Kissorphin improves spatial memory and cognitive flexibility impairment induced by ethanol treatment in the Barnes maze task in rats.

Acute and chronic ethanol intake, as well as ethanol withdrawal, exert learning disabilities. Of all the neurotransmitters in the brain, endogenous opioid peptides are thought to participate in ethanol effects. Kisspeptins, including kisspeptin-10, are peptides produced in the part of brain involved in the consolidation of memory and orientation. A new derivative of kisspeptin-10 is kissorphin (Tyr-Asn-Trp-Asn-Ser-Phe-NH2), a peptide with anti-opioid-activity. Hence, the aim of our study was to reveal whether kissorphin (1, 3, and 10 nmol, i.v.) was able to prevent or reverse learning deficits such as spatial memory retention and reversal learning induced by acute ethanol administration (1 × 1.75 g/kg., i.p.) and reversal learning induced by ethanol withdrawal (11-13 days from 'binge-like' ethanol input-5.0 g/kg, i.g. for 5 days) in the Barnes maze task in rats. Our study demonstrated that acute kissorphin administration prevented spatial memory (higher doses) impairments and attenuated reversal learning deficits induced by acute ethanol administration, although the reversal learning impairment may have been due to spatial learning impairments rather than cognitive flexibility impairments. Moreover, kissorphin given prior to first reversal learning trial for 3 consecutive days in the Barnes maze task during withdrawal from 'binge-like' ethanol administration, significantly attenuated cognitive flexibility impairment in the ethanol-withdrawal rats. In the acute and chronic ethanol experiments, kissorphin was the most effective at the dose of 10 nmol. In conclusion, the ethanol-induced spatial memory impairment may be reversed by pharmacological manipulation of the endogenous opioid system.

Dissociation of nicotinic α7 and α4/ß2 sub-receptor agonists for enhancing learning and attentional filtering in nonhuman primates.

RATIONALE: Nicotinic acetylcholine receptors (nAChRs) modulate attention, memory, and higher executive functioning, but it is unclear how nACh sub-receptors mediate different mechanisms supporting these functions. OBJECTIVES: We investigated whether selective agonists for the alpha-7 nAChR versus the alpha-4/beta-2 nAChR have unique functional contributions for value learning and attentional filtering of distractors in the nonhuman primate. METHODS: Two adult rhesus macaque monkeys performed reversal learning following systemic administration of either the alpha-7 nAChR agonist PHA-543613 or the alpha-4/beta-2 nAChR agonist ABT-089 or a vehicle control. Behavioral analysis quantified performance accuracy, speed of processing, reversal learning speed, the control of distractor interference, perseveration tendencies, and motivation. RESULTS: We found that the alpha-7 nAChR agonist PHA-543613 enhanced the learning speed of feature values but did not modulate how salient distracting information was filtered from ongoing choice processes. In contrast, the selective alpha-4/beta-2 nAChR agonist ABT-089 did not affect learning speed but reduced distractibility. This dissociation was dose-dependent and evident in the absence of systematic changes in overall performance, reward intake, motivation to perform the task, perseveration tendencies, or reaction times. CONCLUSIONS: These results suggest nicotinic sub-receptor specific mechanisms consistent with (1) alpha-4/beta-2 nAChR specific amplification of cholinergic transients in prefrontal cortex linked to enhanced cue detection in light of interferences, and (2) alpha-7 nAChR specific activation prolonging cholinergic transients, which could facilitate subjects to follow-through with newly established attentional strategies when outcome contingencies change. These insights will be critical for developing function-specific drugs alleviating attention and learning deficits in neuro-psychiatric diseases.

In a Model of Neuroinflammation Designed to Mimic Delirium, Quetiapine Reduces Cortisol Secretion and Preserves Reversal Learning in the Attentional Set Shifting Task.

Quetiapine, an atypical antipsychotic medication has lacked pre-clinical validation for its purported benefits in the treatment of delirium. This laboratory investigation examined the effects of quetiapine on the attentional set shifting task (ASST), a measure of cognitive flexibility and executive functioning, in a rodent model of lipopolysaccharide (LPS) mediated neuroinflammation. 19 Sprague Dawley female rats were randomly selected to receive intraperitoneal placebo (N = 5), LPS and placebo (N = 7) or LPS and quetiapine (n = 7) and performed the ASST. We measured trials to criterion, errors, non-locomotion episodes and latency to criterion, serum cortisol and tumor necrosis factor alpha (TNF-α) levels. TNF-α levels were not different between groups at 24 h. Cortisol levels in the LPS + Quetiapine group were reduced compared to LPS + Placebo (P < 0.001) and did not differ from the placebo group (P = 0.15). Analysis between LPS + Quetiapine and LPS + Placebo treated rats demonstrated improvement in the compound discrimination reversal (CD Rev1) (P = 0.016) and the intra-dimensional reversal (ID Rev2) (P = 0.007) discriminations on trials to criterion. LPS + Quetiapine treated rats had fewer errors than LPS + Placebo treated animals in the compound discrimination (CD) (P = 0.007), CD Rev1 (P = 0.005), ID Rev2 (P < 0.001) discriminations. There was no difference in non-locomotion frequency or latency to criterion between the three groups in all discriminations (P > 0.0167). We demonstrated preserved reversal learning, no effect on attentional set shifting and normalized cortisol levels in quetiapine-treated rats in this neuroinflammatory model of delirium. This suggests that quetiapine's beneficial effects in delirium may be related to the preservation of reversal learning and potential downstream effects related to reduction in cortisol production. Graphical Abstract.

Chronic treatment with galantamine rescues reversal learning in an attentional set-shifting test after experimental brain trauma.

Approximately 10 million new cases of traumatic brain injury (TBI) are reported each year worldwide with many of these injuries resulting in higher order cognitive impairments. Galantamine (GAL), an acetylcholine esterase inhibitor (AChEI) and positive allosteric modulator of nicotinic acetylcholine receptors (nAChRs), has been reported to ameliorate cognitive deficits after clinical TBI. Previously, we demonstrated that controlled cortical impact (CCI) injury to rats resulted in significant executive function impairments as measured by the attentional set-shifting test (AST), a complex cognitive task analogous to the Wisconsin Card Sorting Test (WCST). We hypothesized that chronic administration of GAL would normalize performance on the AST post-TBI. Isoflurane-anesthetized adult male rats were subjected to moderate CCI (2.8 mm tissue deformation at 4 m/s) or sham injury. Rats were then randomized into one of three treatment groups (i.e., 1 mg/kg GAL, 2 mg/kg GAL, or 1 mL/kg saline vehicle; VEH) or their respective sham controls. GAL or VEH was administered intraperitoneally daily commencing 24 hours post-surgery and until AST testing at 4 weeks post-injury. The AST data revealed significant impairments in the first reversal stage after TBI, seen as increased trials to reach criterion and elevated total errors (p < 0.05). These behavioral flexibility deficits were equally normalized by the administration of both doses of GAL (p < 0.05). Additionally, the higher dose of GAL (2 mg/kg) also significantly reduced cortical lesion volume compared to TBI + VEH controls (p < 0.05). In summary, daily GAL administration provides an efficacious treatment for cognitive deficits and histological recovery after experimental brain trauma. Clinically, these findings are promising considering robust results were attained using a pharmacotherapy already used in the clinic to treat mild dementia.

Increased training compensates for OX1R blockage-impairment of spatial memory and c-Fos expression in different cortical and subcortical areas.

It has been suggested that the orexin system modulates learning and memory-related processes. However, the possible influence that training could have on the effect of the blockade of orexin-A selective receptor (OX1R) on a spatial memory task has not been explored. Therefore, the present study attempts to compare the effects of OX1R antagonist SB-334867 infusion on spatial memory in two different conditions in the Morris Water Maze (MWM). This experiment evaluated the animals' performance in weak training (2 trials per session) vs strong training (6 trials per session) protocols in a spatial version of the MWM. We found that in the 2-trial condition the post-training SB-334867 infusion had a negative effect on consolidation as well as on the retention and reversal learning of the task 72 h later. This effect was not apparent in the 6-trial condition. In addition, while the strong training groups showed a general increase in c-Fos expression in several brain areas of the hippocampal-thalamic-cortical circuit, SB-334867 administration had the opposite effect in areas that have been previously reported to have a high density of OX1R. Specifically, the SB-infused group in the 2-trial condition showed a decrease in c-Fos immunoreactivity in the dentate gyrus, granular retrosplenial and prelimbic cortices, and centrolateral thalamic nucleus. This was not observed for subjects in the 6-trial condition. The activation of these areas could constitute a neuroanatomical substrate involved in the compensatory mechanisms of training upon SB-334867 impairing effects on a MWM spatial task.

The adenosine A2A receptor agonist, CGS 21680, attenuates a probabilistic reversal learning deficit and elevated grooming behavior in BTBR mice.

Restricted interests and repetitive behaviors (RRBs) are a defining feature of autism spectrum disorder (ASD). To date there are limited options for treating this core symptomology. Treatments that stimulate adenosine A2A receptors may represent a promising approach for reducing RRBs in ASD. This is because A2A receptors are expressed on striatal neurons of the basal ganglia indirect pathway. Under activation of this pathway has been associated with RRBs while activation of A2A receptors leads to increased activity of the indirect basal ganglia pathway. The present studies investigated whether acute, systemic treatment with CGS21680, an A2A receptor agonist attenuates elevated self-grooming and a probabilistic reversal learning deficit in the BTBR T+ Itpr3tf /J (BTBR) mouse model of idiopathic autism. The effects of this treatment were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, comparable to one in which ASD individuals exhibit deficits, CGS 21680 (0.005 and 0.01mg/kg) attenuated a reversal learning deficit in BTBR mice. Enhancement in probabilistic reversal learning performance resulted from CGS 21680 improving the consistent maintenance of new adaptive behavioral choice patterns after reversal. CGS 21680 at 0.01 mg, but not 0.005 mg, also reduced self-grooming behavior in BTBR mice. CGS 21680 did not affect self-grooming or reversal learning in B6 mice. These findings demonstrate that A2A receptor agonists may be a promising receptor target in the treatment of RRBs in ASD. Autism Res 2018, 11: 223-233. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The present experiments determined whether the drug, CGS 21680, that facilitates activation of adenosine A2A receptors in the brain, would reduce repetitive and inflexible behaviors in the BTBR mouse model of idiopathic autism. CGS 21680 treatment in BTBR mice reduced repetitive and inflexible behaviors. In the control C57BL/6J (B6) mouse strain, CGS 21680 did not affect performance. These findings suggest that stimulation of brain adenosine A2A receptors may be a promising therapeutic strategy in ASD.

The chemotherapeutic agent paclitaxel selectively impairs reversal learning while sparing prior learning, new learning and episodic memory.

Chemotherapy is widely used to treat patients with systemic cancer. The efficacy of cancer therapies is frequently undermined by adverse side effects that have a negative impact on the quality of life of cancer survivors. Cancer patients who receive chemotherapy often experience chemotherapy-induced cognitive impairment across a variety of domains including memory, learning, and attention. In the current study, the impact of paclitaxel, a taxane derived chemotherapeutic agent, on episodic memory, prior learning, new learning, and reversal learning were evaluated in rats. Neurogenesis was quantified post-treatment in the dentate gyrus of the same rats using immunostaining for 5-Bromo-2'-deoxyuridine (BrdU) and Ki67. Paclitaxel treatment selectively impaired reversal learning while sparing episodic memory, prior learning, and new learning. Furthermore, paclitaxel-treated rats showed decreases in markers of hippocampal cell proliferation, as measured by markers of cell proliferation assessed using immunostaining for Ki67 and BrdU. This work highlights the importance of using multiple measures of learning and memory to identify the pattern of impaired and spared aspects of chemotherapy-induced cognitive impairment.

Adult neurogenesis reduction by a cytostatic treatment improves spatial reversal learning in rats.

Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hippocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromodeoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60° sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus.

Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers: A Randomized Trial.

Importance: Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. Objective: To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. Design, Setting, and Participants: Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. Main Outcome and Measures: A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. Results: The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P < .05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P < .05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline. Conclusions and Relevance: There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others. Trial Registration: clinicaltrials.gov Identifier: NCT00830739.

Interactions between estradiol and haloperidol on perseveration and reversal learning in amphetamine-sensitized female rats.

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner.

Effects of HIV/TAT protein expression and chronic selegiline treatment on spatial memory, reversal learning and neurotransmitter levels in mice.

Neurotoxic viral protein TAT may contribute to deficits in dopaminergic and cognitive function in individuals infected with human immunodeficiency virus. Transgenic mice with brain-specific doxycycline-induced TAT expression (TAT+, TAT- control) show impaired cognition. However, previously reported TAT-induced deficits in reversal learning may be compromised by initial learning deficits. We investigated the effects of TAT expression on memory retention/recall and reversal learning, and neurotransmitter function. We also investigated if TAT-induced effects can be reversed by improving dopamine function with selegiline, a monoamine oxidase inhibitor. Mice were tested in the Barnes maze and TAT expression was induced after the task acquisition. Selegiline treatment continued throughout behavioral testing. Dopamine, serotonin and glutamate tissue levels in the prefrontal/orbitofrontal cortex, hippocampus and caudate putamen were measured using high performance liquid chromatography. Neither TAT expression nor selegiline altered memory retention. On day 2 of reversal learning testing, TAT+ mice made fewer errors and used more efficient search strategies than TAT- mice. TAT expression decreased dopamine turnover in the caudate putamen, increased serotonin turnover in the hippocampus and tended to increase the conversion of glutamate to glutamine in all regions. Selegiline decreased dopamine and serotonin metabolism in all regions and increased glutamate levels in the caudate putamen. In the absence of impaired learning, TAT expression does not impair spatial memory retention/recall, and actually facilitates reversal learning. Selegiline-induced increases in dopamine metabolism did not affect cognitive function. These findings suggest that TAT-induced alterations in glutamate signaling, but not alterations in monoamine metabolism, may underlie the facilitation of reversal learning.

Reversal learning in gonadectomized marmosets with and without hormone replacement: are males more sensitive to punishment?

This study examined sex differences in executive function in middle-aged gonadectomized marmosets (Callithrix jacchus) with or without hormonal replacement. We tested ten castrated male (mean age 5.5 years) marmosets treated with testosterone cypionate (T, n = 5) or vehicle (n = 5) on Reversal Learning, which contributes to cognitive flexibility, and the Delayed Response task, measuring working memory. Their performance was compared to that of 11 ovariectomized females (mean age = 3.7 years) treated with Silastic capsules filled with 17-ß estradiol (E2, n = 6) or empty capsules (n = 5), previously tested on the same tasks (Lacreuse et al. in J Neuroendocrinol 26:296-309, 2014. doi: 10.1111/jne.12147). Behavioral observations were conducted daily. Females exhibited more locomotor behaviors than males. Males and females did not differ in the number of trials taken to reach criterion on the reversals, but males had significantly longer response latencies, regardless of hormone replacement. They also had a greater number of refusals than females. Additionally, both control and T-treated males, but not females, had slower responses on incorrect trials, suggesting that males were making errors due to distraction, lack of motivation or uncertainty. Furthermore, although both males and females had slower responding following an incorrect compared to a correct trial, the sex difference in response latencies was disproportionally large following an incorrect trial. No sex difference was found in the Delayed Response task. Overall, slower response latencies in males than females during Reversal Learning, especially during and following an incorrect trial, may reflect greater sensitivity to punishment (omission of reward) and greater performance monitoring in males, compared to females. Because these differences occurred in gonadectomized animals and regardless of hormone replacement, they may be organized early in life.

17ß-estradiol replacement in ovariectomized female rats slows set 1 dorsolateral striatial-dependent learning and enhances learning of set 2 in an extradimensional set-shifting paradigm.

The role of estrogen in extradimensional set-shifting was evaluated with replacement of 17ß-estradiol (E2) in ovariectomized (OVX) female rats. Rats were reinforced with food when they entered an arm of a plus-maze that was distinguished by visual and/or tactile cues (Set 1). In Set 2, reinforcement was shifted to construct a new association between food and visual/tactile cues that were different from Set 1. The purpose of using this extradimensional set-shifting task was to differentiate the effect of acute or continuous E2 on the dorsolateral (DLS) versus dorsomedial (DMS) striatum and medial prefrontal cortex (mPFC), because Set 1 and 2 learning, respectively, are associated with these particular brain regions. Results showed that compared to controls, acute E2-replaced female rats required more training trials to reach criterion in Set 1. Moreover, E2-replaced females showed a significant delay in the rate of acquisition of Set 1 learning compared to controls. In Set 2 there were no group differences in perseverative errors, which are reduced by mPFC activation, or when learning took place in a previously reinforced arm, a DMS-mediated effect. Despite this, control females required more training trials to learn Set 2 compared to Set 1, suggesting that prior learning in Set 1 interfered with Set 2 performance in non-E-replaced rats. In contrast, E2 groups learned Set 2 in fewer training trials than Set 1. These data suggest that E2 facilitates set shifting, apart from any apparent enhancement of DMS or mPFC function, perhaps by interfering with DLS-mediated Set 1 learning.

Effects of the nicotinic agonist varenicline on the performance of tasks of cognition in aged and middle-aged rhesus and pigtail monkeys.

RATIONALE: Due to the rising costs of drug development especially in the field of neuropsychiatry, there is increasing interest in efforts to identify new clinical uses for existing approved drugs (i.e., drug repurposing). OBJECTIVES: The purpose of this work was to evaluate in animals the smoking cessation agent, varenicline, a partial agonist at α4ß2 and full agonist at α7 nicotinic acetylcholine receptors, for its potential as a repurposed drug for disorders of cognition. METHODS: Oral doses of varenicline ranging from 0.01 to 0.3 mg/kg were evaluated in aged and middle-aged monkeys for effects on the following: working/short-term memory in a delayed match to sample (DMTS) task, distractibility in a distractor version of the DMTS (DMTS-D), and cognitive flexibility in a ketamine-impaired reversal learning task. RESULTS: In dose-effect studies in the DMTS and DMTS-D tasks, varenicline was not associated with statistically significant effects on performance. However, individualized "optimal doses" were effective when repeated on a separate occasion (i.e., improving DMTS accuracy at long delays and DMTS-D accuracy at short delays by approximately 13.6 and 19.6 percentage points above baseline, respectively). In reversal learning studies, ketamine impaired accuracy and increased perseverative responding, effects that were attenuated by all three doses of varenicline that were evaluated. CONCLUSIONS: While the effects of varenicline across the different behavioral tasks were modest, these data suggest that varenicline may have potential as a repurposed drug for disorders of cognition associated with aging (e.g., Alzheimer's disease), as well as those not necessarily associated with advanced age (e.g., schizophrenia).

PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments.

RATIONALE: N-methyl-D-aspartate receptor (NMDA-R) hypofunction has been proposed to account for the pathophysiology of schizophrenia. Thus, NMDA-R blockade has been used to model schizophrenia in experimental animals. Acute and repeated treatments have been successfully tested; however, long-term exposure to NMDA-R antagonists more likely resembles the core symptoms of the illness. OBJECTIVES: To explore whether schizophrenia-related behaviors are differentially induced by acute and subchronic phencyclidine (PCP) treatment in mice and to examine the neurobiological bases of these differences. RESULTS: Subchronic PCP induced a sensitization of acute locomotor effects. Spontaneous alternation in a T-maze and novel object recognition performance were impaired after subchronic but not acute PCP, suggesting a deficit in working memory. On the contrary, reversal learning and immobility in the tail suspension test were unaffected. Subchronic PCP significantly reduced basal dopamine but not serotonin output in medial prefrontal cortex (mPFC) and markedly decreased the expression of tyrosine hydroxylase in the ventral tegmental area. Finally, acute and subchronic PCP treatments evoked a different pattern of c-fos expression. At 1 h post-treatment, acute PCP increased c-fos expression in many cortical regions, striatum, thalamus, hippocampus, and dorsal raphe. However, the increased c-fos expression produced by subchronic PCP was restricted to the retrosplenial cortex, thalamus, hippocampus, and supramammillary nucleus. Four days after the last PCP injection, c-fos expression was still increased in the hippocampus of subchronic PCP-treated mice. CONCLUSIONS: Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects.

Contributions of ß2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice.

RATIONALE: Deficits in executive functions underlie compulsive drug use, and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that ß2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known. OBJECTIVES: In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the ß2 subunit-containing nAChR gene (ß2+/- or ß2-/-) performing an operant cognitive flexibility task. RESULTS: Visual discrimination learning was not affected in saline-treated ß2 nAChR mutants as compared to the wild-type (ß2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes, and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in ß2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between ß2+/+ and ß2-/- mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in ß2+/- mice. CONCLUSIONS: Collectively, these findings suggest that ß2 subunit-containing nAChRs are not critical for visual discrimination learning and extra dimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies.

Impaired cognition after stimulation of P2Y1 receptors in the rat medial prefrontal cortex.

We hypothesize that cortical ATP and ADP accumulating in the extracellular space, eg during prolonged network activity, contribute to a decline in cognitive performance in particular via stimulation of the G protein-coupled P2Y1 receptor (P2Y1R) subtype. Here, we report first evidence on P2Y1R-mediated control of cognitive functioning in rats using bilateral microinfusions of the selective agonist MRS2365 into medial prefrontal cortex (mPFC). MRS2365 attenuated prepulse inhibition of the acoustic startle reflex while having no impact on startle amplitude. Stimulation of P2Y1Rs deteriorated performance accuracy in the delayed non-matching to position task in a delay dependent manner and increased the rate of magazine entries consistent with both working memory disturbances and impaired impulse control. Further, MRS2365 significantly impaired performance in the reversal learning task. These effects might be related to MRS2365-evoked increase of dopamine observed by microdialysis to be short-lasting in mPFC and long-lasting in the nucleus accumbens. P2Y1Rs were identified on pyramidal cells and parvalbumin-positive interneurons, but not on tyrosine hydroxylase-positive fibers, which argues for an indirect activation of dopaminergic afferents in the cortex by MRS2365. Collectively, these results suggest that activation of P2Y1Rs in the mPFC impairs inhibitory control and behavioral flexibility mediated by increased mesocorticolimbic activity and local disinhibition.

Specific impairments in instrumental learning following chronic intermittent toluene inhalation in adolescent rats.

RATIONALE: Inhalant abuse is prevalent in adolescent populations, with chronic use resulting in neurobiological and cognitive abnormalities in adulthood. However, the nature and persistence of cognitive dysfunction, particularly following adolescent inhalant abuse, remain equivocal. OBJECTIVE: The present study assessed specific cognitive processes beginning in late adolescence and adulthood following adolescent inhalation of toluene, a main component of many compounds readily abused. METHODS: Adolescent male Wistar rats (postnatal day (PN) 27) were exposed to chronic intermittent inhaled toluene (10,000 ppm) for 1 h/day, 3 days/week for 4 weeks (PN 27-52) to mimic the patterns observed in human adolescent inhalant abusers. Following toluene exposure, motor and cognitive function was assessed. RESULTS: Adolescent toluene exposure did not alter motor learning in the Rotarod task (PN 58) or acquisition, reversal, or retention of spatial learning in the Morris water maze (PN 55-64). In contrast, it delayed acquisition of instrumental responding for sucrose (5 % w/v) and impaired operant reversal learning and cue-induced reinstatement of sucrose seeking in adulthood (PN 57-100). CONCLUSION: This study demonstrates that exposure to toluene at an abuse concentration during adolescence results in specific impairments in aspects of instrumental learning, without altering motor function and spatial learning in late adolescence/early adulthood. Our data imply that persistent alterations in reward processing may occur following adolescent inhalant misuse.

Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-ß and cerebrovascular pathology.

Animal models of Alzheimer's disease (AD) are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months) and aged (>18 months) bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of transforming growth factor-ß1 (TGF-ß1). A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aß) and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aß pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone's efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.

Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history.

Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ~6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [¹¹C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4ß2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.