Effect of oxytocin nasal spray on auditory automatic discrimination measured by mismatch negativity.

RATIONALE: As a treatment for cognitive dysfunction in schizophrenia, oxytocin nasal sprays potentially improve social cognition, facial expression recognition, and sense of smell. Mismatch negativity (MMN) is an event-related potential (ERP) reflecting auditory discrimination while MMN deficits reflect cognitive function decline in schizophrenia. OBJECTIVES: To determine whether oxytocin nasal spray affects auditory MMN METHODS: We measured ERPs in healthy subjects during an auditory oddball task, both before and after oxytocin nasal spray administration. Forty healthy subjects were randomly assigned to either the oxytocin or placebo group. ERPs were recorded during the oddball task for all subjects before and after a 24 international unit (IU) intranasal administration, and MMN was compared between the two groups. RESULTS: Participants who received oxytocin had significantly shorter MMN latencies than those who received a placebo. Oxytocin had no significant effect on the Change in MMN amplitude. CONCLUSIONS: The shortened MMN latencies that were observed after oxytocin nasal spray administration suggest that oxytocin may promote the comparison-decision stage.

Δ9-tetrahydrocannabinol: Drug discrimination abuse liability testing in female Lister Hooded rats: Trials, tribulations and triumphs.

INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.

Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal.

Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.

Coffee time: Low caffeine dose promotes attention and focus in zebrafish.

In this study we investigated the ability of zebrafish to discriminate visual signs and associate them with a reward in an associative-learning protocol including distractors. Moreover, we studied the effects of caffeine on animal performance in the task. After being trained to associate a specific image pattern with a reward (food) in the presence of other, distractor images, the fish were challenged to locate the exact cue associated with the reward. The distractors were same-colored pattern images similar to the target. Both the target and distractors were continually moved around the tank. Fish were exposed to three caffeine concentrations for 14 days: 0 mg/L (control, n = 12), 10 mg/L (n = 14), and 50 mg/L (n = 14). Zebrafish spent most of the time close to the target (where the reward was offered) under the effects of 0 and 10 mg/L caffeine, and the shortest latency to reach the target was observed for the 10-mg/L caffeine group. Both caffeine treatments (10 and 50 mg/L) increased the average speed and distance traveled when compared to the control group. This study confirms previous results showing that zebrafish demonstrate conditioned learning ability; however, low-dose caffeine exposure seems to favor visual cue discrimination and to increase zebrafish performance in a multicue discrimination task, in which primarily focus and attention are required in order to obtain the reward.

Spoken words are processed during dexmedetomidine-induced unresponsiveness.

BACKGROUND: Studying the effects of anaesthetic drugs on the processing of semantic stimuli could yield insights into how brain functions change in the transition from wakefulness to unresponsiveness. Here, we explored the N400 event-related potential during dexmedetomidine- and propofol-induced unresponsiveness. METHODS: Forty-seven healthy subjects were randomised to receive either dexmedetomidine (n=23) or propofol (n=24) in this open-label parallel-group study. Loss of responsiveness was achieved by stepwise increments of pseudo-steady-state plasma concentrations, and presumed loss of consciousness was induced using 1.5 times the concentration required for loss of responsiveness. Pre-recorded spoken sentences ending either with an expected (congruous) or an unexpected (incongruous) word were presented during unresponsiveness. The resulting electroencephalogram data were analysed for the presence of the N400 component, and for the N400 effect defined as the difference between the N400 components elicited by congruous and incongruous stimuli, in the time window 300-600 ms post-stimulus. Recognition of the presented stimuli was tested after recovery of responsiveness. RESULTS: The N400 effect was not observed during dexmedetomidine- or propofol-induced unresponsiveness. The N400 component, however, persisted during dexmedetomidine administration. The N400 component elicited by congruous stimuli during unresponsiveness in the dexmedetomidine group resembled the large component evoked by incongruous stimuli at the awake baseline. After recovery, no recognition of the stimuli heard during unresponsiveness occurred. CONCLUSIONS: Dexmedetomidine and propofol disrupt the discrimination of congruous and incongruous spoken sentences, and recognition memory at loss of responsiveness. However, the processing of words is partially preserved during dexmedetomidine-induced unresponsiveness. CLINICAL TRIAL REGISTRATION: NCT01889004.

Magnesium administration after experimental traumatic brain injury improves decision-making skills.

After sustaining a traumatic brain injury (TBI), a person's ability to make daily decisions can be affected. Simple tasks such as, deciding what to wear are no longer effortless choices, but are instead difficult decisions. This study explored the use of a discrimination task with a magnesium treatment in order to examine how decision-making skills are affected after TBI and if the treatment helped to attenuate cognitive and motor impairments. Thirty-one male rats were separated into MAG/TBI, VEH/TBI, or VEH/Sham groups. Pre-TBI, rats were trained to dig in the sand for a reinforcer. After establishment of consistent digging behavior rats received a bilateral frontal cortex injury. Rats received either an i.p. injection of 2 mmol/kg magnesium chloride or control at 4, 24, 72 h post-surgery. Dig task testing began 7 days post-injury, lasting for 4 weeks. The discriminations included two scent pairings; basil (baited) versus coffee then the reversal and then cocoa (baited) versus cumin then the reversal. The results indicated that the magnesium treatment was successful at attenuating cognitive and motor deficits after TBI. The results also indicated that the dig task is a sufficient operant conditioning task in the assessment of frontal functioning after TBI.

Pharmacological manipulation of GABA activity in nucleus subpretectalis/interstitio-pretecto-subpretectalis (SP/IPS) impairs figure-ground discrimination in pigeons: Running head: SP/IPS in figure-ground segregation.

Figure-ground segregation is a fundamental visual ability that allows an organism to separate an object from its background. Our earlier research has shown that nucleus rotundus (Rt), a thalamic nucleus processing visual information in pigeons, together with its inhibitory complex, nucleus subpretectalis/interstitio-pretecto-subpretectalis (SP/IPS), are critically involved in figure-ground discrimination (Acerbo et al., 2012; Scully et al., 2014). Here, we further investigated the role of SP/IPS by conducting bilateral microinjections of GABAergic receptor antagonist and agonists (bicuculline and muscimol, respectively) and non-NMDA glutamate receptor antagonist (CNQX) after the pigeons mastered figure-ground discrimination task. We used two doses of each drug (bicuculline: 0.1 mM and 0.05 mM; muscimol: 4.4 mM and 8.8 mM; CNQX: 2.15 mM and 4.6 mM) in a within-subject design, and alternated drug injections with baseline (ACSF). The order of injections was randomized across birds to reduce potential carryover effects. We found that a low dose of bicuculline produced a decrement on figure trials but not on background trials, whereas a high dose impaired performance on background trials but not on figure trials. Muscimol produced an equivalent, dose-dependent impairment on both types of trials. Finally, CNQX had no consistent effect at either dose. Together, these results further confirm our earlier hypothesis that inhibitory projections from SP to Rt modulate figure-ground discrimination, and suggest that the Rt and the SP/IPS provide a plausible substrate that could perform figure-ground segregation in avian brain.

The Discriminative Stimulus Properties of Drugs Used to Treat Depression and Anxiety.

Drug discrimination is a powerful tool for evaluating the stimulus effects of psychoactive drugs and for linking these effects to pharmacological mechanisms. This chapter reviews the primary findings from drug discrimination studies of antidepressant and anxiolytic drugs, including novel pharmacological mechanisms. The stimulus properties revealed from these animal studies largely correspond to the receptor affinities of antidepressant and anxiolytic drugs, indicating that subjective effects may correspond to either therapeutic or side effects of these medications. We discuss drug discrimination findings concerning adjunctive medications and novel pharmacologic strategies in antidepressant and anxiolytic research. Future directions for drug discrimination work include an urgent need to explore the subjective effects of medications in animal models, to better understand shifts in stimulus sensitivity during prolonged treatments, and to further characterize stimulus effects in female subjects. We conclude that drug discrimination is an informative preclinical procedure that reveals the interoceptive effects of pharmacological mechanisms as they relate to behaviors that are not captured in other preclinical models.

Impaired Cognitive Function after Perineuronal Net Degradation in the Medial Prefrontal Cortex.

Perineuronal nets (PNNs) are highly organized components of the extracellular matrix that surround a subset of mature neurons in the CNS. These structures play a critical role in regulating neuronal plasticity, particularly during neurodevelopment. Consistent with this role, their presence is associated with functional and structural stability of the neurons they ensheath. A loss of PNNs in the prefrontal cortex (PFC) has been suggested to contribute to cognitive impairment in disorders such as schizophrenia. However, the direct consequences of PNN loss in medial PFC (mPFC) on cognition has not been demonstrated. Here, we examined behavior after disruption of PNNs in mPFC of Long-Evans rats following injection of the enzyme chondroitinase ABC (ChABC). Our data show that ChABC-treated animals were impaired on tests of object oddity perception. Performance in the cross-modal object recognition (CMOR) task was not significantly different for ChABC-treated rats, although ChABC-treated rats were not able to perform above chance levels whereas control rats were. ChABC-treated animals were not significantly different from controls on tests of prepulse inhibition (PPI), set-shifting (SS), reversal learning, or tactile and visual object recognition memory. Posthumous immunohistochemistry confirmed significantly reduced PNNs in mPFC due to ChABC treatment. Moreover, PNN density in the mPFC predicted performance on the oddity task, where higher PNN density was associated with better performance. These findings suggest that PNN loss within the mPFC impairs some aspects of object oddity perception and recognition and that PNNs contribute to cognitive function in young adulthood.

Garlic active constituent s-allyl cysteine protects against lipopolysaccharide-induced cognitive deficits in the rat: Possible involved mechanisms.

Neuroinflammation is known as a risk factor for cognitive deficit and dementia and its incidence increases with aging. S-allyl cysteine (SAC) is the active and main component of aged garlic extract with anti-inflammatory, neuroprotective, and nootropic potential. In this study, the protective effect of SAC against lipopolysaccharide (LPS)-induced cognitive deficit in the rat was investigated. For induction of learning and memory impairment and neuroinflammation, LPS was intraperitoneally injected at a dose of 167µg/kg for 7 days and SAC was administered p.o. at doses of 25, 50, or 100mg/kg/day, 30min after LPS, for seven days. Treatment of LPS-injected rats with SAC at a dose of 100mg/kg improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination task, and retention and recall in passive avoidance test. In addition, SAC at the latter dose mitigated lipid peroxidation marker malondialdehyde (MDA) and augmented key antioxidant defensive elements including superoxide dismutase (SOD), catalase and glutathione (GSH) in hippocampal homogenate and lowered acetylcholinesterase activity. Meanwhile, SAC down-regulated hippocampal nuclear factor-B, toll-like receptor 4 (TLR4), glial fibrillary acidic protein (GFAP), and interleukin 1ß (IL-1ß) and up-regulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in addition to lowering iba1-immunoreactive intensity in the hippocampus of LPS-injected group. Taken together, SAC administration could mitigate LPS-induced cognitive deficits via attenuation of oxidative stress, neuroinflammation, astrogliosis, and acetylcholinesterase activity.

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed.

Nicotine Deprivation Produces Deficits in Pain Perception that are Moderately Attenuated by Caffeine Consumption.

During withdrawal, nicotine users experience aversive withdrawal symptoms, such as increased nociceptive processing, which may be responsible for subsequent use. Smokers often consume more caffeine than non-smokers and the combined effects of these two psychoactive drugs result in an enhanced analgesic effect of nicotine. We examined the effects of caffeine (via coffee consumption) and nicotine withdrawal on pain perception in minimally deprived smokers and non-smokers. Pain threshold and pain tolerance were assessed using a radiant heat stimulus before and 30 minutes after caffeine consumption. Nicotine deprivation (2 hrs) produced increases in pain threshold and decreases in pain tolerance representative of hyperalgesia. When smokers are nicotine deprived, caffeine consumption diminished baseline elevations in pain threshold, but had no effect on pain tolerance. These data suggest that caffeine consumption can dampen deficits in sensory discrimination related to pain during nicotine deprivation by reducing pain threshold to levels representative of non-smoking controls.

The continuous performance test (rCPT) for mice: a novel operant touchscreen test of attentional function.

RATIONALE: Continuous performance tests (CPTs) are widely used to assess attentional processes in a variety of disorders including Alzheimer's disease and schizophrenia. Common human CPTs require discrimination of sequentially presented, visually patterned 'target' and 'non-target' stimuli at a single location. OBJECTIVES: The aims of this study were to evaluate the performance of three popular mouse strains on a novel rodent touchscreen test (rCPT) designed to be analogous to common human CPT variants and to investigate the effects of donepezil, a cholinesterase inhibitor and putative cognitive enhancer. METHODS: C57BL/6J, DBA/2J and CD1 mice (n = 15-16/strain) were trained to baseline performance using four rCPT training stages. Then, probe tests assessed the effects of parameter changes on task performance: stimulus size, duration, contrast, probability, inter-trial interval or inclusion of flanker distractors. rCPT performance was also evaluated following acute administration of donepezil (0-3 mg/kg, i.p.). RESULTS: C57BL/6J and DBA/2J mice showed similar acquisition rates and final baseline performance following rCPT training. On probe tests, rCPT performance of both strains was sensitive to alteration of visual and/or attentional demands (stimulus size, duration, contrast, rate, flanker distraction). Relative to C57BL/6J, DBA/2J mice exhibited (1) decreasing sensitivity (d') across the 45-min session, (2) reduced performance on probes where the appearance of stimuli or adjacent areas were changed (size, contrast, flanking distractors) and (3) larger dose- and stimulus duration-dependent changes in performance following donepezil administration. In contrast, CD1 mice failed to acquire rCPT (stage 3) and pairwise visual discrimination tasks. CONCLUSIONS: rCPT is a potentially useful translational tool for assessing attention in mice and for detecting the effects of nootropic drugs.

Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market.

When synthetic cannabinoid compounds became controlled by state and federal governments, different, noncontrolled compounds began to appear as marijuana substitutes. Unlike the scheduled cannabinoids, the newer compounds have not been characterized for potency and efficacy in preclinical studies. The purpose of these experiments was to determine whether some of the more recent synthetic compounds sold as marijuana substitutes have behavioral effects similar to those of Δ-tetrahydrocannabinol (Δ-THC), the pharmacologically active compound in marijuana. The compounds UR-144, XLR-11, AKB-48 (APINACA), PB-22 (QUPIC), 5F-PB-22, and AB-FUBINACA were tested for locomotor depressant effects in male Swiss-Webster mice and subsequently for their ability to substitute for Δ-THC (3 mg/kg, intraperitoneally) in drug discrimination experiments with male Sprague-Dawley rats. UR-144, XLR-11, AKB-48, and AB-FUBINACA each decreased locomotor activity for up to 90 min, whereas PB-22 and 5F-PB-22 produced depressant effects lasting 120-150 min. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC. These findings confirm the suggestion that these compounds have marijuana-like psychoactive effects and abuse liability.

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure.

BACKGROUND: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment's efficacy in decreasing cocaine consumption is unknown. METHODS: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. RESULTS: In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. CONCLUSIONS: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.

Deficits in discrimination after experimental frontal brain injury are mediated by motivation and can be improved by nicotinamide administration.

One of the largest challenges in experimental neurotrauma work is the development of models relevant to the human condition. This includes both creating similar pathophysiology as well as the generation of relevant behavioral deficits. Recent studies have shown that there is a large potential for the use of discrimination tasks in rats to detect injury-induced deficits. The literature on discrimination and TBI is still limited, however. The current study investigated motivational and motor factors that could potentially contribute to deficits in discrimination. In addition, the efficacy of a neuroprotective agent, nicotinamide, was assessed. Rats were trained on a discrimination task and motivation task, given a bilateral frontal controlled cortical impact TBI (+3.0 AP, 0.0 ML from bregma), and then reassessed. They were also assessed on motor ability and Morris water maze (MWM) performance. Experiment 1 showed that TBI resulted in large deficits in discrimination and motivation. No deficits were observed on gross motor measures; however, the vehicle group showed impairments in fine motor control. Both injured groups were impaired on the reference memory MWM, but only nicotinamide-treated rats were impaired on the working memory MWM. Nicotinamide administration improved performance on discrimination and motivation measures. Experiment 2 evaluated retraining on the discrimination task and suggested that motivation may be a large factor underlying discrimination deficits. Retrained rats improved considerably on the discrimination task. The tasks evaluated in this study demonstrate robust deficits and may improve the detection of pharmaceutical effects by being very sensitive to pervasive cognitive deficits that occur after frontal TBI.

d-Cycloserine augmentation of cognitive remediation in schizophrenia.

d-Cycloserine (DCS) has been shown to enhance memory and, in a previous trial, once-weekly DCS improved negative symptoms in schizophrenia subjects. We hypothesized that DCS combined with a cognitive remediation (CR) program would improve memory of a practiced auditory discrimination task and that gains would generalize to performance on unpracticed cognitive tasks. Stable, medicated adult schizophrenia outpatients participated in the Brain Fitness CR program 3-5 times per week for 8weeks. Subjects were randomly assigned to once-weekly adjunctive treatment with DCS (50mg) or placebo administered before the first session each week. Primary outcomes were performance on an auditory discrimination task, the MATRICS cognitive battery composite score and the Scale for the Assessment of Negative Symptoms (SANS) total score. 36 subjects received study drug and 32 completed the trial (average number of CR sessions=26.1). Performance on the practiced auditory discrimination task significantly improved in the DCS group compared to the placebo group. DCS was also associated with significantly greater negative symptom improvement for subjects symptomatic at baseline (SANS score ≥20). However, improvement on the MATRICS battery was observed only in the placebo group. Considered with previous results, these findings suggest that DCS augments CR and alleviates negative symptoms in schizophrenia patients. However, further work is needed to evaluate whether CR gains achieved with DCS can generalize to other unpracticed cognitive tasks.

Neuropharmacological modulation of the P3-like event-related potential in a rat two-tone auditory discrimination task with modafinil and NS9283, a positive allosteric modulator of α4ß2 nAChRs.

The P300 (P3) event-related potential (ERP) is a neurophysiological signal believed to reflect cognitive processing of salient cues, and is thus used as a measure of attention and working memory. Additionally, P3 amplitude and latency is altered in neurological diseases and can be pharmacologically modulated. As P3-like ERPs can be recorded in rodents, it may serve as a potential translational biomarker of value for drug discovery. Here we investigated whether a positive allosteric modulator of α4ß2 nicotinic acetylcholine receptors, NS9283, and the psychostimulant modafinil could modulate P3-like ERPs in healthy adult rats performing an auditory oddball discrimination task. ERPs were recorded with electroencephalography electrodes implanted into mediodorsal (MD) thalamus, medial prefrontal cortex, hippocampus and auditory cortex (AC). P3-like ERPs were detected in all brain regions, displaying larger amplitudes in target trials compared to non-target trials. Administration of modafinil (64 mg/kg) decreased P3-like ERP latency in MD thalamus and AC, whereas NS9283 augmented P3-like ERP amplitude in MD thalamus at 0.3 mg/kg and in AC at 3.0 mg/kg. Additionally, N1 pre-attention peak amplitude in MD thalamus was increased with 0.3 mg/kg NS9283. Neither of the compounds enhanced task performance. Rather, modafinil lowered correct rejections in non-target trials. In summary, our findings reveal pharmacological modulation of the rat P3-like ERP in cortical and subcortical regions by modafinil and NS9283. These findings encourage further exploration of the rat P3-like ERP in order to promote the understanding of its meaning within cognition, as well as its applicability as a translatable biomarker in drug development.

Prenatal alcohol exposure is associated with altered subcellular distribution of glucocorticoid and mineralocorticoid receptors in the adolescent mouse hippocampal formation.

BACKGROUND: Accumulating evidence indicates that several of the long-term consequences of prenatal alcohol exposure (PAE) are the result of changes in the development and function of cortico-limbic structures, including the hippocampal formation. The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are key regulators of hippocampal formation development, structure, and functioning and, thus, are potential mediators of PAE's effects on this brain region. In the present studies, we assessed the impact of PAE on components of corticosteroid signaling pathways in the mouse hippocampal formation. METHODS: Throughout pregnancy, mouse dams were offered either 10% (w/v) ethanol sweetened with 0.066% (w/v) saccharin (SAC) or 0.066% (w/v) SAC alone using a limited (4-hour) access, drinking-in-the-dark paradigm. The hippocampal formation was isolated from naïve postnatal day 40 to 50 offspring, and subcellular fractions were prepared. Using immunoblotting techniques, we measured the levels of GR, MR, 11-ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), and the FK506-binding proteins 51 (FKBP51, FKBP5) and 52 (FKBP52, FKBP4). Finally, we determined the effect of PAE on context discrimination, a hippocampal-dependent learning/memory task. RESULTS: PAE was associated with reduced MR and elevated GR nuclear localization in the hippocampal formation, whereas cytosolic levels of both receptors were not significantly altered. FKBP51 levels were reduced, while FKBP52 levels were unaltered, and 11ß-HSD1 levels were increased in postnuclear fractions isolated from PAE mouse hippocampal formation. These neurochemical alterations were associated with reduced context discrimination. CONCLUSIONS: The data support a model in which PAE leads to increased nuclear localization of GRs secondary to reductions in FKBP51 and increases in 11ß-HSD1 levels in the adolescent mouse hippocampal formation. Persistent dysregulation of GR subcellular distribution is predicted to damage the hippocampal formation and may underlie many of the effects of PAE on hippocampal-dependent functioning.