Psychopharmacology 2

Question 1

What is self-administration

Answer 1

Drug infusion as a result of performance of a particular behaviour e.g. lever pressing
Looks at addiction

Question 2

What is conditioned place preference/aversion

Answer 2

Assesses rewarding/aversive actions of drugs

Given drug and placed into arena and then control. Animal links specific area it is placed in e.g. floor texture and shape of area to the drug/control. If animal goes to drug area more and stays longer then has interest in that drug

Question 3

What is drug discrimination

Answer 3

Investigate subjective response to drugs. To enable reward need to discriminate internal state and response appropriately.
E.g. - links behaviour of when on drug to drug so does the same thing but not seen with control

Question 4

What is behavioural tolerance

Answer 4

Decrease in drug effectiveness at the same dose so more needed to give specific effect

Question 5

What is behavioural dependency

Answer 5

Effects of cessation of drug following chronic treatment e.g. withdrawal effects

Question 6

How does cannbinoids effect these behaviours

Answer 6

Very variable - tolerance , self-administration and place preference

Likely due to different strains, different species, different methodology

Question 7

What is the main psychoactive drug in cannabis

Answer 7

Tetrahydrocannabinol (THC)

Question 8

What are the cannabinoid receptors called

Answer 8

CB1 - brain, peripheral neurons, nerve terminals, controls neurotransmitter release
CB2 - elsewhere

Question 9

What are the two endogenous ligands for cannabinoid receptors

Answer 9

Anadamide
2-archydonyl glycerol (2-AG)

Question 10

Give some features of the cannabinoid receptors

Answer 10

Coupled to G proteins
Selective agonists identified
Selective antagonists identified
Endogenous ligands identified
Present in immune cells

Question 11

What does cannabinoid (CB1) agonists do to food intake

Answer 11

Increase food intake

Question 12

What does cannabinoid (CB1) antagonist (rimonabant) do to food intake

Answer 12

Significant decrease in food intake

Question 13

What was seen with the CB1 antagonist AM251 over a 24hrs period in rats

Answer 13

Significant decrease in food intake, body weight and feeding behaviour over a 24hr and 12hr period - Riedel et al 2009

Question 14

What was seen with the CB1 antagonist AM251 over a 4 days period in rats with repeated doses

Answer 14

Significant decrease in food intake, body weight and feeding behaviour over a 24hr and 12hr period - Riedel et al 2009

Question 15

What was seen over a 2 day period with using THCV (novel chemical from marijuana without psychotic effects) in rats

Answer 15

Significant decrease in body weight, food intake and feeding orientated behaviours

Question 16

Why are cannabinoid antagonists important

Answer 16

As they reduce feeding behaviour and food intake - possible obesity treatment

Question 17

Why are cannabinoid agonists important

Answer 17

As they increase feeding behaviour and food intake - possible obesity model

Question 18

Where are the CB1 receptors found in the CNS

Answer 18

Hippocampus - therefore indicates a role of cannabinoids in spatial learning and memory

Question 19

What have studies using various behavioural paradigms shown regarding cannabinoid agonists

Answer 19

Induce impairments in spatial learning and memory

Question 20

What role has SR141716A been shown to have on spatial learning and memory

Answer 20

Reverse these effects caused by cannabinoid agonists

Question 21

What does CB1 knockout mice show regarding learning and memory

Answer 21

CB1 knockout mice also have enhanced learning and memory

Question 22

What is the water maze and why is it important

Answer 22

Pool of water where the only way to get to land is a platform underneath the water surface where they can stand.
Important for spacial learning and memory, need to check animal vision first.
Expected that over-time they get quicker at finding the platoform.

Question 23

How is vision checked with the water maze

Answer 23

Two striped pictures where they put the smaller lines where platform is and the mice linked the smaller stripes with the platform and kept going back to it.

Showed that cannaboids had no effect on mice vision.

Question 24

What is WIN-2

Answer 24

WIN-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.

Question 25

What effects did WIN-2 have on long term and short term memory

Answer 25

Gave systemic infusion of WIN-2 impairs long-term memory but not short term memory.
Determined memory was short or long via time between trials (minutes vs 1 day)

Question 26

How do we ensure the desired dose is reaching the desired site (hippocampus)

Answer 26

Intrahippocampal infusions via minipump.

Question 27

What effects did intrahippocampal injections of WIN-2 have on long and short term memory

Answer 27

Impairs long term memory
No effect on short term memory
More pronounced than systemic administration
Also shows that the systemic effects of WIN-2 are due to it acting on the hippocampus

Question 28

What is the underlying neuronal pathway for these CB1 receptors in the hippocampus

Answer 28

So the theory we have is that we know that the CB1 receptors are located within the CA1 region of the hippocampus and they are co-localised on pyramidal cells with CCK and GABA neurons

Question 29

What is paired pulse depression and what role does CB1 have in paired pulse depression

Answer 29

Paired pulse depression (PPD) is a common form of short-term synaptic plasticity.

Was shown that WIN-2 reduces PPD
Reversed if use AM281 with WIN2

Shows that there is no desensitization or internalization of receptors.

Question 30

What effects does cannabinoids have

Answer 30

Appetite - stimulation
Pain - anti-noncioceptive effects
Cognition - memory impairment
Motor activity - reduction in spontaneous locomotor activity

Question 31

What therapeutic potential do cannabinoids have

Answer 31

Treatment of eating disorders
Analgesics for suppression of chronic pain
Muscle spasticity in Multiple sclerosis
Anti-epileptic properties
Anti-emesis actions
Gluacoma
CB1 antagonists alleviate cognitive deficits

Question 32

Using WIN-2 and the water maze in rats, what was discovered about its effects on memory

WIDER READING - Robinson et al 2010

Answer 32

WIN-2 is a synthetic cannabinoid and it was shown to impair long term but not short term memory when given to rats intraperiotneal.
This was reversed by cbolinesterase inhibitor rivastigmine but not CB1 antagonist rimonabant - suggests that spatial reference memory is caused by decreased cholinergic activation by WIN2 possibly not through CB1 binding.

Question 33

How can cannabinoids help phenytoin as an anti-epileptic in mice

WIDER READING - Chesher et al 1974

Answer 33

Mice given electroshocks and chemoshocks and it was shown that δ 9-THC significantly potentiated the anticonvulsant effectiveness of phenytoin against electroshock seizures and this effect was further potentiated by the concurrent administration of CBD.
Unsure of the mechanisms but believed to be CNS related not metabolically related

Question 34

How have cannabinoids shown to work in glaucoma

WIDER READING - Miller et al 2016

Answer 34

Lower IOP pressure - Used rebound tonometry in normal mice and ocular hypertension model mice and checked pressures at 1,6 and 12hrs afterwards.
Novel CB1-positive allosteric modulator (PAM) GAT229 reduces IOP in ocular hypertensive mice and enhanced CB1-mediated IOP reduction when combined with subthreshold CB1 orthosteric ligands in normotensive mice.

Question 35

How have cannabinoids been shown to be useful in tremor and spasticity

WIDER READING - Baker et al 2000

Answer 35

Biozzi ABH mice (relapse and remitting autoimmune encephalitis - like MS).
These mice experience spasticity and tremor. It was shown that using cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, Δ9-tetrahydrocannabinol, methanandamide and JWH-133, these quantitatively reduced tremory and spasticity in diseased mice.
Also - antagonism of CB1 and CB2 using SR141716A was shown to indicate that the endogenous cannabinoid system may play a role in tremor and spasticity

Shows that cannabis may have role for MS symptoms

Question 36

Why can’t rimonabant be used today

WIDER READING - Van Gaal et al 2008

Answer 36

High risk of poor mental health - occurred more frequently with 20 mg rimonabant versus placebo (most commonly, depressive disorders [1.9 vs. 0.8%], nausea [1.4 vs. 0.1%], mood alterations with depressive symptoms [1.0 vs. 0.6%], and anxiety [1.0 vs. 0.3%]). A thorough review of psychiatric and neurological adverse events was performed.