Links between learning,

memory and addiction

Associative learning:
• Recall: Classical conditioning - Brain
makes association between two unrelated
stimuli
• Important area of brain involved in learning
and memory: Hippocampus
• Hypothesis: learning and memory
mechanisms play important roles in
lasting alterations induced by addiction
The Hippocampus has connections with NAc and
prefrontal cortex (A.K.A. reward pathways)

• NAc receives glutamate input from

hippocampus

Glutamate

Hippocampus Nucleus Accumbens

• LTP can also occur at glutamate synapses in Nac

• i.e., strengthening of connections between hippocampus and reward pathway
 Reward pathway
in the brain
• Mesolimbic dopamine pathway called the
medial forebrain bundle
• VTA: Ventral tegmental area. Contains
dopaminergic cells
• Projects to NAc (nucleus accumbens)
• NAc synapses use dopamine
• NAc and hippocampus synapsis
together
• Also contains the hypothalamus
(controls homeostasis)
• Addiction alters the body ability to cope
Evidence: Opioids modifies LTP in
hippocampus (Pu et al. 2002)
• Chronic exposure of rats to morphine or heroin, induce severe drug tolerance
and dependence
• Markedly reduced the capacity of hippocampal CA1 LTP during the period of
drug withdrawal (from ∼190% in control to ∼120%)
• Behavioural test (water maze test), which measures behavioral consequences of
synaptic plasticity, showed parallel learning deficits after chronic exposure to
opiates
• Recall: PKA/PKC has been shown to be a critical element in hippocampal CA1
LTP by modulating activity of AMPA receptors
• Chronic morphine treatment leads to the upregulation of PKA activity in the rat hippocampus
• At overactivated levels, PKA serves to saturate LTP via phosphorylation of AMPA receptors
or upregulation of CaMKII (Ca/calmodulin kinase) activity, thus blocking further induction
of LTP
More Evidence: Cocaine modifies LTP in
hippocampus
• Behavioural data from rats: stimulation of
hippocampus can induce cocaine relapse
• Cellular studies: cocaine administration results in
enhanced LTP in hippocampus
• None (or very little) dopamine transporter in this
region
• How is cocaine affecting LTP in hippocampus?
Currently unknown
Learnin and memory
and drug addiction
• Many molecular and cellular
changes occur during
addiction
• Leaning and Memory don’t
last long enough to account
for long-term behavioural
changes during drug
addiction
Steps needed in understanding L and M and drug
addiction fields

1. Understand how stimulus produces immediate

effects on synapses in brain
2. Identify changes that occur after repeated
application of stimulus
3. How do changes in brain cells lead to
behavioural changes?
• Biggest challenge to researchers
• Full understanding of circuits in brain – not yet
possible
What does the Fos
say?
• DFosB is a transcription factor in the NAc
• Opiate-induced reorganization of network connectivity is supported by
transcriptional and structural features of the brain
• Induction of c-Fos (genes) occurs following both acute and chronic exposure to drugs
of abuse and during withdrawal, and its expression is correlated with drug-induced
behavioral changes
• “Genes implicated in LTP were among the most significantly associated with increased
FOS correlation networks following chronic opiate exposure” (Brynildsen, 2020)
• Many drugs of abuse, including opioids, induce synaptic plasticity, suggesting
that this may be a common mechanism underlying the development of
substance use disorders
Experimental evidence for role of DFosB
(Zachariou et al. 2006)
• Over-expressed DFosB in NAc in mice produced:
1. Increased sensitivity of the mice to the rewarding effects of morphine led to
exacerbated physical dependence
2. Reduced their sensitivity to the analgesic effects (pain relief) of morphine and led
to faster development of analgesic tolerance
• The opioid peptide dynorphin seemed to be one target through which
DFosB produced this behavioral phenotype (down-regulates dynorphin)
• DFosB is very stable in Nac = may drive behavioural changes for weeks
but it does gradually degrade and is completely gone within 2 months of
drug withdrawal

• SUSTAINED MOLECULAR SWITCH

• Initiates and maintains state of addiction?
Mechanisms of permanent
plastic changes in brain
• Changes in DFosB not long-lived
enough to account for life-long
addictions

• What underlies the stable changes

in brain?
• Hypothesis: Structural
changes in neurons of reward
pathway are responsible
Mechanisms of permanent plastic
changes in brain
• ΔFosB or other transcription factors (e.g., CREB), may mediate more
long-lived changes in neuronal morphology and synaptic structure:
dendritic spine formation = could mediate long-lived sensitized
responses to drugs of abuse or environmental cues

Copyright 2001,
Structural changes in reward pathways of the
brain
Evidence from chronic cocaine use:
• Increases # of dendrites of NAc neurons – persist for months
• BUT - no current direct evidence that increased # of dendrites
underlie long-lived behavioural changes
• ΔFosB or CREB may also promote longer-lived changes in gene
expression by regulating other modifications of chromatin (e.g.,
DNA or histone methylation)
• Analogous to learning and memory field – difficult to associate
cellular changes with behavioural changes
Structural changes in reward
pathways of the brain
Evidence from fentanyl, bidirectional effect (Lin
et al. 2009):
• Fentanyl at different concentrations induced
bidirectional changes on the density of
dendritic spines and synaptic AMPA receptors
• At low concentrations, chronic treatment with
fentanyl caused collapse of preexisting
dendritic spines whereas, high concentrations
induced the emergence of new dendritic spines
• Fentanyl at a low concentration caused the
removal of AMPA receptors from synapses
whereas fentanyl at high concentrations
increased the number of synapses that
contained AMPA receptors
 • Clinical puzzle:
Structur • Treatment of chronic pain with
al fentanyl causes fewer incidents
of cognitive deficits than
changes treatment with morphine in
elderly patients
in • Anesthesiologists were surprised
that high-dose fentanyl caused
reward significantly fewer incidents of

pathways postoperative cognitive

dysfunction than low dose
of the • Drug abusers well….choose your
adeventure….no idea about dosage
brain pf fentanyl in the street supply
Summary
1. LTP (L and M) in drug addiction (e.g., chronic use opioids
of and cocaine): cAMP, PKA CREB in brain cells
2. LTP and chronic drug addiction: increase in # of dendrites
for cocaine and high concentrations of fentanyl
3. DeltaFosB: long-lasting changes underlying drug
addiction

BUT:
• LTP / DFosB : too short-lived to account for life-long
changes
• Downstream affects of activating transcription factors (e.g.,
chromatin)
Animal studies
looking at links
between learning
and drug addiction
1. Is power superior to drugs?
• M.Nader: Uni in N. Carolina
• Macaque monkeys
• Findings:
• Socially dominant animals less prone to getting hooked
on drugs (cocaine), compared to sub-ordinate animals
• Lever pressing for cocaine: dominant animals showed no
preference for cocaine over saline
• Dominant animals showed 20% increase in binding
capacity of dopamine receptors – more action in reward
areas of brain!
2. Effects of prior cocaine self-administration on cognitive
performance in female cynomolgus monkeys

• Kromrey et al; Psychopharmacology Jan 31, 2015

• Detrimental effects of drug use on cognitive
function:
• eg., Weighing multiple options and making
complex decisions
• Little known about how long cognitive impairments
last after ceasing drug use
• Drug abusers show increases in cognitive functions at
6 months abstinence compared to 6 weeks
Study Methods
• 16 adult female monkeys:
• 7 – Drug use for 3 mths (6?)
• 9 – “Drug-naive:” – no drugs given

• Drug administration discontinued 8 weeks before

experiments
• All animals trained on touch-sensitive screen – no
difference in learning this task
Study Methods
• Simple discrimination task (SD)
• 3 shapes – touching only one produces food
pellet reward

FOOD
Study Methods
• SD trials: randomized order of shapes. Monkey
has to touch correct shape to get food pellet
• Measured acquisition of behaviour (and number
of errors)

FOOD
 Study Methods
• Reversal of discrimination task: (SDR):
• New shape gives food pellet (no cue
provided). Monkey has to learn that new
shape provides food pellet

FOOD
Main Findings:
SD task:
1. No sig.
difference on SD
task
(though drug
monkeys needed
more trials and
made more errors)
Main Findings:
SDR task: (reversal)

1. Significant difference
in # trials required and
# of errors made by
cocaine monkeys

2. TWO cocaine
monkeys failed to ever
learn the reversal task
(not included in these
Main Findings:
• Animals were tested weekly for next 3 months
• Drug monkeys behaved more poorly on tasks over
first month, but this difference disappeared by end
of 3rd month

Conclusions of authors:
•“Acquisition of certain novel tasks may be more
difficult for abstinent drug users, but performance can
improve with practice and time”
•“Drug-induced cognitive impairments are reversible if
abstinence can be maintained”
 3. Effect of Fentanyl and Low Doses of Alcohol on
Neuropsychological Performance in Healthy Subjects

• Schneider et al. 1999

• 24 healthy male volunteers were split into two groups:
• In group 1, 6 subjects received fentanyl (0.2 µg/kg body weight) in the
order of fentanyl/placebo and 6 subjects in the order of placebo/fentanyl
• Group 2 received alcohol in a similar procedure by continuous
intravenous infusion, leading to a blood alcohol concentration (BAC) of
0.03%
• Cognitive impairment was measured via different
neuropsychological tests
• The results:
• Fentanyl in concentrations commonly used in out-patient surgical
4.
Hippocampa • Pu et al. 2002
l Long-Term • Chronic exposure to
Potentiation opiates functionally alters
the capacity of rat
Is Reduced hippocampal LTP and
by Chronic results in an opiate
Opiate dependence of LTP
Treatment
Study Methods
• Animals were chronically treated by subcutaneous injection of morphine
(10 mg/kg) or heroin (1 mg/kg) twice per day at 12 hr intervals for 10 d
• These dosages are known to produce significant tolerance and
dependence to the drugs
• Control rats were treated similarly, except that normal saline was injected
instead of morphine (NS)
• Implanted electrodes into the CA1 region of the dorsal hippocampus
• Measured CA1 activity via fEPSPs (field excitatory postsynaptic
potential)
• LTP was induced by high-frequency stimulation using 20 pulses at 200
Hz, repeated three times at a 30 sec interval
 Main Findings
• The capacity of LTP
measured 12 hr after
the termination of 10 d
morphine treatment,
was greatly reduced
(from 190% to 120% of
baseline), compared
with that recorded
before the treatment for
the same group of rats
• In contrast, the control
rats injected with saline
Similar
Results for
Heroin…

• Significant
reduction of LTP
was also
observed in the
animals after 10
d exposure to
heroin
 Opioid Tolerance and Dependence on
LTP
• Since development of opiate tolerance
and dependence is well known to depend
on repeated exposure to opiates, they
further tested whether the reduction of
LTP also requires the chronic use of
opiates
• A single injection of morphine or heroin
had no significant effect on hippocampal
LTP
• In contrast, LTP was significantly
reduced in rats after 5 d of daily
treatment with opiates
• The reduction seemed to reach a plateau
level after 10 d
Restoration of hippocampal
LTP by re-exposure to opiates
• When opiate dependence is developed, the neural systems adapt to
the repeated drug exposure and only function normally in the
presence of the drug
• Further examined whether the capacity of LTP can be influenced by
opiate re-exposure….
• It was found that a single injection (10 mg/kg, 30 min before LTP
induction) of morphine or heroin at 12 hr after the termination of
chronic opiate treatment could indeed restore the capacity of LTP to
the normal levels
What does this mean?
• Reduced LTP is restored by re-exposure of the animals
to opiates = that the hippocampal plasticity becomes
opiate-dependent after chronic opiate treatment/use
• In other words, the hippocampal function has been
adapted to the presence of opiates!
 • Zhang et al. 2016
5. Effect of • Review article
Opioid on • Opiate drugs in general cause
Adult a loss of newly born neurons
in the subgranular zone of
Hippocamp dentate gyrus
• Either by modulating
al proliferation or by
Neurogene interfering with
differentiation and
sis maturation (integration)
Effect of opiods on Neural
Stem/Progenitor cells
Summary
• Not a surprise that drugs and drug addiction impact
learning and memory!
• Many brain changes occur, re-wiring due to drug use
• Drug abusers experience problems in many of the
same areas of the brain as dementia patients!
• The chronic use of certain drugs may also
increase the risk of developing dementia in later
life (Hulse, 2008)