Reward & Addiction

Question 1

DEPENDENCE/TOLERANCE/WITHDRAWAL

i) What is addiction/substance dependence defined as?
ii) is dependence physical or psychological?
iii) what is withdrawal defined as?
iv) what is tolerance defined as?
v) in tolerance - what is required to get the same drug effect?

Answer 1

i) dependence is a persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences
ii) can be both physical and psychological
iii) withdrawal is negative physiological & emotional features that occur when a drug is not taken
iv) tolerance is diminished response to the effect of a given amount of drug following repeated exposure
v) increasingly larger doses of drug are required to induce the same effect

Question 2

ACTION OF DRUGS IN THE BRAIN

i) what system do drugs hijack?
ii) which two systems are involved in reward and reinforcement?
iii) what areas of the brain is involved in addiction? (3)
iv) what do each of these brain areas control in addiction?
v) what is self monitoring?

Answer 2

i) drugs hijack the natural reward system
ii) reward and reinforcement are the mesocortical and mesolimbic system = mesocorticolimbic pathway
iii) addiction = pre frontal cortex, hippocampus and amygdala
iv) PFC = impulse decision making and self monitoring, hippocampus = memory formation which can be associated with context of taking the drug, amygdala = emotional response
v) self monitoring is the ability to not give into impulses

Question 3

ANTICIPATION OF REWARD

i) what area of the brain does anticipation of reward recruit?
ii) where is this structure found?
iii) is this response seen in punishment?
iv) which chemical mediates this response?

Answer 3

i) the nucleus accumbens
ii) found in the ventral striatum
iii) no this response is seen exclusively and extensively in reward
iv) dopamine mediates this response

Question 4

MONKEY TASK AND PREDICTION OF REWARD

i) what area of the brain does this involve? what type of neurons fire?
ii) what happens to neuronal firing at the arrival of an unexpected reward?
iii) once the animal has learnt how to get the reward what happens to neuronal firing?
iv) what happens if you do the task but dont get the reward? is there firing?

Answer 4

i) involves the nucleus accumbens and firing of dopamine neurons
ii) firing of lots of action potentials when an unexpected reward arrives
iii) once learnt the neurons will fire in anticipation of the reward
iv) if you do the task but no reward there is silence (but the neurons have previously fired in anticipation) = error signal

Question 5

what area of the brain is activated in the presence of

i) an unpredicted stimulus
ii) a predicted stimulus

Answer 5

i) unpredicted stimulus = NAcc
ii) predicted stimulus = temporal lobe

Question 6

THE REINFORCEMENT SYSTEM

i) where are neurons that produce the response found?
ii) which three chemicals does the system involve?
iii) which brain area decides if the behaviour happens? and what does this consequently cause?
iv) which brain area feeds DA signals back to the PFC?
v) what happes when there is decreased Glu in the PFC?
vi) how does hypofrontality lead to symptoms of schizphrenia?

Answer 6

i) found in the dorsal striatum
ii) involves Glu, GABA and DA
iii) PFC decides if behaviour happens and this will cause Glu release which will act on GABA neurons in the VTA
iv) VTA sends DA signals back to the PFC
v) decreased Glu in the PFC = hypofrontality
vi) less Glu in PFC means less inhibition of GABA neurons in VTA which means more activation of DA neurons in NAcc which becomes out of control and causes symptoms of schz eg hallucinations

Question 7

THE MESOCORTICOLIMBIC DA SYSTEM

i) involves projections from the VTA to where?
ii) what pathway involves this system?
iii) what do natural reinforcers such as food and sex cause?
iv) what can be hijacked by drugs to make natural reinforcers lose their appeal?
v) addictive drugs can cause more reliable and powerful activation of this system - true or false?
vi) how can the reward effects seen in this system be blocked?

Answer 7

i) VTA to NAcc to cortex
ii) involes the reward and reinforcement system
iii) natural reinforcers cause DA release in the NAcc
iv) DA release from the NAcc can be hijacked to make natural reinforcers lose their appeal
v) yes addictive drugs can reliably activate this system
vi) reward effects of drugs can be blocked by blocking DA in this region

Question 8

DRUG EFFECTS ON THE DA SYSTEM

i) which neurons in which area do psychostimulants work on?
ii) which neurons/area do opioids work on? what does this cause?
iii) what does alcohol cause?
iv) what does nicotine cause? is this direct or indirect?
v) which two drugs cause indirect disnhibition of DA neurons in the VTA?

Answer 8

i) psychostimulants work on DA neurons in the NAcc
ii) opioids work in GABA interneurons by inhibiting them - this causes disnhibition of VTA DA neurons (activation of DA neurons)
iii) alcohol causes disinhibition of VTA DA neurons
iv) nicotine causes increased DA from NAcc by stimulating nicotinic cholinergic receptors on MCL DA neurons
v) opioids and alcohol

Question 9

VTA NAcc pathway

i) in the basal state - DA neurons in the VTA release dopamine which are recieved by dendrites in which brain area?
ii) after acute drug exposure - what happens to DA release from VTA neurons? what does this cause?
iii) after repeated drug exposure what has happened to structures in the VTA and NAcc?
iv) after repeated exposure - what effect does the same amount of DA have on NAcc neuron
v) what may happen to dendrites of neurons in the NAcc after repeated opioid use?

Answer 9

i) DA from VTA is recieved by NAcc neurons
ii) after acute drug exposure the VTA releases more DA therefore this has a bigger effect on the NAcc
iii) repeated drug exposure = morphological change - causes VTA neurons to shrink and NAcc neurons to get bigger therefore they are more sensitive to DA
iv) after repeated exposure the same amount of DA has increased effect on NAcc neurons
v) repeated opioid use = loss of some dendrites in NAcc and less responsive to DA

Question 10

DA RECEPTORS

i) which receptors are excitatory? what molecules do these cause activation of (2)
ii) what is the short term effect of PKA?
iii) what is the long term effect of PKA?
iv) which receptors are inhibitory? what molecules and process is therefore inhibited?

Answer 10

i) D1,3,5 are excite - causes activation of cAMP and PKA
ii) short term effects of PKA = depol of ion channels
iii) long term effect of PKA = changes in gene expression and structural change of synapse
iv) D2 and 4 are inhibitory and inhibit cAMP and gene expression

Question 11

COCAINE AND AMPHETAMINES

i) what level do they work at? and what do they do here?
ii) how do they potentiate monoamine transmission (increase)?
iii) what transporter does cocaine bind? what effect does it have here and what does this cause?
iv) what effect does amphetamine have to on the transporter it binds? what does this cause?
v) activation at which transporter is most directly related to reinforcing effects?
vi) what is the overal effect of these drugs? what feeling are felt as a result of this?

Answer 11

i) work at the level of the NAcc and increase DA here
ii) they increase monoamine transmission by inhibiting DA, 5HT and noradrenaline reuptake transporters
iii) cocaine binds the DA transporter and blocks/inhibits it to prolong the pool of extracellular DA
iv) amphetamine binds the DA transporter and reverses it to cause it to release DA and increase extracellular levels
v) activation of the dopamine transporter (DAT) is related to reinforcing effects
vi) overall effect is increased synaptic DA which can cause feeling of euphoria

Question 12

EFFECTS OF COCAINE & IMAGING

i) where does cocaine bind in the brain?
ii) how long after admin does it take for the effects to wear off?
iii) what can many doses cause?

Answer 12

i) binds the NAcc in the striatum
ii) takes 20-30mins to wear off
iii) many doses can cause paranoia and psychosis

Question 13

EFFECTS OF COCAINE AND AMPHETAMINE

i) what type of behaviour is seen?
ii) what are the adverse long term effects on the brain?
iii) what is hypofrontality associated with?
iv) what cellular/molecular changes are seen?

Answer 13

i) psychotic behaviour (DA seen in positive symp of schz)
ii) adverse long effects are decreased DA transporters in VTA neurons
iii) hypofrontality is associated with bad decision making and information processing
iv) cell and molec changes increase activity of VTA tyrosine hydroyxlases, CREB, AMPA

Question 14

INCREASED EXCITATORY STRENGTH

i) the ratio of which two receptors are increased by all drugs of abuse?
ii) how is this measured in the lab?
iii) post drug admin - an increase in basal excitatory synaptic strength between which two areas is seen?
iv) how long do changes last after one drug admin? what happens when there are persistent injections for two weeks?
v) what do long term effects of drug admin lead to? what does this cause?

Answer 14

i) AMPA/NMDA ratio
ii) measured in lab by injecting different drugs or saline into a rodent and looking at receptor activity
iii) increased basal excite synap strength between the VTA and the NAcc
iv) one injection persists for 5 days but persistent injections for two weeks causes persistent changes in the VTA
v) long term effects are shrinking of VTA neurons and sensitisation to small amounts of the drug

Question 15

LONG TERM EFFECTS OF ADDICITION

i) what is the main hallmark of this?
ii) which brain area is afffected?
iii) what does this ultimately cause
iv) what are these changes likely responsible for?

Answer 15

i) fewer D2 receptors
ii) fewer D2 receptors in the striatum
iii) ultimately contributes to the compulsive drug taking and cues assciated with drug taking as D2 usually causes inhibition and supression of drug taking behaviours
iv) these changes are likely responsible for reduced sensitivity to natural rewards that develop with addiction

Question 16

D2 receptors

i) which drug specifically causes a reduction in these?
ii) what is their normal function?
iii) what does a reduction in these cause?

Answer 16

i) cocaine
ii) normal function is central to conditioning and motivation - cause inhibition and suppress drug taking behaviours
iii) reduction in D2 receptors causes reduced sensitivity to natural rewards that develop with addiction

Question 17

give three examples of emotional effects seen in psychomotor stimulants

Answer 17

dysphoria, anhedonia, anxiety on withdrawal

Question 18

COMPENSATORY CHANGES TO LOWER DA TRANSMISSION

i) activation of which receptors triggers this process?
ii) what three molecules are then activated to trigger downstream events?
iii) this causes the release of which endogenous opioid from the VTA? which receptor does this opioid act on?
iv) what is the effect of the opioid acting at its receptor? what does this ultimately cause?
v) when does this process happen? and what does it lead to?

Answer 18

i) increased activity at D1 receptors in the NAcc
ii) adenylyl cyclase, cAMP and PKA
iii) causes release of dynorphin (DYN) from the VTA which binds the K opioid receptor
iv) DYN binding K opioid R causes inhibition of VTA neurons and less DA release from the NAcc
v) happens in the absence of drug taking and leads to anhedonia, dysphoria etc because there isnt enough DA around for the natural reward system

Question 19

when is this system moderated?

Answer 19

to lower dopamine tranmission on overactivation of D1 receptors

Question 20

ASSOCIATIVE LEARNING & DRUG ADDICTION

i) what will co-incident firing between sensory pathways and the mesocorticolimbic pathway induce? what does this lead to?
ii) which mechanism may create long term memories about drug taking? where does this take place?
iii) why do you get DA release in anticipation of taking a drug?

Answer 20

i) firing between sensory pathays and the MCL pathway will induce LTP which leads to strengthening of these synaptic connections
ii) LTP occurs in synapses on DA afferents in striatal neurons
iii) because sensory info that is present when drug induced DA occurs can become associated with taking the drug so being in that place can cause anticipatory DA release

Question 21

DA and LTP

i) how does DA enhance LTP?
ii) which transmitter does it modify?
iii) which protein mediates gene expression in late phase LTP?
iv) what does synaptic remodelling do? (2)
v) how long after abstinence may molecular and cellular changes occur? what may this lead to?

Answer 21

i) DA works on the D1 receptor and activates adenlyl cyc, cAMP, PKA
ii) modifies Glu transmission
iii) CREB mediated gene expression can occur in late phase LTP causes by glutamate
iv) synaptic remodelling increases spines and dendritic branches of neurons
v) months after abstinence - may lead to relapse

Question 22

OPIATES

i) give two examples of opiates
ii) which G protein are endogenous opioid receptors coupled to? and what does this cause?
iii) what are three opioid receptor types? which receptor are most analgesic and reward properties mediated through?

Answer 22

i) morphine and heroin
ii) coupled to Gi - causes decreased adenylyl cyclase and K+ channels open/Ca2+ channels close
iii) mu, k, d opioid receptors - most analgesic/reward properties are mediated via mu

Question 23

OPIATES & REWARD

i) disinhibition of which neurons in the VTA mediates reward and reinforcement? how does this happen?
ii) what effect does activation of the mu opioid receptor on GABA neurons have? what will this in turn cause?
iii) what is another area in which opiates act? is this DA mediated?

Answer 23

i) disinhibition of DA neurons in the VTA - happens as DA neurons fire tonically but are usually inhibited by GABA interneurons (opioids inhib GABA INs so the inhib on DA neruons is relieved)
ii) activation of mu receptor on GABA interneurons will inhibit them and this then relieves the inhibition on DA neurons allowing them to fire
iii) opiates also act in the NAcc but this is indepedent of DA release

Question 24

ALCOHOL

i) what is its action at the GABAa and NMDA receptor?
ii) what effect does large doses have on VG ion channels?
iii) how does alcohol cause DA release in the NAcc? (inv VTA)
iv) what can block the reward effects of alcohol? what does this demonstrate?
v) name an opiate antagonist that can be used in alcohol addiction treatment

Answer 24

i) agonist
ii) causes inhibition of most VG ion channels
iii) antagonism of cortical input to the VTA which disinhibits VTA DA neurons therefore DA release in NAcc
iv) block effects using a DA antagonist which demonstrates the mechanism works via DA relase in the NAcc
v) naltrexone

Question 25

How do opiates cause DA release in the NAcc (cortex, VTA and NAcc)?

i) which opioid receptor does morphine work through? and which neurons does it target?
iii) which drug can work as an NMDA antagonist in the cortex to increase DA release?

Answer 25

opiates inhibit excitatory Glu inputs from the cortex to the VTA there the inhibitory GABA neurons are not activated which allows DA firing in the NAcc

i) morphine works through mu opioid receptor and targets GABAergic neurons in the VTA
iii) alcohol can work as an NMDA antagonist in the cortex to increase DA release

Question 26

What class of drug is A?

what does this ultimately cause?

Answer 26

opiate

ultimately causes DA release in NAcc as inhibition is lifted

Question 27

NICOTINE

i) which receptors does it act at? are these found pre or post synaptically?
ii) are nicotine receptors ligand gated or GPCRs?
iii) what is the effect of nicotine on DA? how is this facilitated?
iv) which drug can block nicotine induced behaviours eg smoking. what does this demonstrate?

Answer 27

i) acts at nicotinic Ach receptors found both pre and post synaptically
ii) ligand gated
iii) increases DA in NAcc due to activation of receptors on cell body in VTA as well as activating pre synaptic receptors in the NAcc
iv) naltrexone can block nicotine induced behaviours which demonstrates opioid involvement

Question 28

which neurotransmitter is mimicked by

i) opiates
ii) psychostimulants eg cocaine and amphetamine
iii) nicotine
iv) alcohol

Answer 28

i) endorphins
ii) dopamine
iii) nicotine
iv) GABA and glutamate (agonist at GABAa and antag at NMDA)

Question 29

PHYSICAL DEPENDENCE TO OPIATES

i) what is the main system that opiate receptors are present in?
ii) what is the locus coruleus and what is it involved in?
ii) what does acute morphine administration cause? what is the effect of this?
iv) what does chronic morphine admin cause?
v) what firing pattern is seen in the LC in opiate withdrawal? what can this trigger?
vi) which agent can block withdrawal symptoms?

Answer 29

i) mesocorticolimbic system but also spinal cord and pain pathways
ii) LC contains a noradrenergic nuclei that controls arousal and vigillance (elicits fight or flight response)
iii) acute morphine - inhibits firing of LC neurons which reduces arousal and vigilance
iv) chronic moprhine causes LC to return to normal firing rates
v) in withdrawal the LC neurons dramatically increase firing which triggers overactivation of ANS fight or flight response
vi) clonidine can block thie response (a2 adrenergic receptor agonist)

Question 30

OPIOID TOLERANCE AND INTRACELLULAR MECHANISMS

i) why do LC neurons return to normal firing on chronic opioid admin?
ii) what G protein pathway does acute morphine admin work through? what does this cause?
iii) which pathway is upregulated by chronic morphine admin?
iv) why does withdrawal cause a dramatic increase in LC firing?

Answer 30

i) due to a homeostatic mechanism that compensates for the functional changes that lead to tolerance and physical dependence - upregulates Gs to match Gi
ii) acute admin works through Gi and inhibits firing of LC neurons
iii) Gs is upregulate to match Gi from acute admin
iv) when there is no opiate there is no Gi activation - this causes Gs hypersensitivity therefore increase in LC neuron firing

Question 31

what does this demonstrate in relation to opiates?

Answer 31

Opiates not present to activate Gi therefore Gs is hypersensitive and causes increase firing of locus corueleus neurons = WITHDRAWAL

Question 32

PHYSICAL DEPENDENCE TO ALCOHOL

i) what are the acute effects of alcohol? (what receptors does it agonise/antag and what does this cause)
ii) what does chronic alcohol use cause and how does it do this?
iii) does the balance shift to excitation or inhibition in withdrawal? which physical symptoms do you therefore get?

Answer 32

i) agonise the GABAa receptor and antagonise NMDA receptor (glu) therefore cells are inhibited from firing
ii) chronic alcohol use causes less inhib and more excite by downreg of GABAa receptors and upreg of NMDA
iii) in withdrawal the balance shifts to excite - get symptoms such as agitation, tremors, hypertension and seizures

Question 33

what type of alcohol effect is responsible for picture A and picture B?

what receptor is represented in red and which is represented in yellow?

Answer 33

A = acute admin of alcohol

B = chronic effects of alcohol

red = GABAa and yellow = NMDA