Varenicline and GZ-793A differentially decrease methamphetamine self-administration under a multiple schedule of reinforcement in rats.

Methamphetamine is a potent psychostimulant with high abuse rates. Currently, there is no Food and Drug Administration-approved pharmacotherapy for methamphetamine addiction. Ideally, a pharmacotherapy should selectively decrease methamphetamine self-administration without affecting responding for other reinforcers. One way to test this is with the use of a multiple schedule of reinforcement, in which drug and food are available in alternating components within a session. The present study evaluated GZ-793A, a vesicular monoamine transporter-2 inhibitor, and varenicline, a partial agonist at α4ß2 and full agonist at α7 nicotinic acetylcholine receptors, for their ability to decrease methamphetamine and food self-administration using a multiple schedule of reinforcement. Male Sprague-Dawley rats self-administered methamphetamine (0.03 mg/kg/intravenous infusion) and food pellets under a multiple schedule of reinforcement. GZ-793A or varenicline was administered before multiple schedule sessions. GZ-793A (5 and 20 mg/kg) significantly decreased methamphetamine intake compared with saline and did not alter food-maintained responding. In contrast, varenicline decreased methamphetamine intake less specifically across time. The results suggest that vesicular monoamine transporter-2 inhibition may be a viable pharmacological target for the treatment of methamphetamine-use disorders.

Behavioral Effects of Vaporized Delta-8 Tetrahydrocannabinol, Cannabidiol, and Mixtures in Male Rats.

Background: The popularity of delta-8 tetrahydrocannabinol (THC) and cannabidiol (CBD) products has seen a sharp increase in use during recent years. Despite the rise in use of these minor cannabinoids, there are little to no pre-clinical behavioral data on their effects, with most pre-clinical cannabis research focusing on the behavioral effects of delta-9 THC. The current experiments aimed to characterize the behavioral effects of delta-8 THC, CBD, and mixtures of these two drugs using a whole-body vapor exposure route of administration in male rats. Methods: Rats were exposed to vapor that contained different concentrations of delta-8 THC, CBD, or CBD/delta-8 THC mixtures during 10 min of exposure. Following 10 min of vapor exposure, locomotor behavior was monitored, or the warm-water tail withdrawal assay was conducted to measure the acute analgesic effects of the vapor exposure. Results: CBD and CBD/delta-8 THC mixtures resulted in a significant increase in locomotion across the entire session. Although delta-8 THC alone had no significant effect on locomotion across the session, the 10 mg concentration of delta-8 THC had a hyperlocomotion effect in the first 30 min of the session followed by a hypolocomotor effect later in the session. In the tail withdrawal assay, a 3/1 mixture of CBD/delta-8 THC resulted in an immediate analgesic effect compared to vehicle vapor. Finally, immediately following vapor exposure, all drugs had a hypothermic effect on body temperature compared to vehicle. Conclusion: This experiment is the first to characterize the behavioral effects of vaporized delta-8 THC, CBD, and CBD/delta-8 THC in male rats. While data were generally congruent with previous research investigating delta-9 THC, future studies should explore abuse liability and validate plasma blood concentrations of these drugs following administration through whole-body vapor exposure.

Effect of D-cycloserine in conjunction with fear extinction training on extracellular signal-regulated kinase activation in the medial prefrontal cortex and amygdala in rat.

D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity [phospho-extracellular signal-regulated kinase (pERK)] markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24-28 days old) increased c-fos- and pERK-stained neurons in both the prelimbic and infralimbic division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus of the central amygdala. Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in the mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in the infralimbic prefrontal cortex, prelimbic prefrontal cortex intercalated cells and lateral nucleus of the central amygdala, compared with saline control. In the synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared with context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS, the conjunction with extinction training led to an increase in iGluR subunit expression, compared with the extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei.

Neurobehavioral effects of environmental enrichment and drug abuse vulnerability: An updated review.

Environmental enrichment consisting of social peers and novel objects is known to alter neurobiological functioning and have an influence on the behavioral effects of drugs of abuse in preclinical rodent models. An earlier review from our laboratory (Stairs and Bardo, 2009) provided an overview of enrichment-specific changes in addiction-like behaviors and neurobiology. The current review updates the literature in this extensive field. Key findings from this updated review indicate that enrichment produces positive outcomes in drug abuse vulnerability beyond just psychostimulants. Additionally, recent studies indicate that enrichment activates key genes involved in cell proliferation and protein synthesis in nucleus accumbens and enhances growth factors in hippocampus and neurotransmitter signaling pathways in prefrontal cortex, amygdala, and hypothalamus. Remaining gaps in the literature and future directions for environmental enrichment and drug abuse research are identified.

Behavioral analysis of NR2C knockout mouse reveals deficit in acquisition of conditioned fear and working memory.

N-methyl-D-aspartate (NMDA) receptors play an important role in excitatory neurotransmission and mediate synaptic plasticity associated with learning and memory. NMDA receptors are composed of two NR1 and two NR2 subunits and the identity of the NR2 subunit confers unique electrophysiologic and pharmacologic properties to the receptor. The precise role of NR2C-containing receptors in vivo is poorly understood. We have performed a battery of behavioral tests on NR2C knockout/nß-galactosidase knock-in mice and found no difference in spontaneous activity, basal anxiety, forced-swim immobility, novel object recognition, pain sensitivity and reference memory in comparison to wildtype counterparts. However, NR2C knockout mice were found to exhibit deficits in fear acquisition and working memory compared to wildtype mice. Deficit in fear acquisition correlated with lack of fear conditioning-induced plasticity at the thalamo-amygdala synapse. These findings suggest a unique role of NR2C-containing receptors in associative and executive learning representing a novel therapeutic target for deficits in cognition.

Nicotine and cocaine self-administration using a multiple schedule of intravenous drug and sucrose reinforcement in rats.

There appears to be a relatively narrow range of contingencies in which intravenous (i.v) infusions of nicotine will maintain responding in rats. The schedule of reinforcement typically used when investigating i.v. nicotine self-administration is a simple fixed-ratio (FR) schedule. This study determined if responding in rats could be established using a multiple schedule of either i.v. cocaine or nicotine and sucrose reinforcement. Following training of individual components with each reinforcer, rats were placed on an FR15 60-s timeout multiple schedule of cocaine (0.3 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement or an FR5 60-s timeout multiple schedule of nicotine (0.03 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement. Both cocaine and nicotine maintained significant levels of responding under the multiple schedule. Pretreatment with the dopamine D1 antagonist SCH 23390 increased cocaine-maintained responding, but not sucrose responding. Acute pretreatment with the nicotinic antagonist mecamylamine or SCH 23390 specifically decreased nicotine self-administration. Extinction of the individual nicotine and sucrose components resulted in decreases in responding in each component under extinction. These results indicate that i.v. nicotine maintains responding under a multiple schedule. This procedure may be useful when studying the specificity of drug pretreatments on nicotine self-administration.

Advancing the translation between clinical and preclinical models of individual differences in vulnerability in substance use disorders.

Whereas the majority of individuals in society experiment with drugs and alcohol, only a small subset develops problems or disorders related to such use. Individual difference factors that influence (i.e., either increase or decrease) vulnerability to drug and alcohol use disorders include environmental, trait, and genetic factors. These factors are prime targets for (a) identification of those at high risk to develop problematic use, (b) prevention of transition from social to disordered use, and (c) development of personalized treatments to reduce risks and consequences. The goal of this special section is to highlight translational clinical and preclinical research that focuses on individual differences in environment, traits, and genetics that affect vulnerability to drugs and alcohol. Bringing together researchers who study these risk and protective factors in both nonhuman animal and human models will advance translational approaches in this field through improved collaborations between research laboratories and better translation and backtranslation of models and designs. This special section aims to present reviews and original research addressing these different individual factors and to catalyze future translational research in the field. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Environmental enrichment increases cue-dependent freezing and behavioral despair but decreases anxiety-like behavior in rats.

While post-traumatic stress disorder (PTSD) can develop after exposure to severe traumatic events, data have shown that individuals with high sensation-seeking personality traits are less prone to developing PTSD. The current study used the rodent environmental enrichment preclinical model of sensation-seeking to determine if similar sensation seeking effects in animal models of PTSD-like behaviors were found. The study also attempted to determine whether environmental enrichment altered the effects of midazolam on these PTSD-like behaviors. Male Sprague-Dawley rats were received at postnatal day (PND) 21 and placed into either an enriched (EC), isolated (IC), or social (SC) condition. Beginning on PND 51, the animals underwent 3 fear conditioning trials where a tone was paired with a 2 s 0.7 mA footshock. Twenty-four hours later, rats were given 15-min i.p. pretreatments of 0, 0.5, or 1.5 mg/kg midazolam, before being placed into fear conditioning chambers for a test of expression of conditioned fear response in a novel context. Following fear conditioning, rodents were also tested in the elevated plus maze (EPM) and the forced swim task (FST) following pretreatments of midazolam. Results from fear conditioning indicated IC rats showed a significant decrease in freezing during acquisition compared to EC and SC rats. Also, during expression, IC rats had lower freezing following saline injections and 0.5 mg/kg midazolam but were equal in time freezing to EC and SC rats following 1.5 mg/kg midazolam. In the EPM there were no effects of midazolam and IC rats showed decreased time spent in the open arms compared to EC and SC rats. In FST, IC rats spent less time immobile and more time swimming compared to EC and SC rats. Overall, results suggest that the rodent environmental enrichment model of sensation-seeking seems to parallel the effects of sensation-seeking on likelihood of PTSD symptoms seen in humans.

Enrichment-induced differences in methamphetamine drug discrimination in male rats.

Rats raised in an enriched environment show a decrease in sensitivity to the subjective effects of the psychostimulant d-amphetamine. The purpose of the present study was to determine if environmental enrichment during development alters the subjective effects of the more commonly abused drug methamphetamine. Male Sprague-Dawley rats were raised in either an enriched (EC) or an isolated condition (IC). EC and IC rats were trained on a two-lever operant procedure to discriminate 1.0 mg/kg (i.p.) methamphetamine from saline. Following acquisition of the discrimination a methamphetamine generalization curve (0.1-1.0 mg/kg) was determined. The antagonistic effects of dopamine D1 receptor antagonist SCH23390 (0.0075-0.06 mg/kg) and the dopamine D2 receptor antagonist eticlopride (0.01-0.3 mg/kg) were also tested. Finally, the ability of nicotine (0.05-0.5 mg/kg) to generalize and the ability of the nicotinic receptor antagonist mecamylamine (0.125-0.5 mg/kg) to antagonize the discriminative stimulus effects of methamphetamine were determined. EC rats were less sensitive to discriminative stimulus effects of methamphetamine compared to IC rats at a low 0.3 mg/kg dose and showed full antagonism of methamphetamine discrimination following SCH23390 compared to IC rats. There were no environmentally-induced differences in the effects of eticlopride. Nicotine only partially generalized to the effects of methamphetamine in both EC and IC rats. While mecamylamine failed to antagonize the effects of methamphetamine in either EC or IC rats. These results suggest that environmental enrichment decreases sensitivity to the discriminative effects of methamphetamine and the differences may be mediated through changes in the D1 dopamine receptor.

Differential effect of NMDA receptor GluN2C and GluN2D subunit ablation on behavior and channel blocker-induced schizophrenia phenotypes.

The GluN2C- and GluN2D-containing NMDA receptors are distinct from GluN2A- and GluN2B-containing receptors in many aspects including lower sensitivity to Mg2+ block and lack of desensitization. Recent studies have highlighted the unique contribution of GluN2C and GluN2D subunits in various aspects of neuronal and circuit function and behavior, however a direct comparison of the effect of ablation of these subunits in mice on pure background strain has not been conducted. Using knockout-first strains for the GRIN2C and GRIN2D produced on pure C57BL/6N strain, we compared the effect of partial or complete ablation of GluN2C and GluN2D subunit on various behaviors relevant to mental disorders. A large number of behaviors described previously in GluN2C and GluN2D knockout mice were reproduced in these mice, however, some specific differences were also observed possibly representing strain effects. We also examined the response to NMDA receptor channel blockers in these mouse strains and surprisingly found that unlike previous reports GluN2D knockout mice were not resistant to phencyclidine-induced hyperlocomotion. Interestingly, the GluN2C knockout mice showed reduced sensitivity to phencyclidine-induced hyperlocomotion. We also found that NMDA receptor channel blocker produced a deficit in prepulse inhibition which was prevented by a GluN2C/2D potentiator in wildtype and GluN2C heterozygous mice but not in GluN2C knockout mice. Together these results demonstrate a unique role of GluN2C subunit in schizophrenia-like behaviors.

Impulsive choice and environmental enrichment: effects of d-amphetamine and methylphenidate.

Individual differences in impulsive choice and rearing in differential environments are factors that predict vulnerability to drug abuse. The present study determined if rearing influences impulsive choice, and if d-amphetamine or methylphenidate alters impulsive choice in differentially reared rats. Male Sprague-Dawley rats were raised from 21 days of age in either an enriched condition (EC) or an isolated condition (IC) and were tested as young adults on an adjusting delay task. In this task, two levers were available and a response on one lever yielded one 45mg food pellet immediately, whereas a response on the other yielded three pellets after an adjusting delay. The delay was initially set at 6s, and it decreased or increased by 1s following responses on the immediate or delayed levers, respectively. A mean adjusted delay (MAD) was calculated upon completion of each daily session, and it served as the quantitative measure of impulsivity. Once MADs stabilized, rats were injected with saline, d-amphetamine (0.5, 1.0, or 2.0mg/kg, s.c.), or methylphenidate (2.5, 5.0, or 10.0mg/kg, s.c.) 15min prior to adjusting delay sessions. EC rats had higher baseline MADs (were less impulsive) than IC rats. Additionally, administration of d-amphetamine, but not methylphenidate, dose-dependently increased impulsive choice (decreased MADs) in EC rats. In IC rats, d-amphetamine and methylphenidate dose-dependently decreased impulsivity (increased MADs). These results indicate that rearing environment influences impulsive choice and moderates the effect of psychostimulants on impulsive choice. Specifically, psychostimulants may decrease environment-dependent impulsive choice in individuals with high levels of impulsivity (e.g., those with ADHD), whereas they may increase impulsive choice in individuals with low levels of impulsivity.

Rate-dependent effects of bupropion on nicotine self-administration and food-maintained responding in rats.

Bupropion has been found to be a useful pharmaceutical agent in furthering smoking abstinence. Preclinical research investigating the effects of bupropion on nicotine self-administration has indicated bupropion has selective effects on nicotine self-administration. However since response rates maintained by nicotine were significantly lower than rates of response maintained by the non-drug reinforcers, bupropion may have resulted in rate-dependent effects. The current experiments attempted to decrease the high response rate maintained through non-drug reinforcers in order to have more comparable control rates when investigating the selectivity of bupropion for nicotine self-administration. The effects of bupropion on nicotine self-administration (0.03 mg/kg/inf) were compared to food-maintained responding at two levels of food deprivation (deprived and satiated). Rats were satiated prior to the experimental session in order to decrease the overall response rates maintained through food reinforcement. Bupropion increased nicotine intake, but dose-dependently decreased food intake, when rats were food-deprived. However, when more comparable rates of behavior in the food-satiated group were investigated, bupropion had similar effects on nicotine and food-maintained responding. The data indicate that the effects of bupropion can be influenced by the control rate of responding. The results from these experiments also indicate that bupropion may not exert a selective effect on nicotine self-administration, since low rates of food and drug maintained responding were increased by the drug. These results indicate the importance of controlling for differences in response rates when attempting to assess the effects of drugs on responding maintained by different reinforcers. Furthermore, the results from the present study suggest that motivational variables (i.e. food deprivation) may be used to control for response rate differences maintained by drug and non-drug reinforcers.

Nicotine drug discrimination and nicotinic acetylcholine receptors in differentially reared rats.

RATIONALE: Individuals vary in sensitivity to the behavioral effects of nicotine, resulting in differences in vulnerability to nicotine addiction. The role of rearing environment in determining individual sensitivity to nicotine is unclear. The neuropharmacological mechanisms mediating the effect of rearing environment on the behavioral actions of nicotine are also poorly understood. OBJECTIVES: The contribution of rearing environment in determining the sensitivity to the interoceptive effects of nicotine was determined in rats reared in isolated conditions (IC) or enriched conditions (EC). The role of dopamine receptors and α4ß2*-nicotinic acetylcholine (nACh) receptors in mediating the differential effect of IC and EC on the interoceptive action of nicotine was determined. METHODS: The interoceptive action of nicotine was measured as the discriminative stimulus effect of nicotine. Mecamylamine- and eticlopride-inhibition of the nicotine stimulus were used to examine nACh and dopamine receptors, respectively. α4ß2*-nACh receptor expression in the mesolimbic dopamine pathway was determined by quantitative autoradiography of [125I]-epibatidine binding. RESULTS: EC-reared rats are less sensitive than IC-reared rats to the discriminative stimulus effects of nicotine at all but maximally effective doses. Mecamylamine inhibited the nicotine stimulus threefold more potently in EC-reared rats (IC50 = 0.25 mg/kg) compared to IC-reared rats (IC50 = 0.75 mg/kg); eticlopride inhibition was not different. [125I]-epibatidine binding in the ventral tegmental area of EC-reared rats was reduced (2.8 ± 0.3 fmol) compared to that of IC-reared rats (4.0 ± 0.4 fmol); there was no difference in the nucleus accumbens. CONCLUSIONS: Rearing environment regulates the sensitivity to the interoceptive effects of nicotine and α4ß2*-nACh receptor expression in the mesolimbic dopamine pathway.

Lobelane decreases methamphetamine self-administration in rats.

Lobelane, a minor alkaloid of Lobelia inflata and a synthetic, des-oxy analog of lobeline, has good affinity for the vesicular monoamine transporter and the dopamine transporter. The current study examined the ability of lobelane to specifically decrease methamphetamine self-administration. Rats were trained on a fixed ratio 5 schedule of reinforcement to self-administer methamphetamine (0.05 mg/kg/infusion, i.v.) or to respond for sucrose pellets. Upon reaching stable responding, rats were pretreated with lobelane (0.1, 1, 3, 5.6, or 10 mg/kg, s.c.) or saline, 15 min prior to the operant session. To assess the effect of repeated lobelane on methamphetamine self-administration, rats were pretreated with lobelane (5.6 or 10 mg/kg, s.c.) for 7 sessions. Behavioral specificity was further investigated by assessing the effects of lobelane (0.1, 1, 3, 5, or 10 mg/kg, s.c.) or saline on locomotor activity. Within the dose range tested, lobelane dose-dependently decreased methamphetamine self-administration, while having no effect on sucrose-maintained responding. Locomotor activity was decreased following only the highest dose of lobelane (10 mg/kg). Across repeated pretreatments, tolerance developed to the effect of lobelane on methamphetamine self-administration, demonstrating that the ability of lobelane to specifically decrease methamphetamine self-administration is a transient effect. Thus, taken together, the results show that although lobelane interacts with the pharmacological targets believed to be responsible for its ability to decrease methamphetamine self-administration, removal of the oxygen functionalities from the lobeline molecule may have afforded a compound with an altered pharmacokinetic and/or pharmacodynamic profile.

Effects of environmental enrichment on d-amphetamine self-administration following nicotine exposure.

Adolescent nicotine exposure has been shown to lead to further psychostimulant use in adulthood. Previous preclinical research in rats has shown that environmental enrichment may protect against drug abuse vulnerability. The current study was designed to examine whether environmental enrichment can block the ability of adolescent nicotine exposure to increase d-amphetamine self-administration in adulthood. Male Sprague-Dawley rats were raised in either enriched conditions (ECs) or isolated conditions (ICs) and then injected with saline or nicotine (0.4 mg/kg, sc) for 7 days during adolescence. In adulthood rats were allowed to self-administer d-amphetamine under a fixed ratio (FR; 0, 0.006, 0.01, 0.02, 0.06, and 0.1 mg/kg/infusion) and progressive ratio (PR; 0, 0.006, 0.06, and 0.1 mg/kg/infusion) schedule of reinforcement. Nicotine-treated IC rats self-administered more d-amphetamine at 0.006, 0.01, and 0.02 mg/kg/infusion doses compared with their saline-treated IC counterparts regardless of the schedule maintaining behavior. This effect of nicotine was reversed in EC rats on a fixed ratio schedule. These findings indicate that environmental enrichment can limit the ability of adolescent nicotine exposure to increase vulnerability to other psychostimulant drugs, such as d-amphetamine. (PsycINFO Database Record

The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function.

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2C-containing NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK-801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatory-inhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders.

The effects of environmental enrichment on nicotine condition place preference in male rats.

Environmental enrichment has previously been shown to alter sensitivity to psychostimulants and opiates in various preclinical models. However, little research has been conducted studying the effects of environmental enrichment on the more commonly abused drug, nicotine. The current study raised male rats in either enriched conditions (EC) or isolated conditions (IC) and tested the animals' sensitivity to acquisition, extinction and reinstatement of nicotine conditioned place preference (CPP). Using a 3-chamber CPP apparatus, male Sprague-Dawley rats were conditioned with 1 of 3 doses of nicotine (0.4, 0.6, and 0.8 mg/kg) or saline on alternating days across 8 conditioning trials, followed by a test day for a nicotine-induced CPP response. Next, the animals had 5 extinction sessions followed by a nicotine-primed reinstatement session. EC rats displayed nicotine CPP at all 3 doses, whereas IC rats failed to show significant nicotine CPP relative to saline controls. EC rats also showed extinction of the nicotine-induced CPP response by the fifth extinction session for all 3 nicotine doses tested. However, only the 2 highest doses of the nicotine prime reinstated a CPP response in EC rats relative to saline controls. Taken together, these findings suggest that environmental enrichment may increase sensitivity to the rewarding effects of nicotine.

Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity.

The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC and hippocampus. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2B-containing receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders such as autism.

Effects of environmental enrichment on nicotine-induced sensitization and cross-sensitization to d-amphetamine in rats.

INTRODUCTION: Research indicates that adolescent nicotine exposure may predispose individuals to use other psychostimulants later in adulthood, offering support for the incentive-sensitization theory of addiction. Preclinical studies testing the incentive-sensitization theory show that repeated nicotine exposure in adolescent rats can lead to an increased sensitivity to the motor stimulant effects of nicotine and other psychostimulants in adulthood. Although previous nicotine exposure can increase sensitivity to stimulant drugs, rats raised in enriched conditions (EC) show, decreased sensitivity to psychostimulant drugs compared to rats raised in isolation conditions (IC). METHODS: We examined whether nicotine sensitization or cross-sensitization to d-amphetamine induced by adolescent nicotine exposure is altered by exposure to environmental enrichment. Adolescent EC and IC male rats received subcutaneous (s.c.) injections of saline or 0.4mg/kg of nicotine once daily for seven days. Thirty-five days following the last nicotine injection EC and IC animals were challenged with saline, nicotine (0.2 or 0.4mg/kg) or d-amphetamine (0.5 or 1.0mg/kg). RESULTS: EC rats failed to show nicotine sensitization at either nicotine dose tested while IC rats showed nicotine sensitization following the 0.4mg/kg nicotine dose. EC rats also failed to show nicotine-induced cross-sensitization to the 0.5mg/kg dose of d-amphetamine while IC rats displayed cross-sensitization. However, EC rats did exhibit nicotine-induced cross-sensitization to the 1.0mg/kg dose of d-amphetamine. CONCLUSION: These findings indicate that environmental enrichment can alter the ability of adolescent nicotine exposure to induce sensitization and cross-sensitization in adulthood and may be used as a protectant factor against adolescent nicotine exposure.

Deletion of glutamate delta-1 receptor in mouse leads to enhanced working memory and deficit in fear conditioning.

Glutamate delta-1 (GluD1) receptors are expressed throughout the forebrain during development with high levels in the hippocampus during adulthood. We have recently shown that deletion of GluD1 receptor results in aberrant emotional and social behaviors such as hyperaggression and depression-like behaviors and social interaction deficits. Additionally, abnormal expression of synaptic proteins was observed in amygdala and prefrontal cortex of GluD1 knockout mice (GluD1 KO). However the role of GluD1 in learning and memory paradigms remains unknown. In the present study we evaluated GluD1 KO in learning and memory tests. In the eight-arm radial maze GluD1 KO mice committed fewer working memory errors compared to wildtype mice but had normal reference memory. Enhanced working memory in GluD1 KO was also evident by greater percent alternation in the spontaneous Y-maze test. No difference was observed in object recognition memory in the GluD1 KO mice. In the Morris water maze test GluD1 KO mice showed no difference in acquisition but had longer latency to find the platform in the reversal learning task. GluD1 KO mice showed a deficit in contextual and cue fear conditioning but had normal latent inhibition. The deficit in contextual fear conditioning was reversed by D-Cycloserine (DCS) treatment. GluD1 KO mice were also found to be more sensitive to foot-shock compared to wildtype. We further studied molecular changes in the hippocampus, where we found lower levels of GluA1, GluA2 and GluK2 subunits while a contrasting higher level of GluN2B in GluD1 KO. Additionally, we found higher postsynaptic density protein 95 (PSD95) and lower glutamate decarboxylase 67 (GAD67) expression in GluD1 KO. We propose that GluD1 is crucial for normal functioning of synapses and absence of GluD1 leads to specific abnormalities in learning and memory. These findings provide novel insights into the role of GluD1 receptors in the central nervous system.