DBB: 12 - Drug experience-dependent plasticity - glutamate and environment

how is all the evidence from (DBB: 11) a correlation

drug exposure → neuronal changes

drug exposure → behavioural changes

• happen at the same time but does mean they caused each other

what causation do we want to find and how do we do that

the neuronal changes CAUSES behavioural changes

• we would remove the neuronal changes to see if it also removes the behavioural changes

what do cocaine injections do to AMPAR surface expression and AMPAR/NMDAR ratios in the accumbens

increase them

what are the 2 types of major AMPARs

• GluR2-containing AMPAR

• GluR2-lacking AMPAR

explain what GluR2-containing AMPARs are

most adult neurons have AMPARs with GluR2-subunits

• passes Na+ but NOT Ca2+

explain what GluR2-lacking AMPARs are

juvenile neurons have AMPARs withOUT GluR2-subunits - rare in adults

• passes Na+ AND Ca2+

what does it mean that it passes both

more positivity → more plasticity (because Ca2+ has encourages more plasticity)

can look at the receptor specifically with NASPM antagonist

(1) Conrad et al (2008) procedure and findings

long term withdrawal from cocaine self-administration increases cocaine-seeking and altered AMPAR composition in NAc

• rat self-administered for 10 days

• looked at drug seeking on day 1 and 45 drug free in relation to NAc AMPAR subtypes

found:

• drug seeking goes up as time goes on (incubation of cocaine-seeking) - we know this for all drugs

• at day 1 - receptors were typical GluR2-containing

• at day 45 - found more GluR2-lacking AMPARs

is this casual though

not yet - use NASPM antagonist

• if we infuse NASPM directly into NAc to block GluR2-lacking receptors at day 1 and 45

what do we find

• day 1 = drug seeking didn’t change (since there wasn’t anything to block yet)

• day 45 = cocaine-seeking went down as GluR2-lacking receptors are now ‘blocked’

what we 3 studies findings on the importance of drug environment interactions

• drug effects are influenced by ‘set and setting’

• the environment modulates cocaine-induced alterations in NAc neuronal morphology

• the environment modulates cocaine-induced glutamate release in NAc

what were 2 commonalities of these studies

• repeated cocaine injections in ‘novel’ compared to home environments /context produced more robust locomotor sensitisation and more NAc spine density/glutamate release

• cocaine administration environment modulates cocaine induced behaviour and neuronal activity

by why

because rats make cocaine-context association

• its a learned association → association was recalled → produced a bigger effect when taking cocaine

how did Hubel and Wiesels work on the visual cortex inspire research into this question

they found that a specialised group or ‘ensemble’ of neurons encode specific stimuli

• used in vivo electrophysiology revealed in visual cortex that a subset of neurons respond to bars of light in a certain orientation

• e.g. a group of neurons responds to only diagonal bar, another group only to vertical bar etc.

so what is the hypothesis in relation to drug, environment and sensitisation

there must be a specific group of neurons that respond and store memories about specific environments and drug effects

what other technique can look at neuronal ensembles

imagine techniques

do neuronal ensembles also react to specific environments? Study (2)

distinct neuronal ensembles are activated by different environments contexts in hippocampus

• a mouse explores two different environments (A and B) - differnet in terms of visual look

• e.g. wall and floor pattern

• hippocampus imaged live with activity sensors in mice

• some neruons specifically react to context A, and others Context B

how does this relate to cocaine and context

well the NAc gets its information from the hippocampus which stores a lot of information about the environment and sends excitatory projections

study (3) Koya et al procedure and findings

cocaine-context associations modulate cocaine-induced behaviour and neuronal activity

• paired group (aka novel group - taken to square chamber for cocaine)

• once a day for 7 days → 7 days drug free test in square chamber → get sensitised (obvs)

• non-paired group (control group - taken to a ‘non-home environment’ for cocaine injections)

• once a day for 7 days → 7 days drug free test in square chamber (not location they got cocaine injection) → not sensitised at all

what does this show

that learned association between cocaine and cocaine administration environment plays a big role in modulating the two responses of behaviour and neuronal activity

• need the previous learned cocaine association to get the sensitisation response

how can we show a potential causation for this

in the paired group about 2-3% of NAc neurons have Fos (more neurons activated → more sensitised)

• so if this is what is causing sensitised response… remove Fos neurons to see if you still have that sensitised response

how would you selectively silence the Fos containing neurons

• take regular rats but where Fos expressing neurons also have a beta-gal protein in them

• Daun02 is a prodrug which interacts with beta-gal and causes neuronal death

so if you inject Daun02 into NAc → active neurons will express Fos → therefore beta-gal → and die

how did they do this in the original ‘paired group’ study

gave the Daun02 compound in the accumbens to paired group rats on ‘context day’ (with cocaine as well obvs)

• this silences context A ensemble → kills of those cocaine-context neurons

• and then on test day - sensitisation goes down

what happens when you bring rats to a different environment and inject cocaine

you should have a different group of neurons turned on and expressing beta-gal

• so if you kill those neurons, the context A ensemble stay intact → if you bring them back to context A → the neurons aren’t damaged so they will sensitise