FIGURE 21–8 Endogenous cannabinoid system. Activation of postsynaptic group I metabotropic glutamate receptors (mGluR1/5) leads to the G protein-mediated membrane-delimited activation of phospholipase C (PLC) that produces the second messengers inositol trisphosphate (IP3, not shown) and diacylglycerol (DAG). DAG can then be converted to the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) by DAG lipase. 2-AG is then released by unknown mechanisms to diffuse across the synaptic cleft where it acts as a full agonist at CB1 cannabinoid receptors on the presynaptic terminals. Activation of CB1 receptors by either endocannabinoids or exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) results in the inhibition of presynaptic neurotransmitter release.
activating a specific cannabinoid receptor, CB1. CB1 receptors are expressed at high levels in many brain regions, and they are primarily located on presynaptic terminals (Figure 21–8). Several endogenous brain lipids, including anandamide and 2-arachidonylglycerol (2-AG), have been identified as CB1 ligands. These ligands are not stored, as are classic neurotransmitters, but instead are rapidly synthesized by neurons in response to calcium influx or activation of metabotropic receptors (eg, by acetylcholine and glutamate). In further contradistinction to classic neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: they are released from postsynaptic neurons and travel backward across synapses, activating CB1 receptors on presynaptic neurons and suppressing transmitter release. This suppression can be transient or long lasting, depending on the pattern of activity. Cannabinoids may affect memory, cognition, and pain perception by this mechanism.
B. Nitric Oxide
The CNS contains a substantial amount of nitric oxide synthase (NOS) within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. Nitric oxide diffuses freely across membranes and thus has been hypothesized to be a retrograde messenger, although this has not been demonstrated conclusively. Perhaps the strongest case for a role of nitric oxide in neuronal signaling in the CNS is for long-term depression of synaptic transmission in the cerebellum.
C. Purines
Receptors for purines, particularly adenosine, ATP, UTP, and UDP, are found throughout the body, including the CNS. High concentrations of ATP are found in and released from catecholaminergic synaptic vesicles, and ATP may get converted to adenosine extracellularly by nucleotidases. Adenosine in the CNS acts on metabotropic A1 receptors. Presynaptic A1 receptors inhibit calcium channels and inhibit release of both amino acid and monoamine transmitters. ATP co-released with other neurotransmitters can bind to two classes of receptors. The P2X family of ATP receptors includes nonselective ligand-gated cation channels, whereas the P2Y family is metabotropic. The physiological roles for ATP co-release remain elusive, but pharmacological studies suggest these receptors are involved in memory, wakefulness, and appetite and may play roles in multiple neuropsychiatric disorders.