PPDA Flashcards
Define addiction
a chronic relapsing disorder characterised by:
1) compulsion to seek and take the drug
2) Loss of control in limiting intake
3) Emergence of a negative emotional state e.g anxiety
it is defines in the DSM-5 as a maladaptive pattern of substance use leading to clinically significant impairment or distress , as manifested by 2 or more of the following occurring with a 12 month period
- withdrawal reaction , tolerence effects , cravings etc…
factors contributing to vulnerability - genetic, envir9mental and drug induced effects
drug addiction has aspects of both impulse control disorders and compulsive disorders .
Impulse control disorders are characterized by an increasing sense of tension or arousal before committing an impulsive act, pleasure, gratification or relief at the time of committing the act, and possibly regret, self-reproach or guilt following the act
In contrast, compulsive disorders are characterized by anxiety and stress before committing a compulsive repetitive behaviour, and relief from the stress by performing the compulsive behaviour.
As an individual moves from an impulsive disorder to a compulsive disorder there is a shift from positive reinforcement driving the motivated behaviour to negative reinforcement driving the motivated behaviour
Stages of addiction
acute reinforcement/social drug-taking compulsive use dependence withdrawal protracted withdrawal recovery
Relapse can occur from withdrawal and protracted withdrawal stage
Tolerance
reaction to a drug decrease such that longer doses are needed to achieve the same effect
Metabolic tolerance = change in the
metabolism of the drug (e.g. enzyme that
degrades the drug such as alcohol
dehydrogense)
• Cellular tolerance = change in a receptor
or reuptake site e.g. dopamine transporter
Dependence
is an adaptive state that develops from repeated drug administration and which results in the emergence of physical and emotional withdrawal symptoms upon cessation of drug uses
-physical characterised by abstinence syndrome : sweating , irritability , aggression etc..
Psychological, craving to avoid withdrawal effects
Amphetamine
-psychostimulant
-DA releaser
- increase alertness , euphoria, anorexia , decreased physical and mental fatigue
- Therapeutic uses - ADHD, Appetite suppressant , narcolepsy
withdrawal syndrome - deep sleep , lethargy , depression , anxitey , hunger
Cocaine
- central stimulant
- blocks DA transporter
- euphoria, locomotor stimulation, heightened pleasure
- activates HPA axis
MDMA
- psychotomimetic
- Inhibit monoamine transporter, mainly 5-HT
- withdrawal syndrome - depression, anxitey, irritibility ,increase aggression
Opioids
- tolerance seen within 12-24 hours
- heroine inhibit release of GABA (inhibitory neutransmitter ) increasing DA
- inhibit HPA axis
- withdrawal of heroin symptons - swaeting , irritibility , aggression
Alcohol
- general depressant
- MOA- potentiates GABA -mediated inhibition , inhibits presynaptic ca2+ relase so inhibit transmitter release , disinhibit mesolimbic DAergic neurons to increase reward
- withdrawal symptoms - tremor , nausea, sweating ,fever, hallucination
Nicotine
- highly addictive
- nACh receptor agonist
- cortex and hippocampus( cognitive function ), VTA area for reward
- alpha 4 beta 2 subtype
- increase alertness , decrease irritability
- presynaptic and postsynaptic
- withdrawal symptoms -irritability , hunger , weight gain , impaired cognitive and motor performance
chronic effect of drugs
Homeostatic compensatory neuroadaptation
Depressants - there is increase in calcium channels
stimulatnts - depleates releasable tranmitter
hallucinogens - down regulates - 5-HT2 receptots
opioids- desentises- increase inadenyl cyclase activity
bezodiazapines - increase endogenous ligand
- neuroimaging shows descreased striatal D2 binding and decreased frontal cortex activity
Relapse
PFC modulates stress
Hippocampus invloved with memory of the drug
amygdala - emotional connection to drug
an increased glutamate in the PFC , amygdala , hippocmapus asscoiated with relapse
increase in CRF also shown in relapse
Transition from non -addicted brain to an addicted one
the reward system is connected to various regions liek Dstr, PFC ,OFC ,amyg, HIP
there is inhbitory actins from PFC to OFC which is in crontrol of saliency - normal brain
but in an addicted brain those conncection between the rewards sytem and the amyg, hip, pfc ofc becomes much more stronger. also transition from ventral straitum to dorsal striatum. also the inhibitory control from pfc to ofc weekens
define construct, face and predictive validity
-Construct validity– the model has a sound theoretical rationale
(neurobiological or psychological mechanisms, aetiology)
• Face validity– phenomenological similarity between the model and the
disorder being modelled (symptoms)
• Predictive validity– manipulations known to influence the pathological state
should have similar effects in the model (drugs)
Understand and describe the animal models used in addiction research
Drug abuse / taking :
- taken by animals (self administration ) : Rat can tap a lever or poke a nose -hole with infrared beam to get the drug
- given by the scientist - intravenous, subcutaneous , intraperitoneal , intra cerebral , intramuscular
Drug Seeking Behaviour :
- initial test for side-prefernce , then give the drug in non-prefered side , give saline in prefered side and test for conditioned place preference after 5-10 days
heroine induced cpp in C57BL/6J and DBA/2J showed a higher increase in time spent in c57 than dba
Drug addiction /dependence :
Chronic “intermittent” escalating dose heroin (s.c.) treatment of C57BL/6J and DBA/2J mice
showed that in day 5 4mg/kg had totala ctivity of 3000 counts but same was acheived with 8 mg/kg on day 7
locomotor sensitaton - same amount of drug produces more total activity on day 3 comapred to 1
Withdrawal effect :
Naloxone precipitated opioid withdrawalNaloxone precipitated opioid withdrawal
-naloxone injection in chronic morphine treated -naloxone injection in chronic morphine treated mice will precipitate acute physical withdrawal
check for weh=ght loss, urine and fecal matter , diarrehea score , jumping , face wash freq, paw tremor frq, and etc..
Long term withdrawal :
first chronic saline or escalating dose of drug given and abstinence and assess emotional like behaviour and put in a 3- chambered box to asees social interaction ( Long-tem morphine abstinence abolishes social
preference)
4 -way tall bridge created with 2 closed wall and 2 open wall showed Increase of anxiety-like behaviour following long-term opioid abstinence
Forced swim test-Increase in depressive-like behaviour following long-term opioid abstinence
Compulsive use :
Rat seld-administration along wiht electric shock
Relapse :
Cue could be a light that comes on when
they get i.v cocaine.
• Drug could be a small dose of cocaine or
similar drug.
• Stress could be tail pinch, foot shock, food
or water restriction - give morphine , then saline then force swim then test for place prefernce - showed a higher time spent in drug paired c maprtment after forced swin reistatment
Gene association :
knock out -mice
Describe the mechanism of action of amphetamines as psychostimulants
-Psychostimulants include legal substances (e.g., caffeine, nicotine), prescribed medication
(e.g., Ritalin) and drugs of abuse (e.g., MDMA)
-increase alertness, energy, social disinhibition and pleasure
Amphetamines :
- class of synthetic psychoactive drug
-Ephedrine is a precursor for all synthetic amphetamine
-share structural similarities between DA and NA
-competitively re-uptake into the the presynaptic nerve terminal via the DAT and NET , means less DA and NA taken up
- it is also taken into vesicles via VMAT/2, it accumulates in vesicles and disrupt pH gradient require for transport function meaning VMAT1/2 becomes non -functional and DA and NA accumulate in the cytosol
- it also activate intracellular TAAR1 receptors which reverses the DAT and NET as well as the removal of the transporter form the plasma membrane ultimately increasing DA and NA in the cleft
Describe the mechanism of action of MDMA as a psychostimulant
- MDMA is best known as a recreational drug of abuse with psychostimulant and psychedelic properties
- MDMA shares structural similarities with dopamine and noradrenaline
- competitively re-uptake into the the presynaptic nerve terminal via the DAT and NET and SERT , means less DA and NA and 5-HT taken up
- MDMA inhibits VMAT1/2 – DA, NA and 5-HT accumulate in the cytosol
- MDMA activates intracellular TAAR1 receptors, which can lead to the reversal of DAT, NET and SERT and the removal of DAT, NET and SERT from the plasma membrane
- Increase in DA, NA and 5-HT in the synaptic cleft, leading to increased DA, NA and 5-HT post-synaptic receptor activation
Describe the mechanism of action of cocaine and cathinones as psychostimulants
COCAINE
-Cocaine shares minor structural similarities with dopamine and noradrenaline
- its a non-competitive blocker of the DAT/NET
-This means less DA and NA are taken up into the pre-
synaptic terminal
- This leads to an increase in DA and NA in thesynaptic cleft, leading to increased DA and NA post-synaptic receptor activation
KHAT (cathinones)
- Cathinone shares structural similarities with dopamine and noradrenaline
- MOA same as cocaine
Outline the effect of psychostimulants on dopaminergic and noradrenergic neurotransmission
Dopaminergic
- all 4 psychostimulants increase dopamine
-GPCR
- D1/D5 -presynaptic - coupleto Gs proteine to stimulates adenylate cyclase
- D2-4 -are both pre and post synpatically present - Gi/0- inhibit adenylate cyclase
metablosied by MAO
4 major pathway :
- tuberohypophyseal - hyptho-pit, -prolactin release
- nigrostrital - subtanita nigra - Dstr, - movement
- mesocortical - VTA-pfa , cognitive control, motivation,emotion
-mesolimibic - VTA-NuAcc, Reward
Noradrenergic
-GPCR
- α1 couples to Gq proteins to activate phospholipase C
- α2 couples to Gi/o and inhibits adenylate cyclase
- β1 and β2 couple to Gs and activate adenylate cyclase
-The locus coeruleus is a small nucleus located bilaterally in the pons –noradrenergic
projections to vast parts of the central nervous system (CNS).
- Attention, Arousal, Sleep and wakefulness, Learning and memory ,Pain, Mood
-PNS: rest and digest (ACh) fight or flight (NA)
-increased energy and focus
Describe the mechanism of action of barbiturates and benzodiazepines as psychodepressants
-Activate ligand-gated ion channel (GABAA) and G-protein coupled (GABAB) receptors
- GABAA receptor a key drug target for anxiety
disorders and insomnia (amongst other conditions
- GABA binds to it’s receptor which opens the
ligand gated Cl- channel allowing for the
influx of it ions: Cl- ions hyperpolarises the membrane reducing firing of action potentials.
- pentameric structure , 2 alpha 2 beta y common configuration
benzodiazapine acts on alpha gamma –binds to extracellular
barbiturate - beta subunit- m2 and m3 - binds intracellualr
BARBITURATES
- increase direct GABAA agonist
• Glycine receptor – stabilises open channel
• nAChR & 5-HT3 receptor blockade
• AMPA/kainate receptor blockade
all of this increase inhibition and decrease excitation
-used for epilespsy and genral anesthsia
BENZODIAZEPINES
-Benzodiazepines bind to a distinct regulatory site on GABAA receptors
• Benzodiazepines stabilise the GABAA receptor binding site for GABA in the open configuration
-Benzodiazepines therefore increases GABA affinity for its binding site and produces a general enhancement of its neuroinhibitory actions
• Benzodiazepines are therefore classed as positive allosteric modulators
-Benzodiazepines are “cleaner” compounds compared to the barbiturates – do not activate other receptors (e.g. glycine, glutamate receptors)
- antidote - flumazenil - comp antag
usage- anasthetic , hypnotic, anxiolytic depending on duartion of action
Describe how barbiturates and benzodiazepines can lead to tolerance and withdrawal symptoms
in symtomatic patients there are less Gaba receptors and more glumate rceptr
Barbituarte and benzodiaspine use will increase gaba receptr and body will repson to this by increrasing numbe rof glutamate recpot to restore to what it was menaing more is needed to reach the same level of effect
Describe the mechanism of action of GBL/GHB as psychodepressants
bindind activates Gi/o which dissociate from GABAb receptor
activates econdary messenger pathway inhibiting adenyl cyclase whic reduces levels of cAMP leading to activation of K+ chnnels - efflux of K+ ions ..in additon voltage gated ca2+ channels are blocked togther it causes hyperpolarisation
used as anethetic and narcolepsy but abused as party drug and date rape drug
GHB:
-at GHB receptor it acts with high affinity, full agonist
-at GABA b recpetr - acts with low affinity but full agonist
-GHB initially causes an increase in dopaminesecretion due to the activation of GHB receptors
-At increasing concentrations, GHB can subsequently inhibit dopamine secretion due to the activation of GABAB receptors
- Increasing concentrations of GHB can inhibit the
mesocortical pathway,
Describe the mechanism of action of ketamine and phencyclidine (PCP) as psychodepressants
NMDA recpetor :
-3 subunit - GluN1, GluN2,GluN3
- hetero- tertameric
- all binding site must be occupied for channel opening
- mg2+ block at resting membrane potential
-Phencyclidine (PCP) is a non-competitive antagonist of the NMDA receptor with anaesthetic and analgesic properties – associated with prolonged emergence delirium
- Ketamine is a structural analogue of phencyclidine
(PCP) – it is associated with a lower potency, shorter duration of action and lower incidence of adverse emergence effects
-use - anatheitc and fordepression , abused as party drug
-blocks the influx of positively charged sodium and calcium ions
- low conc= excitatory effects
- high conc- inhibitory
The basis of metabolic tolerance to alcohol
- alcohol to acetaldehyde by alcohol dehydrogenase
- acetaldehyde to acetic acid by acetaldehyde dehydrogenase
- acetic acid to carbon dioxide by oxidation reaction
- metabolic tolerance causes induction of CYP2E1
- this causes increased levels of acetyl aldehyde when acetyl aldheyde dehydrogenase is lessa ctive which can cause flushing, nusea , headchae , and increased hr
Mechanisms of action of alcohol in the CNS
Non -specific effects :
- alters lipid composition
-interacts with polar heads of phospholipids
- disturbs the relationship of protein in membrane
Specific :
- acts at neurotransmitter binding site
- modifies gating mechanism inside channels
- direct interaction with channel protein
stimulates Gs which is linked to adenyl cyclase
Alcohol has an inhibitory effect on glutamate
neurotransmission
•Alcohol has greatest effect on NMDA receptors (ligand-gated channel made up of 4 subunits that allow Ca2+ and Na+ to enter and cause localized depolarization)
Neurochemical changes caused by alcohol and their contribution to alcohol withdrawal syndrome
-Elevated glutamate during withdrawal causes excessive Ca2+ influx which contributes to cell death
-Frequent withdrawal episodes may be responsible for some of the irreversible brain damage seen in alcoholism
-to see which regions of the brain were more or less active while drinking, researchers gave a group of subjects a PET scan after injecting them with harmless radioactive glucose, the brain’s preferred source of energy. Highly active regions consume more glucose, and those regions are brightly lit during the PET scan, whereas less active regions are dimmer.
-The regions of the brain with the greatest decrease in activity were the prefrontal cortex and the temporal cortex. Decreased activity in the prefrontal cortex, the region responsible for decision making and rational thought, further explains why alcohol causes us to act without thinking
- alcohol shared properties with classical depressants, like Valium. Experiments in mice showed that when given Valium regularly, not only did they develop a tolerance to it, but they also developed an increased tolerance to alcohol. Called cross-tolerance, it indicates that both drugs act at the same receptor, the GABA receptor
-Repeated exposure to ethanol reduces the
potentiation of GABAA-mediated Cl– flux
•Reduced effect of positive allosteric modulators
•Alterations in relative levels of receptor subunit
mRNA (eg decrease in α1, increase in α4)
•Chronically treated animals have decreased
sensitivity to sedative, motor incoordination,
acute cognitive impairment (all have GABAA
receptor mediated components)
•Chronically treated animals in withdrawal are
sensitive to seizure activity
-Chronic alcohol results in depression of mesolimbic function by various mechanisms, including receptor downregulation and DA synthesis.
•In animals, withdrawal of alcohol after chronic use reduces the firing rate of mesolimbic neurons and decreases DA release in the nucleus accumbens
•NB not the only reward pathway – block of the mesolimbic pathway does not extinguish reward seeking behaviour (eg alcohol self-administration)
The contributions made by positive and negative reinforcement to alcohol abuse
-Alcohol abuse is initially driven by positive reinforcement, then by negative reinforcement
-The mesolimbic system plays a significant role in reinforcement and motivational mechanisms.
• The terminal region, the nucleus accumbens is involved in integration of primary reinforcing cues that lead to repeated drug use and motivation for the drug
Understand the pharmacology of nicotine
-nicotine mimics some of the actions of acetylcholine
-readily absorbed through skin
-passes freely thru BBB
-reaches brain in 11 secs
-main metabolite of nicotine is cotinine
- half life of nicotin e-2 hrs and continine is 19hr
-stimulant effect
-Ligand-gated ion channels (mostly Na+/K+ )
• Widespread in the CNS
• Acetylcholine (Ach) is the endogenous
ligand
-Pentamer
-5 polypeptide subunits
- nicotine is a potent agonist at the nicotinic alpha 4 beta2 receptor
