12. Increased Dopamine Concentration Flashcards
1
Q
intracranial self stimulation
A
- extremely sensitive to electrode location
- midbrain dopaminergic neurons project from ventral tegmental area to NAc
- medial forebrain bundle (axon - MFB - medial forebrain bundle) contains axons of VTA neurons projecting to NAc (effective stimulation target)
- gives you dopamine at NAc level
2
Q
Hedonic hotspots of NAc, what does it do?
A
- electrical stimulation of NAc alters response to rewarding and aversive stimuli
- brain locations to do with reward are evolutionarily preserved, but conditioned responses evolutionary preserved as well (tongue out to aversive stimuli)
- if you activate specific subregions of the NAc we see discrete spatial changes in response
- if you give a rat a treat whilst stimulating its NAc it will increase its hedonic value
- stimulating the more caudal (posterior) region whilst giving the rat a treat it reduces its hedonic value (negative reinforcement)
- can do negative/positive reinforcement by stimulating different regions of the NAc (different projections converging on discrete locations on the NAc
3
Q
Reward/Behaviour associations in the NAc
A
- brain circuits equiped to encorporate sensory and motivational information and alter motor output
- need to know the value of something every time you get it and need to know about a stimulus (all converges at the NAc)
- Afferent (inwards) projections to the NAc:
= WHAT is the stimulus - Amygdala
- PFC
- Hippocampus
= STIMULUS IS REWARDING - Ventral Tegmental Area
4
Q
Outputs from the NAc
A
- two functionally distinct output pathways from the NAc
- Premotor related output (Dorsolateral ventral pallidum)
- Reward/emotion related output (ventromedial ventral pallidum)
- system needs to be able to tell animal to/to not get stimulus again
- basal ganglia thought to be responsible for action selection (tonically inhibitory)
- anything rewarding goes through the basal ganglia and it decides whats most important to attend to
- stimulation of the NAc might bias that, for this to happen it must have some kind of input into the system ( which is does via substantia nigra)
5
Q
Three major dopaminergic pathways (need to know 1)
A
- MESOLIMBIC PATHWAY = originates in VTA and innervates NAc (and other limbic structures)
- dopamine transmission is coincident with rewarding stimuli and thus facilitates reinforcment
- mesocortical pathway = from VTA to frontal cortex. modulates the activity in dorsolateral PFC (higher order cognition)
- nigrostriatal pathway = substantia nigra to striatum (motor control)
- dopamine is modulatory so will do different things in each of the pathways
6
Q
what does dopamine do in terminal areas?
A
- what DA does at its terminals depends on the neurotransmitter released (more or less likely to fire - D1 > D5)
- dopaminergic cell bodies mainly found in the VTA and substantia nigra, wide terminal regions include the NAc and PFC
- DA acts through G protien couples receptors (D1 and D2 like)
- D1 like = activates adenylyl cyclase, increasing intracellular concentration of cyclic adenosine monophosphate (cAMP)
- D2 like = inhibits adenylyl cyclase, decreasing intracellular levels of cAMP
7
Q
cAMP
A
cyclic adenosine monophosphate
- key secondary messenger that regulates neural excitation
8
Q
what causes DA concentration at the NAc?
A
- mesolimbic DA pathway crucial for reward
- rat NAc dopamine levels increase during:
- operant response to obtain reward (Roitman et al., 2004)
- classically conditioned sensory stimuli (Setlow et al., 2003)
- primary rewards (food and water; Roitman et al., 2005)
- exposure to receptive females (Robinson et al., 2001)
- goal directed behaviours (Di Chiara., 2002)
9
Q
substances that hijack the reward system (drugs) should target the NAc….
A
rat self administration
- rats will self administer drugs into certain areas of the brain
- strong site specificity in responses with anatomy similar to that of electrical stimulation (VTA, NAc)
- if you administer into the mesolimbic DA pathway, dopamine levels will increase in the NAc
10
Q
will rats self administer?
A
- drugs usually administered to mesolimbic pathway in studies (only get pleasurable effects)
- injecting systemically will increase DA wherever it was delivered, thats why recreational drugs have vast effects (affects different locations = alcohol = pleasure but also movement)
- selective drugs can target specific receptors if given at right doses but if wrong can affect other receptors (die to similar chemical makeup of all receptors in the brain e.g. adrenaline/noreadrenaline)
11
Q
what drugs are most reinforcing when delivered to the NAc?
A
cocaine and amphetamine
12
Q
what drugs are most reinforcing when delivered to the ventral tegmental area?
A
morphine, heroin, GABA antagonists and nicotine
13
Q
3 main of neurons that are thought to modulate effects of drug abuse when delivered here
A
- cell bodies for VTA project to the target neuron of the NAc
- interneurons in the VTA
14
Q
cocaine
A
- reinforcing when delivered to the NAc due to the terminals of DA VTA neurons projecting to target neurons in NAc
normal transmission
- vesicular release of DA from presynaptic neuron
- increased DA concentration in synaptic cleft
- DA binds to post synaptic neuron
- excess DA removed by dopamine transporter (DAT - binding of sodium required here)
in presence of cocaine
- cocaine acts to block binding site of sodium on DAT
- reuptake of DA to presynaptic neuron is blocked (stays in cleft)
- continues to agonise post-synaptic neuron and availability of DA in synapse increases
- gives you drive to require more as its rewarding
- primary reward (cocaine) then influences non-specific stiumuli that have now become rewarding as dopamine levels cannot be terminated
15
Q
amphetamine
A
- similar to cocaine but amphetamine is a substrate of DAT, competitively inhibiting DA uptake
- actively binds to DA transporter (what substrate means) so presynaptic neuron takes in amph instead
- once in the cell, amph interferes with the monoamine transporter (VMAT) and impedes the filling of synaptic vesicles
- this increases cytoplasmic levels of DA
- this promotes DAT-mediated reverse transport of DA into cleft independent of AP induced vesicular release (concentration gradient)
- COMPETES AND INCREASES
- needs a release of dopamine to start cycle
- reinforces neutral stimuli as well
