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How do addictive hedonic drugs affect the brain?

- much about the brain mechanisms of reward and motivation has come from the study of addictive hedonic drugs
- studied in rats:
- coronal section shows where heroin binds
- indicates regions of the brain heroin acts on: also suggests where endogenous factors must interact with these structures
- the search for these endogenous factors lead to the discovery of the opioid peptides

- exact profound and coordinated effects on the brain
- if there are receptors sitting there waiting for an opiate to come along there must be an endogenous substance like that
- if that is where heroin is binding, it must also be where endogenous compounds are produced
- this was how endogenous opoids were discovered, encephalens and endorphins
- neurotransmitter pathway, doesn't do lots of other things.


What was a significant advance linking brain structures to motivation?

- Olds and Milner in 1949
- self stimulation sites in the brain
- why would a rat self-stimulate regions of its brain to the exclusion of all else?
- behaviour was incredibly reinforcing

- sites in the brain that produced huge self stimulation responses included a path from the ventral medial forebrain to the rostral brainstem, centred around a fibre tract called the median forebrain bundle

- lateral hypothalamus
- analogue of medial prefrontal cortex
- ventral tegmental area

- pathway from the midbrain --> basal forebrain --> prefrontal cortex
- key structure is median forebrain bundle if you want to induce this behaviour


What is the VTA?

- ventral tegmental area
- source (via the median forebrain bundle) of dopamine to prefrontal cortex and associated basal ganglia regions
- so is dopamine the "reward system" of the brain?
- the mode of action of some hedonic drugs (such as opiates) facilitate dopamine release by VTA neurons on frontal regions
- some dopaminergic agonists (e.g. amphetamines) are powerful elevators of mood

VTA project through the median forebrain bundle and innervating this basal ganglia-like structure called the nucleus accumbens (and the cortex)


What is the dopaminergic pathway involved in addictive behaviour?

Rat brain
- dopamine neurons of ventral tegmental area
- stimulated by heroin and nicotine
- nucleus accumbens stimulated by dopamine (via VTA) or cocaine

Human brain
- substantia nigra supply dopamine to the basal ganglia and the motor control circuits
- VTA in midbrain
- supplies dopamine to prefrontal areas and accumbens part of basal ganglia
- dopamine is the only thing involved in reward or reinforced behaviour
- other pathways involve dopamine e.g. one pathway linked to control of pituitary function
- VTA and substania nigra are relatively small nuclei
- large neurons that are fairly scattered
- highly divergent projection
- unusual synaptic connections (en passant)
- modulatory effect: subltly changes function
- modulator


What is the functional and anatomical organisation of the limbic loop?

signals relevant to emotional reinforcement

cortical input: amygdala, hippocampus, orbitofrontal, anterior cingulate, temporal cortex
>> ( + )
striatum: ventral striatum (aka Nucleus accumbens)
>> ( – )
pallidum: ventral pallidum, substantia nigra, pars reticulata
>> ( – )
thalamus: mediodorsal nucleus
>>> ( + )
anterior cingulate, orbital frontal cortex, amygdala

dopamine from VTA - synaptic potentiation in the ventral striatum (nucleus accumbens) i.e. makes these neurons more excitable
- leads to greater inhibition of ventral pallidum
- which means there is now less inhibition of MD thalamus (disinhibited)
- leads to greater excitation of limbic cortex
- reinforcement of behaviours

- needs to be incredibly plastic so we can learn which behaviours lead to reward


How do drugs affect dopamine projections from the VTA to the nucleus accumbens?

- hedonic drugs seem to act on this pathway
- opiates have a strong affect in increasing VTA neuron activity
- do it indirectly: inhibit GABA-nergic neurons so that VTA neurons are relased from GABAnergic inhibition (more active)
- probably also act directly on accumbens to excite them

- cocain and amphetamines increase the amount of dopamine in the synapse

- even though these substances make you really happy, you decrease the ability to motivate or structure your behaviour around other goals
- reinforced is the behaviour of seeking and obtaining and taking drugs

- neurons in the VTA become more sensitive to inputs
- enzyme that is part of the pathway that makes dopamine increased tyrosine hydroxylases upregulated
- glutamate receptor that responds to input is upregulated
- CREB (second messenger pathway that leads to gene transcriptions) is also upregulated
- these neurons become sensitised. more ready to release dopamine
- only in response to the drug induced pathway
- become less sensitive to endogenous pathways

- accumbens: changes in gene transcription, again only to stimulated/drug induced dopamine, less sensitive to inputs from the cortex

- lose the memory of what you want to do in the future: replaced by one goal, getting more drugs
- pleasurable effect of the drug does tend to wear off
- getting and obtaining the drug becomes much more important than the effect of the drug
- pleasure state doesn't seem to be maintained with prolonged use


So what are rats experiencing when they self-stimulate?

- self-stimulation of dopaminergic pathways can dominate behaviour in rodents
- reports from self-stimulating humans suggests a mental state other than reward (perhaps anticipation of a potential rewarding state)
- addictive behaviour may relate to reward or the anticipatory state, but seems to be dopaminergic

- what is that VTA neuron activity represents?
- the circuits described show the plastic link between actions and reward; VTA is crucial, but what is it representing?


Reward: wanting or enjoying?

- taste liking and disliking behaviours are conserved, involving regions of ventral striatum
- rats depleted of striatal dopamine do not seek food, but exhibit liking and disliking behaviours for palatable (sugar) and unpalatable (quinine) food

- appears that dopamine is not really about pleasure, it's about wanting pleasure (rather than enjoying them)


What is the activity of VTA dopamine neurons during stimulus-reward learning?

- reward delivered, burst in activity of VTA --> dopamine is reward? this is in unconditioned animal

- conditioned animal: give conditioned stimulus, burst in VTA activaty, later give reward

- plastically changed so that dopamine indicates forthcoming reward

- if you start giving conditioned stimulus and not reward, still peaks after stimulus but VTA activity is suppressed when no reward arrives
- therefore dopamine is behaving like a predictor of award, but not award itself


How can reward undermine motivation?

- dopamine tells you something about whether or not you will get your reward
- e.g. get two groups of people to perform a task, one group gets rewarded, the other doesn't
- in the first session they are the same
- in the second session when the rewarded group are told they are no longer getting the reward, they don't have any motivation
- so reward can be demotivating when you take it away
- most effective way to reward is to do it randomly


Dopamine is not "reward" or "pleasure" so what is it?

- reward predication error:
delta(t) = r(t) + gamma V (t + 1) - V(t)

- RPE = actual reward now + discounted predicted reward later - predicted reward now
- hypothetical


How does the consideration of the site of drug action often lead to the diffuse modulatory systems of the central nervous system?

1. a nucleus or cluster of nuclei with relatively few neurons (thousands rather than millions)
2. most o fhte nuclei are in the "central core" or the brain: the brainstem and basal forebrain
3. each neuron can influence many (maybe hundreds of thousands) of neurons elsewhere in the brain – this is called highly divergent projection
4. the synapses made by these cells are typically "en passant" - terminal that keeps going to make another etc etc

unlike norepinephrine, seratonin and acetylcholine systems has very few regions to which it synapses - only basal ganglia and prefrontal cortex

core bits of the brainstem important in global type behaviours

drugs act on these sites of reuptake
if you can change the neurotransmission you change the overall function of the brain (subtly)


So is dopamine "pleasure" or "reward"?

- dopamine does other things, and other agents afect reward and motivation
- the underlying causes of behaviour in experimental animals is difficult to ascribe
- dopamine's locus of action is broad (divergent projections)
- self-stimulation at high rates is not associated with concomitantly high levels of dopamine release
- dopamine depletion leads to anhedonia but does not eliminate behaviours associated with pleasurable and aversive experiences