Adolescent nicotine administration impacts working memory and reversal learning but not cognitive flexibility.

There has been increased interest in early exposure to nicotine through tobacco products and vaping specifically as it relates to addiction, yet fewer studies have focused on whether behavioral effects resulting from early nicotine exposure may persist into adulthood. Our experiments tested the hypothesis that exposure to nicotine during adolescence would impair selective aspects of behavioral cognition in rodents in adulthood. Male and female adolescent rats received either nicotine (0.4 mg/kg) or vehicle injections (intraperitoneal) once daily for 10 days (PND 29-38) followed by a washout period before behavioral testing. Animals were followed in a longitudinal design and evaluated on a battery of both behavioral and cognitive tasks during adulthood (PND 90+) that included locomotor activity, working memory (novel object recognition), cognitive flexibility (attentional set-shifting task, ASST), and anxiety-like behaviors. Data suggested that subchronic exposure to nicotine during adolescence produced significant changes in working memory, in two reversal problems in the ASST, and in anxiety-related behaviors. Taken together these data may suggest that limited early exposure to nicotine may produce selective longer term impairments in cognitive and behavioral processes related to working memory and reversal learning.

Predicting the stalking of celebrities from measures of persistent pursuit and threat directed toward celebrities, sensation seeking and celebrity worship.

The stalking of celebrities is a serious issue for thousands of celebrities worldwide who are occasionally confronted by fans who merit the label "fanatic." We administered measures of obnoxious celebrity stalking, celebrity worship, persistent pursuit of celebrities, threat directed toward celebrities, boredom susceptibility, disinhibition, experience seeking, thrill and adventure seeking, relationship styles, and anger to 596 college students from the U.S.A. We developed a model consisting of all but the latter five measures that successfully predicted actual obnoxious stalking behaviors of celebrities. Our results partially replicate earlier research and presents some new findings. Individuals who have personal thoughts about their favorite celebrity frequently, feel compelled to learn more about them, pursue them consistently, threatened to harm them and were prone to boredom were more likely to engage in celebrity stalking. Controlling for these predictors, individuals who admire their favorite celebrity almost exclusively because of their ability to entertain were less likely to engage in celebrity stalking.

RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents.

Neuronal nicotinic α7 acetylcholine receptors (α7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at α7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human α7nAChR (K(i) = 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human α7nAChRs with an EC(50) of 0.8 µM (oocytes) and 7.7 µM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC(50) = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: ≤0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating.

Double dissociation of attentional resources: prefrontal versus cingulate cortices.

Efficient attention to our environment facilitates the decisions that need to be executed in daily life. Filtering critical from noncritical information may require the neural organization of multiple brain regions. Combining lesion techniques and the rodent version of the Wisconsin card sorting task in humans, we show at least two types of attentional processing systems reside in the cingulate and prefrontal cortices depending on task demands requiring shifts of attention within or between sets of meaningful cues, respectively. This neural organization for shifting attention either within or between perceptual dimensions is task dependent, and this type of organization provides evidence of attentional systems that transcend separate modality processing systems while subdividing executive control of attention. The results suggest that the anterior and posterior cingulate cortices are critical when shifting attention to closely related meaningful cues (i.e., within a perceptual dimension or attentional set) by suppressing interference of irrelevant background information, whereas the prefrontal cortex is critical when shifting attention between disparate sets of meaningful cues (i.e., between perceptual dimensions or attentional sets) (Dias et al., 1996a,b; Birrell and Brown, 2000). Based on the theories of Mackintosh (1965, 1975; Sutherland and Mackintosh, 1971), it is suggested that the cingulate cortex may be important for decreasing attention to irrelevant information. In general, attention deficit disorders affect both children and adults, and current medications may affect the prefrontal and associated parietal cortical systems more or less than the cingulate cortical system.

Selective nicotinic acetylcholine receptor agonists: potential therapies for neuropsychiatric disorders with cognitive dysfunction.

Cognitive impairment is one of the most functionally debilitating aspects of neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease, despite treatment with available pharmacotherapies. There is emerging evidence that nicotine improves cognitive function in humans and nonhuman species and this has sparked interest in the development of novel nicotinic treatments for cognitive dysfunction. The examination of selective alpha7 and alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonists suggests that both receptor subtypes mediate improvement in attention, learning and working memory. When compared with available pharmacotherapies, specific nAChR agonists may represent unique targets for the treatment of neuropsychiatric and neurodegenerative disorders that feature cognitive impairment as a key symptom.

Suppression of cocaine- and food-maintained behavior by the D2-like receptor partial agonist terguride in squirrel monkeys.

RATIONALE: The D2-like receptor partial agonist terguride has a profile of behavioral effects in rats that suggests potential benefit as a pharmacotherapy for cocaine addiction. OBJECTIVES: The present study investigated the effects of terguride on cocaine- and food-maintained behavior in squirrel monkeys. METHODS: Squirrel monkeys were trained to respond on a second-order schedule (FI 10 min, FR 10 or 30:S) of either i.v. cocaine injection or food pellet delivery. Additional monkeys were studied using quantitative observational techniques to construct side effect profiles. Under each procedure, the effects of terguride were compared with those of the reference D2-like receptor antagonist nemonapride and the D2-like receptor full agonist quinpirole. RESULTS: Terguride and nemonapride, but not quinpirole, dose-dependently reduced cocaine-maintained behavior. In animals self-administering food, terguride decreased response rates at doses lower than those required to suppress cocaine-maintained behavior. Effective doses of terguride had no systematic effect on motor activity or muscle rigidity, whereas effective doses of nemonapride virtually eliminated motor activity and induced severe catalepsy. The primary observable effects of terguride were a modest increase in self-directed behavior (a D2-receptor agonist-like effect) at intermediate doses and a small increase in static posture (a D2-receptor antagonist-like effect) at the highest dose tested. CONCLUSIONS: The results suggest that terguride has advantages over conventional D2-like receptor antagonists and agonists as a candidate pharmacotherapy for cocaine abuse; however, terguride significantly reduces food-maintained behavior at lower doses than those needed to decrease cocaine-maintained behavior suggesting limitations on the utility of terguride as a medication for cocaine addiction.

Self-administration of cocaine, alfentanil, and nalbuphine under progressive-ratio schedules: consumer demand and labor supply analyses of relative reinforcing effectiveness.

Progressive-ratio (PR) schedules of intravenous (i.v.) drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs. The authors compared the reinforcing effects of the high-efficacy opioid alfentanil, the low-efficacy opioid nalbuphine, and cocaine using a PR schedule of i.v. drug injection in rhesus monkeys in which the response requirement increased during the experimental session and the initial response requirement (IRR) was varied. Analyses based on either consumer demand or labor supply models of behavioral economics revealed that the relative reinforcing effectiveness of cocaine and alfentanil was greater than that of nalbuphine. These results suggest that PR schedules with varying IRRs can provide meaningful estimates of the relative reinforcing effectiveness of abused drugs.

Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats.

A number of selective phosphodiesterase (PDE) inhibitors have been demonstrated to improve learning in several rodent models of cognition. Given that schizophrenia is associated with impairments in frontal lobe-dependent cognitive functions (e.g., working memory and cognitive flexibility), we examined whether PDE inhibitors would attenuate cognitive deficits associated with schizophrenia. Persistent suppression of N-methyl-D-aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that subchronic treatment with NMDA receptor antagonists (e.g., phencyclidine, PCP) may represent a useful preclinical model of neurobiological and related cognitive deficits associated with schizophrenia. We treated male Long-Evans rats with subchronic PCP (5 mg/kg, ip, BID, 7 d) or saline and then examined the effects of acute treatment with selected doses of PDE inhibitors that have been demonstrated to regulate both intracellular levels of cAMP and/or cGMP, and to improve cognitive function. We used an extradimensional-intradimensional (ED/ID) test of cognitive flexibility similar to those used in humans and non-human primates for assessing executive function. Subchronic treatment with PCP produced a selective impairment on ED shift (EDS) performance without significant impairment on any other discrimination problem when compared to saline-treated control animals. Selected doses of the four PDEIs evaluated (PDE2: BAY 60-7550; PDE4: rolipram; PDE5: sildenafil; PDE10A: papaverine) were able to significantly attenuate this cognitive deficit in EDS performance. This suggests that this rodent model of executive function was sensitive to pro-cognitive effects of intracellular effects resulting from PDE inhibition. Together, these data suggest that inhibition of PDE activity may represent valuable therapeutic targets to improve cognition associated with neuropsychiatric disorders that feature cognitive dysfunction as a key symptom.

Environmental enrichment ameliorates phencyclidine-induced cognitive deficits.

Recent work has suggested that environmental enrichment during development can enhance aspects of learning and memory, however its effects on executive function and cognitive flexibility have not been well studied. The goal of this research was to evaluate whether environmental enrichment (EE) that included wheel running would improve cognitive performance in young male Long Evans rats that received subchronic administration of either phencyclidine (PCP) or saline. We used a sensitive extradimensional/intradimensional (ED/ID) test of cognitive flexibility similar to that used in humans and nonhuman primates for assessing executive function. PCP-treated rats demonstrated a selective impairment on ED shift (EDS) performance without significant impairment on other discrimination problems when compared to saline treated control animals. A separate group of animals that received PCP + EE demonstrated significantly improved performance on EDS and reversal learning problems, whereas the saline + EE group demonstrated a non-selective improvement in overall performance when compared to non-enriched saline controls. The saline + EE group demonstrated greater activity levels as measured by wheel running when compared to the PCP + EE group, but no significant associations were found between wheel running and cognitive performance. Together, these data suggest that EE that features wheel running may have promoted a general cognitive enhancement while also selectively acting upon neurobiological mechanisms that subserve executive function and cognitive flexibility in impaired animals. Development of novel treatment methodologies that target mechanisms underlying the ameliorative effects of EE in this model of cognitive impairment may be a useful tool in the development of new therapeutic strategies for disorders that feature cognitive dysfunction as a key symptom.

Emerging role of sertindole in the management of schizophrenia.

The atypical antipsychotic sertindole is a phenylindole-derived compound that has affinity for and functions as an antagonist at a number of receptor systems, including dopamine D2 receptors, 5-HT(2A) and 5-HT(2C) receptors, and α-1-noradrenergic receptors. Although previous data suggested that sertindole was well tolerated and had good efficacy against both positive and negative symptom clusters, reports of QT prolongation with sertindole prompted its voluntary removal from the market in 1998. After further safety analyses, it recently regained approval and was reintroduced to the European market for the treatment of schizophrenia, where its role in therapy among available atypicals remains unclear. This article evaluates the preclinical and clinical data regarding sertindole's effectiveness and concludes that sertindole continues to demonstrate a number of strengths, including effective management of both positive and negative symptoms, well-tolerated side effects (including little or no sedation, weight gain, and extrapyramidal side effects), and a superior procognitive profile that is unique among atypical antipsychotics. However, minor concerns regarding its sexual side effects and the major consideration of QT prolongation suggest that additional comparative effectiveness studies are needed to determine the superiority of sertindole vs other atypical antipsychotics recently introduced.

AM 251 differentially effects food-maintained responding depending on food palatability.

Ligands functioning as antagonists and inverse agonists at the cannabinoid CB(1)-receptor (e.g., AM 251, AM 281, and rimonabant (previously identified as SR141716)) have been demonstrated to have effects on satiety, consumption of, and the motivation to work for, or obtain food. These represent behavioral effects that may also be linked to characteristics such as food palatability or motivation to obtain food. Given the recent removal of rimonabant from clinical trials, a thorough characterization of ingestive behaviors that are associated with other likely candidate drugs is warranted. In the present study, normal weight male Long Evans rats were trained to respond for grain or chocolate-flavored food pellets under progressive-ratio schedules of reinforcement. Rats received acute injections of the CB(1) receptor antagonist AM 251 (0.3-3.0 mg/kg) or vehicle prior to daily testing sessions. Administration of AM 251 produced significant dose-dependent reductions in responding for, deliveries of, and break points (BP) associated with chocolate-flavored but not grain pellets. These data add to the literature demonstrating the ability of CB(1) antagonists to selectively reduce motivation to obtain highly palatable reinforcers.

Naltrexone reverses age-induced cognitive deficits in rats.

We evaluated young (3-4 months) and aged (22-24 months) male Sprague-Dawley rats in an attentional set-shifting procedure that assessed reversal, intradimensional shift (IDS), and extradimensional shift (EDS) discrimination learning tasks within one test session. These aspects of discrimination learning are sensitive to damage to distinct regions of frontal cortex. Compared to young animals, aged rats were significantly impaired on the EDS task and did not demonstrate significant impairment on the reversal or IDS tasks. The opioid antagonist naltrexone (2mg/kg, ip) was administered to young and aged rats prior to testing to assess possible improvements in aged-related cognitive impairments. Naltrexone (2mg/kg) attenuated the impairments in cognitive function in the EDS task for aged animals, but did not alter any task performance in the younger group. These results suggest that normal aging in rats is associated with impaired medial frontal cortex function as assessed by this attentional set-shifting procedure and opioid mediated mechanisms may represent a therapeutic target for drugs to improve cognitive deficits associated with aging.

Reversal of subchronic PCP-induced deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist: comparison among antipsychotics.

Currently accepted treatments for schizophrenia can effectively control positive symptoms but have limited impact on cognitive deficits in schizophrenia. The purpose of these experiments was to address this unmet need by characterizing the effects of classical and second-generation antipsychotics on cognitive impairments associated with schizophrenia. An additional aim was to characterize the part(s) of the pharmacological profile of drugs that were important to reverse deficits. Cognitive deficits were assessed using a frontally mediated attentional set-shifting task in rats that is analogous to tasks used in humans and nonhuman primates that assess executive function. Mirroring findings in patients with schizophrenia, the classical antipsychotic haloperidol was ineffective in treating set-shifting deficits induced by subchronic treatment with phencyclidine (PCP). Similarly, second-generation antipsychotics, risperidone, clozapine, and olanzapine were ineffective. In contrast, selected doses of sertindole and the 5-HT(6) receptor antagonist SB 271046 attenuated PCP-induced set-shifting deficits. Finally, the 5-HT(2A) receptor antagonist M100907 was without effect. Further examination revealed that repeated treatment (21 days) with sertindole, but not olanzapine, also was effective in reversing the executive function deficit. These data suggest that the combination of 5-HT(6) antagonistic activity and the absence of antimuscarinic activity may represent key characteristics of the pharmacological profile for improved antipsychotic drugs for schizophrenia.

Self-Administration of cocaine-opioid combinations by rhesus monkeys: evaluation of the role of mu receptor efficacy using labor supply analysis.

Cocaine and heroin often are abused by self-administering the drugs in combination as a "speedball". We evaluated the extent to which intrinsic efficacy at the mu-opioid receptor influences combined cocaine-opioid self-administration and used the behavioral economic model termed "labor supply" to quantitatively evaluate the reinforcing effects of cocaine-opioid combinations. Rhesus monkeys (n = 8) were trained under a progressive-ratio schedule of i.v. cocaine injection in which the response requirement increased during the experimental session and the initial response requirement was varied. Combination of cocaine with heroin enhanced self-administration compared with the drugs individually, with ineffective doses of both drugs maintaining self-administration when combined. These effects also were observed with the high-efficacy mu agonist alfentanil and low-efficacy agonist nalbuphine. Using the labor supply economic model, combinations of heroin, alfentanil, or nalbuphine with relatively low doses of cocaine were found to increase the number of injections per session ("income") and total responses per session ("labor"). Combination of a relatively high dose of cocaine with either heroin or alfentanil, but not nalbuphine, also resulted in only a small reduction in income concomitant with increased labor, suggesting that heroin and alfentanil made cocaine consumption more resistant to increasing response costs, or more "inelastic." Collectively, these findings suggest that speedball self-administration may occur even with relatively low levels of intrinsic efficacy at mu-opioid receptors and that an inelastic relationship between drug consumption and labor may contribute to the persistence of speedball abuse.

PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats.

Persistent suppression of N-methyl-d-aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that chronic NMDA receptor antagonism in animals may represent a useful model of neurobiological and related cognitive deficits in schizophrenia. Schizophrenia is associated with impairments in frontal lobe-dependent cognitive functions, including working memory and attentional shifting. Deficits in attention and executive function have not been well characterized in animal models of schizophrenia using chronic NMDA receptor antagonist administration. We investigated whether subchronic systemic administration of the NMDA receptor antagonist phencyclidine (PCP) to rats followed by a drug washout period would produce enduring cognitive deficits on an attentional set-shifting task. The task is functionally analogous to a sensitive test of frontal function in humans and non-human primates. Subchronic PCP administration selectively impaired extradimensional shift learning without affecting other discrimination or reversal tasks. Moreover, acute treatment with the PDE10A inhibitor papaverine immediately prior to testing attenuated the PCP-induced deficits in extradimensional shift learning across a range of doses. These data suggest that subchronic PCP administration may model effectively some of the cognitive deficits that are observed in schizophrenia, and that PDE10A inhibition may be an effective therapeutic route to improve executive function deficits associated with schizophrenia.

Central blockade of muscarinic cholinergic receptors disrupts affective and attentional set-shifting.

Impairments in multiple aspects of attentional and executive function follow damage to cholinergic neurons in the central nervous system. Affective and attentional set-shifting represent two aspects of executive function controlled by different sectors of the prefrontal cortex. The involvement of cholinergic neural mechanisms in these aspects of executive function has not been specified. To determine whether central muscarinic cholinergic receptors were involved in affective and/or attentional set-shifting, we tested rats on a series of discrimination learning problems, which included affective (reversal learning) and attentional set (extradimensional shift)-shifting components, under the systemic influence of scopolamine, a muscarinic antagonist. Scopolamine impaired both reversal learning and extradimensional shifting, but was without effect on learning new discrimination problems that did not require an affective or attentional shift. Systemic administration of methylscopolamine, which does not cross the blood-brain barrier, did not impair affective or attentional set-shifting, indicating that the scopolamine effects were centrally mediated. These data implicate muscarinic receptors in the central nervous system in the control of executive function. Taken together with other recent data, they may also suggest an important role for cholinergic receptors outside of the neocortex in regulating these aspects of attention and executive function.