Exam 4 Flashcards
Addiction is a progressive behavorial syndrome characterized by _____ and ____ drug-seeking and consumption.
compulsive and out of control
Addiction is/isn’t curable and to determine effective treatment, we need to understand ________ and _________.
is not
physiology and pathology of motivated behaviors
Reward vs. Reinforcing (drugs do both)
Reward– a stimulus that is interpreted by the brain as intrinsically positive, or something that should be approached. (brain likes it)
Reinforcing– an increase in the probability of the occurence of a behavior that is paired (brain wants it)
________ is an experimental setup used to assess drug reward. How does it work?
conditioned place preference
Animals learn to associate one environment with passive drug adminsstration, and they will spend more time in the context in which they received the drug. (form of pavlovian conditioning
_________ is an experimental setup used to assess drug reinforncement. How does it work?
drug self-administration
Getting the drug is contingent on a specific behavior (lever-pressing)
The drug is interpreted as a reinforcer if it increases the occurrence of lever pressing.
The drug-induced _________ may be an important ______ for initial drug use in humans.
euphoria
reinforcing drive
Three central dopaminergic pathways
1) Nigrostriatal system:
SNc –> Striatum (putamen, caudate nucleus)
2) Mesolimbic system:
VTA –> NAc
3) Mesocortical:
VTA -> PFC
The nigrostriatal dopaminergic pathway is responsible for ______, but the _______ and ___ constitute the endogenous reward pathway
initiation of voluntary movement
mesolimbic and mesocortical
the mesocortical and mesolimbic systems are thought to be responsible for (2)
perception of reward
positive reinforcement
Dopamine produces overall inhibition of _____ in the _____ via activation of postsynaptic _____ receptors
GABAergic projection neurons
NAc
D2 (which is Gi coupled)
____________ allows for the identification of brain regions involved in reinforcement
intracranial self-stimulation
lever press leads to electrical stimulation of brain region
Stimulation of this region contains, which contains__________ elicits strongest reinforcement of self-stimulation behavior
medial forebrain bundle
mesocorticolimbic dopaminergic fibers
How do cocaine and amphetamine increase monoaminergic transmission
Cocaine inhibits monoamine transporter
Amphetamine induces reverse transport of monoamines
______________________ dramatically reduces the reinforcing effects of psychostimulants
Blockade of dopaminergic transmission in NAc (by administration of dopamine antagonists or dopaminergic neurotoxin)
The three types (name them) of opioid receptors are ____-coupled
mu, kappa, and delta
Gi
Action of opiates (2 mechanisms)
1) disinbition of VTA dopamine neurons via mu activation in GABAergic neurons, resulting in dopamine in NAc
2) dopamine-independent actions on mu and delta receptors, leading it inhibition of NAc projection neurons leading to reinforcement
___ and ___ receptors mediate the reinforcing effects of opiates, but ____ receptors cause _______, thus mediating aversion to opiates
mu and delta
kappa, reduction in dopamine release mediating aversive effects
Naltrexone, a ____________ reduces ethanol self-administration in animals
opioid receptor antagonist
Three actions of ethanol
1) directly activates VTA dopamine neurons, which
2) may inhibit GABA release onto dopamine neurons
3) induces relase of endogenous opioids in VTA or NAc
Two actions of nicotine
1) activates VTA dopamine neurons via nicotinic ACh
2) induce release of endogenous opioids
Three types of long-term changes in addiction course:
1) Compensatory adaptations in the brain regions that control somatic function (locus coeruleus)- days to two weeks
2) Adaptations in reward circuit (several weeks to lifetime)
3) Production of memories realated to drug use
LC compensatory adaptation is produced by _______ and ____ but not _____
opiates, alcohol
psychostimulants
Three adaptations in the brain reward circuit
1) tolerance— decrease in reinforcing effects of a drug which leads to a higher dosage
2) dependence– demad for drug to avoid emotional and physical withdrawal
3) sensitization– an increase in rewarding effexcts of a drg, which leads to more cravings and maybe psychostimulant psychosis
______ expose leads to ____, ____ while ____ exposure leads to ______
continuous– tolerance and dependence
intermittent– sensitization
Cue-induced relapse (examples)
1) relapse of withdrawal symptom if you visit the ste where you used drugs
The therapeutic actions of antidepressants and antipsychotics are dependent on ___________
time dependent adaptive changes in their respective brian regions
THe LC, the major ___________ nucleus, is responsible for three tings
noradrenergic
arousal, autonomic tone, and attention
LC activity is ______ by opiates via _________________
inhibited
activation of mu opioid receptors
How does continuous opioid use lead to tolerance? Dependence?
Tolerance– depressed firing in LC neurons gradually returns to normal after repeated opiate use
Dependence– administration of opioid antagonists causes a huge increase in LC fiting rates
_____________ is both necessary and sufficient to produce physical withdrawal symptoms
overactivation of LC neurons
Two mechanisms of how opiates inhibit LC neurons
1) activation of a certain type of K+ channel vira direct binding of Gi/o ro channel
2) inhibition of Na+ permeable channel via suppression of AC/cAMP cascade
Chronic opiate use leader to upregulation of __________ and ______ expression, leading to increased excitability o LC neurons via ______ activation
AC and PKA
Na+ channel
upregulation of cAMP pathway in LC neurons causes (2)
1) return of LC firing rates to normal in continued opiate admins (tolerance)
2) increased firing above normal levels upon removal of opiates (dependence and withdrawal)
Reinforcing effects of addictive drugs are also mediated by ____________, which keys into emotion and motivation in the context of dependence.
meoslimbic dopaminergic (upregulated = positive emotional state)
cAMP hypothesis of withdrawal
chronic admin of pscyhostimulants, ethanol, opiates causes increased levels of PKA and AC and decreased levels of Gi/o in NAc, which leads to higher cAMP activation and negative emotional states
Dopamine in the NAc does what path?
Inhibits NAc projection neurons and leads to increased reward/reinfrocement
Evidence supporting cAMP hypothesis of withdrawal
1) Inactivating Gi or activating Gs in the NAc leads to lower drug reward
2) Administering a PKA activator or a D1-agonist in the NAc leads to lower drug reward
3) Admin a PKA inhibitor or a D2-agonist leads to higher drug reinforcement
physical and emotional dependence go away relatively rapidly after stopping drugs, so ______________
they don’t account for high incidence of relapse (this is more in the sensitization)
Drug sensitization can be measured in animal models by
an increase in locomotion induce by drug
Locomotor sensitization can only be observed _______
when the drugis administered in the context that was previously paired with it
Drug-induced hyperlocomotion is caused by
overstimulation of the nigrostriatal dopamine system
The nigrostriatal system is also implicated in
habit formation
Sensitization– Adaptations in the SNc and VTA
1) Downregulation of Gi (leads to less D atoreceptor mediated inhibition, an increased drug induced DA release in NAc)
2) Upregulation of AMPA (leads to increased glutamate excitation in DA neurons and increased cue-indced DA release)
In relapse, the role of DA in the NAc is to strengthen and facilitate active ____ input from the ______ and tthe ______
Glu
amygdala and cerebral cortex
(acts as kind of a gatekeeper, chooses which signal is passed along)
Two actions of DA:
1) promote long-term plasticicty: learning, reinfocement etc. in an input-specific manner
2) short-term: make decisions, motivation
(via LTP and LTD)
Clonidine, an _____________, produces effects similar to ________ receptor activation in the LC, thus improving withdrawal symptoms
a2 adrenergic agonist
mu opioid
Naltrexone, ______, can be used in the treatment of ______ because ____
mu opioid antagonist
alcoholism
ethanol induces release endogenous opioids
Methadone
a long-acting mu opioid receptor agonist
Potential treatments for addiction (4)
1) Slow onset long acting DAT blockers– which don’t have a reinforcing effect themselves
2) GABAb agonists to increase GABAb inhibition of VTA Da neurons
3) Vaccines?
4) Drugs that can help extinction during psychotherapy
Learning v memory
learning = process by which behavioral response to stimulus is changed
memory = ability to maintain or retrieve pattern of response that have been previously learned
HM patient underwent
billateral temporal lobe removal including HC for epilepsy (had anterograde amnesia_
Anterograde v. retrograde amnesia (and brain regions)
anterograde– inability to learn new info after trauma (temporal and HC involvement)
retrograde– memory loss of events before trauma (frontal lobe)
Neural conditions to associative memory
1) activation of A-B transmission coincides with excitation of B (by the US) repeatedly– associativity
2) potentiation occurs only in A-B transmission but not C-b transmission– input-specificity
The HC and neocortex are important for
consolidation and storage of declarative memory
LTP has two important properties that make it a good candidate for explaining storage of memories. This requires
associativity and input-sensitivity; coincident pre-synaptic and post-synaptic activity
The ________ can act as a good coincident detector because it requires both _______ and _____ in order to pass current
NMDA receptor
glutamate (pre-synaptic activity) and delopmarization (post-synaptic activity.
NMDA receptor passes ___, which activates _________ which result in LTP
Ca2+
Ca2+ dependent kinases
Two ways Ca kinases result in LTP
1) insertion of more AMPA receptors into the plasma membrane
2) Changing the effectiveness of AMPA receptors already on the membrane
What is dementia
a chronic impairment of learning, short term and long term memory, commonly caused by neuronal loss
Wernicke Korsakoff syndrome is caused by _________
Thiamine B1 deficiency
Pathological hallmarks of AD
1) Amyloid deposition– ab42 plaques in HC, cortex, and cholinergic nuclei (nucleus basalis of Mynert), neuronal loss around these plaques
2) Nuerofibrillary tangles– intracellular accumulation of helicl tau protein
Evidence against ab plaques causing AD (2)
Even though all familial forms of AD share elevated plasma Ab levels,
1) Some aged people have lots of plagues but no cognitive deficits
2) Animal models of brian amylodiosis (overepxressed APP) don’t have all AD symptoms
Early stage AD has fewer ______
fewer synapses in the cortex, maybe “something” is attacking the synapse?
Evidence that ab plaque is not attacking the synapse but soluble ab is
Decrease in synapses occurs before plaques form but the level of soluble ab is correlated with degree of synaptic loss )attacks prior to the signs of memory loss)
In initial stage AD, deficits in _______ occur but _____ is generally unaffected
short-term
long-term
Evidence that solubl Ab causes synaptic defects (3) :
1) plasma levels of soluble AB corraltes with degree of synaptic loss
2) ICV injection of sol AB inhibits hippocampal LTP, with short-term memory loss
3) overexpression of human APP with AD-causing mutations sho deficits in synaptic transmission in HC before development of plaques
3)
Injection of a ab antibody could
reverse impairment and reduce soluble ab in the brain BUT NOT CHANGE plaque levels
Basal forebrain complex
Medial septal nuclei to HC
Basal nucleus of Meynert
It is thought that activation of postsynaptic ACh receptors ___________
lowers the threshold for LTP induction in the HC
______________ may play a role in learning and memory because administration of scopolamine, a ________ causes learning and memory defects
central muscarinic system
muscarinic antagonist
Evidence of hypocholinergic hypothesis of learning memory (2)
1) Lesions of forebrain cholinergic nuclei produce memory defects which can be reversed by drugs that mimic Ach or muscarinic/nicotinic agonsits
2) Acetylcholinesterase inhibitors can bring back some of the cognitive deficits by enhancing LTP in hippocampus
Therapeutic strategies for AD (5)
1) Anti-inflammatory agents – NSAIDS seem to reduce risk of AD
2) Antioxidants (vitamin E slows progression of AD)
3) NMDA receptor enhancer
4) beta-secratase inhibitor
5) Ab antibody
Symptoms of Parkinsons (need 3/4)
Resting tremor
Walk but don’t swing arms, multiple steps while turning etc
Bradykinesia, akinesia
Rigidity and stiffness of limbs
paroxysm
sudden recurrence of symptoms
Three types of seizures
1) generalized– originating and rapidly engaging bilateral networks
2) focal– in one hemispheric network, involving one or multiple foci with conssitent ictal onset
3) unknown
Not all seizures are electrographic– true of false
True (pseudo seizures are a thing_
how to reduce reinforcing effects of psychostimulants
Block the dopamine release in the NAc by using a dopamine receptor antagonist or a dopaminergic neurotoxin
Injection of —— in BLA block fear responses
Ampa antagonist
