Amino Acid Transmitter Systems
Catherine Belzung, Guy Griebel, Florence Dubois-Carmagnat and Jean Michel Darves-Bornoz
Amino acids correspond to a wide range of compounds, including precursors of catecholamine and serotonin synthesis (tyrosin and tryptophan respectively) as well as neurotransmitter systems such as the excitatory amino acids glutamate and aspartate and the inhibitory amino acids y-aminobutyric acid (GABA) and glycine. As few studies revealed anxiolytics acting on excitatory amino acids via the N-methyl-D-aspartate (NMDA) complex and/or the metabotropic glutamate (mGlu) receptors, only a short paragraph will be devoted to such agents. Furthermore, data suggesting abnormalities in excitatory amino acid systems in some anxiety disorders will be mentioned. On the other hand, we will focus on anxiolytic drugs acting on GABAergic neurotransmission, as most anxiolytics act via GABA-related mechanisms, first focusing on the mechanisms underlying the anxiolytic action of some anti-anxiety agents such as benzodiazepines (BZs) and second describing the use of such compounds in the clinic, in an attempt to link the pharmacology with neurochemical changes that have been observed in these disorders.
AMINO ACID NEUROTRANSMISSION
The anti-anxiety-like action of compounds acting on excitatory amino acid neurotransmission has mainly been investigated in pre-clinical studies, using animal models of anxiety. Indeed, because of multiple side effects of such compounds (ataxia, myorelaxation, impairment of learning and memory), such agents cannot be proposed as potential anxiolytic drugs in the clinic.
Glutamate and aspartate bind to two types of receptors: the ionotropic receptors (AMPA, kainite and NMDA receptors) and the metabotropic glutamate receptor. Among the ionotropic receptors, solely the NMDA receptor has been proposed as a potential target for anxiolytic agents in pre-clinical studies.
The NMDA complex consists of various binding sites, including a glutamate recognition site, a polyamine site, a glycine site, a phencyclidine site (channel site) and a Zn2+ site. Low doses of the non-competitive NMDA antagonist MK-801 or of the competitive NMDA antagonists AP5, AP7 and CPP elicited anxiolytic behaviour in several animal tests (see Chojnacka-Wójcik and Klodzinska (2001) for a recent review). Similar effects were observed with antagonists (7-CIKYN and 5, 7-CIKYN) and partial agonists (HA-966, ACPC and D-cycloserine) of the GlycineB receptors; however, none of these agents crosses the blood–brain barrier. Finally, discrepant results were obtained with antagonists of the polyamine site (ifenprodil and eliprodil) as these compounds are endowed with anxiolytic properties in some, but not all animal models of anxiety.
The mGlu receptors are a family of eight receptors designated mGlul through mGlu8. which can be divided in three groups based on the similarity of the amino acid sequence, pharmacology and second messenger coupling. The first group, which consists of mGlul and mGlu5, is positively coupled with phospholipase C and is sensitive to trans-ACPD as well as quisqualate. The second group, which includes mGlu2 and mGlu3, is negatively coupled to adenylate cyclase and is sensitive to trans -ACPD but not quisqualate. The third group, consisting of mGlu4, mGlu6, mGlu7 and mGlu8, is negatively coupled to adenylate cyclase and does not respond to trans-ACPD and quisqualate but rather binds specific compounds. Antagonists of Group I mGlu receptors such as S-4C3HPG or (S)-4CPG, as well as an antagonist of the mGlul (CPCCOEt) or of the mGlu5 (MPEP) elicited anxiolytic effects in pre-clinical models. Furthermore, LY-354740, an agonist of Group II mGlu receptors, displayed anxiolytic activity in several models of anxiety. In fact, as Group II mGlu receptors are localized presynaptically, their receptor agonists may inhibit glutamate release, so that they are parallel to the effects of Group I mGlu receptors antagonists. Finally, regarding Group II mGlu receptors ligands, the issue remains to be clarified as discrepant results have been obtained.
There is evidence suggesting that ethanol, a compound usually termed as alcohol, has been used in prehistoric times. It can therefore be considered as the first anxiolytic compound. Mead, a fermentation product of honey, is considered as the oldest alcoholicbeverage; it seems that it existed in the paleolithic age, about 8000 B.C. Alcoholic beverages are known to produce relaxation, elevation of mood, anxiolysis and disinhibition in response to social constraints. At higher doses it induces sedation. Most alcohol users drink occasionally (75% of the population of the USA). However, 15% of users are considered alcoholics. This highlights the great abuse potential of this compound.