Karius: Neurophysiology of Addiction Flashcards
what is tolerance
-decrease in response to dose of drug
What 2 things comminicate in the core of the reward/pleasure system?
- the Ventral tegmental area (VTA)
- Nucleus Accumbens
What is the VTA?
- major input to the pleasure/reward system
- sends dopamine to target neurons
Where does the VTA receive excitatory input from?
- the prefrontal cortex
- Lateral hypothalamus
- Laterodorsal tegmental nucleus
What does the PFC release?
-EAA
What does the lateral hypothalamus release?
-Orexin
What does the laterodorsal tegmental N nucleus release?-
-Acetylcholine
What does the VTA provide to the Nucleus accumbens and how does it do it?
-VTA provides dopaminergic input to the nucleus accumbens via the MEDIAN FOREBRAIN BUNDLE
What is the nucleus accumbens?
- the third nucleus in the striatum
- often referred to as the ventral striatum
- has the same basic micro-circuitry as the others
Where does the Nucleus accumbens receive excitatory input from?
- PFC
- Amygdala
- Hippocampus
Where does the output from the NAc go to?
- the PFC
- releases GABA onto the pre frontal cortex
Does the NAc also send GABAergic input BACK to the VTA?
- yes
- tells the VTA that it’s had enough
Which cotransmitter is also released in the VTA?
-dynorphin
Where do the pleasure/reward systems receive inputs from?
-multiple opioid paths
What do opioid inputs do to the VTA?
- inhibit a subset of GABAerigic interneurons
- this INCREASES the release of DA in the NAc
Describe the “reward (pleasure) system” and how the following nuclei participate in producing pleasure
- VTA: reveives inputs and releases DA in NAc to lead to feeling of pleasure
- NAc: part of striatum. D1- activate direct; D3 inhibit indirect pathways. When active, GABA is released to produce pleasure
- PFC: Receives input allowing pleasure from NAc
What is input to the NAc mediated by?
-DA!
What is DA’s effect in the NAc?
-inhibitory
At this point, what does the core system of producing pleasure look like?
- VTA releases DA onto the NAc which then decreases its GABA release onto the PFC
- this leads to pleasure
What do NAc neurons do?
-release GABA onto their targets
So then, what is the effect of DA release ?
-to decrease GABA release in the PFC and allow activity of the reward pathways
What 2 things are in that flow chart affecting the VTA?
- PFC, Laterodorsal tegmental nucleus: releases EAA’s onto VTA
- Lateral Hypothalamic nucleus: releases Orexin onto VTA
What does the pathway look like for preventing pleasure?
- PFC, Amygdala, Hippocampus: releases EAA onto NAc
- NAc increases GABA output onto PFC
- this leads to absence of pleasure
So, how do the opioid produce pleasure?
- activate VTA
- VTA releases DA onto NAc
- NAc releases less GABA
- Pleasure happens
Is the pleasure/reward system a positive feedback system?
-Unstable
Describe DA in this lecture
- released by VTA neurons whose axons terminate in the NA
- binds to D1, 2, 3 receptors (2 and 3 are inhibitory)
Describe GABA in this lecture
- released by NA neurons whose axons terminate in the PFC
- also fibers terminating in VTA from NA or interneurons within VTA
Describe the opioids in this lecture
-major action: inhibit GABA interneuron in VTA….VTA releases more DA in NA…. intense feeling of pleasure (euphoria)
So basically, how do we do to produce pleasure?
- activate the VTA
- inhibit the NAc
- Less GABA inthe PFC
- pleasure happens
How doe we inhibit pleasure?
- Acivate the NAc
- more GABA in the PFC
- prevent pleasure
Where are the most prominent changes when we do some memory?
-at the synapses!
What is long term potentiation?
- a series of changes in the pre and post synaptic neurons of a synapse which leads to increased response tot he released NT
- must last for hours after the stimulation
- usually follows strong stimulation
- triggers a series of biochemic events that change gene trascription and translation
- permanently alter synaptic structure
What is synaptic plasticity?
- changes in the anatomy and physiology of synapses associated with learning
- some changes are permanent, others more transient
What is long term potentiation again?
- increase in response to same stimulus
- changes in both the pre and post synaptic neurons
- Includes: increased NT release, increased post-synaptic responses due to changes in the receptors to which the NT binds
How do Opiates work?
- agonist at opioid receptors
- second messenger system (Gi)
How does Cannabis work?
-CB-1 receptor, leads to DA release
Which drugs activate GPCR’s?
-Opiates and Cannabis
Which drugs alter ion channels?
- Nicotine: agonist at nicotinic cholinergic receptors, influx of sodium
- Ethanol/PCP: Antagonist at NMDA receptors (PCP is weak, but ethanol is allegedly pretty good at it)
Which drugs interfere with re-uptake mechanisms?
- CocaineL inhibit re uptake of DA, leads to increase in DA availability at synapes, similar effects on other monoamine system
- Amphetamines: reversal of DA reuptake transporters
How does ethanol activate the reward system?
- activates the opioid inputs (particuluarly to the VTA)
- VTA releases DA onto NAc, that decreases GABA…. pleasure happens
What does PCP and ethanol do to EAA inputs to the NAc?
- disrupts them
- stops the PFC, amygdala, hippocampus from releasing EAA
- EAA can’t activate NAc
- Low GABA to PFC
- pleasure happens
The PFC is working, will pleasure happen?
-yes, if PFC is NOT inhibited by GABA, pleasure seems to happen
What agents will increase the activity of VTA DA neurons?
- cocaine
- amphetamines
- cannabis
What does Nicotine activate?
-Nicotinic AchR on VTA neurons and induces them to release DA
What is the result of increasing the action of dopamine in the NAc?
-euphoria is produced
What are the normal responses to pleasurable stimuli?
- result of DA release in the nucleus accumbens
- Goal: reinforce the occurrence of behaviors that are not necessarily immediately beneficial
- the reward for these behaviors is pleasure
How do the drugs of addiction, how do they work?
- the vast majority of addictive drugs lead to an increase in the DA released within the nucleus accumbens
- The release of DA is not proportional to the normal stimuli
- this leads to euphoria or an exaggerated reward response to even mild stimuli
How does INduction of CREB happens?
- cAMP response element binding ptn
- Part of regulatory region in many genes: neuropeptides, enzymes for making NT, receptors?
What does CREB do to produce effects of drugs?
- within the NAc:
- leads to increased production of dynorphin: opioid substance, binds to kappa-receptors
Does the NAc send GABA-ergic and dynorphin-ergic input back to the ventral tegmental area?
-yes
What does the increase in hynorphin release for the NAc do?
- turns the input from the VTA off, reducing the effect of the drugs
- this is part of the process of desensitization that occurs with drug addiction
What is associated with the Activation of CREB within the locus ceruleus and the periaquaductal grey?
- the physical dependence on the drugs
- the mechanism for this is unclear
are changes in CREB temporary?
- yes
- they return to normal within a week of drug abstinence
What is delta-FosB?
- a long term response to drug addiction
- also a regulator of transcription
Describe the Major features of drug addiction and relate them to the neural changes induced by the drugs?
- The stronger stimulation can produce LTP in VTA neurons: more synapses, more response to released DA, increase in CREB production/activity, Increase dynorphin release in VTA
- Delta FosB: longer lasting effects than CREB, mostly associated with anatomic changes in synapses (more synapses, more dendritic spines)
What is synaptic plasticity?
- changes in the anatomy and physiology of synapses associated with learning
- some changes are permanent, others more transient
What is long-term potentiation?
- increase in response to same stimulus
- changes in both the pre and post synaptic neurons
- include: increased NT release, increased post synaptic responses due to changes in the receptors to which the NT binds
