Neuropharmacology And Drug Abuse Flashcards
Identify neuroanatomical regions involved in addiction and discuss their function (4)
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Red= emotional connection + memory/learning
Yellow= Movement, Motivation, Habit formation (part of basal ganglia)
Green= Reward predication + pleasure
Blue = Motivation + value to reward
Dopamine neurotransmission normal vs w/drugs
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Hijack this pathway = increased + more dopamine release
Stages in Addiction Cycle
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reward pathway not stim. but suppressed, stress pathways activated
Stage 1: Acute Reinforcement
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Acute effects of drugs - (Positive reinforcement)
Different acute targets for drugs of abuse (8)
Opioids - Agonist at mu (and delta and kappa) opioid receptors
Cocaine - Dopamine transporter blocker - indirect DA agonist
Amphetamine - Dopamine releaser - indirect DA agonist
Alcohol - Facilitates GABAA + inhibits NMDA receptor function
Nicotine - Agonist at nACh receptors
Cannabinoids - Agonist at CB1 receptors
Phencyclidine - NMDA receptor antagonist
Hallucinogens - 5-HT2A agonists
Amphetamine (psychostim.) - pharm effects, therapeutic uses, prolonged use (8)
drugs like amph. (methylphenidate & MDMA) release CYTOSOLIC MONOAMINES (DA)
Pharm effects:
- increased alertness and locomotor stimulation(inc. aggression)
- Euphoria / excitement
-Stereotyped behaviour
-Anorexia
- decreased physical and mental fatigue (improves monotonous tasks)
-Peripheral sympathomimetic actions (Peripheral sympathomimetic actions (inc. bp & dec. gastric motility)
-Confidence improves/lack of tiredness
Therapeutic uses:
-ADHD (methylphenidate), appetite suppressants, narcolepsy
Prolonged use neurotoxic
** Degeneration of amine-containing nerve terminals, cell death
Cocaine (central stim.) (6)
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blocks catecholamine reuptake (inc. DA stim. effect)
Pharmacological effects:
-Euphoria
- Locomotor stimulation
** Fewer stereotyped behaviours than amphetamine
-Heightened pleasure
** Lower tendency for delusions, hallucinations and paranoia
Pharmacokinetics:
-HCl salt, inhaled and i.v. administration
** Nasal inhalation less intense, leads to necrosis of nasal mucosa
-Freebase form (‘crack’), smoked, as intense as i.v route
Psychotomimetics: MDMA (5)
- Inhibits monoamine transporters (mainly 5-HT)
** Also releases 5-HT
** Large inc. 5-HT (followed by depletion)
** inc. 5-HT linked to psychotomimetic effects
** inc. DA linked to euphoria (followed by rebound dysphoria)
Opioids: Heroin
- Opioids produce intense
euphoria via acting on MOP
–Diamorphine (heroin) high abuse
potential - Tolerance: Seen within 12 – 24 hours
Opioid Disinhibition Effect
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General Depressants - MoA + pharm effects
Alcohol (8)
MoA:
1)Potentiates GABA-mediated inhibition
2)Inhibits presynaptic Ca2+ through voltage-gated channels
** Inhibits transmitter release
3)Disinhibits mesolimbic DAergic neurons (inc. reward)
4) Induces the release of endogenous opioid peptides
** Reward effect dec. by naltrexone (endogenous opioid involvement)
Pharmacological effects:
- Slurred speech, motor in-coordination, inc. self confidence
-euphoria
-Impaired cognitive and motor performance
-Higher levels linked to labile mood: euphoria and melancholy,
aggression + submission
Social Drugs: Nicotine / tobacco (4)
Highly addictive
Pharm effects:
- nAch receptors, alpha4Beta2 subtype: ** rec., ligand-gated cation channel (pre+post synap.), enhances transmitter release + neuronal excitability including opioid peptides
- Cortex + hippocampus (cog. function.) + ventral tegmental area (DA release + reward)
- inc. alertness, dec. irritability (dep. on dose + situ.)
mechanisms
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Acute effect of drugs of abuse on HPA axis
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Opioids INHIBITS HPA axis in humans
Cocaine ACTIVATES HPA axis
Stage 2: repetitive use/dependence/withdrawal
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Withdrawal Syndrome effects (2)
-Physical, characterised by abstinence syndrome (LC)Physical, characterised by abstinence syndrome (LC)
** Sweating, gooseflesh (cold turkey), irritability, aggression
-Psychological, craving to avoid withdrawal effects
Withdrawal Syndrome Drugs and effects (5)
-Psychostimulants: deep sleep, lethargy, depression, anxiety & hunger
- MDMA (ecstacy):Depression, anxiety,irritability,
incr. aggression - Heroin: Sweating, gooseflesh (cold turkey), irritability, aggression
-Nicotine: Irritability, hunger, weight gain, impaired cognitive + motor performance, craving (persisting many years)
-Alcohol: Tremor, nausea, sweating, fever, hallucinations
** Seizures, confusion, agitation, aggression
Chronic effects of drugs: Mechanism of Dependence & Tolerance
diagram
Mechanism of Dependence (NA)
(Homeostatic compensatory
neuroadaptation)
diagram
Stages in addiction cycle
Wee & Koob (2010) Psychopharmcacol
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Mechanism of dependence (HPA) (5)
- Heroin addicts have
Hyporesponsivity HPA axis - Cocaine addicts have
Hyperesponsivity HPA - CRF in extended Amygdala
increased in withdrawal - CRF antagonist block withdrawal
in animal models - CRF desregulation long lasting
(tolerance kicks in)
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Mechanism of dependence (α4β2*)
Up-regulation of α4β2*
Rapid dev. of tolerance (desensitisation of nACh receptors)
Relapse
- Induced by drug priming, drug related cues, stress
info.
addicted vs unaddicted brain
data, yin yang
Regulation of CREB by addictive drugs
diagram,
CREB (transcription factor)
Also change in FosB activation in withdrawal
Role of dopamine in addiction (5)
- Intake of drugs of abuse leads to increase in dopamine in nucleus accumbens + other limbic regions
- Psychostimulants induce reward via a DA dependent mechanism
- D2 knockout mice show no effect on withdrawal symptoms of
morphine after chronic administration - Opiate and alcohol SA persists when DA projections are
destroyed (DA independent mechanism) - Nicotine activates dopaminergic system via nicotinic receptors
VTA and Nacb
D2 antagonists are largely ineffective in drug addiction treatment
Role of endogenous opioids in addiction (8)
- Mu agonists are reinforcing and cocaine reinforcement is
modulated by opioid antagonists - Mu antagonists are effective in limiting craving and relapse
- Injections of opioids into the VTA generate self-administration
- Mu opioids facilitate intracranial self stimulation
- Mu opioid receptor knockout mice show loss of addictive
responses to opioids, alcohol, cannabinoids and nicotine - Proenkephalin knockout mice show loss of addictive response
to cannabinoids and nicotine - Alcohol and nicotine induce the release of endogenous opioids
- Cocaine induces MOP and KOP upregulation which is
persistent
Role of GABA in addiction (6)
- Firing of dopaminergic neurones in VTA is inhibited by GABA interneurones
- Opioids indirectly remove this inhibition by presynaptic
inhibition of GABA interneurones + responsible for the rewarding effects of opioids - GABAB agonist (baclofen) reduces nicotine reward in humans
- Cannabinoids inhibit GABA release. Effects of cannabinoids
mediated indirectly via opioid receptors - GABA agonist in Amygdala decrease alcohol SA
- Chronic alcohol decreased GABA and increased NMDA
Genetics and addiction (6)
- Human approaches to identify “addiction genes”
-Twin studies
-Identification of SNPs in addicted individuals
-Searching for abnormal mRNAs at autopsy
-Genome-wide scans of addicted vs normal individuals
-Genealogical approach and linkage analysis from genome-wide
scan of families (in populations that are genetically homogeneous)
e.g.’s of genes and addictions (7)
- ADH + alcoholism
- Ppdyn + cocaine addiction
- GABAA2 subunit + alcoholism
- A118G SNP (Asn to Asp) of MOP + heroin addiction
- Low 5HT associated w/ impulsivity
- Co morbidity genes
- COMT association w/ alcoholism, heroin
