ABSTRACT
Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which block the dopamine transporter and/or stimulate the release of dopamine, leading to a global elevation in extrasynaptic dopamine. These drugs are, however, associated with a series of unwanted side effects such as insomnia, anorexia, headache, stomach problems and potential drug abuse. Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. In this study we compare the effects of a selective D4 receptor agonist, A-412997, with methylphenidate or amphetamine in preclinical models of efficacy versus abuse liability. Both methylphenidate and A-412997 improved a temporally induced deficit in the rat novel object recognition task at doses 10-fold lower than those stimulating activity. In both cases, procognitive doses were associated with elevated extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex. In contrast to amphetamine, A-412997 did not mediate reward-related behaviour in the conditioned place preference paradigm, a preclinical rodent test used to assess potential abuse liability. Collectively, these data suggest that selective activation of the D4 receptor may represent a target for the treatment of attention deficit hyperactivity disorder without the potential drug abuse liability associated with current psychostimulant therapies.
Subject(s)
Acetamides/pharmacology , Cognition/drug effects , Dopamine Agonists/pharmacology , Motor Activity/drug effects , Pyridines/pharmacology , Receptors, Dopamine D4/agonists , Reward , Acetylcholine/metabolism , Amphetamine/pharmacology , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Administration Routes , Extracellular Fluid/drug effects , Male , Memory Disorders/drug therapy , Methylphenidate/pharmacology , Microdialysis/methods , Pattern Recognition, Visual/drug effects , Photic Stimulation , Rats , Rats, Sprague-DawleyABSTRACT
Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity and agonist efficacy at GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 subunit. However, which of these particular subtypes are responsible for the anticonvulsant effects of diazepam remains uncertain. In the present study, we examined the ability of diazepam to reduce pentylenetetrazoLe (PTZ)-induced and maximal electroshock (MES)-induced seizures in mice containing point mutations in single (alpha1H101R, alpha2H101R or alpha5H105R) or multiple (alpha125H-->R) alpha subunits that render the resulting GABA(A) receptors diazepam-insensitive. Furthermore, the anticonvulsant properties of diazepam, the alpha1- and alpha3-selective compounds zolpidem and TP003, respectively, and the alpha2/alpha3 preferring compound TP13 were studied against PTZ-induced seizures. In the transgenic mice, no single subtype was responsible for the anticonvulsant effects of diazepam in either the PTZ or MES assay and neither the alpha3 nor alpha5 subtypes appeared to confer anticonvulsant activity. Moreover, whereas the alpha1 and alpha2 subtypes played a modest role with respect to the PTZ assay, they had a negligible role in the MES assay. With respect to subtype-selective compounds, zolpidem and TP003 had much reduced anticonvulsant efficacy relative to diazepam in both the PTZ and MES assays whereas TP13 had high anticonvulsant efficacy in the PTZ but not the MES assay. Taken together, these data not only indicate a role for alpha2-containing GABA(A) receptors in mediating PTZ and MES anticonvulsant activity but also suggest that efficacy at more than one subtype is required and that these subtypes act synergistically.
