Neurophysiology of Drug addiction Flashcards
Describe the core system in producing pleasure
VTA releases dopamine at nucleus Accumbens (Nac)
The VTA receives excitatory input from what 3 areas? what does each area release?
- Prefrontal cortex: EAA
- Lateral Hypothalamus: orexin
- Laterodorsal Tegmental N.: Acetylcholine
The VTA provides a domaminergic input to the Nac via what?
median forebrain bundle
Describe what the Nucleus Accumbens is of the striatum?
- third nucleus
- often referred to as the ventral striatum
In addition to dopaminergic VTA input, the Nac also receive excitatory inputs from where? what do they use?
- Prefrontal cortex
- Amygdala
- Hippocampus
all use EAA
The output from Nac is to where? uses what?
Prefrontal cortex
-uses GABA
The Nac also sends a GABA-ergic input BACK to where? what is the co transmitter released here also
- VTA
- Dynorphin
The opioid inputs to the VTA do what?
The inhibit a subset of GABA-ergic interneurons. This increases the release of dopamine in the Nac
What are the dopamine receptors in the Nac
- D1: activate direct
- D3: inhibit indirect (these predominate)
- the dopamine inhibits the Nac so it releases less GABA in prefrontal cortex leading to pleasure
what are the inputs that activate the VTA leading to the pleasure pathway
- Prefrontal cortex, laterodorsal tegmental nucleus: EAA
- Lateral Hypothalamic Nucleus: orexin
What activates the Nac and prevents pleasure
- Prefontal cortex, amygdala, hippocampus
- release EAA
what is the word used to describe the nature of opioid inputs that reinforces the occurrence of certain behaviors important for our survival
- Diffuse
- also activates locus ceruleus, Periquaductal Grey
what kind of feedback system is the pleasure/reward system
positive
Cannabis and Opiates activate G protein coupled receptors. Describe this further
- Opiates: agonist at opioid receptors, Gi
- Cannabis: CB-1 receptor, leads to dopamine release
What drugs alter ion channels
- Nicotine: agonist at nicotinic cholinergic receptors, influx of Na
- Ethanol/PCP: antagonist at NMDA receptors (weak)
What drugs interfere with re-uptake mechanisms?
- Cocaine: inhibits reuptake of dopamine, leads to increase in DA availability at synapse, Similar effects on other monamine systems (5HT, NA)
- Amphetamines: reversal of dopamine reuptake transporters
What does ethanol activate in the reward pathway
-opioid inputs (particularly the VTA)
PCP and ethanol disrupt what inputs to the Nac
EAA
- leads to less GABA to prefrontal cortex
- No inhibition of pleasure
What agents increase the activity of VTA dopaminergic neurons
- Cocaine
- Amphetamines
- Cannabis
How does nicotine affect the pleasure reward pathway
activates nicotinic AchR on VTA neurons and induces them to release Dopamine
What memory response has been demonstrated in the VTA in response to cocaine and nicotine?
LTP: long term potentiation
some behavioral signs of addiction are prevented if what receptor antagonist is taken before ingestion of cocaine?
NMDA receptor antagonists . . may cause hallucinations in humans
what is a long term change in neurons as a result of addictive drugs
induction of CREB
-cAMP response element binding protein
What does CREB do to produce effects of drugs?
- within Nac: leads to increased production of dynorphin, an opioid substance that binds to kappa receptors
- dynorphin is responsible for dysphoria seen with drug withdrawal
- also responsible for desensitization that occurs with drug addiction because it turns the input from the VTA off and reduces the effect of the drugs
What is associated with physical dependence of drugs
-Activation of CREB within the locus ceruleus and periaqueductal grey
Describe the time frame for changes in CREB
temporary. . they return to normal within a week of drug abstinence
What is a long term response to drug addiction
delta-FosB . . also a regulator of transcription
Describe what delta-FosB does
- Within the Nac, delta-FosB has been shown to lead to production of proteins (BDNF) that are responsible for the remodeling of the dendrites that occurs
- increased # of dendrites and increased # of dendritic spines
