Neurobiology andn neurochemistry of reward and addictive behaviours Flashcards
Define addiction/substance dependence
A persistent disorder of brain function which compulsive drug use occurs despite serious negative consequences for the afflicted individual.
- Homeostatic response to repeated drug administration
- Associated learning processes -synaptic plasticity
Define withdrawal symptoms
Negative physiological and emotional features that occur when the drug is not taken
Different for each drug of abuse but generally opposite to positive experience induced by drug
Define tolerance
Diminished response to the effects of a given amount of drug following repeated exposures to the drug.
This implies that increasingly larger doses of the drug are required to induce the same behavioural effect
Homeostatic changes- neuronal adaptations
Drugs hijack the natural reward system. What is this system?
Which additional structures are implicated in addition?
ADDICTIVE DRUGS ACTIVATE THE MESOCORTICOLIMBIC DOPAMINERGIC SYSTEM
Mesocorticolimbic pathway which is comprised of both the mesolimbic and mesocortical sysems.
It is responsible for reward and reinforcement, provides stimulus salience
Addiction also involves the PFC (impulsiveness, decision making, self monitoring), amygdala and hippocampus
- Anticipation of reward recruits the NAcc
- DA as an ‘error’ or learning signal in instrumental conditioning
What are the functions of the reinforcement system?
-Detect reinforcing stimulus which provides time to learn
and recognises something good has happened
-Strengthen neural connections (LTP) between neurons that detect the stimulus and the neurons that produce the INSTRUMENTAL RESPONSE
Give two examples of natural reinforces. What physiological changes do they induce?
How do addictive drugs fit into this?
Food and sex cause extracellular release of DA in NAcc
Behaviours that activate the system are said to be reinforced
Addictive drugs cause MORE powerful and reliable activation than natural reinforcers (HIJACK)
- Blockade of DA in this region attenuates most measurable reinforcing and rewarding effects of addictive drugs. More likely to be repeated
All drugs have an effect on the dopaminergic system. State the effects of
- psychostimulants
- opiates
- alcohol
- nicotines
- Direct action on DAergic neurons in NAcc
- Indirectly inhibit GABAergic interneurons in VTA = disinhibition of VTA DA neurons. Or action on opiate receptors in the NAcc- independent of DA release
- Disinhibition of VTA DA neurons
- Increases NAcc DA directly and indirectly, stimulates nicotinic cholinergic receptors on mesocorticolimbic DA neurons
Is the dopaminergic response abnormal?
No
The mesolimbic system will be activated in response to many stimuli- central to motivation
What affect does cocaine and amphetamines have on DA?
What do they do?
DA agonists
Potentiate monoaminergic transmission by inhibition of DA, 5-HT and NE reuptake transporters, this increases time for uptake of monoamines
Cocaine: blocks and inhibits transporter to prolong the extracellular pool of DA.
Amphetamines: reverse transporter to increase extracellular pool of DA
Action at DAT most directly related to reinforcing effects
-Feelins of euphoria through activation of this pathway/actions at transporters located elsewhere
Wheere does cocaine bind to following acute administration?
What does this cause?
Its binding site post administration is the STRIATUM (contains the NAcc)
- Psychotic behaviour
- DA involvement in positive symptoms of schizophrenia
- Adverse long term effects on brain
- Cellular/molecular changes that promote dysregulation
- Hypofrontality
What affect do drugs of abuse have on AMPA: NMDA?
The cause a significant increase in AMPA: NMDA
-Increase in basal excitatory synaptic strength
This is the neuronal basis of many forms of learning
There are fewer D2 receptors in addiction. (The dopamine system is central to conditioning and motivation)
Both of these changes are responsible for decreased sensitivity to natural rewards that develop from addiction
Consider emotional dependence
- Which kind of drugs cause it?
- What are its effects?
- Outline the pathophysiology
Psychomotor stimulants
Dysphoria (general dissatisfaction with life), anhedonia, anxiety on withdrawal
Compensatory changes in VTA/NAcc lead to decreased DA transmission:
Increased activity at D1 receptors (Gs coupled) in NAcc
–>
Adenylyl cyclase –> cAMP –> Protein kinase A –> increased dynorphin synthesis –> released in VTA –> acts at k-opioid receptor –> inhibits VTA neurons firing and NAcc DA release –> Less DA release in NAcc
What is associative learning and how does it come about?
How is it implicated in relapse from remission?
Coincident firing between sensory pathways and the mesocorticolimbic pathway –> induces LTP and strengthens synaptic connections
Potential sites for LTP:
- Glutamargic synapses on reciprocal connections between NAcc, VTA, cortex, hippocampas and amygdala. Modification of glutametergic transmisson allows for LTP
- CREB-mediated-gene transcription and new protein synthesis
- Synaptic remodelling (Increases spines and dendrites)
Drug use becomes associated with sensory information, people, places, emotions present during drug taking (specifically DA release). Therefore, there is an increased risk of relapse in clubs where drugs are taken.
Long term molecular and cellular changes remain after abstinence . Memories in these pathways may trigger relapse years later
What effect does alcohol have on GABAa and NMDA receptors?
What effects do they have on voltage gated channels, and DA
GABAa agonist (inhibitory) NMDA antagonist (blocks excitation)
Large doses inhibit functioning of most voltage gated channels
Alcohol increases DA release in NAcc
- NMDA antagonism of cortical inputs to VTA disinhibits VTA DA neurons –> increased DA release in NAcc
- Rewarding effects blocked by DA receptor antagonism in NAcc
How can the opiate system be used to treat alcholism and cause smoking cessation?
Naltrexalone is an opiate antagonist and reduces alcohol self administration
-Used as treatment to decrease alcohol consumption, relapse and craving in alcoholics
Both opiate and DA antagonists can block nicotine induced behaviours and self-administration. Naltrexalone used for smoking cessation, but causes weight gain
