Cocaine addiction is a major health problem for which pharmacological treatments are lacking. Given the failure of many attempted pharmacotherapies and vaccines to reduce relapse, novel treatment strategies are needed. One limitation to standard therapies is that they must be systemically administered, and upon crossing the blood-brain barrier, they globally activate or inhibit neurons that express the receptor they target. Given that many receptors are ubiquitously expressed in different brain regions, our ability to couple this strategy with our existing knowledge of the neural circuitry of addiction is limited. Viral-mediated gene transfer strategies are bringing us one step closer in this effort, by allowing the restricted expression of specific genes in specific neurons. The advent of Designer Receptors Activated Exclusively by Designer Drugs (DREADDs) has brought us to the forefront of this effort. These synthetic receptors are modified muscarinic receptors that are fully functional in terms of their ability to activate G-protein signaling cascades, but have been engineered to no longer respond to their endogenous ligand, acetylcholine, and instead respond to the synthetic ligand, clozapine-N-oxide (CNO). Like standard pharmacotherapies, CNO can be administered systemically and crosses the blood-brain barrier to activate DREADDs. Viral-mediated transfer of DREADDs to specific neurons thus permits the specific targeting of pharmacotherapies to discrete neural circuit components, allowing us to use existing knowledge about addiction circuitry to control drug-seeking behavior. At this stage, the viral infection process is a neurosurgical one, but the process is no more invasive than the neurosurgical implantation of deep-brain stimulating (DBS) electrodes, a strategy which is currently being employed in treatment-resistant addicted patients. Nonetheless, once the viral vector has successfully infected neurons in the brain region of interest, it can be repeatedly activated or inactivated with systemic CNO, depending on the variety of DREADD chosen. For my dissertation work at MUSC, I discovered the infralimbic cortex to be a critical brain region for the inhibition of cocaine seeking (Peters et al., J Neurosi, 2008). This observation is related to the phenomenon of extinction, a procedure akin to cognitive behavioral therapy, which can be modeled in rats and is inversely related to relapse. Evidence suggests that the formation of an extinction memory involves recruitment of the infralimbic cortex to the addiction neural circuit, and when this circuit component is active, cocaine seeking is inhibited. If we take the infralimbic cortex offline using brain-site directed pharmacological inactivation, relapse occurs. Thus, constant activity in infralimbic cortex is necessary to suppress relapse. Unfortunately, extinction memory that is formed naturally through the process of behavioral therapy is relatively weak by comparison to the strong drug memories that drive relapse. Importantly, these drug reminders drive relapse through the prelimbic cortex, which lies just dorsal to the infralimbic cortex. This underscores the importance of therapies that can selectively target the ventral, infralimbic cortex to enhance extinction, without inadvertently promoting relapse through actions in its functional opponent, prelimbic cortex. The DREADD technology provides a way to do just that. My work in conditioned fear suggests that it is possible to pharmacologically simulate extinction memory by activating infralimbic cortex (Peters et al., Science, 2010). In this K01 proposal, I will attempt to elicit similar effects on cocaine seeking using the DREADD approach, which is especially advantageous for repeatedly stimulating infralimbic cortex. Very little is known about the efferent pathways by which infralimbic cortex controls extinction of addictive behaviors.
The second aim of this proposal will couple the DREADD technology with a novel, retrogradely acting CAV2 viral vector, which will permit the exclusive expression of DREADDs in specific infralimbic pathways. I already have a strong hypothesis that the nucleus accumbens shell and lateral hypothalamus may account for these infralimbic-based therapeutic effects. However, the Fos expression analyses I propose will simultaneously permit a more open-ended approach to identifying other candidate regions. Identifying the efferent pathways by which infralimbic cortex inhibits cocaine seeking will allow for more focused interventions and potentially reduce side effects. My strong mentoring team will provide me with state-of-the-art training in the proposed techniques, and I will be immersed in an enriched institutional environment. The proposed research will: 1) identify a novel treatment strategy for addiction with strong translational potential, 2) further establish my current research niche in extinction of addictive memories, and 3) lay the groundwork upon which I can build an independent research program in the addiction field.
Cocaine addiction is a serious public health problem, and there are currently no FDA-approved drugs for its treatment. The experiments outlined in this mentored K01 application will use novel viral-mediated gene transfer strategies, including Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), to artificially boost cognitive control over cocaine seeking by activating infralimbic neurons and simulating extinction memory. The studies are designed with a focus on the translational potential from rats to humans, with the goal of reducing susceptibility to relapse in cocaine addicts.
| Heinsbroek, Jasper A; Furbish, Amelia B; Peters, Jamie (2018) A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse. Neuropsychopharmacology 43:1492-1497 |
| Augur, Isabel F; Wyckoff, Andrew R; Aston-Jones, Gary et al. (2016) Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking. J Neurosci 36:10174-80 |
| Barker, Jacqueline M; Taylor, Jane R; De Vries, Taco J et al. (2015) Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking. Brain Res 1628:68-81 |
