br Acknowledgements br Introduction Benzodiazepine BZ treatm

Acknowledgements
Introduction Benzodiazepine (BZ) treatment is widely used for quick and efficient anxiolytic and sedative responses. However, when the use is extended to longer periods, adverse effects emerge. These include tolerance to the initial drug effect, dependence as revealed by withdrawal symptoms after treatment discontinuation, and abuse problems (O'Brien, 2005, Rosenbaum, 2005). γ-Aminobutyric ha 47 type A (GABAA) receptors mediate the main effects of BZs (Korpi et al., 2002). BZs bind to the GABAA receptor and modulate their properties allosterically, which suggests that receptor adaptation could provide possible mechanisms for the development of tolerance and withdrawal symptoms. Many properties of the GABAA receptor complex have been observed to change during long-term BZ treatment. These include changes in the affinity and number of binding sites of BZs, altered receptor subunit composition, uncoupling of the BZ binding-site from the receptor channel function, and changes in the affinity and number of binding sites of GABA [for review, see Bateson, 2002, Hutchinson et al., 1996, Wafford, 2005]. Furthermore, GABAA receptor subunit-specificity has been suggested to have a role in the development of tolerance to BZs by downregulation of α5 subunit-containing receptors in the hippocampal dentate gyrus (Li et al., 2000, van Rijnsoever et al., 2004). Most of these studies have employed low to moderate doses of BZs, to which tolerance is quickly developed. Other neurotransmitter systems have also been implicated as mechanisms underlying tolerance and dependence to BZs. Especially interesting is the main fast excitatory neurotransmission system in the brain using glutamate as the transmitter. It has been suggested that the BZ-induced increase in inhibitory transmission is counteracted by the glutamatergic system through modified glutamate metabolism and/or modified receptor mechanisms (Allison and Pratt, 2003, Izzo et al., 2001). When mice are chronically co-treated with BZs and an antagonist of N-methyl-d-aspartate (NMDA) receptors, tolerance develops only partially (Steppuhn and Turski, 1993). Development of tolerance to BZs increases mRNA of NMDA receptor NR1 and NR2B subunits, which can be reversed by NMDA receptor antagonist MK-801 (Almirón et al., 2004). Furthermore, withdrawal symptoms are reduced by the administration of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists in a time-dependent manner: the former is effective when given at the time of withdrawal and the latter when given just prior to the appearance of the symptoms (Steppuhn and Turski, 1993). An increase in the number and activity of AMPA receptors in BZ tolerance is evidenced by increased binding of AMPA-receptor ligand [3H]Ro 48-8587 and by increased electrophysiological responses (Allison et al., 2005, Van Sickle and Tietz, 2002). Importantly, the GluR-A (GluR-1) subunit of AMPA-type glutamate receptors has been implicated in neuroadaptational mechanisms, such as long-term potentiation (LTP), learning and memory and drug addiction (Bannerman et al., 2006, Carlezon and Nestler, 2002). During hippocampal synaptic plasticity, GluR-A subunit-containing receptors are targeted to the cell membrane, a pivotal event in LTP (Hayashi et al., 2000, Shi et al., 2001). Pharmacological study of the role of GluR-A subunit-containing AMPA receptors in the development of BZ tolerance is hampered by the lack of a selective ligand. Fortunately, a knockout mouse line has been generated in which the hippocampal LTP is abolished but the synaptic transmission remains largely unmodified (GluR-A−/− mice; Zamanillo et al., 1999). This defect in LTP is rescued by genetic re-expression of the GluR-A subunit (Mack et al., 2001). In the GluR-A−/− mice, chronic morphine administration leads to reduced tolerance and withdrawal symptoms, indicating an interaction between sedative opioid and excitatory glutamate neurotransmitter systems and highlighting the role of AMPA receptor mechanisms in the effects of addictive drugs (Vekovischeva et al., 2001).