Page - (000188) - in Biomedical Chemistry: Current Trends and Developments

Recent evidence also shows that glutamatergic inputs, especially those contacting GABAergic PV-positive interneurons, may be developmentally regulated by repeated exposure to cannabinoids, which can result in disruption of the glutamatergic facilitation of PV- positive interneuron function and underlie the cognitive impairments seen in young adults that chronically abuse these drugs. Overstimulation of the CB1 receptor over the adolescent developmental period seems to alter frontal circuits leading to a schizophrenic-like disorder (Caballero, 2012). 2.4.3 GABAergic Neurotransmission and Cognition The amino acid γ-aminobutyric (GABA) is the main inhibitory neurotransmitter in the CNS. This neurotransmitter is synthesized by the enzyme glutamic acid descarboxylase (GAD) which catalyzes the decarboxylation of glutamate. Although the expression of GABA in the nervous system was first described in 1950 by Eugene Roberts and Jorge Awapara, it was only accepted as a neurotransmitter more than 10 years later (Roberts, 1950; Del Castillo, 1964). The difficulty in the identification of GABA as a neurotransmitter came from its enormous abundance in the vertebrate brain (which is about 1000 fold higher than monoamine transmitters), its simple structure and its role in the Krebs cycle, suggesting that it was likely more involved in metabolism than in intercellular signaling (Schuske, 2004). Cellular release of GABA may be mediated by several different mechanisms (Saransaari, 1992): (1) GABA can be released from neurons by exocytosis through synaptic vesicles, which is the most common mechanism of GABA release under physiological conditions; (2) it may simply leak through plasma membranes; (3) the plasma membrane GABA transporters-GAT may be reversed (due to changes in the electrochemical gradients); and (4) finally, ion channels in the membranes may also mediate GABA release despite the size of this molecule. The release of GABA in extra-synaptic sites activates non-synaptic GABAA receptors to generate tonic inhibitory currents. These synaptic and extra-synaptic modes of GABA action have been termed phasic and tonic effects, respectively, and control neuronal excitability in a different manner (Mody, 2004; Farrant,