Drug addiction

Question 1

• Hollerman and Shultz (1998)

Answer 1

Discrimination learning task and measuring responses of neurons in VTA/SN. DA signal is not indicating the receipt of reward but rather predicting an error in whether the reward is being predicted. DA neurons activated by reward in early tries but activation was reduced progressively as performance was consolidated and became predictable. Neurons activated when rewards occurred at unpredicted times and were depressed when rewards were omitted at predicted times → RPE

Question 2

• Wyvell and Berridge (2000):

Answer 2

Rats trained to press one of 2 levers to obtain sucrose pellet, then rat received bilateral microinjection of intra-accumbens vehicle or amphetamine and level pressing was tested in absence of any reinforcement contingency (and a taste reactivity measure of hedonic impact) conclude that NAc DA specifically mediates the ability of reward cues to trigger wanting (incentive salience) for their associated rewards, independent on both hedonic impact and response reinforcement.

Question 3

• Kringelbach et al (2003):.

Answer 3

Used fMRI in response to sensory stimulation produced by whole food and found a significant correlation between the activation of a region of the human OFC and decrease in subjective pleasantness when food is eaten to satiety consistent with the role of OFC in human emotion and motivation and associated subjective states

Question 4

• Daberkow et al (2013):

Answer 4

Used fast scan voltammetry in freely moving rats and found that amphetamine dose-dependently enhanced evoked DA responses in striatum to phasic like current pulse trains for up to 2 hours. Suggesting that DA release dynamically, drugs of addiction promote reward prediction related signalling→ lead to maladaptive reinforcement of learning and behaviour

Question 5

• Pascoli et al (2015):

Answer 5

Optogenetic targeting of DA neurons, DA neuron self-stimulation evokes synaptic plasticity in NAc, driving relapse → whole cell patch clamp recordings ex vivo released increased AMPAR/NMDAR ratio in the D1R but nor D2R-MSN. Lever pressing for self stimulation of VTA with light drives burst activity in VTA neurons is strongly reinforcing. Show that stimulating VTA DA neurons induce behavioural and cellular hallmarks of addiction indicating sufficiency for induction and progression of disease. OFC neurons are hyperexcitabile in mild resistant to punishment and chemogenetic inhibition of OFC reduces self-stimulation

Question 6

• Picciotto et al (1998):

Answer 6

mice lacking β2 subunit of NAChRs and found that nicotine stimulates DA release in ventral striatum of wt mice but not in the ventral striatum of mutant mice using patch clamp recording, suggest that nAChRs are involved in mediating the reinforcing properties of nicotine

Question 7

• Li et al (2011):.

Answer 7

nicotine administered to rats and unit activity (mini-tetrode) was measured and found that nicotine enhances synchronised activity between paired of VTA DA neurons and thus enhance the DA signal

Question 8

• Rice and Cragg (2004):

Answer 8

ed fast can voltammetry using guinea pig brain slices of dorsal striatum and NAc and showed that nicotine enhances during phasic but not tonic release thus increases the contrast, by nAChR desensitisation, so seems that β2-nAChRs gate the dynamic probability of DA release. Nicotine may therefore facilitate reward-related DA signals, including responses to other primary reinforcers.

Question 9

• Corre et al (2018)

Answer 9

monitored genetically encoded DA (Dlight) and Ca2+ (GCamP6) indicators as well as c-fos in mice to show that heroin activates DA neurons located in medial VTA, preferentially projecting to the medial shell of the NAc and inc DA here. Chemogenetic inhibition of DA neurons and found it suppressed self administration. Used optogenetics of Arch to inhibit VTA DA and found heroin occludes reinforcing effects of self-inhibition of VTA GABA neurons, consistent with disinhibition of DA neurons

Question 10

• Ungless et al (2001

Answer 10

VTA and hippocampal slices and electrophysiological recordings following exposure to cocaine, found it induced LTP of AMPAR mediated currents (inc AMPAR/NMDAR) of excitatory synapses onto DA cells in the VTA, blocked with DAP5. Showing single dose of cocaine can elicit synaptic plasticity

Question 11

• Hearing et la (2016)

Answer 11

): Looked at effects of repetitive morphine on Glu synaptic transmission in the NAc MSN subpopulations and found LTP in D1 and LTD in D2 MSNs in NAc and these changes were paralleled by increases in amplitude and frequency of current with D1 and decrease with D2 suggesting increase probability of D1 MSNs

Question 12

• Robinson and Kolb (1997):

Answer 12

Golgi staining in rat brain slices of MSNs in the NAc and L3 pyramidal neurons in the PFC and found that repeated amphetamine increased density of dendritic spines and number of branched spines.

Question 13

• Samaha et al (2004)

Answer 13

found that rapid infusions potentiated ability of cocaine to block DA uptake (voltammetry), to induce c-fos and arc mRNA expression (esp mesocorticolimbic regions) and to produce psychomotor sensitisation→ drug experience dependant plasticity implicated in addiction
o Variation in IEG expression was not always predicted by variation in DA uptake inhibition.

Question 14

• Donny et al (2003):

Answer 14

.Looked at the interaction between drug and visual cues in a fixed ratio experiment where animals has to work herder and harder during subsequent training for delivery of nicotine infusions as well as visual stimuli. Rats self administered nicotine or food, or received noncontingent nicotine, saline or food with or without a response contingent, unconditioned reinforcing visual stimulus. Found that nicotine influences operant behaviour either by acting as a primary reinforcer when it is contingent upon behaviour and by directly potentiating the reinforcing properties of other stimuli through a non-associative mechanism.

Question 15

• Chen et al (2013):

Answer 15

Rat model of compulsive drug seeking (drug seeking persists in subgroups of rats despite delivery of footshocks). show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex which was more pronounced in compulsive drug-seeking animals. In vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking and whereas optogenetic inhibition caused increased compulsive cocaine seeking. So appears that animals resistant to cocaine seeking have been devalued by punishment

Question 16

• Steeves et al (2009):

Answer 16

PET with raclopride binding comparing DA function in patients with impulse control disorders and comparing DA function following gambling. Enhanced DA release in the ventral striatum during gambling in PD patients with pathological gambling, abnormality may be a marker of vulnerability to addiction
o Looking in PD patients where already abnormalities in DA function.

Question 17

• Wang et al (2001)

Answer 17

PET with raclopride and brain glucose metabolism was assessed with FDG. Found that striatal dopamine DR receptor availability was lower in obese individuals than in controls In obese individuals BMI correlates with measures of D2 and so may suggest that dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of the circuits.

Question 18

• Kuhn et al(2011):

Answer 18

treated one patient with severe alcohol addiction with DBS to the NAc and found one year following that DBS achieved normalisation of addiction and craving.
o Only one patient so needs replicating

Question 19

• Thorgeirsson et al (2010):

Answer 19

): meta-analyses of GWAS of common alleles associating with the number of cigarettes smoked per day in smokers and smoking initiation and found variants in 3 genomic regions associated with CPD, among were genes encoding nicotine-metabolising enzymes and nAChRs. Nominal associations with lung cancer
o Causal? Influence>

Question 20

• Belin et al (2008):

Answer 20

in a 5-choice serial reaction time task found that high novelty seeking task was associated with higher propensity to seek drugs and highly impulse rats had higher likelihood of switch to compulsive drug seeking suggesting that shift from impulsivity to compulsivity occurs during the development of addictive behaviour

Question 21

Johnson and North (1992)

Answer 21

intracellular recordings from VTA DA slices of rat brain invitro, showed that opioids do not affect the principal neurons but hyperpolarise GABA-containing interneurons. The frequency of the synaptic potentials but not their amplitudes was reduced by opioids selective for μ-receptors. So appears that hyperpolarisation of interneurons by opioids reduces the spontaneous GABA-mediated synaptic input to the DA cells and this would lead to excitation of DA cells bu disinhibition