Toluene, a widely used and commonly abused organic solvent, produces various behavioral disturbances, including motor incoordination and cognitive impairment. Toluene alters the function of a large number of receptors and ion channels. Blockade of N-methyl-d-aspartate (NMDA) receptors has been suggested to play a critical role in toluene-induced behavioral manifestations. The present study determined the effects of various toluene doses on motor coordination, recognition memory, body temperature, and intracranial self-stimulation (ICSS) thresholds in mice. Additionally, the effects of sarcosine on the behavioral and physiological effects induced by toluene were evaluated. Sarcosine may reverse toluene-induced behavioral manifestations by acting as an NMDA receptor co-agonist and inhibiting the effects of the type I glycine transporter (GlyT1). Mice were treated with toluene alone or combined with sarcosine pretreatment and assessed for rotarod performance, object recognition memory, rectal temperature, and ICSS thresholds. Toluene dose-dependently induced motor incoordination, recognition memory impairment, and hypothermia and lowered ICSS thresholds. Sarcosine pretreatment reversed toluene-induced changes in rotarod performance, novel object recognition, and rectal temperature but not ICSS thresholds. These findings suggest that the sarcosine-induced potentiation of NMDA receptors may reverse motor incoordination, memory impairment, and hypothermia but not the enhancement of brain stimulation reward function associated with toluene exposure. Sarcosine may be a promising compound to prevent acute toluene intoxications by occupational or intentional exposure.
toluene; motor coordination; recognition memory; body temperature; intracranial self-stimulation
Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
Metabotropic glutamate receptors; agonist; positive allosteric modulators; BINA; nicotine self-administration; rat model; addiction
The role of β4-containing nicotinic acetylcholine receptors (nAChRs) in cognition, anxiety, depression, and analgesia in the absence of nicotine is unclear.
Wild-type (β4+/+) and knockout (β4−/−) mice for the nAChR β4 subunit were tested in behavioral tests assessing cognitive function, affective behaviors, and nociception.
There were no learning and memory deficits in β4−/− mice compared with β4+/+ mice during the acquisition of the Barnes maze, contextual fear conditioning, and Y maze tasks. In the Barnes maze memory retention test, male β4−/− mice showed reduced use of the spatial search strategy, indicating small spatial memory deficits compared with β4+/+ mice. In the cue-induced fear conditioning memory retention test, β4−/− mice exhibited reduced freezing time compared with β4+/+ mice. Compared with β4+/+ mice, β4−/− mice exhibited decreased anxiety-like behavior in the light–dark box. Depression-like behavior in β4−/− mice was decreased in the tail suspension test and increased in the forced swim test compared with β4+/+ mice. β4−/− mice did not differ from β4+/+ mice in basal nociception but were less sensitive to the antinociceptive effect of nicotine in 2 tests of acute thermal pain.
Lack of β4-containing nAChRs resulted in small deficits in hippocampus- and amygdala-dependent memory retention functions. β4-containing nAChRs are involved in anxiety- and depression-like behaviors and contribute to the analgesic effects of nicotine.
Experimental animal studies have shown that repeated administration of psychostimulants, such as methamphetamine (METH), results in an altered behavioral response profile, which includes the sensitization of both locomotor and stereotyped behaviors. Although sensitization of these behaviors has been characterized in detail during bolus, investigator-administered drug administration, little is known about the development or expression of stereotypies during psychostimulant self-administration.
The present study investigated in rats the expression of focused stereotyped behaviors during an extended access, escalation procedure of METH self-administration. Over several weeks during stepwise extended daily access to METH (3-, 6-and 12-h) followed by exposure to 24-h ‘binges’, rats gradually increased daily drug intake.
During the escalation procedure, the rats’ behavioral response evolved from locomotor activation to progressively more focused stereotypies, culminating in continuous oral behaviors (licking, gnawing and chewing), interrupted only by episodic lever presses. Sensitization of stereotyped behaviors was evident, particularly with regard to oral behaviors that exhibited a more rapid onset and intensification in the apparent absence of greater drug intake.
Our data demonstrate that stepwise extended daily access to METH (3-, 6-, 12-and 24-h) self-administration in rats closely approximates motivational, pharmacokinetic, as well as behavioral patterns of human METH abuse. The accompanied appearance of sensitization of intense focused stereotyped behaviors, which is probably a consequence of escalation of drug intake, resembles stereotypies associated with investigator-initiated METH administration and may parallel the development of stimulant-induced psychosis seen in human abusers.
Methamphetamine; self-administration; escalation; binge; stereotypy; sensitization
Positive affect (PA) is closely linked to prevention of, and recovery from, depression. Previous studies have investigated PA reactivity to pleasant situations with respect to its protective properties in relation to mood disorder. The purpose of this study was to examine, and replicate, whether moment-to-moment transfer of PA in daily life (PA persistence) is relevant to the prediction of future course of depression.
Individuals from three different studies (one general population sample (n=540), and two patient samples (n=43 and n=50) with matching controls (n=39 and n=21, respectively)) participated in an Experience Sampling Method (ESM) study. Time-lagged multilevel analyses were used to assess the degree of transfer (or persistence) of momentary positive affective states over time, in relation to naturalistic outcome (study 1) or treatment outcome (studies 2 and 3). Depressive symptoms were measured using the Symptom Checklist (SCL-90R) in sample 1 and the Hamilton Depression Rating Scale (HDRS) in samples 2 and 3.
In study 1, participants with greater momentary PA persistence were less likely to show depressive symptoms at follow-up. In study 2, patients were more likely to respond to treatment if they displayed greater momentary PA persistence, particularly in those with recurrent depression. In study 3, patients with greater momentary PA persistence were similarly more likely to respond to treatment, especially when treated with imipramine rather than placebo.
The ability to transfer PA from one moment to the next is an important factor in the prevention of and recovery from depressive symptoms. Patients with recurrent depression and those who receive antidepressants rather than placebo may benefit most from this effect. The results suggest that treatment-induced improvement in depression is mediated by increased levels of momentary transfer of PA in daily life, acquisition of which may be contingent on duration of exposure to depressive experience.
Depression is a major contributor to the global burden of disease and disability, yet it is poorly understood. Here we review data supporting a novel theoretical model for the biology of depression. In this model, a stressful life event leads to microdamage in the brain. This damage triggers an injury repair response consisting of a neuroinflammatory phase to clear cellular debris, and a spontaneous tissue regeneration phase involving neurotrophins and neurogenesis. During healing, released inflammatory mediators trigger sickness behavior and psychological pain via mechanisms similar to those that produce physical pain during wound healing. The depression remits if the neuronal injury repair process resolves successfully. Importantly, however, the acute psychological pain and neuroinflammation often transition to chronicity and develop into pathological depressive states. This hypothesis for depression explains substantially more data than alternative models, including why emerging data show that analgesic, anti-inflammatory, pro-neurogenic and pro-neurotrophic treatments have antidepressant effects. Thus, an acute depressive episode can be conceptualized as a normally self-limiting but highly error-prone process of recuperation from stress-triggered neuronal microdamage.
life event; stress; emotionally traumatic brain injury; eTBI; remodeling; neuroinflammation; cytokines; psychological hyperalgesia; sickness behavior; central sensitization; psychological nociceptors; psychological hyperalgesic priming; depression; antidepressants; neurogenesis; neurotrophins
Experimental evidence suggests that metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists affect cognitive function, although contradictory findings have been reported. To clarify the role of mGlu2/3 receptor antagonists in one aspect of cognition, the present study investigated the effects of a broad range of doses of the mGlu2/3 receptor antagonist LY341495 on post-training recognition memory components (storage and/or retrieval) in rats. The efficacy of LY341495 in antagonizing the extinction of recognition memory was also investigated. The novel object recognition test was used as the memory test. The highest LY341495 doses administered (0.3, 1, and 3 mg/kg) disrupted performance in this recognition memory procedure in rats at all delay conditions tested, whereas administration of lower doses (0.05 and 0.1 mg/kg) did not impair recognition memory. Moreover, administration of the low LY341495 doses (0.05 and 0.1 mg/kg) counteracted the extinction of recognition memory. The present results indicate that administration of the mGlu2/3 receptor antagonist LY341495 can either impair or enhance recognition memory in rats, depending on the dose of the compound and delay period used. Thus, together with previously reported findings, the present data suggest complex effects of this compound on cognitive function, particularly recognition memory.
metabotropic glutamate (mGlu)2/3 receptor; LY341495; recognition memory; rat
Adolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats.
Male Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward integration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory.
These effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research.
To assess which nicotinic acetylcholine receptors (nAChRs) are involved in the aversive aspects of nicotine withdrawal, brain reward function and the somatic signs of nicotine withdrawal were assessed in mice that lack α7 and β4 nAChR subunits. Brain reward function was assessed with the intracranial self-stimulation (ICSS) procedure, in which elevations in ICSS thresholds reflect an anhedonic mood state. At 3–6 h of spontaneous nicotine/saline withdrawal, thresholds were elevated in nicotinewithdrawing α7+/+ and β4+/+, but not α7−/− or β4−/−, mice compared with saline-withdrawing mice, indicating a delay in the onset of withdrawal in the knockout mice. From 8 to 100 h of withdrawal, thresholds in α7+/+ and α7−/− mice were equally elevated, whereas thresholds in β4+/+ and β4−/− mice returned to baseline levels. Somatic signs were attenuated in nicotine-withdrawing β4−/−, but not α7−/−, mice. Administration of a low dose of the nAChR antagonist mecamylamine induced threshold elevations in α7−/−, but not α7+/+, mice, whereas the highest dose tested only elevated thresholds in α7+/+ mice. Mecamylamine-induced threshold elevations were similar in β4−/− and β4+/+ mice. In conclusion, null mutation of the α7 and β4 nAChR subunits resulted in a delayed onset of the anhedonic aspects of the spontaneous nicotine withdrawal syndrome. Previous findings of attenuated somatic signs of nicotine withdrawal in β4−/−, but not α7−/−, mice were confirmed in the present study, indicating an important role for β4-containing nAChRs in the somatic signs of nicotine withdrawal. The mecamylamine-precipitated withdrawal data suggest that compensatory adaptations may occur in constitutive α7−/− mice or that mecamylamine may interact with other receptors besides nAChRs in these mice. In summary, the present results indicate an important role for α7 and β4-containing nAChRs in the anhedonic or somatic signs of nicotine withdrawal.
Intracranial self-stimulation; Somatic signs; Reward deficit; Anhedonia; Mecamylamine; nAChR
Comparison studies between different analytical methodologies for circulating tumor cells (CTC) detection and molecular characterization are urgently needed, since standardization of assays is essential before their use in clinical practice.
We compared three different CTC molecular assays. To avoid discrepancies due to pre-analytical errors we used the same cDNAs throughout our study. CTC were isolated using anti-EpCAM and anti-MUC1 coated magnetic beads from 2 × 5 ml of peripheral blood of 254 early and 51 metastatic breast cancer patients and 30 healthy individuals. The same cDNAs were analyzed by: a) singleplex RT-qPCR assay for CK-19; b) multiplex RT-qPCR for CK-19, HER-2, MAGE- A3, and PBGD; and c) a commercially available molecular assay (AdnaTest BreastCancer) for GA733-2, MUC-1, HER-2 and beta-actin.
In early breast cancer, CK-19 RT-qPCR, multiplex RT-qPCR and the AdnaTest, were positive for the presence of CTC in 14.2%, 22.8% and 16.5% subjects, respectively. The concordance between the AdnaTest and CK-19 RT-qPCR was 72.4% while between the AdnaTest and multiplex RT-qPCR was 64.6%. In patients with overt metastasis, CK-19 RT-qPCR, multiplex RT-qPCR and the AdnaTest were positive in 41.2%, 39.2% and 54.9% patients, respectively. The concordance between the AdnaTest and CK-19 RT-qPCR was 70.6% while between the AdnaTest and multiplex RT-qPCR was 68.6%.
All CTC assays gave similar results in about 70% of cases. Better agreement was found in the metastatic setting, possibly explained by the higher tumor load in this group. Discordances could be attributed to the different gene transcripts used to evaluate CTC positivity. Our results indicate the importance of CTC heterogeneity for their detection by different analytical methodologies.
Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and γ-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug-free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction.
schizophrenia; phencyclidine; glutamate; GABA; clozapine; antipsychotic; cognition
Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Very high rates of tobacco smoking are seen in patients with schizophrenia. Importantly, smokers with schizophrenia generally have higher nicotine dependence scores, experience more severe withdrawal symptoms upon smoking cessation, have lower cessation rates than healthy individuals, and suffer from significant smoking-related morbidity and premature mortality compared with the general population. Interestingly, significant disturbances in cholinergic function are reported in schizophrenia patients. The high smoking-schizophrenia comorbidity observed in schizophrenia patients may be an attempt to compensate for this cholinergic dysfunction. Cholinergic neurotransmission plays an important role in cognition and is hypothesized to play an important role in schizophrenia-associated cognitive deficits. In this review, preclinical evidence highlighting the beneficial effects of nicotine and subtype-selective nicotinic receptor agonists in schizophrenia-associated cognitive deficits, such as working memory and attention, is discussed. Furthermore, some of the challenges involved in the development of procognitive medications, particularly subtype-selective nicotinic receptor agonists, are also discussed. Amelioration of schizophrenia-associated cognitive deficits may help in the treatment of schizophrenia-smoking comorbidity by promoting smoking cessation and thus help in the better management of schizophrenia patients.
Based on phenomenological similarities between anhedonia (reward deficits) associated with drug withdrawal and the negative symptoms of schizophrenia, we showed previously that the atypical antipsychotic clozapine attenuated reward deficits associated with psychostimulant withdrawal. Antagonism of α2 adrenergic and 5-HT2A receptors may contribute to these effects of clozapine. We investigated here whether blockade of α2 or 5-HT2A receptors by idazoxan and M100907, respectively, would reverse anhedonic aspects of psychostimulant withdrawal. Idazoxan treatment facilitated recovery from spontaneous nicotine, but not amphetamine, withdrawal by attenuating reward deficits and increased number of somatic signs. Thus, α2 adrenoceptor blockade may have beneficial effects against nicotine withdrawal and may be involved in the effects of clozapine previously observed. M100907 worsened the anhedonia associated with nicotine and amphetamine withdrawal suggesting that monotherapy with M100907 may exacerbate the expression of the negative symptoms of schizophrenia or nicotine withdrawal symptoms in people, including schizophrenia patients, attempting to quit smoking.
DHβE; brain reward thresholds; somatic signs of withdrawal; anhedonia
Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia, and other neuropsychiatric disorders. Over the past three decades, the clinical definition of anhedonia has remained relatively unchanged, although cognitive psychology and behavioral neuroscience have expanded our understanding of other reward-related processes. Here, we review the neural bases of the construct of anhedonia that reflects deficits in hedonic capacity, and is also closely linked to the constructs of reward valuation, decision-making, anticipation, and motivation. The neural circuits subserving these reward-related processes include the ventral striatum, prefrontal cortical regions, and afferent and efferent projections. Understanding anhedonia and other reward-related constructs will facilitate diagnosis and treatment of disorders that include reward deficits as key symptoms.
Systemic administration of the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was previously shown to selectively attenuate nicotine self-administration without affecting food-maintained responding in rats. Glutamatergic neurotransmission in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) shell plays an important role in the reinforcing effects of nicotine. To determine the brain sites that may mediate the systemic effects of MPEP on nicotine self-administration, the present study investigated the effects of MPEP microinfusions into the VTA or the NAcc shell on nicotine and food self-administration in separate groups of rats. Administration of low MPEP doses (0, 0.5, 1, and 2 μg/0.5 μl/side) microinfused into the NAcc shell had no effect on nicotine self-administration, whereas higher MPEP doses (0, 10, 20, and 40 μg/0.5 μl/side) microinfused into the NAcc shell dose-dependently attenuated nicotine self-administration without affecting food-maintained responding. Microinfusions of MPEP into the VTA (0, 10, 20, and 40 μg/0.5 μl/side) significantly decreased both nicotine and food self-administration at 20 μg/0.5 μl/side but did not affect responding for either reinforcer at 40 μg/0.5 μl/side. This lack of effect of 40 μg/0.5 μl/side MPEP on either nicotine or food self-administration when administered into the VTA may be attributable either to actions of MPEP at presynaptic mGlu5 receptors or at targets other than mGlu5 receptors. Importantly, anatomical control injections 2 mm above the NAcc shell or the VTA using the most effective MPEP dose in the two regions did not result in attenuation of nicotine self-administration. In conclusion, MPEP microinfusions in the VTA or NAcc shell attenuates the reinforcing effects of nicotine possibly via blockade of mGlu5 receptors located in these regions.
The 5-choice serial reaction time task (5-CSRTT) is a valuable cognitive test that permits the simultaneous assessment of several different cognitive modalities, including attention, impulse control, processing speed, and cognitive flexibility. Increasing task difficulty on test days through various challenges can further enhance the versatility of this test by selectively enhancing the cognitive load on different aspects of the task. Systematic comparisons of the effects of different test day challenges on 5-CSRTT performance are essential to verify how these challenges affect different task measures and which manipulations are best suited for future studies of different aspects of cognition. We trained Wistar rats in the 5-CSRTT under standard conditions, then challenged them on the test days by (1) decreasing the duration of the stimulus to be detected, (2) increasing the time interval between trials (intertrial interval, ITI), (3) randomly varying the ITI, or (4) adding a flashing light distractor. All test day challenges produced distinct profiles of performance disruption that reflected differential effects on different cognitive modalities. Decreased stimulus duration selectively impaired attentional performance, while increased ITI increased impulsive-like premature responses and decreased trials completed. Variable ITI induced only mild, nonsignificant disruptions in response inhibition and processing speed, while the flashing light distractor produced comprehensive impairment affecting multiple aspects of 5-CSRTT performance, including disrupted attention and increased premature and timeout responses. This improved understanding of the effects of different test day challenges in the 5-CSRTT will allow researchers to use these manipulations of a valuable cognitive test to their full potential.
cognition; 5-choice serial reaction time task; attention; impulsivity; behavioral tasks
Anhedonia is a major symptom of cocaine withdrawal, whereas euphoria characterizes the effects of acute administration of this drug in humans. These mood states can be measured quantitatively in animals with brain reward thresholds obtained from the intracranial self-stimulation (ICSS) procedure. Studies have previously reported the reward-enhancing effects of acute cocaine administration using the ICSS procedure in mice, but the effects of chronic cocaine administration and withdrawal on brain reward thresholds have not been widely investigated in this species. Cocaine withdrawal was induced in C57BL/6J mice by removal of intraperitoneal osmotic minipumps that delivered cocaine (90 or 180 mg/kg/day, salt) for 72 h. Mice were tested in the ICSS procedure 3–100 h post-pump removal. Anxiety-like behavior was assessed in the light-dark box 24 h post-pump removal. After an 18-day washout period, tolerance and sensitization to the reward-enhancing effects of cocaine were assessed by injecting bolus cocaine intraperitoneally (0, 2.5, 5, and 10 mg/kg). The results indicated that 72 h administration of 90 and 180 mg/kg/day cocaine significantly lowered brain reward thresholds. Withdrawal from 90 and 180 mg/kg/day of cocaine administration elevated ICSS thresholds to similar extents. No anxiety-like behavior was observed in the light-dark box during withdrawal from chronic cocaine administration, although the number of transitions between compartments and locomotion in the dark compartment markedly decreased. Chronic cocaine administration did not induce tolerance or sensitization to the reward-enhancing effects of acute cocaine. In conclusion, alterations in mood states induced by cocaine administration and withdrawal in mice can be measured using the ICSS procedure.
Intracranial self-stimulation; light-dark box; anhedonia; anxiety
The metabotropic glutamate 2/3 (mGlu2/3) receptor agonist LY379268 ([−]-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate) attenuates both nicotine self-administration and cue-induced nicotine seeking in rats. In this study, the effects of LY379268 (1 mg/kg) or saline pretreatment on nicotine-induced increases in nucleus accumbens (NAcc) shell dopamine were evaluated using in vivo microdialysis under different experimental conditions: (i) nicotine (0.4 mg/kg, base) was experimenter-administered subcutaneously to nicotine-naïve rats; (ii) nicotine was experimenter-administered either subcutaneously (0.4 mg/kg) or by a single experimenter-administered infusion (0.06 mg/kg, base) in rats with a history of nicotine self-administration (nicotine experienced) in the absence of a nicotine-associated context (ie, context and cues associated with nicotine self-administration); (iii) nicotine (0.06 mg/kg) was self-administered or experimenter-administered in nicotine-experienced rats in the presence of a nicotine-associated context. In saline-pretreated nicotine-naïve and nicotine-experienced rats, nicotine increased NAcc shell dopamine regardless of the context used for testing. Interestingly, LY379268 pretreatment blocked nicotine-induced increases in NAcc shell dopamine in nicotine-experienced rats only when tested in the presence of a nicotine-associated context. LY379268 did not block nicotine-induced increases in NAcc shell dopamine in nicotine-naïve or -experienced rats tested in the absence of a nicotine-associated context. These intriguing findings suggest that activation of mGlu2/3 receptors negatively modulates the combined effects of nicotine and nicotine-associated contexts/cues on NAcc dopamine. Thus, these data highlight a critical role for mGlu2/3 receptors in context/cue-induced drug-seeking behavior and suggest a neurochemical mechanism by which mGlu2/3 receptor agonists may promote smoking cessation by preventing relapse induced by the combination of nicotine and nicotine-associated contexts and cues.
motivation; self-administration; metabotropic glutamate receptor; microdialysis; dopamine; neuropharmacology; addiction & substance abuse; dopamine; glutamate; motivation; self-administration; microdialysis; metabotropic; nicotine
Group II metabotropic glutamate (mGlu) receptors consist of the metabotropic glutamate 2 (mGlu2) and metabotropic glutamate 3 (mGlu3) receptor subtypes which modulate glutamate transmission by second messenger activation to negatively regulate the activity of adenylyl cyclase. Excessive accumulation of glutamate in the perisynaptic extracellular region triggers mGlu2 and mGlu3 receptors to inhibit further release of glutamate. There is growing evidence that the modulation of glutamatergic neurotransmission by small molecule modulators of Group II mGlu receptors has significant potential for the treatment of several neuropsychiatric and neurodegenerative diseases. This review provides an overview of recent progress on the synthesis and pharmacological characterization of positive and negative allosteric modulators of the Group II mGlu receptors.
mGlu2; mGlu3; allosteric modulators; schizophrenia; memory; anxiety; drug dependence; sleep-wake architecture
Nicotine is known to enhance long-term hippocampus dependent learning and memory in both rodents and humans via its activity at nicotinic acetylcholinergic receptors (nAChRs). However, the molecular basis for the nicotinic modulation of learning is incompletely understood. Both the mitogen activated protein kinases (MAPKs) and cAMP response element binding protein (CREB) are known to be integral to the consolidation of long-term memory and the disruption of MAPKs and CREB are known to abrogate some of the cognitive effects of nicotine. In addition, the acquisition of contextual fear conditioning in the presence of nicotine is associated with a β2-subunit containing nAChR-dependent increase in jnk1 (mapk8) transcription in the hippocampus. In the present study, chromatin immunoprecipitation (ChIP) was used to examine whether learning and nicotine interact to alter transcription factor binding or histone acetylation at the jnk1 promoter region. The acquisition of contextual fear conditioning in the presence of nicotine resulted in an increase in phosphorylated CREB (pCREB) binding to the jnk1 promoter in the hippocampus in a β2-subunit containing nAChR dependent manner, but had no effect on CREB binding; neither fear conditioning alone nor nicotine administration alone altered transcription factor binding to the jnk1 promoter. In addition, there were no changes in histone H3 or H4 acetylation at the jnk1 promoter following fear conditioning in the presence of nicotine. These results suggest that contextual fear learning and nicotine administration act synergistically to produce a unique pattern of protein activation and gene transcription in the hippocampus that is not individually generated by fear conditioning or nicotine administration alone.
Nicotine dependence is maintained by the aversive, depression-like effects of nicotine withdrawal and the rewarding effects of acute nicotine. GABAB receptor antagonists exhibit antidepressant-like effects in rodents, whereas GABAB receptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABAB receptor positive modulators showed that these compounds represent potentially improved medications for the treatment of nicotine dependence because of fewer side-effects than GABAB receptor agonists. Thus, GABAB receptor agonists and antagonists, and GABAB receptor positive modulators may have efficacy as smoking cessation aids by targeting different aspects of nicotine dependence and withdrawal. The present study assessed the effects of the GABAB receptor agonist CGP44532, the GABAB receptor antagonist CGP56433A, and the GABAB receptor positive modulator BHF177 on the anhedonic aspects of nicotine withdrawal. Rats were prepared with stimulating electrodes in the posterior lateral hypothalamus. After establishing stable intracranial self-stimulation (ICSS) thresholds, rats were prepared with subcutaneous osmotic minipumps delivering either nicotine or saline for 7 or 14 days. ICSS thresholds were assessed 6 h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and BHF177 were administered 30 min prior to ICSS testing. Both GABAB receptor activation (CGP44532 and BHF177) and blockade (CGP56433A) elevated ICSS thresholds in all groups, resulting in exacerbated effects of nicotine withdrawal in the nicotine-treated groups. These similar effects of GABAB receptor activation and blockade on the anhedonic depression-like aspects of nicotine withdrawal were surprising and perhaps reflect differential efficacy of these compounds at presynaptic hetero- and autoreceptors, as well as postsynaptic, GABAB receptors.
GABA; positive modulators; CGP44532; CGP56433A; BHF177; depression-like state; ICSS; brain stimulation reward
Disturbed information processing observed in neuropsychiatric disorders is reflected by deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). Long-term, higher-dose methamphetamine (METH) abuse patterns are associated with cognitive impairments, mania and/or schizophrenia-like psychosis. The present study investigated in rats METH-induced impairment of sensorimotor gating using an intravenous self-administration (IVSA) escalating dose procedure. In this procedure, rats escalated drug intake during weekly extended access periods to METH IVSA (1, 3, and 6-h), where PPI was assessed after each access period and thus at various times of drug exposure. Despite increased drug intake over the course of extended access to METH, disruption of sensorimotor gating was only seen after the access period of 6-h. The data suggest that METH-induced impairment of sensorimotor gating in IVSA-tasks is rather attributed to continuous and higher-dose exposure than to actual amounts of drug present at the time of testing. IVSA procedures, comprising stepwise stimulant escalation may serve as a useful translational model in rats that approximate important aspects of human abuse pattern in the context of stimulant-induced cognitive and behavioral deficits.
methamphetamine; self-administration; escalation; sensorimotor gating
The modification of 3′-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior drug-like properties. These analogues are more potent than 1 in vitro, and are highly selective for mGluR2 vs. other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence.
Metabotropic glutamate receptors; agonist; positive allosteric modulators; BINA; cocaine self-administration
Somatostatins have been shown to be involved in the pathophysiology of motor and affective disorders, as well as psychiatry disorders, including schizophrenia. We hypothesized that in addition to motor function, somatostatin may be involved in somatosensory gating and reward processes that have been shown to be dysregulated in schizophrenia. Accordingly, we evaluated the effects of intracerebroventricular administration of somatostatin-28 on spontaneous locomotor and exploratory behavior measured in a behavioral pattern monitor, sensorimotor gating, prepulse inhibition (PPI) of the acoustic startle reflex, and brain reward function (measured in a discrete trial intracranial self-stimulation procedure) in rats. Somatostatin-28 decreased spontaneous locomotor activity during the first 10 min of a 60 min testing session with no apparent changes in the exploratory activity of rats. The highest somatostatin-28 dose (10 μg/5 μl/side) induced PPI deficits with no effect on the acoustic startle response or startle response habituation. The somatostatin-induced PPI deficit was partially reversed by administration of SRA-880, a selective somatostatin 1 (sst1) receptor antagonist. Somatostatin-28 also induced elevations in brain reward thresholds, reflecting an anhedonic-like state. SRA-880 had no effect on brain reward function under baseline conditions. Altogether these findings suggest that somatostatin-28 modulates PPI and brain reward function but does not have a robust effect on spontaneous exploratory activity. Thus, increases in somatostatin transmission may represent one of the neurochemical mechanisms underlying anhedonia, one of the negative symptoms of schizophrenia, and sensorimotor gating deficits associated with cognitive impairments in schizophrenia patients.
sensorimotor gating; intracranial self-stimulation; reward thresholds; anhedonia; schizophrenia; SRA-880
Early life adversity or parental neglect is linked to the development of a number of psychiatric illnesses, including major depression and substance use disorder. These two disorders are often comorbid and characterized by anhedonia, defined as the reduced ability to experience pleasure or reward. The aim of the present study was to determine the effects of neonatal maternal separation in Long Evans rats, a model of early life stress, on anhedonia under baseline conditions and in response to drug and stress exposure during adulthood. Three hours of daily maternal separation from postnatal day 1 to 14 led to marked decreases in arched-back nursing, licking, and grooming of pups by their dams. In adulthood, brain reward function was assessed using intracranial self-stimulation of the lateral hypothalamus. Decreased current thresholds derived from this procedure are interpreted as reward-enhancing effects, whereas elevations in thresholds are an operational measure of anhedonia. Maternally separated rats did not exhibit anhedonia under baseline conditions compared with non-handled controls but exhibited a greater reward-enhancing effect of acute amphetamine administration. Acute social defeat produced anhedonia in non-handled controls, but not in maternally separated rats. Conversely, control rats habituated to 7 days of repeated social defeat, whereas maternally separated rats developed an increased anhedonic response to the repeated stressor. One week after termination of stress exposure, maternally separated rats still exhibited an increased reward-enhancing effect of acute amphetamine administration compared with non-handled controls, regardless of prior social defeat experience. These data indicate that early life stress increases the reward-enhancing properties of amphetamine, protects against the anhedonic effects of acute stress exposure, and exacerbates the anhedonic response to repeated stress. Thus, early life stress may increase an individual’s vulnerability to depressive or addictive disorders when confronted with stress or drug challenge in adulthood.
Early life stress; Maternal care; Anhedonia; Depression; ICSS; Psychostimulant