Psychopharmacology 2 Flashcards
What is self-administration
Drug infusion as a result of performance of a particular behaviour e.g. lever pressing
Looks at addiction
What is conditioned place preference/aversion
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
What is drug discrimination
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
What is behavioural tolerance
Decrease in drug effectiveness at the same dose so more needed to give specific effect
What is behavioural dependency
Effects of cessation of drug following chronic treatment e.g. withdrawal effects
How does cannbinoids effect these behaviours
Very variable - tolerance , self-administration and place preference
Likely due to different strains, different species, different methodology
What is the main psychoactive drug in cannabis
Tetrahydrocannabinol (THC)
What are the cannabinoid receptors called
CB1 - brain, peripheral neurons, nerve terminals, controls neurotransmitter release
CB2 - elsewhere
What are the two endogenous ligands for cannabinoid receptors
Anadamide
2-archydonyl glycerol (2-AG)
Give some features of the cannabinoid receptors
Coupled to G proteins
Selective agonists identified
Selective antagonists identified
Endogenous ligands identified
Present in immune cells
What does cannabinoid (CB1) agonists do to food intake
Increase food intake
What does cannabinoid (CB1) antagonist (rimonabant) do to food intake
Significant decrease in food intake
What was seen with the CB1 antagonist AM251 over a 24hrs period in rats
Significant decrease in food intake, body weight and feeding behaviour over a 24hr and 12hr period - Riedel et al 2009
What was seen with the CB1 antagonist AM251 over a 4 days period in rats with repeated doses
Significant decrease in food intake, body weight and feeding behaviour over a 24hr and 12hr period - Riedel et al 2009
What was seen over a 2 day period with using THCV (novel chemical from marijuana without psychotic effects) in rats
Significant decrease in body weight, food intake and feeding orientated behaviours
Why are cannabinoid antagonists important
As they reduce feeding behaviour and food intake - possible obesity treatment
Why are cannabinoid agonists important
As they increase feeding behaviour and food intake - possible obesity model
Where are the CB1 receptors found in the CNS
Hippocampus - therefore indicates a role of cannabinoids in spatial learning and memory
What have studies using various behavioural paradigms shown regarding cannabinoid agonists
Induce impairments in spatial learning and memory
What role has SR141716A been shown to have on spatial learning and memory
Reverse these effects caused by cannabinoid agonists
What does CB1 knockout mice show regarding learning and memory
CB1 knockout mice also have enhanced learning and memory
What is the water maze and why is it important
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.
How is vision checked with the water maze
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.
What is WIN-2
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.
What effects did WIN-2 have on long term and short term memory
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)
How do we ensure the desired dose is reaching the desired site (hippocampus)
Intrahippocampal infusions via minipump.
What effects did intrahippocampal injections of WIN-2 have on long and short term memory
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
What is the underlying neuronal pathway for these CB1 receptors in the hippocampus
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
What is paired pulse depression and what role does CB1 have in paired pulse depression
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.
What effects does cannabinoids have
Appetite - stimulation
Pain - anti-noncioceptive effects
Cognition - memory impairment
Motor activity - reduction in spontaneous locomotor activity
What therapeutic potential do cannabinoids have
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
Using WIN-2 and the water maze in rats, what was discovered about its effects on memory
WIDER READING - Robinson et al 2010
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.
How can cannabinoids help phenytoin as an anti-epileptic in mice
WIDER READING - Chesher et al 1974
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
How have cannabinoids shown to work in glaucoma
WIDER READING - Miller et al 2016
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.
How have cannabinoids been shown to be useful in tremor and spasticity
WIDER READING - Baker et al 2000
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
Why can’t rimonabant be used today
WIDER READING - Van Gaal et al 2008
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.
