There are at least two subtypes of the cannabinoid receptor CB1 and CB2 receptors. The CB1 receptors are highly expressed throughout the peripheral and central nervous systems. Specifically, the CB1 receptors are highly expressed in the hippocampus, cortex, basal ganglia, cerebellum and spinal cord. This distribution accounts for the effects of cannabinoids on memory, cognition and movement. Both CB1 and CB2 cannabinoid receptors are coupled to inhibitory G-proteins. Activation of the cannabinoid receptors causes inhibition of adenylate cyclase and a subsequent decrease in the concentration of cAMP in the cell, resulting in the inhibition of neurotransmission.
There are at least two subtypes of the cannabinoid receptor CB1 and CB2 receptors. The CB2 receptors are highly expressed throughout the peripheral nervous system and are closely associated with the immune system. Both CB1 and CB2 cannabinoid receptors are coupled to inhibitory G-proteins. Activation of the cannabinoid receptors causes inhibition of adenylate cyclase and a subsequent decrease in the concentration of cAMP in the cell, resulting in the inhibition of neurotransmission.
The active ingredient of cannabis is ∆9-tetrahydrocannabinol (∆9-THC) and it is thought to exert its effect by binding to cannabinoid CB1 receptors on pre-synaptic nerve terminals in the brain. ∆9-THC binding to CB1 receptors activates G-proteins that activate/inhibit a number of signal transduction pathways. The G-proteins directly inhibit N and P/Q-type voltage dependant calcium channels and sodium channels and indirectly inhibit A-type calcium channels via inhibition of adenylate cyclase. ∆9-THC binding and G-protein activation also activates inwardly rectifying potassium channels and the MAP kinase signalling pathway. The cumulative effect of these pathways is the euphoric feelings associated with cannabis use.
Perhaps the best known use of cannabis in a therapeutic setting is as an analgesic in the management of cancer pain, post-operative and phantom limb pain. Cannabinoids have also been used in the prevention of nausea and vomiting caused by anticancer drugs and to stimulate appetite in palliative care for anorexia caused by opioids, antiviral drugs, AIDS-related illnesses or terminal cancer. Other effects include a bronchodilator effect on the small airways of the lungs and an ability to decrease intraocular pressure. It is paradoxical that cannabinoids have been reported to be of therapeutic value in neurological disorders associated with spasticity, ataxia and muscle weakness because similar symptoms can be caused by cannabis itself.
High-dose amphetamine can modify the action of dopamine and noradrenaline in the brain. At high doses, amphetamine increases the concentration of dopamine in the synaptic cleft in 4 ways: (1) it can bind to the pre-synaptic membrane of dopaminergic neurones and induce the release of dopamine from the nerve terminal; (2) amphetamine can interact with dopamine containing synaptic vesicles, releasing free dopamine into the nerve terminal;(3) amphetamine can bind to monoamine oxidase in dopaminergic neurones and prevent the degradation of dopamine, leaving free dopamine in the nerve terminal; and (4) amphetamine can bind to the dopamine re-uptake transporter, causing it to act in reverse and transport free dopamine out of the nerve terminal. High-dose amphetamine has a similar effect on noradrenergic neurones; it can induce the release of noradrenaline into the synaptic cleft and inhibit the noradrenaline re-uptake transporter.
Low-dose amphetamine can modify the action of dopamine and noradrenaline in the brain. Amphetamine increases the concentration of dopamine in the synaptic cleft in 3 ways: (1) It can bind to the pre-synaptic membrane of dopaminergic neurones and induce the release of dopamine from the nerve terminal; (2) amphetamine can interact with dopamine containing synaptic vesicles, releasing free dopamine into the nerve terminal; and (3) amphetamine can bind to the dopamine re-uptake transporter, causing it to act in reverse and transport free dopamine out of the nerve terminal. Amphetamine can also cause an increased release of noradrenaline into the synaptic cleft.
Amphetamine-like drugs are sometimes used in the treatment of narcolepsy, a sleep disorder with episodes of uncontrollable sleepiness during waking hours. The increased stimulation of the CNS by amphetamine enables such people to remain awake. Paradoxically, amphetamine-like drugs can help treat attention deficit hyperactivity disorder (ADHD), a behavioural disorder characterized by inattention, hyperactivity and impulsivity. The benefit derived by affected children is unclear, but they show an improved ability to concentrate and are less distracted and impulsive.
Cocaine modifies the action of dopamine in the brain. The dopamine rich areas of the brain are the ventral tegmental area, the nucleus accumbens and the caudate nucleus – these areas are collectively known as the brain’s ‘reward pathway’. Cocaine binds to dopamine re-uptake transporters on the pre-synaptic membranes of dopaminergic neurones. This binding inhibits the removal of dopamine from the synaptic cleft and its subsequent degradation by monoamine oxidase in the nerve terminal. Dopamine remains in the synaptic cleft and is free to bind to its receptors on the post synaptic membrane, producing further nerve impulses. This increased activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with cocaine use.
The local anaesthetic effect of cocaine has been known for some time and it was previously used in dentistry and ophthalmology. Cocaine prevents action potential generation by physically blocking sodium channels via two alternative mechanisms. The uncharged species reaches the blocking site within the channel via the membrane (hydrophobic pathway), while the charged species reaches the site via the open channel gate (hydrophilic pathway). The blockade prevents voltage-dependent Na+ conductance, which results in local nerve block.
Heroin modifies the action of dopamine in the nucleus accumbens and the ventral tegmental area of the brain – these areas form part of the brain’s ‘reward pathway’. Once crossing the blood-brain barrier, heroin is converted to morphine, which acts as a weak agonist at the delta and kappa opioid receptors subtypes. This binding inhibits the release of GABA from the nerve terminal, reducing the inhibitory effect of GABA on dopaminergic neurones. The increased activation of dopaminergic neurones and the release of dopamine into the synaptic cleft results in activation of the post-synaptic membrane. Continued activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with heroin use. Morphine is a powerful agonist at the opioid mu receptor subtype and activation of these receptors has a strong activating effect on the dopaminergic reward pathway.
Heroin modifies the action of dopamine in the nucleus accumbens and the ventral tegmental area of the brain – these areas form part of the brain’s ‘reward pathway’. Once crossing the blood-brain barrier, heroin is converted to morphine, which acts as a powerful agonist at the mu opioid receptors subtype. This binding inhibits the release of GABA from the nerve terminal, reducing the inhibitory effect of GABA on dopaminergic neurones. The increased activation of dopaminergic neurones and the release of dopamine into the synaptic results in sustained activation of the post-synaptic membrane. Continued activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with heroin use. Morphine is a weak agonist at the opioid kappa and delta receptor subtypes and activation of these receptors has a weak activating effect on the dopaminergic reward pathway.
Opioids are effective as analgesics when given in minute doses. They excite neurones in the periaqueductal grey matter and nucleus reticularis paragigantocellularis, which project to the nucleus raphe magnus. Descending pathways from the midbrain exert a strong inhibitory effect on pain transmission in the dorsal horn (mediated by 5-HT, enkephalins and noradrenaline). Opioids also inhibit pain transmission by acting directly on the dorsal horn, and by inhibiting excitation of peripheral nociceptive afferent neurones.
Acute alcohol administration has a number of effects on the receptors in the brain. Alcohol enhances the action of 5-HT and acetylcholine at 5-HT3 and nicotinic acetylcholine receptors, increasing excitatory neurotransmission at these receptors. Acute alcohol exposure can also inhibit the action of NMDA and kainite at glutamate receptors, inhibit voltage-sensitive Ca2+ channels and enhance the action of GABA at inhibitory GABA A receptors. Acute alcohol administration would decrease the output of a theoretical neurone expressing all of these receptors. However, due to the excitatory effect of alcohol on certain receptors, acute alcohol administration can lead to feelings of euphoria and the ‘high’ often associated with alcohol consumption.