Neurobiology and neurochemistry of reward and addictive behaviours Flashcards
Definition of addiction/substance dependence
- A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual(both physical and psychological)
- Homeostatic response to repeated drug administration
- Unmasked by withdrawal
What are withdrawal symptoms
- Negative physiological and emotional features that occur when the drug is not taken
- Different for each drug abuse, but generally opposite to positive experience induced by the drug
What is tolerance
- Diminished response to the effects of a given amount of drug following repeated exposures to the drug
- This implies that increasingly larger dosed of the drug are required to induce the same behavioural effect.
What parts of the brain do addicive drugs affect
- Mesolimbic + mesocortical system(mesocorticolimbic pathway - reward pathway)
- Prefrontal cortex(impulsiveness, decision making, self monitoring)
- Amygdala
- Hippocampus
Where does addiction begin in the brain
- Addiction begins in the mesolimbic dopaminergic system and then produces long-term changes in other brain regions that receive input from these neurons
What part of the brain does anticipation of reward recruit
- Anticipation of rewards rather than the reward itself that causes the recruitment of the Nucleus Accumbens
- Anticipation of certain reward recruits NAcc more than when outcome not certain – may be punished or have no outcome.
Effect of anticipation of punishment on NAcc
- No activation so determined by other pathway
What is the primary activating neurotransmitter for the reward pathway
- Dopamine
What is classical conditioning
- Learning via association
What is instrumental conditioning
- a learning process in which behaviour is modified by the reinforcing or inhibiting effect of its consequence.
What happens to dopamine activity when a reward is expected and there is none
- If reward does not come, then there is still an anticipation spike but there is a fall in dopaminergic effect at the time that reward would have come
Where is there activity when a reward is unexpected
- Nucleus accumbens - think of this as a response that ‘tells’ our brain that there is something we should be learning
Where is there activity when a reward is expected
- Once it is learnt ie predictable, this response disappears from NAcc
- Response is seen in the temporal lobes - indicating that learning has taken place
Purpose of the reinforcement system
- A learning process in which behaviour is modified by the reinforcing or inhibiting effect of its consequence
- When prefrontal cortex is not activated enough, it will lead to impairment of thinking and other functions
How does drug-induced synaptic plasticity contribute to addiction
By consolidating
- Drug wanting
- Drug seeking
- Drug taking
Pathway for reward and reinforcement
- Natural reinforcers such as food and sex cause extracellular DA release in NAcc
- Addictive drugs activate this system
What area of the brain do psychostimulants act on
Direct action on daergic neurons in NAcc
Action of opiates in the brain
Indirectly - inhibit GABAergic interneurons in VTA = disinhibition of VTA DA neurons
Action of alcohol in the brain
- Disinhibition of VTA DA neurons
Action of nicotine in the brain
- Increases NAcc DA directly and indirectly, stimulates nicotinic cholinergic receptors on mesocorticolimbic DA neurons
What does the mesocorticolimbic system consist of
- Consists of DAergic cells in the ventral tegmental area(VTA) that project to various forebrain regions including the nucleus accumbens
Effect of repeated exposure to most drugs of abuse on VTA neurons
- VTA neurons decrease in size
- Repeated psychostimulant or nicotine exposure induces dendritic outgrowth in NAcc neurons
- However, repeated opiate exposure has the opposite effect.
- Several other effects have been noted after repeated psychostimulant exposure, including decreased basal DAlevels in the Nacc and enhanced DA release induced by a stimulus (e.g., drug exposure or stressor).
Effect of D1-like receptors on adenylyl cyclase activity
- D1-like receptors (D1R) are associated with stimulatory G-proteins (Gs and Golf) that when activated, increase the activity of the membrane bound enzyme adenylyl cyclase (AC)
How does adenylyl ccyclase affect gene expression and cellular activity
- Active AC catalyzes the conversion of ATP to cAMP, which leads to the activation of (PKA)
- increases in gene expression (through the phosphorylation
of transcription factors (CREB)) and cellular activity (through the phosphorylation of membrane bound depolarizing ion channels)
What is sensitization
- Repeated administration elicits escalating effects
- Effect of psychostimulants(used in animal models)
Effect of cocaine and amphetamine on DA activity
- Potentiate monoaminergic transmission by inhibition of DA, serotonin(5-HT) and norepinephrine(NE) reuptake transporters
- Increase in extracellular DA in NAcc
How does cocaine cause an increase in dopamine levels
- Cocaine blocks and inhibits dopamine reuptake transporter on the presynaptic membrane to prolong pool of extracellular DA
- Acutely increases synaptic dopamine
How does amphetamine cause an increase in dopamine levels
- Amphetamines enter dopamine neurons via their reuptake transporters and interact intracellularly with the vesicular monoamine transporter (VMAT) to
release dopamine into the presynaptic terminal. Dopamine (DA) is then
“reverse transported” out of the neuron into the synapse.
Adverse effects of cocaine and amphetamine
- Psychotic behaviour(evidence DA involvement in the positive symptoms of schizophrenia)
- Adverse long-term effects on the brain eg DA transporters/terminals
- Cellular and molecular changes that promote dysregulation eg increased activity of VTA tyrosine hydroxylase, CRED, GluRQ(AMPA)
- Hypofrontality
Link between AMPA receptors and learning
- Insertion of additional AMPA receptors in the postsynaptic DA neurons, normally mediated by glutamatergic NMDA receptors, is the neural basis of many forms of learning.
- A single injection of an addictive drug produces synaptic strengthening in the VTA that lasts for about 5 days.
- If an animal receives cocaine for about 2 weeks, the changes in VTA persist.
Effect of cocaine addiction on dopamine receptors
- Decrease in number of D2 receptors
- The dopamine system central to conditioning and motivation
- Changes above likely responsible for reduced sensitivity to natural rewards that develops with addiction
What causes acquisition of a drug addiction
- Release of DA in the NAcc
What causes establishment of the drug taking habit
- Changes in the dorsal striatum
What causes release of DA in the dorsal striatum
- In addicted individuals, DA is released in the dorsal striatum, not by the drug itself, but by the stimuli associated with procuring and taking the drug, including places where the drug was taken and people with whom it was taken
Emotional withdrawal effects of psychotics
- Dysphoria
- Anhedonia
- Anxiety
Biochemical withdrawal effects of psychotics
- Compensatory changes in VTA/NAcc to lower DA transmission
- Increased activity at D1 receptors(Gs coupled) in NAcc
- Adenylyl cyclase - cAMP - PKA - downstream events
- Increased dynorphin(DYN) synthesis(endogenous opioid)
- Dynorphin released in VTA acts at K opioid receptor
- Inhibits VTA neuron firing and NAcc DA release
- Less DA release in NAcc
Link between LTP and drug addiction
- Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce lTP and strengthen synaptic connections
- A persistent strengthening of synapses based on recent patterns of activity used to explain memory
Where are potential sites for LTP in drug addiction
- Glutamergic synapses on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala
- Thus sensory info, people, places, emotions etc present at the time when drug induced DA release occurs will become associated with taking the drug
How does dopamine enhance LTP
- Dopamine at D1 receptor(Gs coupled)
- Adenylyl cyclase - cAMP - PKA
- Modifies glutamergic transmission allowing LTP
- CREB mediated gene transcription and new protein synthesis
- Synaptic remodelling - increased spines and dendritic branches
- Long term molecular and cellular changes remain months after abstinence
- Memories in these pathways may trigger relapse years later
Examples of opiates
- Morphine and heroin
Action of opiates
- Endogenous opioid receptors(Gi coupled)
- Inhibitory - decrease adenylyl cyclase activity, lead to open K+ channels and close Ca2+ channels
- Different receptor substypes on different cells in different brain regions
What type of receptors are most of morphine’s analgesic and rewarding properties through
- mu receptors
How do opiates cause reward and reinforcement
- Disinhibition of DA neurons in VTA(DA neurons fire tonically but are inhibited by GABA interneurons - mu receptor activation on GABA neurons inhibits them from firing - relieving inhibition on DA neurons
- Action at opiate receptors in the NAcc - independent of DA release
What is naltrexone
- Opioid receptor antagonist
- It blocks the feeling of pleasure when opiates are taken
What is naloxone
- Is a different opiate receptor blocker to naltrexone
- Used clinically in emergencies to inverse opiate intoxication
Effect of alcohol on GABA receptors
- GABAa agonist(inhibitory)
Effect of alcohol on NMDA receptors
- NMDA antagonist(blocks excitation)
- large doses inhibit functioning of most voltage gated channels
Effect of alcohol on DA release in NAcc
- NMDA antagonism of cortical inputs to vTA disinhibits VTA DA neurons - resulting in increased DA release in NAcc
- Ethanol rewarding effects blocked by DA receptor antagonists in NAcc
Effect of naltrexone on alcohol activity
- reduces alcohol self-administration in animals
- Used as a treatment to reduce alcohol consumption, relapse and craving in alcoholics
Effect of nicotine on DA release in the NAcc
- Acts at nicotinic acetylcholine receptors
- Ligand gated ion channels located pre or post-synaptically(throughout brain)
- Presynaptic receptors - influx of Ca2+ - transmitter release
- Increases DA release in the NAcc
What is the release of DA likely due to in nicotine consumption
- Activation of receptors on cell body in the VTA(increasing cell firing)
- Facilitation of DA release by pre-synaptic receptors in NAcc
Effect of opiate and DA antagonists
- Block nicotine induced behaviours and self administration
What neurotransmitter do opiates mimic
- Endorphins
What neurotransmitter do psychostimulants(cocaine, amphetamine) mimic
- Dopamine
Drug receptors for endorphins and opiates
- mu and delta opioid receptors
What neurotransmitter does nicotine mimic
- Ach
Drug receptors for nicotine
alpha2beta4 nAChR(agonist)
What neurotransmitters does alcohol mimic
- GABA Glutamate
Drug receptors for alcohol
- GABAa(agonist), NMDA(antagonist)
What is the locus coeruleus
- noradrenergic nuclei controlling attention, arousal and vigilence(responsible for eliciting ‘fight or flight’ autonomic responses)
What does chronic activation of opiate receptors lead to
- Homeostatic mechanism that compensates for the functional changes leading to tolerance and physical dependence
Effect of acute morphine levels on LC neurons
- Inhibits firing of LC neurons
- Through Gi pathway
Effect of chronic morphine treatment on LC neurons
- LC neurons return to their normal firing rates(Gs pathway component upregulate to match Gi)
- Withdrawal leads to dramatic increase in LC firing(in absence of Gi inhibition Gs hypersensitive)
- Correlates with the physical withdrawal symptoms
What is clonidine
- alpha2 adrenergic receptor agonist that blocks withdrawal effects of opiates, alcohol and smoking)
Acute effects of alcohol on GABA and NMDA receptors
- Agonist at GABAa receptor
- Antagonist at NMDA receptor
- Cells inhibited from firing
Effects of chronic alcohol on GABA and NMDA receptors
- Down regulation of GABAa receptors
- upregulation of NMDA receptors
- In presence of alcohol, firing rates return to normal
Effects of alcohol withdrawal on GABA and NMDA receptors
- In absence of alcohol, balance shifts to excitation
- Physical symptoms - agitation, tremors, hypertension, seizures
Cellular effects of D2 receptor activation
- D2-like receptors (D2R), instead, are coupled to
inhibitory G-proteins (Gi and Go) - When D2Rs are activated, the alpha subunit of these G-proteins inhibits the activity of AC, leading to decreased cAMP production,
PKA activity, gene expression, and cellular activity.
