Anxiety Disorders: Licata SC

Licata SC, Rowlett JK. · McLean Hospital/Harvard Medical School, Behavioral Psychopharmacology Research Laboratory, 115 Mill Street, Belmont, MA 02478, United States. · Pharmacol Biochem Behav. · Pubmed #18295321 links to  free full text

Abstract: Over the past several decades, benzodiazepines and the newer non-benzodiazepines have become the anxiolytic/hypnotics of choice over the more readily abused barbiturates. While all drugs from this class act at the GABA(A) receptor, benzodiazepine-type drugs offer the clear advantage of being safer and better tolerated. However, there is still potential for these drugs to be abused, and significant evidence exists to suggest that this is a growing problem. This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs. Moreover, the pharmacological and putative biochemical basis of the abuse-related behavior is discussed.

Licata SC, Platt DM, Cook JM, Sarma PV, Griebel G, Rowlett JK. · Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA. · J Pharmacol Exp Ther. · Pubmed #15687371 links to  free full text

Abstract: Benzodiazepines (BZs) are prescribed for a variety of disorders, including those involving anxiety and sleep, but have unwanted side effects that limit their use. Elucidating the GABA(A) receptor mechanisms underlying the behavioral effects of BZs will help develop new drugs having both maximum clinical benefit and minimum adverse side effects. A recently developed compound is SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one], which is a full agonist at GABA(A) receptors containing alpha(2)and alpha(3) subunits and a partial agonist at GABA(A) receptors containing alpha(1) and alpha(5) subunits. We assessed the ability of SL651498 to engender anxiolytic-like, motor, and subjective effects characteristic of BZ-type drugs in nonhuman primates. Anxiolytic-like activity was assessed with a conflict procedure in rhesus monkeys. Motor effects were evaluated in squirrel monkeys using observational techniques, and the subjective effects of SL651498 were assessed in squirrel monkeys trained to discriminate the nonselective BZ triazolam from saline. SL651498 engendered anxiolytic-like effects similar to conventional BZs. In addition, SL651498 fully induced muscle relaxation, but unlike conventional BZs, engendered minimal ataxia. In drug discrimination studies, SL651498 partially substituted for triazolam. This effect was blocked with the alpha(1) GABA(A) subtype-preferring antagonist beta-CCT (beta-carboline-3-carboxylate-t-butyl ester), implicating alpha(1) GABA(A) effects receptors in the subjective of SL651498. Together, these studies suggest that compounds such as SL651498 that have high intrinsic efficacy at alpha(2)GABA(A) and/or alpha(3)GABA(A) receptors may have clinical potential as anxiolytics and muscle relaxants. Moreover, a compound with reduced efficacy at alpha(1) GABA(A) and/or alpha(5) GABA(A) receptors may lack some of the motor and subjective effects associated with conventional BZs.