes, including:

1. Unconsciousness (loss of awareness)
2. Analgesia (loss of response to pain)
3. Amnesia (loss of memory)
4. Immobility (loss of motor reflexes)
5. Paralysis (skeletal muscle relaxation and normal muscle relaxation)

General anaesthesia should not be used as prophylaxis in patients with a history of contrast medium-induced anaphylaxis.

Biochemical mechanism of action

The biochemical mechanism of action of general anaesthetics is not well understood. Theories need to explain the function of anaesthesia in animals and plants. To induce unconsciousness, anaesthetics have myriad sites of action and affect the central nervous system (CNS) at multiple levels. Common areas of the central nervous system whose functions are interrupted or changed during general anaesthesia include the cerebral cortex, thalamus, reticular activating system, and spinal cord. Current theories on the anaesthetized state identify not only target sites in the CNS but also neural networks and loops whose interruption is linked with unconsciousness. Potential pharmacologic targets of general anaesthetics are GABA, glutamate receptors, voltage-gated ion channels, and glycine and serotonin receptors.

Halothane has been found to be a GABA agonist, and ketamine is an NMDA receptor antagonist.

Preanaesthetic evaluation

Prior to a planned procedure, the anesthesiologist reviews medical records and/or interviews the patient to determine the best combination of drugs and dosages and the degree to which monitoring will be required to ensure a safe and effective procedure. Key factors in this evaluation are the patient's age, body mass index, medical and surgical history, current medications, and fasting time. Thorough and accurate answering of the questions is important so that the anaesthetist can select the proper drugs and procedures. For example, a patient who consumes significant quantities of alcohol or illicit drugs could be undermedicated if they fail to disclose this fact, and this could lead to anaesthesia awareness or intraoperative hypertension. Commonly used medications can interact with anaesthetics, and failure to disclose such usage can increase the risk to the patient.

An important aspect of pre-anaesthetic evaluation is an assessment of the patient's airway, involving inspection of the mouth opening and visualisation of the soft tissues of the pharynx. The condition of teeth and location of dental crowns are checked, and neck flexibility and head extension are observed.

Premedication

Prior to administration of a general anaesthetic, the anaesthetist may administer one or more drugs that complement or improve the quality or safety of the anaesthetic.

One commonly used premedication is clonidine, an alpha-2 adrenergic agonist. Clonidine premedication reduces the need for anaesthetic induction agents, for volatile agents to maintain general anaesthesia, and for postoperative analgesics. It also reduces postoperative shivering, postoperative nausea and vomiting, and emergence delirium. In children, clonidine premedication is at least as effective as benzodiazepines and has less serious side effects. However, oral clonidine can take up to 45 minutes to take full effect, and drawbacks include hypotension and bradycardia.

Midazolam, a benzodiazepine characterized by a rapid onset and short duration, is effective in reducing preoperative anxiety, including separation anxiety in children. Dexmedetomidine and certain atypical antipsychotic agents may be used in uncooperative children.

Melatonin has been found to be effective as an anaesthetic premedication in both adults and children because of its hypnotic, anxiolytic, sedative, antinociceptive, and anticonvulsant properties. Unlike midazolam, melatonin does not impair psychomotor skills or hinder recovery. Recovery is more rapid after premedication with melatonin than with midazolam, and there is also a reduced incidence of post-operative agitation and delirium. Melatonin premedication also reduces the required induction dose of propofol and sodium thiopental.

Another example of anaesthetic premedication is the preoperative administration of beta adrenergic antagonists to reduce the incidence of postoperative hypertension, cardiac dysrhythmia, or myocardial infarction. Anaesthesiologists may administer an antiemetic agent such as ondansetron, droperidol, or dexamethasone to prevent postoperative nausea and vomiting, or subcutaneous heparin or enoxaparin to reduce the incidence of deep vein thrombosis. Other commonly used premedication agents include opioids such as fentanyl or sufentanil, gastrokinetic agents such as metoclopramide, and histamine antagonists such as famotidine.

Non-pharmacologic preanaesthetic interventions include playing relaxing music, massage, and reducing ambient light and noise levels in order to maintain the sleep-wake cycle. These techniques are particularly useful for children and patients with intellectual disabilities. Minimizing sensory stimulation or distraction by video games may help to reduce anxiety prior to or during induction of general anaesthesia. Larger high-quality studies are needed to confirm the most effective non-pharmacological approaches for reducing this type of anxiety. Parental presence during premedication and induction of anaesthesia has not been shown to reduce anxiety in children. It is suggested that parents who wish to attend should not be actively discouraged, and parents who prefer not to be present should not be actively encouraged to attend.

Stages of anaesthesia

Guedel's classification, introduced by Arthur Ernest Guedel in 1937, describes four stages of anaesthesia. Despite newer anaesthetic agents and delivery techniques, which have led to more rapid onset of—and recovery from—anaesthesia (in some cases bypassing some of the stages entirely), the principles remain.

Stage 1

Stage 1, also known as induction, is the period between the administration of induction agents and loss of consciousness. During this stage, the patient progresses from analgesia without amnesia to analgesia with amnesia. Patients can carry on a conversation at this time.

Stage 2

Stage 2, also known as the excitement stage, is the period following loss of consciousness and marked by excited and delirious activity. During this stage, the patient's respiration and heart rate may become irregular. In addition, there may be uncontrolled movements, vomiting, suspension of breathing, and pupillary dilation. Because the combination of spastic movements, vomiting, and irregular respiration may compromise the patient's airway, rapidly acting drugs are used to minimize time in this stage and reach Stage 3 as fast as possible.

Stage 3

In Stage 3, also known as surgical anaesthesia, the skeletal muscles relax, vomiting stops, respiratory depression occurs, and eye movements slow and then stop. The patient is unconscious and ready for surgery. This stage is divided into four planes:

1. The eyes roll, then become fixed;
2. Corneal and laryngeal reflexes are lost;
3. The pupils dilate and light reflex is lost;
4. Intercostal paralysis and shallow abdominal respiration occur.

Stage 4

Stage 4, also known as overdose, occurs when too much anaesthetic medication is given relative to the amount of surgical stimulation and the patient has severe brainstem or medullary depression, resulting in a cessation of respiration and potential cardiovascular collapse. This stage is lethal without cardiovascular and respiratory support.

Induction

General anaesthesia is usually induced in a medical facility, most commonly in an operating theatre or in a dedicated anaesthetic room adjacent to the theatre. However, it may also be conducted in other locations, such as an endoscopy suite, radiology or cardiology department, emergency department, or ambulance, or at the site of a disaster where extrication of the patient may be impossible or impractical.

Anaesthetic agents may be administered by various routes, including inhalation, injection (intravenous, intramuscular, or subcutaneous), oral, and rectal. Once they enter the circulatory system, the agents are transported to their biochemical sites of action in the central and autonomic nervous systems.

Most general anaesthetics are induced either intravenously or by inhalation. Intravenous injection works faster than inhalation, taking about 10–20 seconds to induce total unconsciousness. This minimizes the excitatory phase (Stage 2) and thus reduces complications related to the induction of anaesthesia. Commonly used intravenous induction agents include propofol, sodium thiopental, etomidate, methohexital, and ketamine. Inhalational anaesthesia may be chosen when intravenous access is difficult to obtain (e.g., children), when difficulty maintaining the airway is anticipated, or when the patient prefers it. Sevoflurane is the most commonly used agent for inhalational induction, because it is less irritating to the tracheobronchial tree than other agents.

As an example sequence of induction drugs:

1. Pre-oxygenation to fill lungs with oxygen to permit a longer period of apnea during intubation without affecting blood oxygen levels
2. Fentanyl for systemic analgesia for intubation
3. Propofol for sedation for intubation
4. Switching from oxygen to a mixture of oxygen and inhalational anesthetic

Laryngoscopy and intubation are both very stimulating and induction blunts the response to these maneuvers while simultaneously inducing a near-coma state to prevent awareness.

Physiologic monitoring

Several monitoring technologies allow for a controlled induction of, maintenance of, and emergence from general anaesthesia.

1. Continuous electrocardiography (ECG or EKG): Electrodes are placed on the patient's skin to monitor heart rate and rhythm. This may also help the anaesthesiologist to identify early signs of heart ischaemia. Typically lead II and V5 are monitored for arrhythmias and ischemia, respectively.
2. Continuous pulse oximetry (SpO2): A device is placed, usually on a finger, to allow for early detection of a fall in a patient's haemoglobin saturation with oxygen (hypoxaemia).
3. Blood pressure monitoring: There are two methods of measuring the patient's blood pressure. The first, and most common, is non-invasive blood pressure (NIBP) monitoring. This involves placing a blood pressure cuff around the patient's arm, forearm, or leg. A machine takes blood pressure readings at regular, preset intervals throughout the surgery. The second method is invasive blood pressure (IBP) monitoring. This method is reserved for patients with significant heart or lung disease, the critically ill, and those undergoing major procedures such as cardiac or transplant surgery, or when large blood loss is expected. It involves placing a special type of plastic cannula in an artery, usually in the wrist (radial artery) or groin (femoral artery).
4. Agent concentration measurement: anaesthetic machines typically have monitors to measure the percentage of inhalational anaesthetic agents used as well as exhalation concentrations. These monitors include measuring oxygen, carbon dioxide, and inhalational anaesthetics (e.g., nitrous oxide, isoflurane).
5. Oxygen measurement: Almost all circuits have an alarm in case oxygen delivery to the patient is compromised. The alarm goes off if the fraction of inspired oxygen drops below a set threshold.
6. A circuit disconnect alarm or low pressure alarm indicates failure of the circuit to achieve a given pressure during mechanical ventilation.
7. Capnography measures the amount of carbon dioxide exhaled by the patient in percent or mmHg, allowing the anaesthesiologist to assess the adequacy of ventilation. MmHg is usually used to allow the provider to see more subtle changes.
8. Temperature measurement to discern hypothermia or fever, and to allow early detection of malignant hyperthermia.
9. Electroencephalography, entropy monitoring, or other systems may be used to verify the depth of anaesthesia. This reduces the likelihood of anaesthesia awareness and of overdose.

Airway management

Anaesthetized patients lose protective airway reflexes (such as coughing), airway patency, and sometimes a regular breathing pattern due to the effects of anaesthetics, opioids, or muscle relaxants. To maintain an open airway and regulate breathing, some form of breathing tube is inserted after the patient is unconscious. To enable mechanical ventilation, an endotracheal tube is often used, although there are alternative devices that can assist respiration, such as face masks or laryngeal mask airways. Generally, full mechanical ventilation is only used if a very deep state of general anaesthesia is to be induced for a major procedure, and/or with a profoundly ill or injured patient. That said, induction of general anaesthesia usually results in apnea and requires ventilation until the drugs wear off and spontaneous breathing starts. In other words, ventilation may be required for both induction and maintenance of general anaesthesia or just during the induction. However, mechanical ventilation can provide ventilatory support during spontaneous breathing to ensure adequate gas exchange.

General anaesthesia can also be induced with the patient spontaneously breathing and therefore maintaining their own oxygenation which can be beneficial in certain scenarios (e.g. difficult airway or tubeless surgery). Spontaneous ventilation has been traditionally maintained with inhalational agents (i.e. halothane or sevoflurane) which is called a gas or inhalational induction. Spontaneous ventilation can also be maintained using intravenous anaesthesia (e.g. propofol). Intravenous anaesthesia to maintain spontaneous respiration has certain advantages over inhalational agents (i.e. suppressed laryngeal reflexes) however it requires careful titration. Spontaneous Respiration using Intravenous anaesthesia and High-flow nasal oxygen (STRIVE Hi) is a technique that has been used in difficult and obstructed airways.

Eye management

General anaesthesia reduces the tonic contraction of the orbicularis oculi muscle, causing lagophthalmos, or incomplete eye closure, in 59% of patients. In addition, tear production and tear-film stability are reduced, resulting in corneal epithelial drying and reduced lysosomal protection. The protection afforded by Bell's phenomenon (in which the eyeball turns upward during sleep, protecting the cornea) is also lost. Careful management is required to reduce the likelihood of eye injuries during general anaesthesia.

Neuromuscular blockade

Syringes prepared with medications that are expected to be used during an operation under general anaesthesia maintained by sevoflurane gas:
- Propofol, a hypnotic
- Ephedrine, in case of hypotension
- Fentanyl, for analgesia
- Atracurium, for neuromuscular block
- Glycopyrronium bromide (here under trade name Robinul), reducing secretions

Paralysis, or temporary muscle relaxation with a neuromuscular blocker, is an integral part of modern anaesthesia. The first drug used for this purpose was curare, introduced in the 1940s, which has now been superseded by drugs with fewer side effects and, generally, shorter duration of action. Muscle relaxation allows surgery within major body cavities, such as the abdomen and thorax, without the need for very deep anaesthesia, and also facilitates endotracheal intubation.

Acetylcholine, the natural neurotransmitter at the neuromuscular junction, causes muscles to contract when it is released from nerve endings. Muscle relaxants work by preventing acetylcholine from attaching to its receptor. Paralysis of the muscles of respiration—the diaphragm and intercostal muscles of the chest—requires that some form of artificial respiration be implemented. Because the muscles of the larynx are also paralysed, the airway usually needs to be protected by means of an endotracheal tube.

Paralysis is most easily monitored by means of a peripheral nerve stimulator. This device intermittently sends short electrical pulses through the skin over a peripheral nerve while the contraction of a muscle supplied by that nerve is observed. The effects of muscle relaxants are commonly reversed at the end of surgery by anticholinesterase drugs, which are administered in combination with muscarinic anticholinergic drugs to minimize side effects. Novel neuromuscular blockade reversal agents such as sugammadex may also be used. Examples of skeletal muscle relaxants in use today are pancuronium, rocuronium, vecuronium, cisatracurium, atracurium, mivacurium, and succinylcholine.

Maintenance

The duration of action of intravenous induction agents is generally 5 to 10 minutes, after which spontaneous recovery of consciousness will occur. In order to prolong unconsciousness for the required duration (usually the duration of surgery), anaesthesia must be maintained. This is achieved by allowing the patient to breathe a carefully controlled mixture of oxygen, sometimes nitrous oxide, and a volatile anaesthetic agent, or by administering medication (usually propofol) through an intravenous catheter. Inhaled agents are frequently supplemented by intravenous anaesthetics, such as opioids (usually fentanyl or a fentanyl derivative) and sedatives (usually propofol or midazolam). With propofol-based anaesthetics, however, supplementation by inhalation agents is not required. General anesthesia is usually considered safe; however, there are reported cases of patients with distortion of taste and/or smell due to local anesthetics, stroke, nerve damage, or as a side effect of general anesthesia.

At the end of surgery, administration of anaesthetic agents is discontinued. Recovery of consciousness occurs when the concentration of anaesthetic in the brain drops below a certain level (usually within 1 to 30 minutes, depending on the duration of surgery).

In the 1990s, a novel method of maintaining anaesthesia was developed in Glasgow, Scotland. Called target controlled infusion (TCI), it involves using a computer-controlled syringe driver (pump) to infuse propofol throughout the duration of surgery, removing the need for a volatile anaesthetic and allowing pharmacologic principles to more precisely guide the amount of the drug used by setting the desired drug concentration. Advantages include faster recovery from anaesthesia, reduced incidence of postoperative nausea and vomiting, and absence of a trigger for malignant hyperthermia. At present, TCI is not permitted in the United States, but a syringe pump delivering a specific rate of medication is commonly used instead.

Other medications are occasionally used to treat side effects or prevent complications. They include antihypertensives to treat high blood pressure; ephedrine or phenylephrine to treat low blood pressure; salbutamol to treat asthma, laryngospasm, or bronchospasm; and epinephrine or diphenhydramine to treat allergic reactions. Glucocorticoids or antibiotics are sometimes given to prevent inflammation and infection, respectively.

Emergence

Emergence is the return to baseline physiologic function of all organ systems after the cessation of general anaesthetics. This stage may be accompanied by temporary neurologic phenomena, such as agitated emergence (acute mental confusion), aphasia (impaired production or comprehension of speech), or focal impairment in sensory or motor function. Shivering is also fairly common and can be clinically significant because it causes an increase in oxygen consumption, carbon dioxide production, cardiac output, heart rate, and systemic blood pressure. The proposed mechanism is based on the observation that the spinal cord recovers at a faster rate than the brain. This results in uninhibited spinal reflexes manifested as clonic activity (shivering). This theory is supported by the fact that doxapram, a CNS stimulant, is somewhat effective in abolishing postoperative shivering. Cardiovascular events such as increased or decreased blood pressure, rapid heart rate, or other cardiac dysrhythmias are also common during emergence from general anaesthesia, as are respiratory symptoms such as dyspnoea.

Postoperative care

Anaesthetized patient in postoperative recovery.

Hospitals strive for pain-free awakening from anaesthesia. Although not a direct result of general anaesthesia, postoperative pain is managed in the anaesthesia recovery unit with regional analgesia or oral, transdermal, or parenteral medication. Patients may be given opioids, as well as other medications like non steroidal anti-inflammatory drugs and acetaminophen. Sometimes, opioid medication is administered by the patient themselves using a system called a patient controlled analgesic. The patient presses a button to activate a syringe device and receive a preset dose or "bolus" of the drug, usually a strong opioid such as morphine, fentanyl, or oxycodone (e.g., one milligram of morphine). The PCA device then "locks out" for a preset period to allow the drug to take effect. If the patient becomes too sleepy or sedated, he or she makes no more requests. This confers a fail-safe aspect that is lacking in continuous-infusion techniques. If these medications cannot effectively manage the pain, local anesthetic may be directly injected to the nerve in a procedure called a nerve block.

In the recovery unit, many vital signs are monitored, including oxygen saturation, heart rhythm and respiration, blood pressure, and core body temperature.

Postanesthetic shivering is common. Apart from causing discomfort and exacerbating pain, shivering has been shown to increase oxygen consumption, catecholamine release, cardiac output, heart rate, blood pressure, and intraocular pressure. A number of techniques are used to reduce shivering, such as warm blankets, or wrapping the patient in a sheet that circulates warmed air, called a bair hugger. If the shivering cannot be managed with external warming devices, drugs such as dexmedetomidine, or other α2-agonists, anticholinergics, central nervous system stimulants, or corticosteroids may be used.

In many cases, opioids used in general anaesthesia can cause postoperative ileus, even after non-abdominal surgery. Administration of a μ-opioid antagonist such as alvimopan immediately after surgery can help reduce the severity and duration of ileus.

The major complication of general anaesthesia is malignant hyperthermia. Hospitals have procedures in place and emergency drugs to manage this dangerous complication.

Perioperative mortality

Most perioperative mortality is attributable to complications from the operation, such as haemorrhage, sepsis, and failure of vital organs. Current estimates of perioperative mortality in procedures involving general anaesthesia range from one in 53 to one in 5,417. However, a 1997 Canadian retrospective review of 2,830,000 oral surgical procedures in Ontario between 1973 and 1995 reported only four deaths in cases in which an oral and maxillofacial surgeon or a dentist with specialized training in anaesthesia administered the general anaesthetic or deep sedation. The authors calculated an overall mortality rate of 1.4 per 1,000,000.

Mortality directly related to anaesthetic management is very uncommon but may be caused by pulmonary aspiration of gastric contents, asphyxiation, or anaphylaxis. These in turn may result from malfunction of anaesthesia-related equipment or, more commonly, human error. A 1978 study found that 82% of preventable anaesthesia mishaps were the result of human error. In a 1954 review of 599,548 surgical procedures at 10 hospitals in the United States between 1948 and 1952, 384 deaths were attributed to anaesthesia, for an overall mortality rate of 0.064%. In 1984, after a television programme highlighting anaesthesia mishaps aired in the United States, American anaesthesiologist Ellison C. Pierce appointed the Anesthesia Patient Safety and Risk Management Committee within the American Society of Anesthesiologists. This committee was tasked with determining and reducing the causes of anaesthesia-related morbidity and mortality. An outgrowth of this committee, the Anesthesia Patient Safety Foundation, was created in 1985 as an independent, nonprofit corporation with the goal "that no patient shall be harmed by anesthesia".

As with perioperative mortality rates in general, mortality attributable to the management of general anaesthesia is controversial. Estimates of the incidence of perioperative mortality directly attributable to anaesthesia range from one in 6,795 to one in 200,200.

Reward system

From Wikipedia, the free encyclopedia

The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., motivation and "wanting"; desire or craving for a reward), associative learning (primarily positive reinforcement and classical conditioning), and positively-valenced emotions, particularly ones involving pleasure as a core component (e.g., joy, euphoria and ecstasy). Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.

Examples of primary rewards. From top: water, food, sex, and parental care.

 

Addiction and dependence glossary
addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake) drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose drug withdrawal – symptoms that occur upon cessation of repeated drug use physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens) psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia) reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach sensitization – an amplified response to a stimulus resulting from repeated exposure to it substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

The reward system motivates animals to approach stimuli or engage in behaviour that increases fitness (sex, energy-dense foods, etc.). Survival for most animal species depends upon maximizing contact with beneficial stimuli and minimizing contact with harmful stimuli. Reward cognition serves to increase the likelihood of survival and reproduction by causing associative learning, eliciting approach and consummatory behavior, and triggering positively-valenced emotions. Thus, reward is a mechanism that evolved to help increase the adaptive fitness of animals. In drug addiction, certain substances over-activate the reward circuit, leading to compulsive substance-seeking behavior resulting from synaptic plasticity in the circuit.

Primary rewards are a class of rewarding stimuli which facilitate the survival of one's self and offspring, and they include homeostatic (e.g., palatable food) and reproductive (e.g., sexual contact and parental investment) rewards. Intrinsic rewards are unconditioned rewards that are attractive and motivate behavior because they are inherently pleasurable. Extrinsic rewards (e.g., money or seeing one's favorite sports team winning a game) are conditioned rewards that are attractive and motivate behavior but are not inherently pleasurable. Extrinsic rewards derive their motivational value as a result of a learned association (i.e., conditioning) with intrinsic rewards. Extrinsic rewards may also elicit pleasure (e.g., euphoria from winning a lot of money in a lottery) after being classically conditioned with intrinsic rewards.

Definition

In neuroscience, the reward system is a collection of brain structures and neural pathways that are responsible for reward-related cognition, including associative learning (primarily classical conditioning and operant reinforcement), incentive salience (i.e., motivation and "wanting", desire, or craving for a reward), and positively-valenced emotions, particularly emotions that involve pleasure (i.e., hedonic "liking").

Terms that are commonly used to describe behavior related to the "wanting" or desire component of reward include appetitive behavior, approach behavior, preparatory behavior, instrumental behavior, anticipatory behavior, and seeking. Terms that are commonly used to describe behavior related to the "liking" or pleasure component of reward include consummatory behavior and taking behavior.

The three primary functions of rewards are their capacity to:

1. produce associative learning (i.e., classical conditioning and operant reinforcement);
2. affect decision-making and induce approach behavior (via the assignment of motivational salience to rewarding stimuli);
3. elicit positively-valenced emotions, particularly pleasure.

Neuroanatomy

Overview

The brain structures that compose the reward system are located primarily within the cortico-basal ganglia-thalamo-cortical loop; the basal ganglia portion of the loop drives activity within the reward system. Most of the pathways that connect structures within the reward system are glutamatergic interneurons, GABAergic medium spiny neurons (MSNs), and dopaminergic projection neurons, although other types of projection neurons contribute (e.g., orexinergic projection neurons). The reward system includes the ventral tegmental area, ventral striatum (i.e., the nucleus accumbens and olfactory tubercle), dorsal striatum (i.e., the caudate nucleus and putamen), substantia nigra (i.e., the pars compacta and pars reticulata), prefrontal cortex, anterior cingulate cortex, insular cortex, hippocampus, hypothalamus (particularly, the orexinergic nucleus in the lateral hypothalamus), thalamus (multiple nuclei), subthalamic nucleus, globus pallidus (both external and internal), ventral pallidum, parabrachial nucleus, amygdala, and the remainder of the extended amygdala. The dorsal raphe nucleus and cerebellum appear to modulate some forms of reward-related cognition (i.e., associative learning, motivational salience, and positive emotions) and behaviors as well. The laterodorsal tegmental nucleus (LTD), pedunculopontine nucleus (PPTg), and lateral habenula (LHb) (both directly and indirectly via the rostromedial tegmental nucleus) are also capable of inducing aversive salience and incentive salience through their projections to the ventral tegmental area (VTA). The LDT and PPTg both send glutaminergic projections to the VTA that synapse on dopaminergic neurons, both of which can produce incentive salience. The LHb sends glutaminergic projections, the majority of which synapse on GABAergic RMTg neurons that in turn drive inhibition of dopaminergic VTA neurons, although some LHb projections terminate on VTA interneurons. These LHb projections are activated both by aversive stimuli and by the absence of an expected reward, and excitation of the LHb can induce aversion.

Most of the dopamine pathways (i.e., neurons that use the neurotransmitter dopamine to communicate with other neurons) that project out of the ventral tegmental area are part of the reward system; in these pathways, dopamine acts on D1-like receptors or D2-like receptors to either stimulate (D1-like) or inhibit (D2-like) the production of cAMP. The GABAergic medium spiny neurons of the striatum are components of the reward system as well. The glutamatergic projection nuclei in the subthalamic nucleus, prefrontal cortex, hippocampus, thalamus, and amygdala connect to other parts of the reward system via glutamate pathways. The medial forebrain bundle, which is a set of many neural pathways that mediate brain stimulation reward (i.e., reward derived from direct electrochemical stimulation of the lateral hypothalamus), is also a component of the reward system.

Two theories exist with regard to the activity of the nucleus accumbens and the generation liking and wanting. The inhibition (or hyper­polar­ization) hypothesis proposes that the nucleus accumbens exerts tonic inhibitory effects on downstream structures such as the ventral pallidum, hypothalamus or ventral tegmental area, and that in inhibiting MSNs in the nucleus accumbens (NAcc), these structures are excited, "releasing" reward related behavior. While GABA receptor agonists are capable of eliciting both "liking" and "wanting" reactions in the nucleus accumbens, glutaminergic inputs from the basolateral amygdala, ventral hippocampus, and medial prefrontal cortex can drive incentive salience. Furthermore, while most studies find that NAcc neurons reduce firing in response to reward, a number of studies find the opposite response. This had led to the proposal of the disinhibition (or depolarization) hypothesis, that proposes that excitation or NAcc neurons, or at least certain subsets, drives reward related behavior.

After nearly 50 years of research on brain-stimulation reward, experts have certified that dozens of sites in the brain will maintain intracranial self-stimulation. Regions include the lateral hypothalamus and medial forebrain bundles, which are especially effective. Stimulation there activates fibers that form the ascending pathways; the ascending pathways include the mesolimbic dopamine pathway, which projects from the ventral tegmental area to the nucleus accumbens. There are several explanations as to why the mesolimbic dopamine pathway is central to circuits mediating reward. First, there is a marked increase in dopamine release from the mesolimbic pathway when animals engage in intracranial self-stimulation.^[8] Second, experiments consistently indicate that brain-stimulation reward stimulates the reinforcement of pathways that are normally activated by natural rewards, and drug reward or intracranial self-stimulation can exert more powerful activation of central reward mechanisms because they activate the reward center directly rather than through the peripheral nerves.^[8][29][30] Third, when animals are administered addictive drugs or engage in naturally rewarding behaviors, such as feeding or sexual activity, there is a marked release of dopamine within the nucleus accumbens.^[8] However, dopamine is not the only reward compound in the brain.

Key pathway

Diagram showing some of the key components of the mesocorticolimbic ("reward") circuit.

Ventral tegmental area

• The ventral tegmental area (VTA) is important in responding to stimuli and cues that indicate a reward is present. Rewarding stimuli (and all addictive drugs) act on the circuit by triggering the VTA to release dopamine signals to the nucleus accumbens, either directly or indirectly.^{[citation needed]} The VTA has two important pathways: The mesolimbic pathway projecting to limbic (striatal) regions and underpinning the motivational behaviors and processes, and the mesocortical pathway projecting to the prefrontal cortex, underpinning cognitive functions, such as learning external cues, etc. 
• Dopaminergic neurons in this region converts the amino acid tyrosine into DOPA using the enzyme tyrosine hydroxylase, which is then converted to dopamine using the enzyme dopa-decarboxylase.

Striatum (Nucleus Accumbens)

• The striatum is broadly involved in acquiring and eliciting learned behaviors in response to a rewarding cue. The VTA projects to the striatum, and activates the GABA-ergic Medium Spiny Neurons via D1 and D2 receptors within the ventral (Nucleus Accumbens) and dorsal striatum. 
• The Ventral Striatum (the Nucleus Accumbens) is broadly involved in acquiring behavior when fed into by the VTA, and eliciting behavior when fed into by the PFC. The NAc shell projects to the pallidum and the VTA, regulating limbic and autonomic functions. This modulates the reinforcing properties of stimuli, and short term aspects of reward. The NAc Core projects to the substantia nigra and is involved in the development of reward-seeking behaviors and its expression. It is involved in spatial learning, conditional response, and impulsive choice; the long term elements of reward.
• The Dorsal Striatum is involved in learning, the Dorsal Medial Striatum in goal directed learning, and the Dorsal Lateral Striatum in stimulus-response learning foundational to Pavlovian response. On repeated activation by a stimuli, the Nucleus Accumbens can activate the Dorsal Striatum via an intrastriatal loop. The transition of signals from the NAc to the DS allows reward associated cues to activate the DS without the reward itself being present. This can activate cravings and reward-seeking behaviors (and is responsible for triggering relapse during abstinence in addiction).

Prefrontal Cortex

• The VTA dopaminergic neurons project to the PFC, activating glutaminergic neurons that project to multiple other regions, including the Dorsal Striatum and NAc, ultimately allowing the PFC to mediate salience and conditional behaviors in response to stimuli.
• Notably, abstinence from addicting drugs activates the PFC, glutamatergic projection to the NAc, which leads to strong cravings, and modulates reinstatement of addiction behaviors resulting from abstinence. The PFC also interacts with the VTA through the mesocortical pathway, and helps associate environmental cues with the reward. 

Hippocampus

• The Hippocampus has multiple functions, including in the creation and storage of memories . In the reward circuit, it serves to contextual memories and associated cues. It ultimately underpins the reinstatement of reward-seeking behaviors via cues, and contextual triggers. 

Amygdala

• The AMY receives input from the VTA, and outputs to the NAc. The amygdala is important in creating powerful emotional flashbulb memories, and likely underpins the creation of strong cue-associated memories. It also is important in mediating the anxiety effects of withdrawal, and increased drug intake in addiction.

Pleasure centers

Pleasure is a component of reward, but not all rewards are pleasurable (e.g., money does not elicit pleasure unless this response is conditioned). Stimuli that are naturally pleasurable, and therefore attractive, are known as intrinsic rewards, whereas stimuli that are attractive and motivate approach behavior, but are not inherently pleasurable, are termed extrinsic rewards. Extrinsic rewards (e.g., money) are rewarding as a result of a learned association with an intrinsic reward. In other words, extrinsic rewards function as motivational magnets that elicit "wanting", but not "liking" reactions once they have been acquired.

The reward system contains pleasure centers or hedonic hotspots – i.e., brain structures that mediate pleasure or "liking" reactions from intrinsic rewards. As of October 2017, hedonic hotspots have been identified in subcompartments within the nucleus accumbens shell, ventral pallidum, parabrachial nucleus, orbitofrontal cortex (OFC), and insular cortex. The hotspot within the nucleus accumbens shell is located in the rostrodorsal quadrant of the medial shell, while the hedonic coldspot is located in a more posterior region. The posterior ventral pallidum also contains a hedonic hotspot, while the anterior ventral pallidum contains a hedonic coldspot. Microinjections of opioids, endocannabinoids, and orexin are capable of enhancing liking in these hotspots. The hedonic hotspots located in the anterior OFC and posterior insula have been demonstrated to respond to orexin and opioids, as has the overlapping hedonic coldspot in the anterior insula and posterior OFC. On the other hand, the parabrachial nucleus hotspot has only been demonstrated to respond to benzodiazepine receptor agonists.

Hedonic hotspots are functionally linked, in that activation of one hotspot results in the recruitment of the others, as indexed by the induced expression of c-Fos, an immediate early gene. Furthermore, inhibition of one hotspot results in the blunting of the effects of activating another hotspot. Therefore, the simultaneous activation of every hedonic hotspot within the reward system is believed to be necessary for generating the sensation of an intense euphoria.

Wanting and liking

Tuning of appetitive and defensive reactions in the nucleus accumbens shell. (Above) AMPA blockade requires D1 function in order to produce motivated behaviors, regardless of valence, and D2 function to produce defensive behaviors. GABA agonism, on the other hand, does not requires dopamine receptor function.(Below)The expansion of the anatomical regions that produce defensive behaviors under stress, and appetitive behaviors in the home environment produced by AMPA antagonism. This flexibility is less evident with GABA agonism.

Incentive salience is the "wanting" or "desire" attribute, which includes a motivational component, that is assigned to a rewarding stimulus by the nucleus accumbens shell (NAcc shell). The degree of dopamine neurotransmission into the NAcc shell from the mesolimbic pathway is highly correlated with the magnitude of incentive salience for rewarding stimuli.

Activation of the dorsorostral region of the nucleus accumbens correlates with increases in wanting without concurrent increases in liking. However, dopaminergic neurotransmission into the nucleus accumbens shell is responsible not only for appetitive motivational salience (i.e., incentive salience) towards rewarding stimuli, but also for aversive motivational salience, which directs behavior away from undesirable stimuli. In the dorsal striatum, activation of D1 expressing MSNs produces appetitive incentive salience, while activation of D2 expressing MSNs produces aversion. In the NAcc, such a dichotomy is not as clear cut, and activation of both D1 and D2 MSNs is sufficient to enhance motivation, likely via disinhibiting the VTA through inhibiting the ventral pallidum.

Robinson and Berridge's 1993 incentive-sensitization theory proposed that reward contains separable psychological components: wanting (incentive) and liking (pleasure). To explain increasing contact with a certain stimulus such as chocolate, there are two independent factors at work – our desire to have the chocolate (wanting) and the pleasure effect of the chocolate (liking). According to Robinson and Berridge, wanting and liking are two aspects of the same process, so rewards are usually wanted and liked to the same degree. However, wanting and liking also change independently under certain circumstances. For example, rats that do not eat after receiving dopamine (experiencing a loss of desire for food) act as though they still like food. In another example, activated self-stimulation electrodes in the lateral hypothalamus of rats increase appetite, but also cause more adverse reactions to tastes such as sugar and salt; apparently, the stimulation increases wanting but not liking. Such results demonstrate that the reward system of rats includes independent processes of wanting and liking. The wanting component is thought to be controlled by dopaminergic pathways, whereas the liking component is thought to be controlled by opiate-benzodiazepine systems.

Anti-Reward system

Koobs & LeMoal proposed that there exists a separate circuit responsible for the attenuation of reward-pursuing behavior, which they termed the anti-reward circuit. This component acts as brakes on the reward circuit, thus preventing the over pursuit of food, sex, etc. This circuit involves multiple parts of the amygdala (the bed nucleus of the stria terminalis, the central nucleus), the Nucleus Accumbens, and signal molecules including norepinephrine, corticotropin-releasing factor, and dynorphin. This circuit is also hypothesized to mediate the unpleasant components of stress, and is thus thought to be involved in addiction and withdrawal. While the reward circuit mediates the initial positive reinforcement involved in the development of addiction, it is the anti-reward circuit that later dominates via negative reinforcement that motivates the pursuit of the rewarding stimuli.

Learning

Rewarding stimuli can drive learning in both the form of classical conditioning (Pavlovian conditioning) and operant conditioning (instrumental conditioning). In classical conditioning, a reward can act as an unconditioned stimulus that, when associated with the conditioned stimulus, causes the conditioned stimulus to elicit both musculoskeletal (in the form of simple approach and avoidance behaviors) and vegetative responses. In operant conditioning, a reward may act as a reinforcer in that it increases or supports actions that lead to itself. Learned behaviors may or may not be sensitive to the value of the outcomes they lead to; behaviors that are sensitive to the contingency of an outcome on the performance of an action as well as the outcome value are goal-directed, while elicited actions that are insensitive to contingency or value are called habits. This distinction is thought to reflected two forms of learning, model free and model based. Model free learning involves the simple caching and updating of values. In contrast, model based learning involves the storage and construction of an internal model of events that allows inference and flexible prediction. Although pavlovian conditioning is generally assumed to be model-free, the incentive salience assigned to a conditioned stimulus is flexible with regard to changes in internal motivational states.

Distinct neural systems are responsible for learning associations between stimuli and outcomes, actions and outcomes, and stimuli and responses. Although classical conditioning is not limited to the reward system, the enhancement of instrumental performance by stimuli (i.e., Pavlovian-instrumental transfer) requires the nucleus accumbens. Habitual and goal directed instrumental learning are dependent upon the lateral striatum and the medial striatum, respectively.

During instrumental learning, opposing changes in the ratio of AMPA to NMDA receptors and phosphorylated ERK occurs in the D₁-type and D₂-type MSNs that constitute the direct and indirect pathways, respectively. These changes in synaptic plasticity and the accompanying learning is dependent upon activation of striatal D1 and NMDA receptors. The intracellular cascade activated by D1 receptors involves the recruitment of protein kinase A, and through resulting phosphorylation of DARPP-32, the inhibition of phosphatases that deactivate ERK. NMDA receptors activate ERK through a different but interrelated Ras-Raf-MEK-ERK pathway. Alone NMDA mediated activation of ERK is self-limited, as NMDA activation also inhibits PKA mediated inhibition of ERK deactivating phosphatases. However, when D1 and NMDA cascades are co-activated, they work synergistically, and the resultant activation of ERK regulates synaptic plasticity in the form of spine restructuring, transport of AMPA receptors, regulation of CREB, and increasing cellular excitability via inhibiting Kv4.2

Disorders

Addiction

ΔFosB (DeltaFosB) – a gene transcription factor – overexpression in the D1-type medium spiny neurons of the nucleus accumbens is the crucial common factor among virtually all forms of addiction (i.e., behavioral addictions and drug addictions) that induces addiction-related behavior and neural plasticity. In particular, ΔFosB promotes self-administration, reward sensitization, and reward cross-sensitization effects among specific addictive drugs and behaviors. Certain epigenetic modifications of histone protein tails (i.e., histone modifications) in specific regions of the brain are also known to play a crucial role in the molecular basis of addictions.

Addictive drugs and behaviors are rewarding and reinforcing (i.e., are addictive) due to their effects on the dopamine reward pathway.

The lateral hypothalamus and medial forebrain bundle has been the most-frequently-studied brain-stimulation reward site, particularly in studies of the effects of drugs on brain stimulation reward. The neurotransmitter system that has been most-clearly identified with the habit-forming actions of drugs-of-abuse is the mesolimbic dopamine system, with its efferent targets in the nucleus accumbens and its local GABAergic afferents. The reward-relevant actions of amphetamine and cocaine are in the dopaminergic synapses of the nucleus accumbens and perhaps the medial prefrontal cortex. Rats also learn to lever-press for cocaine injections into the medial prefrontal cortex, which works by increasing dopamine turnover in the nucleus accumbens. Nicotine infused directly into the nucleus accumbens also enhances local dopamine release, presumably by a presynaptic action on the dopaminergic terminals of this region. Nicotinic receptors localize to dopaminergic cell bodies and local nicotine injections increase dopaminergic cell firing that is critical for nicotinic reward. Some additional habit-forming drugs are also likely to decrease the output of medium spiny neurons as a consequence, despite activating dopaminergic projections. For opiates, the lowest-threshold site for reward effects involves actions on GABAergic neurons in the ventral tegmental area, a secondary site of opiate-rewarding actions on medium spiny output neurons of the nucleus accumbens. Thus the following form the core of currently characterised drug-reward circuitry; GABAergic afferents to the mesolimbic dopamine neurons (primary substrate of opiate reward), the mesolimbic dopamine neurons themselves (primary substrate of psychomotor stimulant reward), and GABAergic efferents to the mesolimbic dopamine neurons (a secondary site of opiate reward).

Motivation

Dysfunctional motivational salience appears in a number of psychiatric symptoms and disorders. Anhedonia, traditionally defined as a reduced capacity to feel pleasure, has been re-examined as reflecting blunted incentive salience, as most anhedonic populations exhibit intact “liking”. On the other end of the spectrum, heightened incentive salience that is narrowed for specific stimuli is characteristic of behavioral and drug addictions. In the case of fear or paranoia, dysfunction may lie in elevated aversive salience.

Neuroimaging studies across diagnoses associated with anhedonia have reported reduced activity in the OFC and ventral striatum. One meta analysis reported anhedonia was associated with reduced neural response to reward anticipation in the caudate nucleus, putamen, nucleus accumbens and medial prefrontal cortex (mPFC).

Mood disorders

Certain types of depression are associated with reduced motivation, as assessed by willingness to expend effort for reward. These abnormalities have been tentatively linked to reduced activity in areas of the striatum, and while dopaminergic abnormalities are hypothesized to play a role, most studies probing dopamine function in depression have reported inconsistent results. Although postmortem and neuroimaging studies have found abnormalities in numerous regions of the reward system, few findings are consistently replicated. Some studies have reported reduced NAcc, hippocampus, medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) activity, as well as elevated basolateral amygdala and subgenual cingulate cortex (sgACC) activity during tasks related to reward or positive stimuli. These neuroimaging abnormalities are complemented by little post mortem research, but what little research has been done suggests reduced excitatory synapses in the mPFC. Reduced activity in the mPFC during reward related tasks appears to be localized to more dorsal regions(i.e. the pregenual cingulate cortex), while the more ventral sgACC is hyperactive in depression.

Attempts to investigate underlying neural circuitry in animal models has also yielded conflicting results. Two paradigms are commonly used to simulate depression, chronic social defeat (CSDS), and chronic mild stress (CMS), although many exist. CSDS produces reduced preference for sucrose, reduced social interactions, and increased immobility in the forced swim test. CMS similarly reduces sucrose preference, and behavioral despair as assessed by tail suspension and forced swim tests. Animals susceptible to CSDS exhibit increased phasic VTA firing, and inhibition of VTA-NAcc projections attenuates behavioral deficits induced by CSDS. However, inhibition of VTA-mPFC projections exacerbates social withdrawal. On the other hand, CMS associated reductions in sucrose preference and immobility were attenuated and exacerbated by VTA excitation and inhibition, respectively. Although these differences may be attributable to different stimulation protocols or poor translational paradigms, variable results may also lie in the heterogenous functionality of reward related regions.

Optogenetic stimulation of the mPFC as a whole produces antidepressant effects. This effect appears localized to the rodent homologue of the pgACC (the prelimbic cortex), as stimulation of the rodent homologue of the sgACC (the infralimbic cortex) produces no behavioral effects. Furthermore, deep brain stimulation in the infralimbic cortex, which is thought to have an inhibitory effect, also produces an antidepressant effect. This finding is congruent with the observation that pharmacological inhibition of the infralimbic cortex attenuates depressive behaviors.

Schizophrenia

Schizophrenia is associated with deficits in motivation, commonly grouped under other negative symptoms such as reduced spontaneous speech. The experience of “liking” is frequently reported to be intact, both behaviorally and neurally, although results may be specific to certain stimuli, such as monetary rewards. Furthermore, implicit learning and simple reward-related tasks are also intact in schizophrenia. Rather, deficits in the reward system are apparent during reward-related tasks that are cognitively complex. These deficits are associated with both abnormal striatal and OFC activity, as well as abnormalities in regions associated with cognitive functions such as the dorsolateral prefrontal cortex (DLPFC).

History

Skinner box

The first clue to the presence of a reward system in the brain came with an accident discovery by James Olds and Peter Milner in 1954. They discovered that rats would perform behaviors such as pressing a bar, to administer a brief burst of electrical stimulation to specific sites in their brains. This phenomenon is called intracranial self-stimulation or brain stimulation reward. Typically, rats will press a lever hundreds or thousands of times per hour to obtain this brain stimulation, stopping only when they are exhausted. While trying to teach rats how to solve problems and run mazes, stimulation of certain regions of the brain where the stimulation was found seemed to give pleasure to the animals. They tried the same thing with humans and the results were similar. The explanation to why animals engage in a behavior that has no value to the survival of either themselves or their species is that the brain stimulation is activating the system underlying reward.

In a fundamental discovery made in 1954, researchers James Olds and Peter Milner found that low-voltage electrical stimulation of certain regions of the brain of the rat acted as a reward in teaching the animals to run mazes and solve problems. It seemed that stimulation of those parts of the brain gave the animals pleasure, and in later work humans reported pleasurable sensations from such stimulation. When rats were tested in Skinner boxes where they could stimulate the reward system by pressing a lever, the rats pressed for hours. Research in the next two decades established that dopamine is one of the main chemicals aiding neural signaling in these regions, and dopamine was suggested to be the brain's "pleasure chemical".

Ivan Pavlov was a psychologist who used the reward system to study classical conditioning. Pavlov used the reward system by rewarding dogs with food after they had heard a bell or another stimulus. Pavlov was rewarding the dogs so that the dogs associated food, the reward, with the bell, the stimulus. Edward L. Thorndike used the reward system to study operant conditioning. He began by putting cats in a puzzle box and placing food outside of the box so that the cat wanted to escape. The cats worked to get out of the puzzle box to get to the food. Although the cats ate the food after they escaped the box, Thorndike learned that the cats attempted to escape the box without the reward of food. Thorndike used the rewards of food and freedom to stimulate the reward system of the cats. Thorndike used this to see how the cats learned to escape the box.

Other species

Animals quickly learn to press a bar to obtain an injection of opiates directly into the midbrain tegmentum or the nucleus accumbens. The same animals do not work to obtain the opiates if the dopaminergic neurons of the mesolimbic pathway are inactivated. In this perspective, animals, like humans, engage in behaviors that increase dopamine release.

Kent Berridge, a researcher in affective neuroscience, found that sweet (liked ) and bitter (disliked ) tastes produced distinct orofacial expressions, and these expressions were similarly displayed by human newborns, orangutans, and rats. This was evidence that pleasure (specifically, liking) has objective features and was essentially the same across various animal species. Most neuroscience studies have shown that the more dopamine released by the reward, the more effective the reward is. This is called the hedonic impact, which can be changed by the effort for the reward and the reward itself. Berridge discovered that blocking dopamine systems did not seem to change the positive reaction to something sweet (as measured by facial expression). In other words, the hedonic impact did not change based on the amount of sugar. This discounted the conventional assumption that dopamine mediates pleasure. Even with more-intense dopamine alterations, the data seemed to remain constant. However, a clinical study from January 2019 that assessed the effect of a dopamine precursor (levodopa), antagonist (risperidone), and a placebo on reward responses to music – including the degree of pleasure experienced during musical chills, as measured by changes in electrodermal activity as well as subjective ratings – found that the manipulation of dopamine neurotransmission bidirectionally regulates pleasure cognition (specifically, the hedonic impact of music) in human subjects. This research demonstrated that increased dopamine neurotransmission acts as a sine qua non condition for pleasurable hedonic reactions to music in humans.

Berridge developed the incentive salience hypothesis to address the wanting aspect of rewards. It explains the compulsive use of drugs by drug addicts even when the drug no longer produces euphoria, and the cravings experienced even after the individual has finished going through withdrawal. Some addicts respond to certain stimuli involving neural changes caused by drugs. This sensitization in the brain is similar to the effect of dopamine because wanting and liking reactions occur. Human and animal brains and behaviors experience similar changes regarding reward systems because these systems are so prominent.