Elucidating the role of the striatal opioid system in cocaine reward and reinforcement.
It is well-established that cocaine-induced increases in dopamine levels within the striatum is important for mediating its rewarding effects. Interestingly, there are also numerous reports that cocaine enhances the expression enkephalin, an opioid peptide, in the striatum. This can lead to higher enkephalin tone and perturbed synaptic plasticity in the ventral pallidum, a region downstream of the striatum. We are investigating the ramifications of increased enkephalin on cocaine taking and seeking, as well as which specific brain regions and enkephalin-expressing neurons are affected by cocaine. To address this, we use a combination of techniques including RNAscope, intra-cranial pharmacology, transgenic mice with cell-selective loss of opioid peptides or receptors, and various behavioral measures of drug reward (e.g., runway model of drug self-administration, conditioned place preference, and operant drug self-administration).
Examining how opioid peptides and their receptors regulate striatopallidal circuit activity.
The endogenous opioid peptide enkephalin is expressed by GABAergic medium spiny neurons (MSNs) in the striatum and by neurons in the ventral pallidum, a region downstream of the striatum. The activity of MSNs and their output projections to the ventral pallidum are important for regulating motor activity and motivated behavior, such as drug seeking and taking. Administration of enkephalin or activation of the Gi-coupled opioid receptors restrains striatal GABA transmission within the striatopallidal circuit. The Dobbs lab is interested in understanding how enkephalin is released from these neurons and where it is acting to exert its effects on synaptic transmission. By using a combination of ex vivo brain slice electrophysiology, fast-scan cyclic voltammetry modified for the detection enkephalin, optogenetics, chemogenetics, and mice with targeted deletion of opioid peptides and receptors, we will investigate how enkephalin affects activity of the striatopallidal circuit in drug naïve and mice and following a history of opiate cocaine co-abuse.
Modeling polysubstance abuse in the mouse.
Research has begun to uncover the substrates underlying the abuse of opiates and cocaine separately; however, it has been difficult to determine the specific substrates and circuits driving the self-administration of opiates and cocaine in combination. This difficulty is due, in part, to a lack of validated rodent models of opiate and cocaine co-abuse and a lack of pharmacologic and genetic tools that target selective substrates. A major goal of the Dobbs lab is to refine rodent models of opiate and cocaine co-abuse by adopting a “reverse translational” approach. To this end, we collaborate with researchers studying human drug abusers and access existing drug intake in human populations to help guide the refinement and development of the rodent models. We are also interested in the development of new technology to facilitate reliable dual intravenous drug self-administration in the mouse.
- Runway Model of Drug Self-Administration
- Conditioned Place Prefernce
- Operant Drug Self-Adminstration
- RNA Scope
- Receptor Pharmacology
- Cell Selective Knockout Mice
- Ex Vivo Electrophysiology
- Ex Vivo Fast Scan Cyclic Voltammetry