Noradrenergic α2A-receptor stimulation in the ventral hippocampus reduces impulsive decision-making.
BACKGROUND
Guanfacine, an α2A-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.


OBJECTIVE
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.


METHODS
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 (α2A-adrenergic receptor agonist), (b) SCH 23390 (dopamine D1 receptor antagonist), and (c) muscimol/baclofen (GABAA/B agonists).


RESULTS
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.


CONCLUSIONS
These data provide the first evidence that guanfacine, a commonly used treatment for ADHD, may derive its clinical benefits through hippocampal stimulation, via α2A-adrenergic receptors.
Department of Psychology, McGill University, Montreal, QC, H3A 1B1, Canada.
Andrew R
AR
Abela
Yogita
Y
Chudasama
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D065786:Delay Discounting / Q000187:drug effects / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D016316:Guanfacine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D020318:Rats, Long-Evans; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D012201:Reward; D013997:Time Factors
D058647:Adrenergic alpha-2 Receptor Agonists; D001552:Benzazepines; D018492:Dopamine Antagonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D018341:Receptors, Adrenergic, alpha-2; D017447:Receptors, Dopamine D1; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C534628:SCH 23390; D009118:Muscimol; D016316:Guanfacine; D001418:Baclofen