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Although treatable with antiretroviral therapy, HIV infection persists in people living with HIV (PLWH). It is well known that the HIV virus finds refuge in places for which antiretroviral medications do not reach therapeutic levels, mainly the CNS. It is clear that as PLWH age, the likelihood of developing HIV-associated neurological deficits increases. At the biochemical level neurological dysfunction is the manifestation of altered cellular function and ineffective intercellular communication. In this review, we examine how intercellular signaling in the brain is disrupted in the context of HIV. Specifically, the concept of how the blood-brain barrier can be a convergence point for crosstalk, is explored. Crosstalk between the cells of the neurovascular unit (NVU) (endothelium, pericytes, astrocytes, microglia and neurons) is critical for maintaining proper brain function. In fact, the NVU allows for rapid matching of neuronal metabolic needs, regulation of blood-brain barrier (BBB) dynamics for nutrient transport and changes to the level of immunosurveillance. This review invites the reader to conceptually consider the BBB as a router or convergence point for NVU crosstalk, to facilitate a better understanding of the intricate signaling events that underpin the function of the NVU during HIV associated neuropathology. [ABSTRACT FROM AUTHOR]

Previous research with the radial maze has found evidence that rats can remember both places that they have already been (retrospective coding) and places they have yet to visit (prospective coding; Cook, R. G., Brown, M. F., & Riley, D. A. (1985). Flexible memory processing by rats: Use of prospective and retrospective information in the radial maze. "Journal of Experimental Psychology: Animal Behaviour Processes, 11", 453-469). Such "dual coding" also has been found in pigeons using a radial maze analog in which insertion of a delay at different points during a trial affects performance differentially depending on where in the trial it is inserted. When a delay is interpolated either early or late in a trial, there is minimal disruption of performance compared with when it is interpolated in the middle of the trial. However, the analysis required with this procedure requires the assumption that if errors made on control trials are subtracted from errors made in delay trials, the remaining errors can be directly attributed to the delay. But errors may also be attributed to the changing criterion for making a response as the trial proceeds. Furthermore, the animal's tendency to choose alternatives in a systematic order may also affect its need to remember the sequence of choices made (and yet to be made) on each trial. In the present research, we avoided having to make this assumption by giving the pigeons a two-alternative choice at the time of testing and by randomly determining for the pigeon the order of predelay choices on each trial. This change in procedure resulted in comparable performance as a function of where in the trial the test occurred on both control and delay trials. The effect of the delay was to produce a general decrement in performance independent of where it occurred in the trial. (Contains 4 figures.)

This study introduces a new methodology that allows for the direct investigation of the interaction between a drug's interoceptive stimulus effects and its reinforcing effects, and how learning shapes that interaction. At this point in the history of the science of behavior, a focus on neuroscience-based outcomes has become dominant in neuropsychiatric fields at the preclinical and clinical levels of analysis. [Extracted from the article]

Substance use disorders (SUDs) are heterogeneous and complex, making the development of translationally predictive rodent and nonhuman primate models to uncover their neurobehavioral underpinnings difficult. Neuroscience‐focused outcomes have become highly prevalent, and with this, the notion that SUDs are disorders of the brain embraced as a dominant theoretical orientation to understand SUD etiology and treatment. These efforts, however, have led to few efficacious pharmacotherapies, and in some cases (as with cocaine or methamphetamine), no pharmacotherapies have translated from preclinical models for clinical use. In this theoretical commentary, we first describe the development of animal models of substance use behaviors from a historical perspective. We then define and discuss three logical fallacies including 1) circular explanation, 2) affirming the consequent, and 3) reification that can apply to developed models. We then provide three case examples in which conceptual or logical issues exist in common methods (i.e., behavioral economic demand, escalation, and reinstatement). Alternative strategies to refocus behavioral models are suggested for the field to better bridge the translational divide between animal models, the clinical condition of SUDs, and current and future regulatory pathways for intervention development. [ABSTRACT FROM AUTHOR]

Emergent harms presented by the co-use of opioids and methamphetamine highlight the broader public health challenge of preventing and treating opioid and stimulant co-use. Development of effective therapeutics requires an understanding of the physiological mechanisms that may be driving co-use patterns, specifically the underlying neurobiology of co-use and how they may facilitate (or be leveraged to prevent) continued use patterns. This narrative review summarizes largely preclinical data that demonstrate clinically-meaningful relationships between the dopamine and opioid systems with direct implications for opioid and stimulant co-use. Synthesized conclusions of this body of research include evidence that changes in the dopamine system occur only once physical dependence to opioids develops, that the chronicity of opioid exposure is associated with the severity of changes, and that withdrawal leaves the organism in a state of substantive dopamine deficit that persists long after the somatic or observed signs of opioid withdrawal appear to have resolved. Evidence also suggests that dopamine supersensitivity develops soon after opioid abstinence and results in increased response to dopamine agonists that increases in magnitude as the abstinence period continues and is evident several weeks into protracted withdrawal. Mechanistically, this supersensitivity appears to be mediated by changes in the sensitivity, not quantity, of dopamine D2 receptors. Here we propose a neural circuit mechanism unique to withdrawal from opioid use with implications for increased stimulant sensitivity in previously stimulant-naïve or inexperienced populations. These hypothesized effects collectively delineate a mechanism by which stimulants would be uniquely reinforcing to persons with opioid physical dependence, would contribute to the acute opioid withdrawal syndrome, and could manifest subjectively as craving and/or motivation to use that could prompt opioid relapse during acute and protracted withdrawal. Preclinical research is needed to directly test these hypothesized mechanisms. Human laboratory and clinical trial research is needed to explore these clinical predictions and to advance the goal of developing treatments for opioid-stimulant co-use and/or opioid relapse prevention and withdrawal remediation. [ABSTRACT FROM AUTHOR]