Reward System

• -originates in the zona compacta of the substantia nigra (SNc). Fibers project primarily to the dorsal striatum
• -identified most strongly in motor function

• -creates dopaminergic cells
• -projections are part of the mesocortical and mesolimbic dopamine systems.

• -A nucleus of the basal forbrain near the septum
• -receives dopamine-secreting terminal buttons from the neurons of the VTA
• -Plays an important role in reinforcing (rewarding) effects of certain categories of stimuli

• Dopaminergic Neurons in the VTA modulate information flow through the limbic circuit by projecting to the NAc, amygdala, hippocampus, PFC, and ventral pallidum (VP).
• -Increased dopaminergic transmission in the limbic nuclei, especially in the NAc underlies the reinforcing effect of almost every abused drug.

• -VTA projections= motivation
• -Nigrastriatal projections= motor control

A measure for metabolic activity and thus an indirect measure of general neuronal activity

• from Roitman article. Shows the voltammetric respone to rewarding (sucrose) and aversive (quanine) stimuli.
• -Average dopamine concentration increased during and after infusion
• -Shows real time chemical responses

• -Green/Purple= oxidation features of dopamine
• -Yellow=reduction features of dopamine
• -Red bar=infusion of sucrose or quanine

C) dopamine levels increase with the administration of sucrose and decrease with quanine in the nucleus accumbens

D) pH (measure of metabolic activity) increases with quanine and first decreases then increases with sucrose.

That dopamine in the dorsal striatum is involved in food motivation in humans that is distinct from its role in regulating reward through the NAc

The increases of extracelluar (outside the cell) dopamine were significant in the dorsal but not the ventral striatum (area that included NAc) and were significantly correlated with self-reports of hunger and desire for food.

• used Raclopride, a D2 receptor ligand that competes with endogenous dopamine for binding to the receptor.
• -also used methylphenidate to block dopamine transporters so that extracelluar dopamine could not be removed.

More Dopamine D2 receptors are occupied by endogenous dopamine

• -Two distinct compartments
• -1 preconditioning day
• -3 days: injected with morphine, confined to one of the compartments for 30 minutes; given saline in the other compartment

A high level of dopamine

• Food (CS) + treatment that causes illness (US)= CR (avoidance)
• Conditioning is robust (occurs even under anesthesia) and happens quickly
• Long lasting effects
• Long delays between CS and US don’t matter
• Adaptive as it lets animals avoid toxins

• Familiar foods less likely to become objects of CTA
• Odor cues much less effective than taste cues
• But, taste potentiation of odor is observed (when presented with taste aversion)
• Protein worse than carbs (due to salience of flavour)

to measure the amount of unchanged raclopride in plasma--which is an indirect indication of the amount of Dopamine already present on the D2 receptors

• A measure of the ratio of the concentration of raclopride in the tissue to the concentration of raclopride in the plasma.
• significant difference in the dorsal striatum during the cocaine views video

• -Dopamine concentration increased in response to appetitive stimuli
• -Majority of NAc neurons responded to sucrose with decrease in firing rate

• -Dopamine release was strongly suppressed in response to aversive stimuli relative to its baseline
• -Majority of NAc neurons responded to quanine with increases in firing rate

• Taste stimuli of opposing hedonic valence evoked opposite patterns of dopamine and metabolic actvity in the NAc
• Chemical signaling may serve to bias motor output toward ingestion or rejection

-Ready availability of addictive drugs, or foods high in fats, salt and sugar tends to displace adaptive behaviors, because they carry a powerful but false signal of fitness benefit

• -Both alter Neuronal Plasticity:
• Drugs- stimulate plasticity mechanisms in reward circuits  sets in motion the process of dependence (i.e. an alteration in homeostatic set point)
• Food (Body Weight vs Energy Balance): also depends on plasticity mechanisms related to set point regulation in central neural pathways

-Include the same neural circuitry

• Found in various networks through brain, but especially within regions involved in emotional regulation, pain and stress response, endocrine regulation, and food intake
• Also markedly affect motivational states
• Thus plays a role in diverse biological processes, mediated by a variety of receptor subtypes and brain loci.

• One of the major areas of research on physiological functions of endogenous opioids
• Pre-discovery of endogenous opioid peptides:Rats voraciously consume food following daily morphine injections
• Post-discovery: Opiate agonists augment feeding
• Opiate antagonists decrease feeding

A major hypothesis: Opiates specifically regulate palatability or hedonic evaluation of foodi.e. Opioids mediate the affective or pleasurable aspects of ingested substance

μ-opioid receptor antagonist; weaker affinity for κ- and δ-opioid receptors. Used to counter effects of opioid overdose (heroin/morphine overdose

-reduces preference for sweet, high-fat foods in bulimics, obese bulimics, and normal weight controls

opioid receptor antagonist as well, but has qualitatively different effects. Used for dependence treatment rather than emergency overdose treatment

-reduces subjective ratings of sweet taste while leaving feelings of hunger unchanged.

Microdialysis-insert pipette into area of the brain and take a chemical sampling

Voltammetry scan- measures real time dopamine activity in awake animals.

palatable food=surge of dopamine=activation of receptors

• -too much dopamine leads to down regulation of receptors to compensate
• -Occurs especially in the striatum--shown using fMRI

• drug use >> acute reinforcement of rewarding effects
• repetition leads to a shift in homeostasis, normal= a drug induced state
• the negative effect of withdraw leads to relapse by way of negative reinforcement (using the drug makes the side effects of withdraw diminish)

drug self administration model >> animals press lever to get injection of drug

• -caudate & putamen=dorsal striatum
• -ventral striatum

-paper found that cocaine cues increased activity in the dorsal striatum vs. the ventral striatum

-increased activity in dorsal striatum=priming for drug use

• feeding, arousal, and walking
• -motivated behavior
• -Lateral Hypothalamus= activated by reward, ie food and drug
• - Perifornical Area= activated by aversive stimuli, ie foot shock

*exogenous activation of LH orexin reinstated extinguished drug seeking behavior in rodents

• using fos:
• staind for orexin neurons
• staind for active neurons
• double labeling= activated orexin neuron

-lesioned orexin neurons in LH with ibotenic acid which lead to no preference in the CPP paradigm

to confirm lesion accuracy, they counted orexin neurons in the LH and PFA, decrease in LH orexin neurons concluded the lesion was site specific

• -unilateral lesion of orexin neurons in LH with NMDA- more selective for orexin neurons than ibotenic acid
• -injected orexin antagonist into VTA on opposite side (contralateral)
• -blocked both pathways for orexin neurons

• -Resulted in no preference for CPP chamber
• -neither were sufficient to block the preference alone

conclusion: LH orexin neurons in contrast PFA neurons and their projections to the VTA are essential for developing associations between environmental cues and drug rewards

• -morphine= a nonselective agonist for opioid system
• injected into 2 sites of the ventral striatum:
• -NAc
• -Ventralmedial Striatum

*both showed significant increase in food intake when injected with morphine, increase in food was relative to increase in morphine

• DAMGO- selective mnu opioid agonist
• -injected into the NAc no increase in water intake
• -increased intake of sucrose, saccharin, and saline
• -no increase of water intake when deprived of H2O

• -fat intake was greatly increased (400%)
• -sugar intake also significantly increased, but much smaller degree (75%)

Results are consistent with the theory that ventral striatal opioids regulate response to highly palatable foods.

-Naloxone blocked the effect of DAMGO

• -maintenence of caloric requirements of survival (DA in the dorsal striatum)
• -rewarding properties of food (DA in the NAc)

• Tastebuds are receptive organs that consist of groups of 20-50 receptor cells each
• -taste receptor cells for synapses with dendrites of bipolar neurons whose axons convey gustatory info and release NT adenosine triphosphate (ATP)

• Food molecule binds with the receptor which produces changes in membrane permeability causing receptor potentials
• -Salty: substance must ionize, receptor is sodium channel
• -Sour: receptor respond to hydrogen ions of acidic solutions
• -Bitter: typical stimulus is quanine. Receptors binds with a bitter molecule and activates a G proteine, which activates an enzyme starting a cycle of chemical reactions to release ATP
• -Sweet: typical stimulus is glucose or fructose. sweet receptors are T1R2& T1R3. metabotropic
• -Umami: Glutamate binds with receptors T1R1 & T1R3

• - Anterior part of the tongue= chorda tympani
• -Posterior part of the tongue= glossopharyngeal nerve
• -Palate and Epiglottis= vagus nerve

Info. is first recieved by the nucleus of the solitary tract of the medulla

• radioactive substance is admitted
• -Xray images are taken
• -points of high contrast= point of high activity

• upper GI symptoms (emesis) >> changes hedonic value=aversion
• lower GI symptons (gas, cramps, etc) >> changes in consumption

• fluid filled space between cerebellum and medulla
• circumventricular= no blood brain barrier
• well positioned to detect chemicals in the blood

• NaCl- no significant change in response to sugar
• LiCl- develops taste aversion in one trial= memory is eliminated

Parabrachial nucleus lesioned rats failed to change response

• Rats trained to avoid sugar solution
• LiCl – upper GI discomfort
• Shock – peripheral pain
• Lactose – lower GI discomfort
• Intake levels decreased (avoidance) but why?Was it dislike (rejection orofacial responses) or danger (acceptance orofacial responses even though they decreased intake)?

Preference changes did not distinguish between different types of aversive consequences

• Input
• - 2 sources:
• abdominal visceral afferents
• Area Postrema [AP] a circumventricular organ {CVO}, lacking a BBB --both sources project to the NTS Nucleus [Tractus Solitarius]
• Output
• From NTS projections to the PCRF [Parvicellular Reticular Formation] --where the range of coordinated outputs insures that ingested food [gastric contents] are not emptied or put into position to be absorbed into the blood
• gastric relaxation and tachyantria – slows gastric emptying
• retroperistalsis from small intestine to stomach and from stomach to intestine to mouth
• abdominal contraction