Extinction Period Research Articles

Region-Specific Reductions in Morphometric Properties and Synaptic Colocalization of Astrocytes Following Cocaine Self-Administration and Extinction.

While much is known about the effects of cocaine use on the cellular structure and function of neurons and synapses within the brain’s reward circuitry, relatively little is known about the effects of cocaine on astrocytes. Given the significant role that astrocytes play in modulating neuronal and synaptic function, this lack of knowledge regarding the role of astroglial adaptations in the neuropathology of drug abuse represents an important investigative need. We recently showed that astrocytes within the nucleus accumbens (NAc) core exhibit decreased volume, surface area, and synaptic colocalization following cocaine self-administration and extinction, compared to NAc astrocytes from saline-administering animals (Scofield et al., 2016b). However, it is unknown whether these cocaine-dependent changes in astrocytes are ubiquitous throughout the brain’s reward circuitry, or represent specific adaptations within the NAc. It is also not known whether the extinction period is necessary for the retracted phenotype, or whether self-administration alone is sufficient to drive these changes. In the current study, we have extended our assessment of the effects of cocaine self-administration on morphometric properties and synaptic colocalization of astrocyte peripheral processes in the prelimbic region of the medial prefrontal cortex (PL) and basolateral nucleus of the amygdala (BLA), both known to also contribute significantly to motivated behaviors. In addition, in order to pinpoint the temporal dimension of previously observed effects, we also examined astrocytes within the NAc following the last self-administration session. While a reduction of astrocyte size and synaptic colocalization was observed in the NAc core of cocaine-extinguished rats as previously shown, no differences in PL or BLA astrocytes were observed between saline- and cocaine-extinguished rats. Moreover, decreased synaptic colocalization of peripheral processes in the NAc was observed with a post-synaptic marker, instead of a presynaptic marker as used previously. In contrast, no significant changes were found in NAc astrocytes after self-administration alone. These results provide insights into the influence of cocaine use on astrocytes within the brain reward circuitry, and inform both regional heterogeneity as well as temporal dynamics of astrocyte responsiveness to cocaine self-administration.

Microinjection of the mGluR2/3 agonist, LY379268, into the nucleus accumbens attenuates extinction latencies and the reinstatement of morphine-induced conditioned place preference in rats.

Previous studies indicate that metabotropic glutamate receptor type 2/3 (mGluR2/3) has a key role in the rewarding properties of morphine-induced conditioning place preference (CPP). Group II mGluR2/3 agonists are offered as a drug addiction treatment. The nucleus accumbens (NAc), which is one of the important areas involved in the reward circuitry, also expresses these receptors. In this study, we evaluated the effects of mGluR2/3 agonist, LY379268, on the extinction and reinstatement of morphine-induced CPP, following its microinjection into the NAc. Adult male Wistar rats (220-250 g) were implanted bilaterally by two separate cannulae into the NAc. After the acquisition of morphine CPP, different doses of LY379268 (0.3, 1 and 3 µg/0.5 μl saline) were microinjected into the NAc every day during the extinction period and, in a different set of experiments, on the reinstatement test day, 60 min before the infusion of a priming dose of morphine (1 mg/kg; subcutaneous). Thereafter, the animals were tested for place preference by the Ethovision software. The intra-accumbal injection of the mGluR2/3 agonist, LY379268, significantly decreased the extinction latencies and reinstatement of morphine-induced CPP at higher doses. It seems that the NAc might be a functional region for mGluR2/3 to play a regulatory role for decreasing drug-seeking behavior in rats. Furthermore, it can be said that mGluR2/3 agonists have a potential role in the treatment of drug-seeking behaviors.

Abdominal Radiography With Digital Tomosynthesis: An Alternative to Computed Tomography for Identification of Urinary Calculi?

ObjectiveTo compare the accuracy of plain abdominal radiography (kidneys, ureter, and bladder [KUB]) with digital tomosynthesis (DT) to noncontrast computed tomography (NCCT), the gold standard imaging modality for urinary stones. Due to radiation and cost concerns, KUB is often used for diagnosis and follow-up of nephrolithiasis. DT, a novel technique that produces high-quality radiographs with less radiation and/or cost than low-dose NCCT, has not been assessed in this situation. Materials and MethodsSeven fresh tissue cadavers were implanted with stones of known size and/or composition and imaged with KUB, DT, and NCCT. Four blinded readers (2 urologists, 2 radiologists) evaluated KUBs for presence and/or location of calculi. They then re-evaluated with addition of tomograms to assess additional value. After a memory extinction period, readers evaluated NCCT images. Accuracy of detection was determined using nearest-neighbor match with generalized linear mixed modeling. ResultsTotal of 59 stones were identified on reference read. Overall, NCCT and DT were both superior to KUB alone (P < .001) while the difference between DT and NCCT was not significant (P = .06). When evaluating uric acid stones, NCCT and DT outperformed KUB (P < .01 and P < .05, respectively) while DT and NCCT were similar (P = .16). Intrarenal stones were better evaluated on DT and NCCT (P < .001 compared to KUB), while DT and NCCT were similar (P = 1.00). Accuracy was lower than anticipated across modalities due to use of the cadaver model. ConclusionOur study demonstrates DT is superior to KUB for identification of intrarenal calculi and could replace routine use of KUB or NCCT for detecting renal stones, even those composed of uric acid.

Role of orexin-1 and orexin-2 receptors in the CA1 region of hippocampus in the forced swim stress- and food deprivation-induced reinstatement of morphine seeking behaviors in rats

Hippocampus (HIP) is an essential brain site to study reward-related learning tasks, such as conditioning place preference (CPP) that can measure the preference for environmental stimuli related to reward. Furthermore, orexin neurons, situated exclusively in the lateral hypothalamus (LH) and link the rewarding effects of drugs of abuse in the LH and the CA1 region of the HIP. Therefore, in this study adult male rats were conditioned with morphine using a CPP paradigm. After the eighth day of the extinction period, on the reinstatement day, orexin-1 and orexin-2 receptor antagonists were administered bilaterally into the CA1 region prior to acute stress. Using two different types of acute stress, forced swim stress (FSS) and food deprivation (FD), the role of orexin-1 and orexin-2 receptors in the CA1 brain region in FSS and FD induced reinstatement was investigated. Our results showed that application of the orexin-1 and orexin-2 antagonists, SB334867 and TCSOX2 29, respectively, reduced the CPP scores in the reinstatement phase. Moreover, it can be concluded that orexin neurons are activated in acute stress states, such as FSS and FD, as blocking the orexin receptors, decreased the effects of acute stress in triggering the reinstatement of morphine-CPP.

The chronology and environmental context of a cave deposit and associated faunal assemblage including megafauna teeth near Wee Jasper, southeastern Australia

A limestone cave on the lower slopes of the southeastern Australian high country reveals a deep, stratified deposit dated from ca. 14,000 to 2000 cal. BP and rich in predominantly non-cultural faunal remains. Located in a sensitive ecological area between the Australian Alps and the Southern Tablelands, the site provides a valuable chronological archive for the interpretation of local environmental change using the faunal record as a proxy, in particular native rodents and other small mammals. Inferred palaeoenvironmental trends include the cessation of periglacial conditions in the surrounding ranges during the Terminal Pleistocene; a shift to warmer conditions and the establishment of forest and wetland habitats from around 13,500 to 10,000 cal. BP, with a significant decline in cold-adapted species at ca. 11,500 cal. BP and a period of significant taxon fluctuation and extinctions corresponding to a possible peak in warm and moist conditions (a ‘Holocene Optimum’), beginning around 8000 cal. BP and lasting perhaps 1500 to 2000 years. Complications to the relatively steady and continuous chronostratigraphy, formed from an AMS radiocarbon sequence from sedimentary charcoal, arose from the presence of several teeth of extinct sthenurine megafauna. These were resolved with direct U-series analysis to establish their much greater antiquity and comparison of the sthenurine teeth with teeth of extant macropodids from the same deposit through fluoride absorption analysis, which also identified the megafauna teeth as anomalous to the sequence. The site provides an important case study for the interpretation of megafauna remains in stratified sedimentary deposits, especially for sites that appear to contain evidence for the co-occurrence of megafauna and humans in primary contexts.

A Bio-physical Assessment of Harmful Algal Bloom (HAB) Outbreak using Multi-dimensional Array Data during 1998–2017

Jeong, J.-Y.; Kang, Y.H.; Park, K.; Um, J.-H., and Son, Y.B., 2018. A bio-physical assessment of Harmful Algal Bloom (HAB) outbreak using multi-dimensional array data during 1998–2017. In: Shim, J.-S.; Chun, I., and Lim, H.S. (eds.), Proceedings from the International Coastal Symposium (ICS) 2018 (Busan, Republic of Korea). Journal of Coastal Research, Special Issue No. 85, pp. 836–840. Coconut Creek (Florida), ISSN 0749-0208.Harmful algal blooms (HABs), Cochlodinium polykrikoides, which related a devastating algal bloom, recently have caused the serious problems of fishery and aquaculture activities in the south coast of Korea (SCK). To understand the evolution of red tide and determine physical factors as a function of the bloom occurrence and disappearance, we used the multi-dimensional data (satellite and in-situ) during 1998–2017. Red tides generally have started with finishing the raining season and then increased with increasing the sea surface temperature and tidal range. To understand the general trend of red tide occurrence, we classify three different scales with cell density, area, and duration of red tides such as small, medium, and large scale red tides. Small and medium scale red tides started in the middle of August. The periods of the maximum cell density and extinction were shown in the early and end of September. SST in small and medium scale red tides was higher than in large scale red tides. Even though the tidal range was relatively small at the beginning of the outbreak, it was increased in the maximum cell density and decreased in the extinction period. Large scale red tides began in the early of August and the maximum cell density appeared at the end of August. SST was the lowest and the tidal range was the largest difference in the beginning outbreak and the lowest difference in the maximum cell density. In particular, the phenomenon of large-scale variation in the overall time series was that the SST and PAR in large scale red tides were relatively low compared to the small and medium scale red tides. Even though the tidal range was less difference before the beginning outbreak, it is analyzed that there was a growing difference in time.

Locomotor- and Reward-Enhancing Effects of Cocaine Are Differentially Regulated by Chemogenetic Stimulation of Gi-Signaling in Dopaminergic Neurons.

Dopamine plays a key role in the cellular and behavioral responses to drugs of abuse, but the implication of metabotropic regulatory input to dopaminergic neurons on acute drug effects and subsequent drug-related behavior remains unclear. Here, we used chemogenetics [Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)] to modulate dopamine signaling and activity before cocaine administration in mice. We show that chemogenetic inhibition of dopaminergic ventral tegmental area (VTA) neurons differentially affects locomotor and reward-related behavioral responses to cocaine. Stimulation of Gi-coupled DREADD (hM4Di) expressed in dopaminergic VTA neurons persistently reduced the locomotor response to repeated cocaine injections. An attenuated locomotor response was seen even when a dual-viral vector approach was used to restrict hM4Di expression to dopaminergic VTA neurons projecting to the nucleus accumbens. Surprisingly, despite the attenuated locomotor response, hM4Di-mediated inhibition of dopaminergic VTA neurons did not prevent cocaine sensitization, and the inhibitory effect of hM4Di-mediated inhibition was eliminated after withdrawal. In the conditioned place-preference paradigm, hM4Di-mediated inhibition did not affect cocaine-induced place preference; however, the extinction period was extended. Also, hM4Di-mediated inhibition had no effect on preference for a sugar-based reward over water but impaired motivation to work for the same reward in a touchscreen-based motivational assay. In addition, to support that VTA dopaminergic neurons operate as regulators of reward motivation toward both sugar and cocaine, our data suggest that repeated cocaine exposure leads to adaptations in the VTA that surmount the ability of Gi-signaling to suppress and regulate VTA dopaminergic neuronal activity.

Revision of some damsel-dragonflies (Odonata, Liassophlebiidae and Anglophlebiidae new family) from the Triassic/Jurassic of England and Antarctica

AbstractFossil insects from the Triassic-Jurassic boundary of England could provide an important resource for investigating the severity of extinction events in the terrestrial realm of the uppermost Triassic. However, the fossil record is poorly understood for this period even though there are abundant historical collections. Many of these collections are still in need of taxonomic revision before they can be used to reconstruct past entomofaunas and make inferences about diversity change through time. This paper is part of a larger project to revise the taxonomy of insects across the Triassic-Jurassic boundary of England to better understand changes in insect diversity through the Triassic-Jurassic boundary and associated extinction period. Herein, the damsel-dragonfly family Liassophlebiidae Tillyard, 1925 is revised and an additional specimen from the Early Jurassic of Antarctica is included.Rossiphlebianew genus is erected forLiassophlebia jacksoniZeuner, 1962;L. batheriTillyard, 1925 is considered nomen dubium and another specimen originally attributed toL. batheriis identified asL. withersiTillyard, 1925.Liassophlebia(?)clavigasterTillyard, 1925 andL.(?)hopei(Brodie, 1845) are considered incertae sedis at the generic level.Liassophlebia giganteaZeuner, 1962 is based on a fragmentary specimen but has several unique key characteristics. We redescribe it inAnglophlebianew genus and tentatively in Anglophlebiidae new family in Heterophlebioptera. Also discussed areL. magnificaTillyard, 1925,L. withersi, andL. pseudomagnificaWhalley, 1985, which are redescribed with updated figures.Caraphlebia antarcticaCarpenter, 1969 was originally described from the Early Jurassic of Antarctica as being closely related toLiassophlebia; it is herein confirmed in Selenothemistidae Handlirsch, 1939.UUID:http://zoobank.org/8fe9a39c-1c3b-4bda-92a6-92c1a0fc95b8

Chronic restraint stress during withdrawal increases vulnerability to drug priming-induced cocaine seeking via a dopamine D1-like receptor-mediated mechanism

BackgroundA major obstacle in the treatment of individuals with cocaine addiction is their high propensity for relapse. Although the clinical scenario of acute stress-induced relapse has been well studied in animal models, few pre-clinical studies have investigated the role of chronic stress in relapse or the interaction between chronic stress and other relapse triggers. MethodsWe tested the effect of chronic restraint stress on cocaine seeking in rats using both extinction- and abstinence-based animal relapse models. Rats were trained to press a lever for I.V. cocaine infusions (0.50 mg/kg/infusion) paired with a discrete tone + light cue in daily 3-h sessions. Following self-administration, rats were exposed to a chronic restraint stress procedure (3 h/day) or control procedure (unstressed) during the first seven days of a 13-day extinction period during which lever presses had no programmed consequences. This was followed by cue- and cocaine priming-induced drug seeking tests. In a separate group of rats, cocaine seeking was assessed during forced abstinence both before and after the same chronic stress procedure. ResultsA history of chronic restraint stress was associated with increased cocaine priming-induced drug seeking, an effect attenuated by co-administration of SCH-23390 (10.0 μg/kg; i.p.), a dopamine D1-like receptor antagonist, with daily restraint. Repeated SCH-23390 administration but not stress during extinction increased cue-induced reinstatement. ConclusionsExposure to chronic stress during early withdrawal may confer lasting vulnerability to some types of relapse, and dopamine D1-like receptors appear to mediate both chronic stress effects on cocaine seeking and extinction of cocaine seeking.

Inhibition of alpha7 nicotinic receptors in the ventral hippocampus selectively attenuates reinstatement of morphine-conditioned place preference and associated changes in AMPA receptor binding.

Recurrent relapse is a major problem in treating opiate addiction. Pavlovian conditioning plays a role in recurrent relapse whereby exposure to cues learned during drug intake can precipitate relapse to drug taking. α7 nicotinic acetylcholine receptors (nAChRs) have been implicated in attentional aspects of cognition and mechanisms of learning and memory. In this study we have investigated the role of α7 nAChRs in morphine‐conditioned place preference (morphine‐CPP). CPP provides a model of associative learning that is pertinent to associative aspects of drug dependence. The α7 nAChR antagonist methyllycaconitine (MLA; 4 mg/kg s.c.) had no effect on the acquisition, maintenance, reconsolidation or extinction of morphine‐CPP but selectively attenuated morphine‐primed reinstatement of CPP, in both mice and rats. Reinstatement of morphine‐CPP in mice was accompanied by a selective increase in [3H]‐AMPA binding (but not in [3H]‐MK801 binding) in the ventral hippocampus that was prevented by prior treatment with MLA. Administration of MLA (6.7 μg) directly into the ventral hippocampus of rats prior to a systemic priming dose of morphine abolished reinstatement of morphine‐CPP, whereas MLA delivered into the dorsal hippocampus or prefrontal cortex was without effect. These results suggest that α7 nAChRs in the ventral hippocampus play a specific role in the retrieval of associative drug memories following a period of extinction, making them potential targets for the prevention of relapse.

Evaluating the Effects of Cholinergic Depletion in the PPTg, LDTg, and VTA on Acoustic Startle Response and Morphine‐Related Reward

Opiate abuse is a worldwide epidemic that costs nations billions of dollars to treat. Rewarding effects of opioids and other drugs of abuse are partially reliant on the activity of dopaminergic neurons located in reward centers of the brain such as the ventral tegmental area (VTA). The VTA receives cholinergic input from only two sources, the pedunculopontine tegmentum (PPTg) and the laterodorsal tegmentum (LDTg). Excitotoxic lesions to the PPTg in rats have previously been shown to reduce the rewarding effect of opiates (Bechara &amp; van der Kooy, 1989; Olmstead &amp; Franklin, 1997; Parker &amp; van der Kooy, 1995). These studies were unable to identify the specific neuronal subtype responsible for the reduced rewarding effect, though they suggested the cholinergic neurons were responsible. By using a diphtheria‐UII fusion toxin to selectively ablate cholinergic neurons in the PPTg and LDTg we were able to test the role of cholinergic projections to the VTA. The toxin was injected bilaterally into the PPTg, LDTg, or VTA of male Sprague‐Dawley rats through stereotaxic surgery. Injection into the VTA creates a retrograde lesion that specifically ablates the cholinergic neurons of the PPTg and LDTg that innervate the VTA.The animals were subjected to an acoustic startle reflex/pre‐pulse inhibition paradigm in weeks 4, 8, and 10 post‐surgery. Animals with cholinergic depletion in the PPTg were unable to startle to the point where pre‐pulse inhibition was unable to be measured. While not significant, there was a trend toward an increase in startle in animals that received a VTA retrograde lesion. These findings suggest that the cholinergic PPTg is necessary for integrating sensory processing and motor output. Cholinergic input to the VTA from both the PPTg and LDTg produced a novel effect. Ten weeks post‐surgery the rats were subjected to a morphine conditioned place preference paradigm (CPP), an extinction period, and then a cocaine CPP paradigm. Animals with lesions to the LDTg were able to form cocaine‐mediated CPP but not morphine‐mediated CPP. PPTg lesioned animals formed preference for both morphine and cocaine. Sham animals and the VTA retrograde animals also formed preference for both drugs. These findings suggest that cholinergic neurons in the LDTg that project to an area that is not the VTA likely play a role in morphine‐related reward, and that the cholinergic output from the PPTg is not required in the formation of morphine conditioned place preference. Taking the results of both experiments together, it can be inferred that the cholinergic LDTg plays a role in reward while the cholinergic PPTg plays a role in sensory processing. It is likely that these two areas work in concert to modulate a variety of behaviors. While these findings don't provide a treatment for opiate abuse, they help to further our understanding of the neuronal mechanisms that drive drug addiction.Support or Funding InformationR00DA024754This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

AMN082—a metabotropic glutamate receptor type 7 allosteric agonist in the NAc facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

Nucleus accumbens (NAc) plays a primary role in opioid reward. The actions of glutamate (which is the most extensive excitatory neurotransmitter in the mammalian central nervous system) are mediated through the activation of the ionotropic and metabotropic glutamate receptors (mGluRs). Previous studies have shown the extensive distributions of the different types of mGluRs, including mGluR7, in regions that are involved in opioid reward, such as NAc. In this study, CPP was used to investigate the effect of mGluR7 on the extinction period, and the reinstatement of morphine. The animals received bilaterally microinjections of AMN082, a selective mGluR7 allosteric agonist, into the NAc. In Experiment 1, the rats received AMN082 (1 and 5 μg/0.5 μl) during the extinction period. In Experiment 2, the CPP morphine-extinguished rats received AMN082 (1, 3 and 5 μg/0.5 μl) five minutes prior to the administration of an ineffective dosage of morphine (1 mg/kg) in order to reinstate the extinguished morphine. The results of the recorded conditioning scores in this study showed that the intra-accumbal administration of AMN08 reduced the extinction period of morphine. Moreover, the administration of AMN082 into the NAc dose-dependently inhibited the reinstatement of morphine. The findings suggested that the mGluR7 in the NAc facilitates the extinction and inhibits the reinstatement of the morphine-induced CPP that could have been mediated by an increase in the release of extracellular glutamate.

Integrated extinction accounting and accountability: building an ark

PurposeWe are currently experiencing what is often called the sixth period of mass extinction on planet Earth, caused undoubtedly by the impact of human activities and businesses on nature. The purpose of this paper is to explore the potential for accounting and corporate accountability to contribute to extinction prevention. The paper adopts an interdisciplinary approach, weaving scientific evidence and theory into organisational disclosure and reporting in order to demonstrate linkages between extinction, business behaviour, accounting and accountability as well as to provide a basis for developing a framework for narrative disclosure on extinction prevention.Design/methodology/approachThe paper is theoretical and interdisciplinary in approach, seeking to bring together scientific theories of extinction with a need for corporate and organisational accountability whilst recognising philosophical concerns in the extant environmental accounting literature about accepting any business role and capitalist mechanisms in ecological matters. The overarching framework derives from the concept of emancipatory accounting.FindingsThe outcome of the writing is to: present an emancipatory “extinction accounting” framework which can be embedded within integrated reports, and a diagrammatic representation, in the form of an “ark”, of accounting and accountability mechanisms which, combined, can assist, the authors argue, in preventing extinction. The authors suggest that the emancipatory framework may also be applied to engagement meetings between the responsible investor community (and non-governmental organisations (NGOs)) and organisations on biodiversity and species protection.Research limitations/implicationsThe exploratory extinction accounting and accountability frameworks within this paper should provide a basis for further research into the emancipatory potential for organisational disclosures and mechanisms of governance and accountability to prevent species extinction.Practical implicationsThe next steps for researchers and practitioners involve development and implementation of the extinction accounting and engagement frameworks presented in this paper within integrated reporting and responsible investor practice.Social implicationsAs outlined in this paper, extinction of any species of flora and fauna can affect significantly the functioning of local and global ecosystems, the destruction of which can have, and is having, severe and dangerous consequences for human life. Extinction prevention is critically important to the survival of the human race.Originality/valueThis paper represents a comprehensive attempt to explore the emancipatory role of accounting in extinction prevention and to bring together the linkages in accounting and accountability mechanisms which, working together, can prevent species extinction.

Hypocretin/orexin deficiency decreases cocaine abuse liability

Compelling evidence indicates that hypocretin/orexin signaling regulates arousal, stress and reward-seeking behaviors. However, most studies on drug reward-related processes have so far described the effects of pharmacological blockers disrupting hypocretin/orexin transmission. We report here an extensive study on cocaine-related behaviors in hypocretin/orexin-deficient mice (KO) and their heterozygous (HET) and wildtype (WT) littermates. We evaluated behavioral sensitization following repeated administrations and preference for an environment repeatedly paired with cocaine injections (15 mg/kg). Mice were also trained to self-administer cocaine (0.5–1.5 mg/kg/infusion). Our observations show that whereas all mice exhibited quite similar responses to acute administration of cocaine, only Hcrt KO mice exhibited reduced cocaine-seeking behaviors following a period of abstinence or extinction, and reduced cocaine incubation craving. Further, if the present findings confirm that Hcrt deficient mice may display a hypoactive phenotype, possibly linked to a reduced alertness concomitant to a decreased exploration of their environment, hypocretin/orexin defiency did not cause any attentional deficit. We thus report that innate disruption of hypocretin/orexin signaling moderately alters cocaine reward but significantly reduces long-term affective dependence that may explain the lack of relapse for cocaine seeking seen in Hcrt KO mice. Overall, with blunted cocaine intake at the highest concentration and reduced responsiveness to cocaine cues after prolonged abstinence, our findings suggest that hypocretin deficient mice may display signs of resilience to cocaine addiction.

Additional free reinforcers increase persistence of problem behavior in a clinical context: A partial replication of laboratory findings.

Behavioral momentum theory is a quantitative framework used to characterize the persistence of behavior during response disruptors as a function of baseline stimulus-reinforcer relations. Results of several investigations have shown that alternative reinforcement can increase the resistance to change of a target response during extinction. In the present study, concomitant variable-interval fixed-time schedules of reinforcement for problem behavior were employed to simulate naturalistic situations involving the superimposition of response-independent reinforcers on a baseline schedule of reinforcement for problem behavior, as in the common use of noncontingent reinforcement treatments. Resistance to change of problem behavior was assessed during postsession periods of extinction by comparing response rates in extinction following sessions with and without additional reinforcer deliveries arranged by fixed-time schedules. For 2 out of 3 participants, problem behavior tended to be more resistant to extinction following periods in which additional fixed-time reinforcers were delivered. These results are discussed in terms of potential effects of noncontingent reinforcement on problem behavior when the intervention is discontinued or implemented without good treatment integrity.

Role of orexin-1 receptors in the dorsal hippocampus (CA1 region) in expression and extinction of the morphine-induced conditioned place preference in the rats

Orexinergic system is involved in reward processing and drug addiction. Objectives here, we investigated the effect of intra-hippocampal CA1 administration of orexin-1 receptor (OX1r) antagonist on the expression, and extinction of morphine-induced place preference in rats. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Two experimental plots were designed; SB334867 as a selective OX1r antagonist was dissolved in 12% DMSO, prepared in solutions with different concentrations (3, 30, and 300 nM), and microinjected into the CA1 and some neighboring regions (0.5 μl/side), bilaterally. CPP score and locomotor activity were recorded during the CPP test. Results demonstrated that intra-CA1 administration of the OX1r antagonist attenuates the expression of morphine-induced CPP. Furthermore, higher concentrations of SB334867 facilitated the extinction period of morphine-induced CPP and reduced its latency. Nevertheless, solely administration of DMSO did not have any influence on the CPP scores and locomotion in both phases. Our findings suggest that OX1rs in the CA1 region of the hippocampus are involved in the expression of morphine CPP. Moreover, blockade of OX1rs could facilitate extinction and may extinguish the ability of drug-related cues. It seems that the antagonist might be considered as a propitious therapeutic agent in suppressing drug-seeking behaviors.

Facilitated acquisition of the classically conditioned eyeblink response in active duty military expressing posttraumatic stress disorder symptoms

ObjectiveLearning diathesis models underscore the role of hyper-conditioning in the development of PTSD following trauma exposure. Eyeblink classical conditioning is one method of examining associative learning biases independent of fear and threat produced by trauma. Facilitated learning is apparent in individuals self-expressing PTSD symptoms, as well as behaviorally inhibited (BI) temperament, a vulnerability factor for PTSD. Here, we examine eyeblink conditioning in active duty military personnel and relate learning with PTSD symptomology. MethodVolunteers were 83 active duty United States Coast Guard personnel (18 females) recruited from small boat stations. Personnel were administered the PTSD Checklist (PCL) to assess current PTSD symptoms using DSM-IV criteria. BI temperament was assessed with the Adult Measure of Behavioural Inhibition (AMBI). Eyeblink conditioning was conducted using a partial reinforcement schedule, whereby paired trials (500-ms pure tone conditioned stimulus co-terminating with a 50-ms air-puff unconditional stimulus) were interpolated with 50% CS-alone trials. ResultsConsistent with previous work, there was a high degree of concordance between BI and incidence of PTSD. Further, PTSD was associated with faster learning during the acquisition period, with conditioned responding sustained through the extinction period. ConclusionsThese results reinforce the relationship between BI and PTSD in an active duty military sample, supporting previous observations in veteran and civilian samples. The conditioning data are consistent with predictions derived from a learning diathesis model of stress and anxiety, suggesting facilitated associative learning may represent an additional vulnerability for the development and maintenance of stress-related pathology.

Conventional vs. reduced field of view diffusion weighted imaging of the prostate: Comparison of image quality, correlation with histology, and inter-reader agreement

PurposeTo evaluate if Field of view Optimized and Constrained Undistorted Single shot (FOCUS) (GE Healthcare, Waukesha, WI) diffusion weighted images (DWI) provide more reliable imaging than conventional DWI, with non-inferior quantitative apparent diffusion coefficient (ADC) results. Material and methodsIRB approval was obtained for this study of 43 patients (44 exams, one patient with two visits) that underwent multiparametric prostate MRI with two DWI sequences and subsequent radical prostatectomy with histology as the gold standard. Randomized DWI sequence images were graded independently by two blinded experienced prostate MRI radiologists with a period of memory extinction between the two separate reading sessions. Blinded images were also reviewed head to head in a later session for direct comparison. Multiple parameters were measured from a region of interest in a dominant lesion as well as two control areas. Patient characteristics were collected by chart review. ResultsThere was good correlation between the mean ADC value for lesions obtained by conventional and FOCUS DWI (ρ=0.85), with no trend toward any systematic difference, and equivalent correlation between ADC measurements and Gleason score. Agreement between the two readers was significantly higher for lesion ROI analysis with the FOCUS DWI derived ADC values (CCC 0.839) compared with the conventional ADC values (CCC 0.618; difference 0.221, 95% CI 0.01–0.46). FOCUS showed significantly better image quality scores (separate review: mean 2.17±0.6, p<0.001) compared to the conventional sequence (mean 2.65±0.6, p<0.001). In 13 cases the image quality was improved from grade of 3+ with conventional DWI to <3 with FOCUS DWI, a clinically meaningful improvement. Head-to-head blinded review found 61 ratings showed strong to slight preference for FOCUS, 13 no preference, and 14 slight preference for the conventional sequence. There was also a strong and equivalent correlation between both sequences and PIRADS version 2 grading (ρ=−0.56 and −0.58 for FOCUS and conventional, respectively, p<0.001 for both). ConclusionFOCUS DWI of the prostate shows significant improvement in inter-reader agreement and image quality. As opposed to previous conflicting smaller studies, we found equivalent ADC metrics compared with the conventional DWI sequence, and preserved correlation with Gleason score.In 52% of patients the improved image quality with FOCUS had the potential to salvage exams with otherwise limited to non-diagnostic DWI.

NMDA receptor dependent changes in c-fos and p-CREB signaling following extinction and reinstatement of morphine place preference.

Neural circuitry comprising the ventral tegmental area, nucleus accumbens (NAc), prefrontal cortex (PFC) and hippocampus (HIP) has a main role in reward phenomena. Previous behavioral studies indicated that intracerebroventricular administration of AP5 (NMDA glutamate receptor antagonist) and CNQX (AMPA/kainate glutamate receptor antagonist) during the extinction and before reinstatement of morphine-induced conditioned place preference (CPP) reduced the extinction period and reinstatement of morphine-CPP. Therefore, in the present study, we tried to evaluate the effect of antagonism of NMDA glutamate receptors on the p-CREB/CREB ratio and c-fos expression in the NAc, PFC and HIP during these two phases of morphine-CPP in male adult albino Wistar rats. The p-CREB/CREB ratio and c-fos levels were estimated by Western blot analysis. The results revealed that these two factors decreased by antagonism of NMDA glutamate receptors (different doses of AP5) compared to saline-control group in aforementioned regions. The reduction of molecular markers, especially the p-CREB/CREB ratio, after AP5 administration was more during the extinction period. Therefore, it can be assumed that consolidation and reconsolidation of morphine memory via intra-PFC, -NAc and -HIP NMDA glutamate receptors are in accordance with changes in p-CREB/CREB ratio and c-fos levels.

Minocycline increases firing rates of accumbal neurons and modifies the effects of morphine on neuronal activity.

Accumulating evidence indicated that minocycline, a glial cell modulator, is able to modify a variety of morphine effects. Here, we investigated minocycline effects on electrical activity of nucleus accumbens (NAc) neurons using single unit recording in urethane-anesthetized rats. In addition, we investigated whether minocycline can modify the effects of morphine on NAc neural activity during reinstatement of morphine-seeking behavior. Minocycline increased the NAc firing activity in intact animals. Electrophysiological recording in morphine-treated animals was performed, following the acquisition of morphine-induced conditioned place preference (5mg/kg, s.c., 3days) and a drug-free extinction period. In acutely minocycline- treated animals, the neurons were recorded for 40minutes following a single injection of either minocycline (50μg/5μl, i.c.v.) or saline. Then a priming dose of morphine (1mg/kg, s.c.) was injected while the recording was continued for an additional 40minutes. Minocycline significantly increased the firing rates of neurons and significantly modified morphine inhibitory effects on NAc neurons. In subchronically minocycline-treated groups, the rats were given daily injections of minocycline (50μg/5μl, i.c.v) during the extinction period. Then, on the reinstatement day, NAc neurons were recorded for 10minutes, the priming dose of morphine was administered and the recording was continued for 45minutes. Our results showed the failure of minocycline to significantly modify the inhibitory effects of morphine. In conclusion, our findings indicated that minocycline modifies morphine-induced decreases in the firing rates of NAc neurons in the reinstatement phase.