Schizophrenia Research Trends

104Stephen I. Deutsch, John Mastropaolo and Barbara L. Schwartzthese, related compounds or related medication strategies as sole or adjuvant approaches forthe treatment of schizophrenia (Deutsch et al., 1997, 2003; Drapalski et al., 2001; Rosse etal., 2002). For example, topiramate is of interest because it addresses what may be“downstream” consequences of NRH, such as a dampening of GABAergic inhibitoryneurotransmission and excessive stimulation of the AMPA/kainate classes of glutamatereceptor. Topiramate is approved for use as an anticonvulsant in the pediatric population; itsprimary mechanisms of action include antagonism of excitatory amino acid receptors (e.g.,kainate receptors) and potentiation of GABAergic neurotransmission in a manner that differsfrom that of the benzodiazepines. Galantamine is of interest because of its action as a positiveallosteric modulator of nicotinic acetylcholine receptors; thus, galantamine would beexpected to potentiate cholinergic neurotransmission. In addition to its action as a positiveallosteric modulator of nicotinic acetylcholine receptors, galantamine is an inhibitor ofacetylcholinesterase and, thus, would be expected to increase and prolong the lifetime ofacetylcholine within the synapse. There are very exciting and provocative data suggestingthat deficient expression of the alpha7 subtype of nicotinic acetylcholine receptor occurs inschizophrenia. Conceivably, galantamine could target deficits of cholinergicneurotransmission, such as deficient expression of the alpha7 nicotinic acetylcholinereceptor. Because of the pathophysiological role attributed to the diminished expression ofalpha7 nicotinic acetylcholine receptors in schizophrenia (e.g., impaired sensory inhibitionand deficits of voluntary smooth pursuit eye movements), our laboratory examined the abilityof anabasine, a direct acting alpha7 nicotinic acetylcholine receptor agonist, to influence MK-801-elicited mouse popping behavior. Anabasine was able to attenuate popping behavior.Unfortunately, the alpha7 nicotinic acetylcholine receptor desensitizes rapidly upon exposureto agonist; thus, anabasine is not likely to be effective when administered chronically, whichwould be necessary in an illness like schizophrenia (Deutsch et al., 2005). However, our datasupport consideration of alpha7 nicotinic acetylcholine receptor agonist strategies that wouldnot be limited by the rapid desensitization of this receptor. From a practical clinicalperspective, our group has been conducting a pilot investigation of a strategy that combinesgalantamine, taking advantage of its property as a positive allosteric modulator of nicotinicacetylcholine receptors in general, with a selective alpha7 nicotinic acetylcholine receptoragonist in an effort to overcome the problem with receptor desensitization. Because ofagonist-induced receptor desensitization, an alpha7 nicotinic acetylcholine receptor agonistcould become a “functional” antagonist when administered for a chronic neuropsychiatricdisorder. From a theoretical perspective, it is hoped that galantamine will preserve thereceptor in a sensitive, as opposed to refractory, state and enhance the efficiency of couplingbetween the binding of the selective alpha7 nicotinic acetylcholine receptor agonist andchannel opening. Importantly, our animal paradigm of MK-801-elicited popping behaviorprovided a compelling preclinical rationale for pursuing alpha7 nicotinic acetylcholinereceptor agonist strategies for the treatment of schizophrenia. In fact, the MK-801-elicitedmouse popping paradigm also provided the preclinical rational for clinical examination oftopiramate and galantamine as sole adjuvant medication interventions (Deutsch et al., 2005).Our laboratory has also investigated MK-801’s ability to raise the threshold voltage forthe elicitation of tonic hindlimb extension in mice (an antiseizure effect of the drug). Thisparadigm reflects the endogenous tone of NMDA receptor-mediated neurotransmission.