Drug addiction is a major health concern. Patients often go untreated or undertreated, leading to relapse. Stress is a major antecedent of relapse. During protracted abstinence, elevated levels of brain norepinephrine (NE) engage maladaptive stress circuitry to promote reinstatement. Agonism at ?2-adrenergic receptors (?2- ARs) can dampen this elevated NE tone. Clonidine and guanfacine are ?2-agonists with positive preclinical results dampening stress-induced reinstatement of drug seeking behavior. However, ultimate rates of relapse in humans are unchanged by this treatment. We hypothesize that this is due to competition among the effects of ?2-AR agonism beyond its commonly cited role as an inhibitory autoreceptor on NE terminals.
We aim to investigate these effects in the bed nucleus of the stria terminalis (BNST), a component of the extended amygdala implicated in the integration of stress and reward in the dependent brain. In rodent models, direct administration of ?2 agonists reduces stress-induced reinstatement behaviors. In the BNST, ?2-AR agonism can inhibit release of both norepinephrine and glutamate from presynaptic terminals, with the latter being a specific effect on afferents from the parabrachial nucleus (PBN). Recently, we have found that ?2-AR agonism can produce enhancement of excitability in BNST. However, the mechanism underlying these effects, as well as the specific identification of the cells activated, are critical unknowns. This proposal aims to determine the mechanism underlying ?2-AR agonism-induced enhancement of glutamatergic transmission in BNST neurons and its relevance to circuit activity, and to begin to determine the impact of this regulation by understanding the population of cells regulated. We hypothesize that activation of postsynaptic ?2A-ARs enhances excitatory responses in a population of BNST neurons through inhibition of HCN channels. To test this hypothesis, we propose to combine electrophysiological studies aimed at uncovering the mechanism of guanfacine activating effects within the BNST with anatomical studies aimed at identifying the guanfacine-activated population of BNST neurons. Through these experiments, we hope to gain a better understanding of non-canonical effects of ?2-AR agonism and enhancement of activity in the BNST. In doing so, we will be able to study the behavioral and circuit relevance of this specific guanfacine effect and open the door for targeted therapeutics to maximize its clinical efficacy.
Drug dependent patients trying to maintain abstinence often relapse to their chosen of drug of abuse, with many citing stress as an antecedent to use and a lack of effective treatment to control the urge to use. Guanfacine is an ?2A-adrenergic receptor agonist that targets receptors for the brain stress neurotransmitter norepinephrine and has been used in both preclinical and clinical trials for addiction, often showing positive results such as reduced craving but not producing changes in ultimate rates of relapse. We hypothesize that the ineffectiveness on relapse is due to competition among the myriad effects of this drug and aim to study a non-canonical neuronal activating effect in the bed nucleus of the stria terminalis, an area of the brain known to be implicated in both stress and addiction disorders, through the complementary use of whole cell electrophysiology and neuroanatomical methods in the hopes that uncovering the mechanism underlying this effect will aid in future treatment of patients dependent on drugs of abuse.
| Harris, Nicholas A; Winder, Danny G (2018) Synaptic Plasticity in the Bed Nucleus of the Stria Terminalis: Underlying Mechanisms and Potential Ramifications for Reinstatement of Drug- and Alcohol-Seeking Behaviors. ACS Chem Neurosci 9:2173-2187 |
| Harris, Nicholas A; Isaac, Austin T; Günther, Anne et al. (2018) Dorsal BNST ?2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors. J Neurosci 38:8922-8942 |
