Noninvasive Brain Stimulation Rescues Cocaine-Induced Prefrontal Hypoactivity and Restores Flexible Behavior.

BACKGROUND: To obtain desirable goals, individuals must predict the outcome of specific choices, use that information to direct appropriate actions, and adjust behavior accordingly in changing environments (behavioral flexibility). Substance use disorders are marked by impairments in behavioral flexibility along with decreased prefrontal cortical function that limits the efficacy of treatment strategies. Restoring prefrontal hypoactivity, ideally in a noninvasive manner, is an intriguing target for improving flexible behavior and treatment outcomes. METHODS: A behavioral flexibility task was used in Long-Evans male rats (n = 97) in conjunction with electrophysiology, optogenetics, and a novel rat model of transcranial alternating current stimulation (tACS) to examine the prelimbic cortex (PrL) to nucleus accumbens (NAc) core circuit in behavioral flexibility and determine whether tACS can restore cocaine-induced neural and cognitive dysfunction. RESULTS: Optogenetic inactivation revealed that the PrL-NAc core circuit is necessary for the ability to learn strategies to flexibly shift behavior. Cocaine self-administration history caused aberrant PrL-NAc core neural encoding and deficits in flexibility. Optogenetics that selectively activated the PrL-NAc core pathway prior to learning rescued cocaine-induced cognitive flexibility deficits. Remarkably, tACS prior to learning the task reestablished adaptive signaling in the PrL-NAc circuit and restored flexible behavior in a relatively noninvasive and frequency-specific manner. CONCLUSIONS: We establish a role of NAc core-projecting PrL neurons in behavioral flexibility and provide a novel noninvasive brain stimulation method in rats to rescue cocaine-induced frontal hypofunction and restore flexible behavior, supporting a role of tACS as a therapeutic to treat cognitive deficits in substance use disorders.

Drug-induced dysphoria is enhanced following prolonged cocaine abstinence and dynamically tracked by nucleus accumbens neurons.

Negative reinforcement models postulate that addicts use drugs to alleviate negative affective states (e.g. dysphoria) associated with withdrawal. In a pre-clinical model, rats exhibit negative affect to a normally rewarding tastant when it predicts impending, but delayed cocaine, and nucleus accumbens (NAc) neurons dynamically track this state. Here, we examined the effects of short versus prolonged experimenter-imposed cocaine abstinence on negative affect, cocaine seeking and self-administration. Rats were given 14 saccharin-cocaine sessions; NAc activity and affective responses to the taste (i.e. taste reactivity) were measured during sessions 1 and 14. Next, following 1 or 30 days of abstinence, taste reactivity and cell firing were recorded in a three-phase test session: (1) intraoral saccharin infusions, (2) extinction and (3) cocaine self-administration. Results showed that 30 days of abstinence led to a significant enhancement of aversive responses to the cocaine-paired tastant, accompanied by a dramatic decline in NAc phasic activity during tastant infusion. While extinction behavior did not differ across groups, NAc phasic firing reemerged during drug seeking. Further, when drug was again readily available, greater aversion to the drug-paired tastant before and after abstinence was associated with increased self-administration following prolonged (30-day) abstinence in rats classified as high (not low) aversive. Collectively, these findings show that drug-induced dysphoria is enhanced following prolonged cocaine abstinence and that NAc neural signaling is dynamic, dampening when negative affect is at its highest (phase 1), but transitioning back 'online' during subsequent drug seeking and taking (phases 2 and 3).

Age- and sex-dependent effects of methamphetamine on cognitive flexibility and 5-HT2C receptor localization in the orbitofrontal cortex of Sprague-Dawley rats.

Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age- and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HT2CR localization in the orbitofrontal cortex (OFC) in an age- and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT2C receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT2C receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT2C receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT2CR co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.

Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes.

RATIONALE: Adolescence is a period of considerable development of brain and behavior and is the time during which most drug use is initiated. OBJECTIVE: Age-dependent differences in motivated behaviors may be one of the factors that contribute to heightened vulnerability to developing substance use disorders, so we sought to compare age differences in methamphetamine (METH) and saccharin seeking. METHODS: Beginning during adolescence or adulthood, male and female Sprague-Dawley rats were trained to self-administer 0.1% saccharin (via liquid dipper cup) or intravenous METH at one of three doses (0.02, 0.05, 0.08 mg/kg/inf) under increasing fixed ratio schedules of reinforcement. Subsequently, responding for METH (0.02, 0.05, 0.08, or 0.1 mg/kg/inf) under progressive ratio response requirements was assessed in rats that acquired METH self-administration at the highest dose (0.08 mg/kg/inf). RESULTS: We found that adult-onset rats acquired METH self-administration more readily and exhibited higher motivation compared to adolescent-onset rats, although there were no differences in METH intake during acquisition. Adult rats also acquired saccharin self-administration more readily, but in contrast to METH, there were age and sex differences in saccharin intake driven by high levels of responding in adult females. CONCLUSIONS: These findings challenge the prevailing notion that adolescents are hypersensitive to reward and instead raise questions about the potential role of methodological factors on which rodent studies often differ.

Effects of ß-hydroxy-ß-methyl butyrate on working memory and cognitive flexibility in an animal model of aging.

OBJECTIVES: Normal aging results in cognitive decline and nutritional interventions have been suggested as potential approaches for mitigating these deficits. Here, we used rats to investigate the effects of short- and long-term dietary supplementation with the leucine metabolite ß-hydroxy-ß-methyl butyrate (HMB) on working memory and cognitive flexibility. METHODS: Beginning ∼12 months of age, male and female Long-Evans rats were given twice daily access to sipper tubes containing calcium HMB (450 mg/kg) or vehicle (285 mg/kg calcium lactate) in a sucrose solution (20% w/v). Supplementation continued for 1 or 7 months (middle- and old-age (OA) groups, respectively) before testing began. Working memory was assessed by requiring rats to respond on a previously sampled lever following various delays. Cognitive flexibility was assessed by training rats to earn food according to a visual strategy and then, once acquired, shifting to an egocentric response strategy. RESULTS: Treatment with HMB improved working memory performance in middle-age (MA) males and OA rats of both sexes. In the cognitive flexibility task, there was a significant age-dependent deficit in acquisition of the visual strategy that was not apparent in OA males treated with HMB. Furthermore, HMB ameliorated an apparent deficit in visual strategy acquisition in MA females. DISCUSSION: Together, these findings suggest that daily nutritional supplementation with HMB facilitates learning and improves working memory performance. As such, HMB supplementation may mitigate age-related cognitive deficits and may therefore be an effective tool to combat this undesirable feature of the aging process.

Perioperative considerations for patients with morbid obesity.

The anesthetic management of the MO patient requires an important focus on a number of issues beginning with a careful preoperative evaluation and synthesizing pre-existing disease processes with the anesthetic management plan. The common misperception that all MO patients are "full stomach" has been challenged and may be a nonissue. New approaches to pre-oxygenation to lessen the likelihood of desaturation during apnea may be a valuable tool if difficulty is encountered in tracheal intubation. In addition, promising results have been demonstrated with the use of the ILMA for ventilation and for blindly establishing tracheal tube placement. Proper patient positioning is essential to aid in successful intubation when a laryngoscope is employed. Intraoperative anesthetic management can be guided with a processed electroencephalogram monitor to help improve emergence and to enhance wakefulness in the PACU. Careful consideration must be given to postoperative analgesic needs by minimizing the use of opioids and employing nonopioid analgesics including NSAIDs, alpha2-adrenergic agonists, and low doses of ketamine.