Noradrenergic α2A-receptor stimulation in the ventral hippocampus reduces impulsive decision-making

Guanfacine, an alpha(2A)-adrenergic receptor agonist, is currently in use for treatment of a variety of psychiatric disorders that are associated with impulsive decision-making (e.g., attention-deficit hyperactivity disorder; ADHD). In animals and humans, the behavioral effects of adrenergic agents are presumed to involve neuromodulation of the prefrontal cortex, consistent with the demonstrated actions of dopaminergic agents. However, recent experimental work has shown that the ventral hippocampus (vHC) contributes to decision-making and impulse control, raising the possibility that the hippocampus may be an important site of action for these drugs. The purpose of this study was to examine the effect of local vHC infusions of guanfacine and other neuropharmacological agents on behavioral decisions that involve a trade-off between reward size and delay. Different cohorts of rats were implanted with bilateral guide cannulae targeting the vHC. We examined the animals' behavior in a touchscreen version of a delay discounting task following intra-vHC infusions of: (a) guanfacine (alpha(2A)-adrenergic receptor agonist), (b) SCH 23390 (dopamine D-1 receptor antagonist), and (c) muscimol/baclofen (GABA(A/B) agonists). Guanfacine led to a dose-dependent reduction in impulsive decision-making, increasing the animals' tolerance for delay in exchange for a larger reward. By contrast, infusion of SCH 23390 had no behavioral effects. Consistent with previous lesion studies, reversible pharmacological inactivation with muscimol/baclofen increased impulsive decision-making. These data provide the first evidence that guanfacine, a commonly used treatment for ADHD, may derive its clinical benefits through hippocampal stimulation, via alpha(2A)-adrenergic receptors.