convulsants, nicotine and cannabinoids

examples of convulsant drugs

• pentylenetetrazol

• penicillin

• bicuculline

• gabazine

• strychnine

Draw a timeline to show the key components of an experiment using a convulsant of

your choice to investigate antiepileptic drugs in a rodent model. It should include

administration of an appropriate convulsant, and examples of tests used to measure

behavioural and other outputs

PTZ, penicillin, bicuculine, gabazine etc.

- Behavioural tests e.g. motor activity, cognitive tests.

- EEG recordings.

- Effect of antiepileptic drugs.

usage of pentylenetetrazol

• induce seizures

• once used in ECT

mechanism of pentylenetetrazol (PTZ)

• GABA-A antagonist

• binds to picrotoxin site on chloride channel, inhibits influx and reduces inhibitory neurotransmission

• NMDA receptor activation

• inc Ca2+ and Na+ influx

penicillin mechanism and usage

• non comp antagonist of GABA-A

• does not cross the BBB

  • applied directly to the cortical surface or intracerebral injection

  • widely used to test anticonvulsants

uses of bicuculine and gabazine

• GABA-A antagonists

• used to block GABA-A activity

• used to dissect CNS circuits pharmacologically

bicuculine

• plant derived alkaloid

• competitive antagonist to GABA-A

gabazine

• potent selective antagonist of GABA-A

• blocks fast inhibitory synaptic transmission

• more effective in vitro then bicuculine

strychnine mechanism

• competitive antagonist to glycine postsynaptic receptors

• spinal cord and brainstem

strychnine effect

• leads to constant muscle contractions

• jaw lock, back arching, breathing difficulties

nicotine mechanism of action

• agonist at nAChR in brain, NMJ and autonomic ganglia

• cell depolarisation

• trigger release of dopamine in mesolimbic system

  • leading to reward and reinforcement

Which subunits of nAChRs are critical for addiction pathways in the brain?

alpha 4 and beta 2

Peripheral effects of nicotine

• stimulates autonomic ganglia

• inc heart rate, bp, epinephrine release

Desensitisation and Addiction with nicotine

• chronic use leads to receptor desensitisation and upregulation

• contributes to tolerance, cravings and withdrawal symptoms

Expression pattern of nAChR with nicotine

• activates and induces receptor desensitisation, chronic administration paraodixcally inc nAChR

• push and pull

behavioural effects of nicotine

• inhibits spinal reflex

• low dose - central arousal, improved reaction time

• higher dose - sedation

• excitation of mesolimbic dopaminergic reward system

how does nicotine inhibit spinal reflex

• stimulation of glycinergic renshaw cells

• spinal inhibitory interneurons - recurrent inhibition

harmful effects/negatives of nicotine

• cough

• cancer

• coronoary heart disease

• COPD

• smell, cost

Ingestion of cannabis provides what effects?

• euphoria

• calmness

• relaxation

• reduced pain

• inc laughter

• hunger

• dizziness

Negatives to cannabis

− ↓ problem-solving, short-term memory, psychomotor performance.

− High doses can lead to personality changes, hallucinations.

− High THC content linked to schizophrenia.

− Minor evidence of tolerance, physical dependence (heavy users?).

active ingredients of cannabis

• mainly THC

• CBD

• cannabinol

which ingredients of cannabis lack psychoactivity

• cannabinol

• CBD

effects of cannabis on the cns

• relaxation

• sharpened awareness

• slowing down of time

• analgesia

• antiemetic activity

peripheral effects of cannabis

• tachycardia

• vasodilation - blood shot eyes

• reduced intraocular pressure

• broncodilation

overdose of cannabis

• mild respiratory depression, confusion, dizziness

• teratogenic in rodents, not seen in humans

chronic thc usage effects

• rapid pharmacological tolerance

• frequent use can cause insomnia, irritability and anxiety upon cessation

• dependency and potential addiction

exogenous effect of THC

• THC affects the DA synapse

• THC binds to CB1

  • release of cAMP

  • dephosphorylation of Ca2+ channel

  • rise of intracellular calcium dec

  • less GABA released

  • less inhibition of DA neuron

  • increased excitability, inc dopamine release

endogenous effects of cannabis

• rise in calcium postsynaptically through NMDA-R

• anandamide and 2AG are synthesised from membrane lipids

• act on CB1 receptors pre synaptically

• retrograde neurotransmission

anandamide and 2AG synthesis

• on demand

• no vesicular release

• analogue switch

distribution of cb1 receptors

• found presynaptically

• High concentrations are found in the basal ganglia, hippocampus, cerebellum, and cerebral cortex.

• can be upregulated in response to dec endocannabinoid signalling

examples where CB1 receptors are upregulated

• Chronic stress

• Cannabinoid withdrawal

• Parkinson’s disease

• Schizophrenia

• Inflammation

endocannabinoid mechanism

• vesicular release of neurtransmitter

• depolarisation of postsynaptic membrane

• calcium influx (POST)

• enzymatic production of endocannabinoids (POST)

• endocannabinoids diffuse back to bind to CB1

• dec activity of calcium channels

• less calcium influx upon depolarisation

• less neurotransmitter release

rimonabant

• selective CB1 inverse agonist

• acts centrally in the hypothalamus to reduce hunger and peripherally in adipose tissue and liver to inc metabolism

• used in - obesity, prader willi syndrome

THC and CB agonist possible therapeutic usage

• reduce motor tics in tourettes

• produced in basal ganglia, dopamine link