Co-transmitters

CGRP is widely distributed throughout the peripheral and central nervous systems and is found ia sensory neurons and ia the autonomic and enteric nervous systems. In many iastances CGRP is co-localized with other neuroregulators, eg, ACh ia motor neurons, substance P, somatostatin, vasoactive intestinal polypeptide (VIP), and galanin ia sensory neurons. It is also present ia the CNS, with ACh ia the parabigeminal nucleus and with cholecystokinin (CCK) ia the dorsal parabrachial area. CGRP functions as a neuromodulator or co-transmitter. 

NPY is primarily (but not exclusively) synthesised and released by neurons, which in the peripheral nervous system are predominantly sympathetic neurons [1]. In most cases, NPY acts as a co-transmitter that is preferentially released upon high frequency nerve stimulation. NPY can be metabolised by the enzyme dipeptidylpeptidase IV (also known as CD26) to generate the biologically active fragment NPY3 36. 

Evidence suggests that co-transmitters in a terminal have their own autoreceptors and, in some cases, activation of their own presynaptic receptor can influence the release of the co-stored, classical transmitter. For instance, activation of P2Y-autoreceptors by ATP is thought to affect the release of noradrenaline from sympathetic neurons. However, in other cases, feedback modulation of release of classical and their associated co-transmitters seems to have separate control mechanisms. This would suggest that either the two types of transmitter are concentrated in different nerve terminals or that mechanisms for regulating release target different vesicles located in different zones of the terminal (Burnstock 1990). 

The basal forebrain is an important way station in the activation of the cerebral cortex from the reticular activating system. AMPA and NMDA injections into the basal forebrain increase wakefulness and reduce sleep (Cape Jones, 2000 Manfridi et al, 1999), effects that are blocked by AMPA and NMDA receptor antagonists (Manfridi et al, 1999). The excitatory cortical projections of the basal forebrain have long been considered purely cholinergic, but many basal forebrain neurons that project to the cortex are now known to contain Glu, which may function as a co-transmitter or even as the primary excitatory neurotransmitter (Manns et al, 2001). The basal forebrain also affects vigilance via synapses to HCT cells in the lateral hypothalamus some of these synapses are glutamatergic (Henny Jones, 2006). 

GABA is the predominant intrinsic transmitter of the basal ganglia. Inhibition and disinhibition are considered to be the most important modes of information transfer in the basal ganglia. Ninety-five percent of all neurons in the striatum are GABAergic medium spiny neurons. These neurons are the striatal output neurons. The medium spiny neurons which give rise to the direct pathway also contain substance P or dynorphin as a co-transmitter, while those striatal output neurons that give rise to the indirect pathway contain enkephalin as a co-transmitter. Most striatal interneurons, as well as neurons in GPe, GPi and SNr are also GABAergic. Because striatal and GPe... 

There is now evidence that the mammalian central nervous system contains several dozen neurotransmitters such as acetylcholine, noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), together with many more co-transmitters, which are mainly small peptides such as met-enkephalin and neuromodulators such as the prostaglandins. It is well established that any one nerve cell may be influenced by more than one of these transmitters at any time. If, for example, the inhibitory amino acids (GABA or glycine) activate a cell membrane then the activity of the membrane will be depressed, whereas if the excitatory amino acid glutamate activates the nerve membrane, activity will be increased. The final response of the nerve cell that receives all this information will thus depend on the balance between the various stimuli that impinge upon it. 

No attempt will be made to give an overview of the main pathways of the several dozen neurotransmitters, neuromodulators and co-transmitters which are possibly involved in the aetiology of mental illness. Instead a summary is given of the relevant pathways involved in the synthesis and metabolism of those transmitters which have conventionally been considered to be involved in the major psychiatric and neurological diseases and through which the psychotropic drugs used in the treatment of such diseases are believed to operate. 

Whittaker VP. Vasoactive intestinal polypeptide (VIP) as a cholinergic co-transmitter some recent results. Cell Biol Int Rep 1989 13 1039-1051. 

Like presynaptic dopamine autoreceptors, presynaptic histamine autoreceptors are activated by the released endogenous transmitter to inhibit further histamine release, as shown by the increase in histamine release caused by antagonists at H3 receptors a definite piece of physiology. Evidence has been presented recently that cardiac postganglionic sympathetic neurons of the guinea pig synthesize and release histamine as a co-transmitter (Li et al. 2003 2006). These noradrenaline-histamine neurons possess H3 autoreceptors which, when activated, depress the release of both noradrenaline and histamine - unlike the D2-like autoreceptors of dopamine-neurotensin neurons which modulate the release of the two cotransmitters in opposite direction (see Section 2.2). It would be of interest to see whether, conversely, activation of ot2-autoreceptors inhibits the release of histamine in the guinea pig heart. 

ATP is a well-established co-transmitter to noradrenaline in the central (Poelchen et al. 2001) as well as peripheral (von Kugelgen and Starke 1991) nervous system. Therefore, the functions of presynaptic P2X receptors have been investigated in various preparations containing noradrenergic nerve terminals (Cunha and Ribeiro 2000). Early evidence for a stimulation and positive feedback modulation of noradrenaline via presynaptic P2X receptors has been obtained in sympathetic neurons (Boehm 1999). At the neuromuscular junction, ATP stimulated the release of acetylcholine (1994), and this effect was suggested to be mediated by presynaptic P2X7 receptors (Moores et al. 2005). 

With regard to the neurotransmitters involved in these circuits, the striatal neurons are mainly GABAergic and they also contain met-enkephalin as a co-transmitter as part of the indirect pathway D2 receptors are also present. In the direct pathway, in addition to GABA, dynorphin and substance P act as co-transmitters D, receptors are predominant in the direct pathway. 

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