Heroin addiction is accompanied by an increase in detected hypocretin (orexin) neurons, and in narcoleptic mice deficient in these neurons, morphine can reverse cataplexy.

The streptozotocin (STZ) experimental model of sporadic Alzheimer’s disease (SAD), the most prevalent form of this type of dementia, has become a valuable tool to study the behavioral and morphological changes that occur during the gradual development of this pathology. We used the STZ experimental model in combination with the novel object recognition test (NORT) and immunohistochemical techniques to evaluate the recognition memory decline and morphological alterations in memory-related structures (hippocampus and cortex). Our analysis included five different time points after intracerebroventricular (ICV) administration of 3 mg/kg of STZ or artificial cerebrospinal fluid (aCSF) as a control. The time points included three distinct stages: early (15 and 30 days), intermediate (60 days), and late (90 and 120 days). We found that recognition memory impairment started in the intermediate stage and persisted through the later stages. Morphologically, we detected significant astrogliosis starting in the early stages, whereas cholinergic changes began in the intermediate stage. No neuronal loss was observed at any of the time points analyzed. Our results further support the hypothesis that astrogliosis constitutes an initial pathological event that may compromise the hippocampal cholinergic system and can contribute to the onset of recognition memory deficits.

Orexin (hypocretin) neuropeptides regulate numerous essential functions including sleep/wake state stability and reward processing. Orexin synthesizing neurons respond to drug cues and undergo structural changes following persistent drug exposure. Postmortem brains from opioid users and opioid-treated rodents have orexin somata that become ∼20% smaller and ∼50% more numerous and are postulated to promote hypermotivation for drug seeking though increased orexin release. Biophysical considerations suggest that the decreased soma size should increase cellular excitability; however, the impact of chronic opioids on firing ability, which drives peptide release, has not been explored. To test this, we assessed the intrinsic electrophysiological properties of orexin neurons by whole-cell recordings in slices from male orexin-EGFP mice treated for 2 weeks by daily morphine or saline injections. Paradoxically, we found that while daily morphine decreased the average soma size, it impaired excitability in a subpopulation of orexin neurons identified by electrophysiological criteria as “H-type” while entirely sparing “D-type” neurons. This impairment was manifest by smaller, broader action potentials, variable firing, and a downscaling of firing gain. These adaptations required more than a single morphine dose and recovered, along with soma size, after 4 weeks of passive withdrawal. Taken together, these observations indicate that daily opioid exposure differentially impacts H-type orexin neurons and predicts that the ability of these neurons to encode synaptic inputs into spike trains and to release neuropeptides becomes impaired in conjunction with opioid dependence.

Orexin (hypocretin) neuropeptides regulate numerous essential functions including sleep/wake state stability and reward processing. Orexin synthesizing neurons respond to drug cues and undergo structural changes following persistent drug exposure. Post-mortem brains from opioid users, and opioid-treated rodents have orexin somata that become ∼20 % smaller and ∼50% more numerous and are postulated to promote hyper-motivation for drug-seeking though increased orexin release. Biophysical considerations suggest that decreased soma size should increase cellular excitability, however the impact of chronic opioids on firing ability, which drives peptide release, has not been explored. To test this, we assessed the intrinsic electrophysiological properties of orexin neurons by whole-cell recordings in slices from male orexin-EGFP mice treated by daily morphine or saline injections for two weeks. Paradoxically, we found that while daily morphine decreased average soma size, it impaired excitability in a subpopulation of orexin neurons identified by electrophysiological criteria as “H-type”, while entirely sparing “D-type” neurons. This impairment was manifest by smaller, broader action potentials, variable firing and a downscaling of firing gain. These adaptations required more than a single morphine dose and recovered, along with soma size, after four weeks of passive withdrawal. Taken together, these observations indicate that daily opioid exposure differentially impacts H-type orexin neurons and predicts that the ability of these neurons to encode synaptic inputs into spike trains and to release neuropeptides becomes impaired in conjunction with opioid dependence. Significance Statement Orexin peptide signaling sustains motivation for opioid and cocaine seeking and chronic use upregulates orexin peptides and induces structural changes consistent with enhanced orexin release. However, the impact of chronic drug exposure on the ability of orexin neurons to fire action potentials which drive peptide release has not been explored. Paradoxically, we found that two weeks of daily morphine exposure selectively and reversibly impaired action potential firing in a distinct subpopulation of orexin neurons (H-cells). These findings further support a functional dichotomy among orexin neurons and imply that the ability of H-cells to encode input signals and release neuropeptides becomes impaired during development of opioid dependence.