Acq/Exp & Neurons/Receptors

What area of the brain is involved in cue-controlled drug-seeking?

dorsal striatum

* hypothesis: is it involved in the start?

How do we test if the dorsal striatum is involved from the start?

1. inactivate the area prior to exp
2. compare lesioned rats w/controls if their acquisition differs

Area 1

detects cue light/drug association
- involves lever press/cravings
- detector + effector --\> acquisition AND expression

Area 2

when association is established, actionable effects are passed to Area 2
- effector \= executes --\> expression ONLY

What are the 3 inactivation techniques?

1. electrolytic lesions
2. chemical lesions (excitotoxic)
3. optogenetics

electrolytic lesion

lesion created by passing an electric current through the tip of an electrode positioned in the brain

chemical lesion (excitotoxic)

- overactivation of AMPA + NMDA receptor
- too much Ca++ enters cell
- enzymatic overload damages cell

optogenetics

treatment that uses combo of light stimulation + genetics to manipulate the activity of individual neurons

6 steps to optogenetics

1. piece together genetic construct
2. insert construct into virus
3. inject virus into brain (aspin is expressed in target neuron)
4. insert optrode, fiber-optic cable + electrode
5. laser light of specific wavelength opens ion channels in neurons
6. activity in neurons is modulated by light

What do inactivation techniques allow us to test?

involvement of specific areas/cells in various behaviors

How do we know which neuron/receptor/NTs are active in an area?

1. measure lvls of **mRNA** that codes a NT to know what neurons are prevalent in an area
2. measure lvls of NTs directly in live animals during expression (**microdialysis**)

What are the clinical implications if: increased DA is present during cue light in reinstatement phase?

- can target DA neurons (ex. antagonist)
- where are the neurons projecting from?
- can we block relapse?

behavioral effects

relapse/reinstatement

3 ways to block behavioral effects (relapse) on a neuro-lvl?

1. antagonist - block DA
2. optogenetics - suppress firing
3. DREADDS

antagonist

can be used systematically (intravenous) or local* (lab)

DREADDS

designer receptors exclusively activated by designer drugs;

* can bind to excite/inhibit
* engineered GPCRs activated by drug-like molecules
* packaged into viral vector + injected
* allows cellular activity to be controlled in a defined spatial/temporal manner

pros + cons of lesions

pro - disables specific area, quick, cheap
con - destroys connections, rough, outdated

pros + cons of optogenetics

pro - better spatial + temporal resolution (in ms/can turn on-off)

con - $$, multiple surgeries, rats restricted by fibre-optic

pros + cons of DREADDS

pro - better spatial resolution, simple execution, cost effective, rats behave normally

con - slightly worse temporal resolution (prolonged effect 20-60mins)

mesolimbic pathway\*\*

VTA → NAc

* neurons release DA
* express AMPA/NMDA receptors (Glu)

nigrostriatal pathway

SNc → CPu

mesocortical pathway

VTA → PFC