Separate GABA Afferents to Dopamine Neurons Mediate Acute Action of Opioids, Development of Tolerance, and Expression of Withdrawal

SummaryGABA release from interneurons in VTA, projections from the nucleus accumbens (NAc), and rostromedial tegmental nucleus (RMTg) was selectively activated in rat brain slices. The inhibition induced by μ-opioid agonists was pathway dependent. Morphine induced a 46% inhibition of IPSCs evoked from the RMTg, 18% from NAc, and IPSCs evoked from VTA interneurons were almost insensitive (11% inhibition). In vivo morphine treatment resulted in tolerance to the inhibition of RMTg, but not local interneurons or NAc, inputs. One common sign of opioid withdrawal is an increase in adenosine-dependent inhibition. IPSCs evoked from the NAc were potently inhibited by activation of presynaptic adenosine receptors, whereas IPSCs evoked from RMTg were not changed. Blockade of adenosine receptors selectively increased IPSCs evoked from the NAc during morphine withdrawal. Thus, the acute action of opioids, the development of tolerance, and the expression of withdrawal are mediated by separate GABA afferents to dopamine neurons

HSD2 neurons and the neural circuitry underlying sodium appetite

Thesis (Ph.D.)--University of Washington, 2018Maintaining sodium homeostasis is critical for survival and is regulated by both dietary ingestion of salt and retention of sodium by the kidney. Beyond the hedonic aspects of sodium intake, animals will develop a voracious appetite for sodium when sodium-deprived and consume sodium at concentrations that are normally strongly aversive. The neural circuitry responsible for motivating this sodium appetite has not been clearly deciphered, although a population of aldosterone-sensitive neurons in the hindbrain have been identified as a likely part of the circuitry. These neurons express the enzyme 11β-hydroxysteroid dehydrogenase type II (HSD2), which is required for a cell to respond to aldosterone. Sodium appetite can be artificially induced with intracranial infusions of aldosterone, and the HSD2 neurons in the hindbrain are activated following a series of manipulations that induce sodium appetite. The purpose of this thesis is to show a causal role for HSD2 neurons in sodium appetite, and to and explore the role of their downstream projections. Using a chemogenetic approach, we found that HSD2 neurons are both necessary and sufficient for sodium appetite, and do not regulate thirst. This appetite is specific for sodium, although activation of HSD2 neurons can decrease food intake. We confirmed the major downstream projections from the HSD2 neurons to unknown neurons in the bed nucleus of the stria terminalis (BNST), and to Foxp2 neurons in the parabrachial nucleus (PBN) and pre-locus coeruleus (pre-LC). However, activation of Foxp2 neurons was not sufficient to drive sodium intake, but does appear to have a role in the regulation of thirst. More specific genetic markers are needed to further define the role of the PBN/pre-LC in sodium appetite and thirst. Collectively, these data start to functionally define how the body regulates sodium intake in order to maintain sodium homeostasis