Neuropharmacology Quiz on Inhibitory Mechanisms

Picrotoxin

• Blocks presynaptic inhibitory responses in the CNS, particularly in the caudate nucleus.
• Specifically blocks GABA-mediated presynaptic inhibition.
• Does not cause stimulant (excitation) action when blocking presynaptic inhibition of drugs like mephenesin.

Strychnine

• An alkaloid extracted from nux-vomica seeds, historically used as rat poison and in suicide attempts.
• Blocks various forms of direct and indirect inhibitory responses in the spinal cord.
• Blocks recurrent inhibitory processes, such as those seen in Renshaw cells, without affecting their firing level.
• Glycine is also involved in the terminal of Renshaw cells and the cell body of the postsynaptic neuron, acting as an inter-neuron collateral.

Cardiac Glycosides

• The Na+/K+ ATPase pump system controls neuronal excitability.
• Activation of this pump leads to inhibition, while blockade causes excitation.
• Digoxin, a cardiac glycoside, blocks the Na+/K+ ATPase pump, leading to an excitatory cardiac effect and convulsions in some laboratory animals.

Mechanisms of Stimulant Drugs' Enhanced Excitatory Neuronal Responses

• Increased release of neurotransmitters by nerve impulses.
• Increased amount of excitatory neurotransmitters.
• Prolongation of excitatory neurotransmitter action by blocking its dissipating enzyme.
• Increased sensitivity of postsynaptic membranes to neurotransmitters.
• Leptazole decreases synaptic recovery time, allowing for repetitive action of a stimulus.
• Leptazole acts directly on the medullary center, making it a good analeptic.
• Leptazole specifically antagonizes trimethadione, a drug used for petit-mal epilepsy.
• Leptazole does not affect neuronal resistance to impulses.
• Barbiturates, such as CHEB (5-cyclohexilydine ethyl barbituric acid) and DMBB, have dextro-isomers that are convulsant (stimulant) and laevo-rotatory forms that are depressant.

Classification of CNS Stimulants

• CNS stimulants are divided into five categories based on their mechanisms of action or sites of action.
• Reinforcers of NA (mimicking or potentiating it):
  • Behavioral stimulants (e.g., cocaine, amphetamines)
  • Clinical antidepressants (e.g., tranylcypromine (MAOIs), amitriptyline (TCAs))
• Miscellaneous behavioral stimulants (e.g., methylphenidate, phenmetrazine, benzphetamine)
• Convulsants (e.g., strychnine, picrotoxin, pentylenetetrazol, bicuculline) primarily block inhibitory synapses within the brain.
• General cellular stimulants (e.g., caffeine) increase cellular metabolism within the brain, leading to nonspecific and less potent behavioral stimulation.
• Stimulants of certain acetylcholine synapses (e.g., nicotine)

Mechanisms of Behavioral Stimulants and Antidepressants:

• Amphetamine, cocaine, and clinical antidepressants potentiate NE action at the synapse, occurring in five ways:
  • Increased rate of NE synthesis.
  • Decreased rate of NE metabolic destruction by inhibiting MAO, an enzyme that metabolizes NE within presynaptic nerve terminals.
  • Triggering the release of NE from presynaptic terminals.
  • Prolongation of NE action at its postsynaptic receptor by blocking its reuptake, which is the primary mechanism for terminating NE action.
  • Direct stimulation of postsynaptic NE receptors.
• Summary of actions:
  • Amphetamine: increases NE release, directly stimulates postsynaptic NE receptors, and blocks NE reabsorption.
  • Cocaine: blocks NE reabsorption.
  • Tricyclic antidepressants: block NE reabsorption.
  • MAO inhibitors: inhibit MAO.
  • Lithium: blocks presynaptic release of NE, decreasing synaptic NE availability.

NE Theory of Mania and Depression:

• The NE system plays a role in emotional behavior.
• Reserpine: an antipsychotic drug depletes NE in the brain, causing severe behavioral depression.
• Lithium: used to treat mania, blocks presynaptic release of NE, reducing synaptic NE levels.
• Lithium paradox: while lithium helps mania by blocking NE release, it can also cause depression, seemingly contradicting the NE hypothesis. This may be due to a slow reduction in NE during treatment, followed by a rebound effect leading to a period of depression.
• Manic-depressive patients: experience mood swings, with fluctuating NE levels. As mania is alleviated, NE levels become more stable, reducing depressive episodes.

Groups of CNS Stimulants:

• Psychoactivators or mood elevators: increase mental activity and alertness (e.g., amphetamine, methylphenidate).
• Analeptics: stimulate nerve cells of the midbrain and medulla, used to maintain respiration during depressant drug overdose (e.g., leptazol, ethamiran, picrotoxin).
• Spinal cord stimulants: exaggerate spinal reflexes (e.g., strychnine).
• Antidepressants: relieve depression without inducing excitement or delirium (e.g., imipramine, MAO-inhibitors).

CNS Stimulants of Clinical Importance:

• Antidepressants:
  • Imipramine: a tricyclic compound that blocks NE reuptake.
  • Monoamine oxidase inhibitors: divided into two groups.
  • Lithium: used to stabilize mood in manic-depressive illness.
• Spinal cord stimulants: (strychnine and tetanus toxin): laboratory tools for studying anticonvulsant drugs, used to induce spinal cord convulsions; toxicological interest.
• Analeptics: (picrotoxin, leptazol, nikethamide):
• Psychoactivators: (amphetamine, methylphenidate, methylamphetamine): elevate mood and stimulate mental activity. Amphetamine's dextro-isomer (D-amphetamine) is particularly effective as a CNS stimulant.