γ-
Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of
drug addiction,
pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar
therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (
BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of
BHF177 were compared with the agonist
baclofen. Unlike the
anxiolytic chlordiazepoxide,
baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and
BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or Vogel conflict test.
Baclofen increased punished drinking in the Vogel conflict test, but this effect may be attributable to the
analgesic actions of
baclofen. At the highest dose tested (2.5 mg/kg),
baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects.
BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not
sedative or pro-
convulsant,
baclofen and
BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that
BHF177 has little
sedative activity, no
anxiolytic-like profile, and minimal impairment of learning and memory in mice.