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Neuropharma Of CNS disorders > Psychoactive Drugs > Flashcards

Psychoactive Drugs Flashcards

1
Q

Psychotometric, psychotropic and psychoactive

A

Drugs that alter perception, behaviour and mood

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2
Q

Hallucigens

A

Alter perceptions, thoughts and feelings eg LSD and psilocybin

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3
Q

Caapi

A

Naturally occurring hallucinogen
Active constituent - harmakine
Motor control but altered perception

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4
Q

Peyote

A

Active constituent - mescaline

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5
Q

Hallucinogen potency

A

Psilocybin - 250 ug for 3 hrs
Mescaline 15 mg for 12
(Psilocybin more potent)

LSD 3ug for 10 hrs (first synthetic drug)

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6
Q

LSD history

A

Clinical use against st anthonies fore (Vado construction of peripheral blood vessels and psychosis) Caused by Ergot alkaloids - but used as hemorages treatment

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7
Q

LSD

A

Derivative of naturally occurring ergots
Caused peripheral vasoconstriction
Effects: somatic (motor and autonomic), perceptual (hallucinations), psychological (synaesthesia)

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8
Q

Cross tolerance (LSD)

A

Tolerance acquired from use of one for both
Mescaline and LSD
Both act at same class receptor site
Both similar to 5-HT

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9
Q

How does LSD act in the periphery

A

As a 5ht2 receptor antagonist

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10
Q

How does LSD work in the brain

A

As a 5ht receptor agonist/partial agonist
5HT synapses release, postsynaptic receptors acted on
Presynaptic auto receptors, 5HT acts on this to fine tune release of 5HT on synapse, -ve feedback loop, 5 HT in synaptic cleft activate these which inhibit release of 5HT

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11
Q

LSD administered, 5HT antagonist. Does metabolite increase or decrease

A

Increase

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12
Q

LSD agonist. Increase or decrease metabolites?

A

Decrease

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13
Q

Where does LSD have its affect in the brain?

A

Potentially Reticular activating formation

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14
Q

Reticular formation

A

Sensory afferents arise and project to brain, synapse in thalamus, thalamus neurones project to primary somatosensory cortex (direct, modality specific) - raphe nucleus, locus coerelous

Axon collaterals, synapse within reticular formation, neurones project to thalamus or broad cortex (indirect, non specific arousal)

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15
Q

LSD impact on raphe neurones

A

LSD decreases firing rate of raphe neurones (5HT1A receptor)
(Raphe neurones send extensive projection to the forebrain)
Dendritic nucleis in raphe nucleus, release 5HT from dendrutes, act on Austin receptors, inhibit activity
LSD acts as 5HT1a partial agonist, decreasing firing rate of neurones

Other drugs don’t do this so not cause of hallucinations

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16
Q

What affect does lesioning the raphe nucleus cause

A

Can still discriminate between saline and LSD
So not key in main experiences of alterations in perception

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17
Q

LSD impact on noradrenergic pathway

A

LSD increases activity in locus coeruleos neurones
LSD increases activity of subsets of neurones in cortex
(Increase release of noradrenaline)

Direct and indirect (noradrenaline and 5HT2 receptors)

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18
Q

Where are 5HT2A receptors found

A

Temporal and prefrontal cortex, and thalamus (processes somatosensory inputs and recieved afferents from locus coeruleus)

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19
Q

Does LSD exerts it’s effects through 5HT2A receptors?

A

Both LSD and phenethylamines use same receptor
Correlations - highest affinity = most potent, least affinity = less potent

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20
Q

LSD perception theory

A

Acts on 5HT2A receptors, highly expressed in cortex, pyramidal neurones, increases activity of layer 5 pyramidal neurones
Imaging studies

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21
Q

Entropic effect

A

Massive activation of different neuronal regions during visual stimulus

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22
Q

Psychotomimetic drugs

A

Phencyclidine (PCP)
Dissociative anaesthetic (same class as ketamine)
Catatonic state
Caused emergence phenomenon (psychotic symptoms, altered body image, cognitive disorganisation, hypnagogic states, euphoria, apathy, hallucinations

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23
Q

PCP interacts with what receptors

A

Sigma opiate receptor - modulates NAdr release (presynaptic terminals)

Antagonist of NMDA (glutamate receptor), ligand gated ion chancel, excitatory, non selective ion - PCP blocks channel, increased conc of PCP = increased firing rate subcorticotical doperminergic excitation

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24
Q

NMDA

A

Expressed in GABA Neurones in subcortical regions of the brain. Regulated by projections from the cortex

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25
Q

Action of PCP

A

Cortical neurones project to NMDA receptors releasing glutamate, activates inhibitory neurones so inhibits dopermenergic neurones I’m VTA

PCP blocks NMDA receptors and so dopermenergic neurones remain activated causing increased activity of subcortical region

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26
Q

Hallucinogenic drugs as models for schizophrenia

A

LSD and PCP used in animal models for schizophrenia

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27
Q

Drugs acting on catecholamine neurotransmission

A

Cocaine and alcohol
Associated with deaths

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28
Q

Cocaine

A

Peesynaptic neurones release catacholamine neurotransmitters
High affinity uptake transporter (transports back into nerve terminal
Cocaine Blocks high affinity reputable
So increase catacholamine in synaptic cleft
Enhance catercholoergic transmission

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29
Q

Actions of cocaine

A

Local anaesthetic (blocks voltage gated NA channels)
Euphoria
Appetite suppressant
Big dose- tremors, convulsions, CNS depression
Susceptible individuals - toxic psychosis (similar to schizophrenia)
Addictive properties

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30
Q

Amphetamine

A

Sympathomimetic amine - mimics effects of sympathetic nerve stimulation

31
Q

Actions of amphetimine

A

Appetite suppressant
Causes euphoria
Hypertensive

Used: weight control, narcolepsy, ADD

Can cause psychosis

32
Q

How does amphetamine work?

A

Reverse transport
Binds to transporter on extracelluar face and reverses transport so dopamine out and AMPH in
Elevates catacholamine transmitters

33
Q

MDMA

A

Effects on empathy, sense of well being
Similar pharma to cocaine and amphetamine

34
Q

How does MDMA work?

A

Increase 5HT by decreasing 5HT serotonin uptake. Blocks MAO (responsible for metabolism of NTs)

Repeated use = toxic. Degeneration of raphe neurones

35
Q

Addiction

A

Persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for affected individual.
Physical and psychological dependence

36
Q

Physical dependence

A

Withdrawal symptoms eg shaking, diohrea

Usually opposite of drug effects

37
Q

Psychological dependence

A

Craving
Brain adapts to presence of drug. Feedback- homeostatic maladapted/adapted

38
Q

Features of addiction

A

Compulsion to take drug
Positive and negative reinforcement

  1. Withdrawal syndrome
  2. Tolerance
39
Q

Which brain region contains dopaminergic neurones?

A

Ventral techmental area

40
Q

Psychotomimetic drugs with abuse potential have common actions on the limbic system of the brain

A

Key focus in addiction: Ventral tegmental area which projects to nucleus accumbens

41
Q

Reward

A

Selections of behaviour appropriate for survival achieved by reward and punishment systems
Motivation and avoidance
In appropriate activation underline addiction

42
Q

Model of reward circuit

A

Good > neural circuit that detects stimulus > neural circuit that controls behaviour > behaviour > reinforcing stimulus > reinforcing system

Drugs interact with reinforcing system

43
Q

James old (1954)

A

Rats implanted with stimulating electrodes in “reticular formation and hypothalamus”
Rats returned to part of cage where stimulated - electrodes actually placed in medial forebrain bundle showing addictive behaviour
Rewarding stimulus = reinforcement

44
Q

Operant chamber

A

Rats self delivers stimulus or drug.
Repeatedly stimulates medial forebrain bundle

45
Q

Medial forebrain bundle

A

Has dopermenergic, seeotomergic and noritergic neurones

Dopermenergic most important in reinforcement
D2 dopamine antagonist blocks reinforcement (not effective as treatment in humans)

46
Q

Reinforcing system

A

Dopamine axons in medial forebrain bundle that project to nucleus accumbens

47
Q

Medial forebrain bundle

A

MDB is a dopamine pathway

VTA to nucleus accumbens and prefrontal cortex

48
Q

Cocaine binds with high affinity to monoamine including dopamine transporters

A

DA transporter knock out (germline mice) = elevated synaptic dopamine (no reputake)
Cocaine normally increases motor activity by more DA in nucleus cuccumbens

Cocaine administered causes no change to baseline DA or locomotion activity
Still administer cocaine so other reinforcing stimulus

49
Q

Dopamine transporter structure

A

12 transmembrane domain protein
F105 important for high affinity cocaine binding but not for DA transport

50
Q

Mouse knock in for mutant DA transporter

A

No longer bind to cocaine
No elevated basal levels of DA
No increase activity of locomotion
So insensitive to actions of cocaine

51
Q

Conditioned place preference test to assess reinforcing properties of cocaine

A

Saline area vs drug
Conditioned
No drug but give choice
Preference for side associated with drug - wild type
Knock in - don’t show rewarding effect (adverse effect)

52
Q

Are there common mechanisms for reinforcement/addiction for other addictive drugs?

A

Evidence for common involvement of limbic system
Evidence for common involvement of dopamine signalling especially VTA projection to nucleus accumbens

Neurotransmitter - dopamine

53
Q

Dopamine - common factor in drugs with abuse potential

A

Ethanol - increases DA release in nucleus accumbens
DA receptor antagonists - block alcohol self administer action
Opiates also increase dopamingerguc transmission in limbic system
Pharmacologically different but same pathway
Not adversive drugs

54
Q

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the Mesolimbic system of freely moving rats

A

Dose dependent (ethanol) increase in amount of dopamine in Mesolimbic system

55
Q

Evidence for altered dopamine signalling in addiction in humans

A

Brain imaging
PET imaging (18-fluoromethylspiroperid) to label dopamine (D2) receptors
Subcortical regions - not cocaine users, 1 month off & 4 month for - degreased receptors even compared to control
Age influence dopamine receptor density, cocaine users always had lower densities at any age

56
Q

Why do users have lower levels if D2 receptors?

A

Cocaine increase DA levels so downrdgulation if receptors to try to bring back to normal levels
Nomeostatic
Compromised reward system and so craving
Also seen in meth, alcohol and heroin

57
Q

What are the long term changes associated with addiction?

A

Evidence - changes gene expression
Eg increased DA binds to dopamine receptor causing increase in cAMP which acts on CREB (transcription factor) which gives rise to immediate early gene expression
Alters lvls of receptor expression eg changes in dopamine receptors

58
Q

Genetic basis for drug addiction

A

More likely to be susceptible due to genes ALDH2, D2, OPRM1

59
Q

ALDH2

A

Aldehyde dehydrogenase enzyme that metabolises alcohol
Alcohol via aldehyde (ADH2) to acetic acid
Lower ADH2 activity, accumulates aldehyde, unpleasant (some still develop addiction but lower levels of alcohol addiction seen in pop)

60
Q

D2 mutants

A

Polymorphisms
Carry increase risk of alcohol and other forms of addiction

61
Q

OPRM1

A

VTA opiate receptor
Variants linked to addictive behaviour

62
Q

Neuro chemical circuits in drug rewards

A

VTA to nucleus coecumbens in basal forebrain (involved in reward)

Nucleus coecumbens to amygdala (involved in negative reinforcement)

63
Q

Ethanol, nicotine, opiates & THC

A

Directly on VTA to stimulate nucleus accumbens

64
Q

Cocaine, amphetamines, opiates and THC

A

Act on nucleus accumbens directly

65
Q

Key idea

A

Different substances work in different parts of same circuit using different neurotransmitters but bet effect is the same - dopamine elevation downstream

66
Q

Addiction more than just rewards

A

Impulsive (positive reinforcement) to compulsive (negative reinforcement) in chronic user

67
Q

Impulsive stage

A

Binge intoxication > pleasurable effects > abstinence, neutral affect > crave reward repeat

68
Q

Compulsive stage

A

Prolonged intoxication > relief > protracted abstinence, negative effect > relief craving repeat

69
Q

Beyond dopamine reward circuit

A

Orbital frontal cortex (decision making and controlling behaviour)
Higher activity in normal than addict

70
Q

Studying alcohil dependence in rat model

A

Can train rats to drink with sucrose
MsP alcohol preferring rats
Amygdala in msp rats corticotropin releasing factor is high in dependent and alcohol preferring (most)

71
Q

CRF

A

Hypothalamic hormone (neuropeptide) that acts on anterior pituitary that release acth on adrenocortex, leads to cortical release

72
Q

CRF in amygdala may be involved in stress and genotype dependent

A

Rat self administers alcohol via lever. Alcohol taken out. Period of behaviour stopped. Foot shock as stressor. Increased lever press
Antagonist present decreased lever press
Same seen in alcohol preferring eats but greater decrease

73
Q

Phencyclidine

A

Selective non competitive antagonist of NMDA receptors

74
Q

Schizophrenia stat

A

Affects 1% of population
Suicide number 1 cause of premature death among people with schizophrenia

Neuropharma Of CNS disorders (5 decks)

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