Ernesto Solis

While prevailing evidence supports that the amyloid cascade hypothesis is a key component of Alzheimer’s disease (AD) pathology, many recent studies indicate that the vascular system is also a major contributor to disease progression. Vascular dysfun

Although it is well established that the direct action of cocaine on centrally-located neural substrates is essential in mediating its reinforcing properties, cocaine induces very rapid immediate neural effects that imply cocaine’s action on peripheral neural substrates. We employed oxygen sensors coupled with high-speed amperometery to examine the effects of standard cocaine HCl that easily enters the blood-brain barrier and its blood-brain barrier-impermeable methiodide analog on oxygen levels in the nucleus accumbens in awake, freely-moving rats. Both drugs induced strong increases in nucleus accumbens oxygen levels, which displayed similarly short, second-scale latencies and a general similarity with oxygen increases induced by an auditory stimulus. This study provides additional support for the view that the immediate neural effects of iv cocaine are triggered via its direct action on peripherally located neural substrates and fast neural transmission to the central nervous system via somatosensory pathways.

While opioid abuse is an established medical and public health issue, the increased availability of highly potent synthetic opioids, such as fentanyl, has given rise to acute health complications, including a comatose state and death during drug overdose. Since respiratory depression that leads to acute hypoxia is the most dangerous complication of opioid drug use, we examined the effects of intravenous heroin and heroin contaminated with 10% fentanyl on oxygen levels in the nucleus accumbens (NAc) monitored using high-speed amperometry in freely moving rats. Additionally, we examined the effects of heroin, fentanyl, and their mixture on locomotion and temperatures in the NAc, temporal muscle, and skin. Both fentanyl and heroin at human-relevant doses (400 and 40 μg/kg, respectively) induced rapid, strong and transient decreases in NAc oxygen, indicative of brain hypoxia. When the heroin-fentanyl mixture was injected, the NAc hypoxic response was greatly potentiated in its duration, suggesting sustained hypoxia. In contrast to modest, monophasic brain temperature increases caused by heroin alone, the heroin-fentanyl mixture induced a biphasic temperature response, with a prominent postinjection decrease resulting from peripheral vasodilation. This hypothermic effect, albeit much smaller and more transient, was typical of fentanyl injected alone. Our findings indicate that accidental use of fentanyl instead of heroin, or even a relatively minor contamination of “street heroin” with fentanyl, poses great danger for acute health complications, including a comatose state and death.

Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100–200 μg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely-vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO₂levels appear to drive tonic increases in NAc glucose via local vasodilation. Heroin-induced changes in oxygen and glucose were rapid and preceded the slow and prolonged increase in brain temperature and were independent of enhanced intra-brain heat production, an index of metabolic activation. A very high heroin dose (3.2 mg/kg), corresponding to doses used by experienced drug users in overdose conditions, caused strong and prolonged brain hypoxia and hyperglycemia coupled with robust initial hypothermia that preceded an extended hyperthermic response. Our data suggest heroin-induced respiratory depression as a trigger for brain hypoxia, which leads to hyperglycemia, both of which appear independent of subsequent changes in brain temperature and metabolic neural activity.

Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds.

Proper entry of oxygen from arterial blood into the brain is essential for maintaining brain metabolism under normal conditions and during functional neural activation. However, little is known about physiological fluctuations in brain oxygen and their underlying mechanisms. To address this issue, we employed high-speed amperometry with platinum oxygen sensors in freely moving male rats. Recordings were conducted in the nucleus accumbens (NAc), a critical structure for sensorimotor integration. Rats were exposed to arousing stimuli of different nature (brief auditory tone, a 1-min novel object presentation, a 3-min social interaction with a conspecific, and a 3-min tail-pinch). We found that all arousing stimuli increased NAc oxygen levels. Increases were rapid (4-10-s onset latencies), modest in magnitude (1-3 M or 5-15% over baseline) and duration (5-20 min), and generally correlated with the arousing potential of each stimulus. Two strategies were used to determine the mechanisms underlying the observed increases in NAc oxygen levels. First, we showed that NAc oxygen levels phasically increase following intra-NAc microinjections of glutamate that excite accumbal neurons. Therefore, local neural activation with subsequent local vasodilation is involved in mediating physiological increases in NAc oxygen induced by arousing stimuli. Second, by employing oxygen monitoring in the subcutaneous space, a highly-vascularized area with no metabolic activity, we determined that physiological increases in NAc oxygen also depend on the rise in blood oxygen levels caused by respiratory activation. Due to the co-existence of different mechanisms governing oxygen entry into brain tissue, NAc oxygen responses differ from fluctuations in NAc glucose, which, within a normal behavioral continuum, are regulated exclusively by neuro-vascular coupling due to glucose’s highly stable levels in the blood. Finally, we discuss the relationship between physiological fluctuations in NAc oxygen and metabolic brain activation assessed by intra-brain heat production.