Preparing Physicians to Treat Addiction: Inclusion of Dedicated Addiction Training During Internal Medicine Residency.

BACKGROUND: Physicians in internal medicine lack comfort and skills required to diagnose and treat substance use disorder (SUD). Formal training in substance use treatment within primary care training has traditionally been inconsistent and sparse. The purpose of this study is to assess the impact of a longitudinal experiential addiction curriculum on the attitudes and experiences of graduates from a primary care/internal medicine residency program that included formal addiction didactics, rotations in an outpatient addiction clinic embedded within the resident primary care clinic, and exposure to addiction medicine faculty across treatment settings. METHODS: A survey was emailed to all graduates from a single academic primary care residency program who graduated between 2016 and 2018 (n = 53). The survey assessed pharmacotherapy for SUD prescribing patterns, comfort with SUD pharmacotherapy, overall comfort treating SUD, experience correcting stigmatizing language, and providing guidance to colleagues on the care of patients with SUD. A subset of respondents (n = 14) were interviewed regarding their experience with the residency program's addiction medicine curriculum and its impact on their current clinical practice. RESULTS: Sixty percent (n = 28) of graduates responded to the survey. All respondents felt comfortable using medications to treat SUD. Eighty-four percent perceived themselves as more comfortable using pharmacotherapy to treat SUD than their colleagues. Qualitative interviews revealed that this addiction medicine training shaped participants' attitudes toward patients with SUD and imparted them with the skills to address stigmatizing language. Participants described how they have become ambassadors of addiction medicine in their workplace and a resource to colleagues with less comfort in the management of SUD. CONCLUSION: Graduates of a primary care/internal medicine residency with a dedicated addiction medicine curriculum are comfortable prescribing pharmacotherapy for SUD, taking an active role in reducing SUD-related stigma, and serving as a resource for colleagues.

Tonic or Phasic Stimulation of Dopaminergic Projections to Prefrontal Cortex Causes Mice to Maintain or Deviate from Previously Learned Behavioral Strategies.

Dopamine neurons in the ventral tegmental area (VTA) encode reward prediction errors and can drive reinforcement learning through their projections to striatum, but much less is known about their projections to prefrontal cortex (PFC). Here, we studied these projections and observed phasic VTA-PFC fiber photometry signals after the delivery of rewards. Next, we studied how optogenetic stimulation of these projections affects behavior using conditioned place preference and a task in which mice learn associations between cues and food rewards and then use those associations to make choices. Neither phasic nor tonic stimulation of dopaminergic VTA-PFC projections elicited place preference. Furthermore, substituting phasic VTA-PFC stimulation for food rewards was not sufficient to reinforce new cue-reward associations nor maintain previously learned ones. However, the same patterns of stimulation that failed to reinforce place preference or cue-reward associations were able to modify behavior in other ways. First, continuous tonic stimulation maintained previously learned cue-reward associations even after they ceased being valid. Second, delivering phasic stimulation either continuously or after choices not previously associated with reward induced mice to make choices that deviated from previously learned associations. In summary, despite the fact that dopaminergic VTA-PFC projections exhibit phasic increases in activity that are time locked to the delivery of rewards, phasic activation of these projections does not necessarily reinforce specific actions. Rather, dopaminergic VTA-PFC activity can control whether mice maintain or deviate from previously learned cue-reward associations.SIGNIFICANCE STATEMENT Dopaminergic inputs from ventral tegmental area (VTA) to striatum encode reward prediction errors and reinforce specific actions; however, it is currently unknown whether dopaminergic inputs to prefrontal cortex (PFC) play similar or distinct roles. Here, we used bulk Ca2+ imaging to show that unexpected rewards or reward-predicting cues elicit phasic increases in the activity of dopaminergic VTA-PFC fibers. However, in multiple behavioral paradigms, we failed to observe reinforcing effects after stimulation of these fibers. In these same experiments, we did find that tonic or phasic patterns of stimulation caused mice to maintain or deviate from previously learned cue-reward associations, respectively. Therefore, although they may exhibit similar patterns of activity, dopaminergic inputs to striatum and PFC can elicit divergent behavioral effects.

D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells.

The D3 dopamine receptor, a member of the Gi-coupled D2 family of dopamine receptors, is expressed throughout limbic circuits affected in neuropsychiatric disorders, including prefrontal cortex (PFC). These receptors are important for prefrontal executive function because pharmacological and genetic manipulations that affect prefrontal D3 receptors alter anxiety, social interaction, and reversal learning. However, the mechanisms by which D3 receptors regulate prefrontal circuits and whether D3 receptors regulate specific prefrontal subnetworks remains unknown. Here, we combine dopamine receptor reporter lines, anatomical tracing techniques, and electrophysiology to show that D3 receptor expression defines a novel subclass of layer 5 glutamatergic pyramidal cell in mouse PFC (either sex). D3-receptor-expressing pyramidal neurons are electrophysiologically and anatomically separable from neighboring neurons expressing D1 or D2 receptors based on their dendritic morphology and subthreshold and suprathreshold intrinsic excitability. D3-receptor-expressing neurons send axonal projections to intratelencephalic (IT) targets, including contralateral cortex, nucleus accumbens, and basolateral amygdala. Within these neurons, D3 receptor activation was found to regulate low-voltage-activated CaV3.2 calcium channels localized to the axon initial segment, which suppressed action potential (AP) excitability, particularly when APs occurred at high frequency. Therefore, these data indicate that D3 receptors regulate the excitability of a unique, IT prefrontal cell population, thereby defining novel circuitry and cellular actions for D3 receptors in PFC.SIGNIFICANCE STATEMENT The D3 dopamine receptor, a member of the Gi-coupled D2 family of dopamine receptors, are expressed throughout limbic circuits, including prefrontal cortex (PFC). They are of broad interest as a site for therapeutic intervention in serious mental illness, yet we know very little about their distribution or function within PFC. Here, we show that D3 receptors define a unique population of glutamatergic principal cells in mouse PFC that largely lack expression of D1 or D2 receptors. Within these cells, we find that D3 receptors regulate the ability to generate high-frequency action potential bursts through mechanisms not supported by other dopamine receptors. These results define unique circuitry and cellular actions for D3 receptors in regulating PFC networks.

ß-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment.

G-protein-coupled receptors (GPCRs) initiate a variety of signaling cascades, depending on effector coupling. ß-arrestins, which were initially characterized by their ability to "arrest" GPCR signaling by uncoupling receptor and G protein, have recently emerged as important signaling effectors for GPCRs. ß-arrestins engage signaling pathways that are distinct from those mediated by G protein. As such, arrestin-dependent signaling can play a unique role in regulating cell function, but whether neuromodulatory GPCRs utilize ß-arrestin-dependent signaling to regulate neuronal excitability remains unclear. Here, we find that D3 dopamine receptors (D3R) regulate axon initial segment (AIS) excitability through ß-arrestin-dependent signaling, modifying CaV3 voltage dependence to suppress high-frequency action potential generation. This non-canonical D3R signaling thereby gates AIS excitability via pathways distinct from classical GPCR signaling pathways.