Cannabidiol Prevents Spontaneous Fear Recovery after Extinction and Ameliorates Stress-Induced Extinction Resistance.

Cannabidiol, the main non-psychotropic constituent of cannabis, has potential as a treatment for anxiety-related disorders since it reduces learned fear expression and enhances fear extinction. The return of fear over time after successful extinction and stress-induced extinction resistance are potential barriers to the treatment of these disorders with extinction-based psychological therapy. In two experiments using rats subjected to auditory fear conditioning, we determined the effects of systemic cannabidiol treatment on (1) delayed extinction and later spontaneous fear recovery, and (2) extinction resistance caused by immediate extinction (the immediate extinction deficit (IED)). In Experiment 1, cannabidiol was given before delayed extinction occurring 24 h after conditioning, with extinction recall and spontaneous fear recovery tested drug-free 1 and 21 days after extinction, respectively. We found that cannabidiol had no effect on extinction recall but it prevented spontaneous fear recovery. In Experiment 2, the IED procedure was first validated, with immediate extinction occurring 30 min after conditioning. We confirmed that immediate extinction impaired extinction recall, compared to delayed extinction. Next, cannabidiol was given before immediate or no extinction, with extinction recall tested drug-free the next day. We found that cannabidiol rescued the IED, which did not involve effects on fear memory consolidation. In summary, cannabidiol prevented spontaneous fear recovery after delayed extinction and ameliorated extinction resistance caused by immediate extinction. Although the pharmacological mechanisms underlying these effects remain to be determined, our results add to evidence indicating that cannabidiol might prove useful as an adjunct for potentiating the psychological treatment of anxiety-related disorders.

Age-related differences in appetitive trace conditioning and novel object recognition procedures.

Appetitive trace conditioning (TC) was examined over 6 months in younger-adult (2-8 months) and middle-aged (12-18 months) male Wistar RccHan rats, to test for early age-related impairment in working memory. Novel object recognition (NOR) was included as a comparison task, to provide a positive control in the event that the expected impairment in TC was not demonstrated. The results showed that TC improved at both ages at the 2 s but not at the 10 s trace interval. There was, however, evidence for reduced improvement from one day to the next in the middle-aged cohort tested with the 2 s trace conditioned stimulus. Moreover, within the 10 s trace, responding progressively distributed later in the trace interval, in the younger-adult but not the middle-aged cohort. Middle-aged rats showed NOR discriminative impairment at a 24 h but not at a 10 min retention interval. Object exploration was overall reduced in middle-aged rats and further reduced longitudinally. At the end of the study, assessing neurochemistry by HPLC-ED showed reduced 5-HIAA/5-HT in the dorsal striatum of the middle-aged rats and some correlations between striatal 5-HIAA/5-HT and activity parameters. Overall the results suggest that, taken in isolation, age-related impairments may be overcome by experience. This recovery in performance was seen despite the drop in activity levels in older animals, which might be expected to contribute to cognitive decline.

Scopolamine Impairs Appetitive But Not Aversive Trace Conditioning: Role of the Medial Prefrontal Cortex.

The muscarinic acetylcholine receptor is an important modulator of medial prefrontal cortex (mPFC) functions, such as the working memory required to bridge a trace interval in associative leaning. Aversive and appetitive trace conditioning procedures were used to examine the effects of scopolamine (0.1 and 0.5 mg/kg, i.p.) in male rats. Follow-up experiments tested the effects of microinfusion of 0.15 µg of scopolamine (0.075 µg of in 0.5 µl/side) in infralimbic (IL) versus prelimbic regions of rat mPFC, in appetitive trace and locomotor activity (LMA) procedures. Systemic scopolamine was without effect in an aversive trace conditioning procedure, but impaired appetitive conditioning at a 2 s trace interval. This effect was demonstrated as reduced responding during presentations of the conditioned stimulus (CS) and during the interstimulus interval (ISI). There was no such effect on responding during food (unconditioned stimulus, US) responding or in the intertrial interval (ITI). In contrast, systemic scopolamine dose-relatedly increased LMA. Trace conditioning was similarly impaired at the 2 s trace (shown as reduced responding to the CS and during the ISI, but not during US presentations or in the ITI) after infusion in mPFC, whereas LMA was increased (after infusion in IL only). Therefore, our results point to the importance of cholinergic modulation in mPFC for trace conditioning and show that the observed effects cannot be attributed to reduced activity.SIGNIFICANCE STATEMENT Events are very often separated in time, in which case working memory is necessary to condition their association in "trace conditioning." The present study used conditioning variants motivated aversively with foot shock and appetitively with food. The drug scopolamine was used to block muscarinic acetylcholine receptors involved in working memory. The results show that reduced cholinergic transmission in medial prefrontal cortex (mPFC) impaired appetitive trace conditioning at a 2 s trace interval. However, scopolamine was without effect in the aversive procedure, revealing the importance of procedural differences to the demonstration of the drug effect. The finding that blockade of muscarinic receptors in mPFC impaired trace conditioning shows that these receptors are critical modulators of short-term working memory.

Role of the anterior cingulate cortex in the retrieval of novel object recognition memory after a long delay.

Previous in vivo electrophysiological studies suggest that the anterior cingulate cortex (ACgx) is an important substrate of novel object recognition (NOR) memory. However, intervention studies are needed to confirm this conclusion and permanent lesion studies cannot distinguish effects on encoding and retrieval. The interval between encoding and retrieval tests may also be a critical determinant of the role of the ACgx. The current series of experiments used micro-infusion of the GABAA receptor agonist, muscimol, into ACgx to reversibly inactivate the area and distinguish its role in encoding and retrieval. ACgx infusions of muscimol, before encoding did not alter NOR assessed after a delay of 20 min or 24 h. However, when infused into the ACgx before retrieval muscimol impaired NOR assessed after a delay of 24 h, but not after a 20-min retention test. Together these findings suggest that the ACgx plays a time-dependent role in the retrieval, but not the encoding, of NOR memory, neuronal activation being required for the retrieval of remote (24 h old), but not recent (20 min old) visual memory.

Effects of manipulating prefrontal activity and dopamine D1 receptor signaling in an appetitive feature-negative discrimination learning task.

Healthy cognition requires inhibitory modulation of associative learning; conversely, impaired inhibitory discrimination is implicated in behavioral disorders. The medial prefrontal cortex (mPFC) and its dopamine innervation are key to understanding inhibition and impulsivity. We therefore examined the role of prelimbic and infralimbic cortices in within-subjects appetitive feature-negative learning using microinfusions of (a) the gamma-aminobutyric acid-A receptor agonist muscimol (0.25 µg in 1.0 µl; N = 35), (b) the dopamine D1 receptor agonist SKF-81297 (0.1 µg in 1.0 µl; N = 33), and (c) the dopamine D1 receptor antagonist SCH-23390 (5 µg in 1.0 µl; N = 35). A conditioned stimulus (CS) was followed by food, but on trials on which the CS (A+) was compounded with the inhibitory cue (AX-), the food delivery was canceled. Difference scores (CS-preCS responding) were used to measure learning. All three experiments showed the feature-negative discrimination (A+/AX-), as decreased responding to AX- versus A+. This discrimination was reduced but preserved following muscimol infusions in Experiment 1. Similarly, in Experiments 2 and 3, infusions of SKF-81297 and SCH-23390 were both without effect on the acquisition of the discrimination. Like muscimol, SCH-23390 reduced difference score responding, consistent with nonspecific effects on the (expression of) learning. Thus, there was no evidence to suggest that inactivation of prelimbic or infralimbic cortices impaired feature-negative discrimination learning and no evidence for dopaminergic modulation of such learning in the medial prefrontal cortex either. These results are discussed in the context of the nonspecific effects of the infusions and the overall inconsistent performance in summation and retardation tests of conditioned inhibition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Dopamine D1-like receptors modulate synchronized oscillations in the hippocampal-prefrontal-amygdala circuit in contextual fear.

Contextual fear conditioning (CFC) is mediated by a neural circuit that includes the hippocampus, prefrontal cortex, and amygdala, but the neurophysiological mechanisms underlying the regulation of CFC by neuromodulators remain unclear. Dopamine D1-like receptors (D1Rs) in this circuit regulate CFC and local synaptic plasticity, which is facilitated by synchronized oscillations between these areas. In rats, we determined the effects of systemic D1R blockade on CFC and oscillatory synchrony between dorsal hippocampus (DH), prelimbic (PL) cortex, basolateral amygdala (BLA), and ventral hippocampus (VH), which sends hippocampal projections to PL and BLA. D1R blockade altered DH-VH and reduced VH-PL and VH-BLA synchrony during CFC, as inferred from theta and gamma coherence and theta-gamma coupling. D1R blockade also impaired CFC, as indicated by decreased freezing at retrieval, which was characterized by altered DH-VH and reduced VH-PL, VH-BLA, and PL-BLA synchrony. This reduction in VH-PL-BLA synchrony was not fully accounted for by non-specific locomotor effects, as revealed by comparing between epochs of movement and freezing in the controls. These results suggest that D1Rs regulate CFC by modulating synchronized oscillations within the hippocampus-prefrontal-amygdala circuit. They also add to growing evidence indicating that this circuit synchrony at retrieval reflects a neural signature of learned fear.

Attitudes to the use of animals in biomedical research: Effects of stigma and selected research project summaries.

Three groups of participants (largely recruited from the UK) completed a survey to examine attitudes to the use of animals in biomedical research, after reading the lay (N = 182) or technical (N = 201) summary of a research project, or no summary (N = 215). They then completed a survey comprising the animal attitude (AAS), animal purpose (APQ), belief in animal mind (BAM) and empathy quotient (EQ) scales. The APQ was adapted to assess attitudes towards the use of animals for research into disorders selected to be perceived as controllable and so 'blameworthy' and potentially stigmatised (addiction and obesity) and 'psychological' (schizophrenia and addiction) versus 'physical' (cardiovascular disease and obesity), across selected species (rats, mice, fish pigs and monkeys). Thus, the APQ was used to examine how the effects of perceived controllability and the nature of the disorder affected attitudes to animal use, in different species and in the three summary groups. As expected, attitudes to animal use as measured by the AAS and the APQ (total) correlated positively with BAM and EQ scores, consistent with the assumption that the scales all measured pro-welfare attitudes. Participants in the two research summary groups did not differentiate the use of rats, mice and fish (or fish and pigs in the technical summary group), whereas all species were differentiated in the no summary group. Participants given the lay summary were as concerned about the use of animals for schizophrenia as for addiction research. APQ ratings otherwise indicated more concern for animals used for addiction research (and for obesity compared to cardiovascular disease in all summary groups). Therefore, the information provided by a research project summary influenced attitudes to use of animals in biomedical research. However, there was no overall increase in agreement with animal use in either of the summary groups.

Dopamine D1 receptor involvement in latent inhibition and overshadowing.

Latent inhibition (LI) manifests as poorer conditioning to a stimulus that has previously been experienced without consequence. There is good evidence of dopaminergic modulation of LI, as the effect is reliably disrupted by the indirect dopamine (DA) agonist amphetamine. The disruptive effects of amphetamine on LI are reversed by both typical and atypical antipsychotics, which on their own are able to facilitate LI. However, the contribution of different DA receptors to these effects is poorly understood. Amphetamine effects on another stimulus selection procedure, overshadowing, have been suggested to be D1-mediated. Thus, in the current experiments, we systematically investigated the role of D1 receptors in LI. First, we tested the ability of the full D1 agonist SKF 81297 to abolish LI and compared the effects of this drug on LI and overshadowing. Subsequently, we examined whether the D1 antagonist SCH 23390 can lead to the emergence of LI under conditions that do not produce the effect in normal animals (weak pre-exposure). Finally, we tested the ability of SCH 23390 to block amphetamine-induced disruption of LI. We found little evidence that direct stimulation of D1 receptors abolishes LI (although there was some attenuation of LI at 0.4 mg/kg SKF 81297). Similarly, SCH 23390 failed to enhance LI. However, SCH 23390 did block amphetamine-induced disruption of LI. These data indicate that, while LI may be unaffected by selective manipulation of activity at D1 receptors, the effects of amphetamine on LI are to some extent dependent on actions at D1 receptors.

Opposing effects of 5,7-DHT lesions to the core and shell of the nucleus accumbens on the processing of irrelevant stimuli.

There is good evidence that forebrain serotonergic systems modulate cognitive flexibility. Latent inhibition (LI) is a cross-species phenomenon which manifests as poor conditioning to a stimulus that has previously been experienced without consequence and is widely considered an index of the ability to ignore irrelevant stimuli. While much research has focused on dopaminergic mechanisms underlying LI, there is also considerable evidence of serotonergic modulation. However, the neuroanatomical locus of these effects remains poorly understood. Previous work has identified the nucleus accumbens (NAc) as a key component of the neural circuit underpinning LI and furthermore, this work has shown that the core and shell subregions of the NAc contribute differentially to the expression of LI. To examine the role of the serotonergic input to NAc in LI, we tested animals with 5,7-dihydroxytryptamine (5,7-DHT) lesions to the core and shell subregions on LI assessed under experimental conditions that produce LI in shams and subsequently with weak stimulus pre-exposure designed to prevent the emergence of LI in shams. We found that serotonergic deafferentation of the core disrupted LI whereas 5,7-DHT lesions to the shell produced the opposite effect and potentiated LI.

Safety Learning in Anxiety, Pavlovian Conditioned Inhibition and COVID Concerns.

Experimental studies of fear conditioning have identified the effectiveness of safety signals in inhibiting fear and maintaining fear-motivated behaviors. In fear conditioning procedures, the presence of safety signals means that the otherwise expected feared outcome will not now occur. Differences in the inhibitory learning processes needed to learn safety are being identified in various psychological and psychiatric conditions. However, despite early theoretical interest, the role of conditioned inhibitors as safety signals in anxiety has been under-investigated to date, in part because of the stringent test procedures required to confirm the demonstration of conditioned inhibition as such. Nonetheless, the theoretical implications of an inhibitory learning perspective continue to influence clinical practice. Moreover, our understanding of safety signals is of additional importance in the context of the increased health anxiety and safety behaviors generated by the COVID-19 pandemic.

URB597 induces subtle changes to aggression in adult Lister Hooded rats.

The endocannabinoid system has been implicated in both social and cognitive processing. The endocannabinoid metabolism inhibitor, URB597, dose-dependently improves non-social memory in adult Wistar and Sprague Dawley rats, whereas its effect on social interaction (SI) is affected by both rat strain and drug dose. Lister Hooded rats consistently respond differently to drug treatment in general compared with albino strains. This study sought to investigate the effects of different doses of URB597 on social and non-social memory in Lister Hooded rats, as well as analyzing the behavioral composition of the SI. Males were tested for novel object recognition (NOR), social preference (between an object and an unfamiliar rat), social novelty recognition (for a familiar vs. unfamiliar rat) and SI with an unfamiliar rat. URB597 (0.1 or 0.3 mg/kg) or vehicle was given 30 min before testing. During SI testing, total interaction time was assessed along with time spent on aggressive and explorative behaviors. Lister Hooded rats displayed expected non-social and social memory and social preference, which was not affected by URB597. During SI, URB597 did not affect total interaction time. However, the high dose increased aggression, compared to vehicle, and decreased anogenital sniffing, compared to the low dose of URB597. In summary, URB597 did not affect NOR, social preference or social recognition memory but did have subtle behavioral effects during SI in Lister hooded rats. Based on our findings we argue for the importance of considering strain as well as the detailed composition of behavior when investigating drug effects on social behavior.

Hippocampal Disinhibition Reduces Contextual and Elemental Fear Conditioning While Sparing the Acquisition of Latent Inhibition.

Hippocampal neural disinhibition, i.e., reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signaling, which play a role in salience modulation. Consequently, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. Therefore, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response (CER) procedure. A flashing light was used as the conditioned stimulus (CS), and conditioned suppression was used to index conditioned fear. In experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin before CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls but could not be detected in picrotoxin-infused rats because of the low level of fear conditioning to the CS. In experiment 2, VH picrotoxin infusions only before CS pre-exposure did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect a disruption of neural processing both within the hippocampus and in projection sites of the hippocampus.

Endocannabinoid metabolism inhibition has no effect on spontaneous fear recovery or extinction resistance in Lister hooded rats.

Endocannabinoid transmission is emerging as a target for treating anxiety-related disorders, given its regulation of fear extinction. Boosting anandamide levels via inhibition of its metabolism by fatty acid amide hydrolase (FAAH) can enhance extinction, whereas inhibiting monoacylglycerol lipase (MAGL) to elevate 2-arachidonoylglycerol levels can impair extinction. However, whether endocannabinoids regulate fear relapse over time or extinction resistance remains unclear. In two experiments using auditory fear conditioned rats, we examined the effects of the FAAH inhibitor URB597 and the MAGL inhibitor JZL184 administered systemically on 1) spontaneous fear recovery after delayed extinction, and 2) extinction resistance resulting from immediate extinction [the immediate extinction deficit (IED)]. In Experiment 1, URB597 or JZL184 was given immediately after delayed extinction occurring 24 h after conditioning. Extinction recall and spontaneous fear recovery were tested drug-free 1 and 21 days later, respectively. We found no effects of either drug on extinction recall or spontaneous fear recovery. In Experiment 2, URB597 or JZL184 was given before immediate extinction occurring 30 min after conditioning and extinction recall was tested drug-free the next day. We also examined the effects of propranolol, a beta-adrenoceptor antagonist that can rescue the IED, as a positive control. JZL184 enhanced fear expression and impaired extinction learning but we found no lasting effects of URB597 or JZL184 on cued extinction recall. Propranolol reduced fear expression but, unexpectedly, had no enduring effect on extinction recall. The results are discussed in relation to various methodological differences between previous studies examining endocannabinoid and adrenergic regulation of fear extinction.

Man's best friends: attitudes towards the use of different kinds of animal depend on belief in different species' mental capacities and purpose of use.

The animal purpose questionnaire (APQ) is a new instrument to measure human attitudes to animal use systematically across both species and purpose of use. This offers a more fine-grained approach to our understanding of how the belief in a specific animal's mental capacities relates to (dis-)agreement with their use for different human purposes. In the present study, 317 participants completed an online survey containing the APQ and the belief in animal mind (BAM) scale in a species-specific format, to test the prediction that levels of (dis-)agreement with animal use should mirror participants' judgements of animal sentience. The results obtained with the APQ confirmed that attitudes to animal use differed significantly across both purpose and species. Key findings included a relatively greater concern for dolphins and dogs over chimpanzees (suggesting that phylogenetic position is not the only determinant of attitudes to animal use). Across the purposes examined, respondents were largely negative about animal usage, with the exception that there was less disagreement if this was for medical research. Participants were also asked to provide demographic details such as gender and dietary preference. Regression analyses revealed high predictive power for species-specific BAM across five different kinds of animal use. General BAM scores, non-meat-eating and being female accounted for 31.5% of the total variability in APQ scores. The results indicate that BAM is a strong predictor of self-reported attitudes for using particular animals. However, the results showed some exceptions in the case of culturally typical 'produce' animals.

Muscimol-induced inactivation of the anterior cingulate cortex does not impair trace fear conditioning in the rat.

Previous studies suggest that trace conditioning depends on the anterior cingulate cortex (ACC). To examine the role of ACC in trace fear conditioning further, 48 rats were surgically prepared for infusion with saline or 62.5 or 125 µg/side muscimol to inactivate ACC reversibly prior to conditioning. A noise stimulus was followed by a 1 mA footshock, with or without a 10-second trace interval between these events in a conditioned suppression procedure. The trace-conditioned groups (10 seconds) showed less test suppression than the control-conditioned groups (0 seconds). Counter to prediction, there was no effect of muscimol infusion on suppression to the noise stimulus in the 10-second trace groups.

Some animals are more equal than others: Validation of a new scale to measure how attitudes to animals depend on species and human purpose of use.

Globally, many millions of animals are used by humans every year and much of this usage causes public concern. A new scale, devised to measure attitudes to animal use in relation to the purpose of use and species, the Animal Purpose Questionnaire (APQ), was completed by in total 483 participants, 415 British nationals and 68 participants from 39 other countries. The APQ was presented in two survey formats, alongside an established Animal Attitudes Scale (AAS). In both surveys, participants also provided demographic details to provide a context to their attitudes to animals. As might be expected, and consistent with the validity of the new scale, overall scores on the AAS and APQ were highly correlated. However, the APQ provided a more differentiated measure of attitudes to animal use across a variety of settings. The results showed that there was overall higher levels of agreement with the use of animals in medical research and basic science, less endorsement for food production and pest control, and the use of animals for other cultural practices was generally disapproved of, irrespective of species. Participants overall disagreed with the use of rabbits, monkeys, badgers, tree shrews (survey 1), chimpanzees, dogs, dolphins and parrots (survey 2), but were neutral about the use of rats, mice, pigs, octopus, chickens, zebrafish (survey 1), carp, chickens, pigs, pigeons, rabbits and rats (survey 2). Interactions between species and purpose were largely driven by the consideration of using diverse species for food production. In general, females and vegetarians expressed less agreement with the use of animals with some differences by purpose of use. Pet keeping consistently predicted reduced willingness to use animals for basic science (only). The APQ provides a new tool to unpack how public attitudes depend on the intersectionality of demographics, species and purpose of use.

Dopamine D1-like receptors in the dorsomedial prefrontal cortex regulate contextual fear conditioning.

RATIONALE: Dopamine D1 receptor (D1R) signalling is involved in contextual fear conditioning. The D1R antagonist SCH23390 impairs the acquisition of contextual fear when administered systemically or infused locally into the dorsal hippocampus or basolateral amygdala. OBJECTIVES: We determined if state dependency may account for the impairment in contextual fear conditioning caused by systemic SCH23390 administration. We also examined if the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens (NAc), and ventral hippocampus (VH) are involved in mediating the effect of systemic SCH23390 treatment on contextual fear conditioning. METHODS: In experiment 1, SCH23390 (0.1 mg/kg) or vehicle was given before contextual fear conditioning and/or retrieval. In experiment 2, SCH23390 (2.5 µg/0.5 uL) or vehicle was infused locally into dmPFC, NAc, or VH before contextual fear conditioning, and retrieval was tested drug-free. Freezing was quantified as a measure of contextual fear. RESULTS: In experiment 1, SCH23390 given before conditioning or before both conditioning and retrieval decreased freezing at retrieval, whereas SCH23390 given only before retrieval had no effect. In experiment 2, SCH23390 infused into dmPFC before conditioning decreased freezing at retrieval, while infusion of SCH23390 into NAc or VH had no effect. CONCLUSIONS: The results of experiment 1 confirm those of previous studies indicating that D1Rs are required for the acquisition but not retrieval of contextual fear and rule out state dependency as an explanation for these findings. Moreover, the results of experiment 2 provide evidence that dmPFC is also part of the neural circuitry through which D1R signalling regulates contextual fear conditioning.

Infusions of scopolamine in dorsal hippocampus reduce anticipatory responding in an appetitive trace conditioning procedure.

INTRODUCTION: Trace conditioning is impaired by lesions to dorsal hippocampus, as well as by treatment with the muscarinic acetylcholine antagonist scopolamine. However, the role of muscarinic receptors within hippocampus has received little attention. METHODS: The present study examined the effects of intra-hippocampal infusion of scopolamine (30 µg/side) in an appetitive (2 vs. 10 s) trace conditioning procedure using sucrose pellets as the unconditioned stimulus (US). Locomotor activity (LMA) was examined in a different apparatus. RESULTS: Intra-hippocampal scopolamine reduced responding to the 2 s trace conditioned stimulus (CS). Intra-hippocampal scopolamine similarly depressed responding within the inter-stimulus interval (ISI) at both 2 and 10 s trace intervals, but there was no such effect in the inter-trial interval. There was also some overall reduction in responding when the US was delivered; significant at the 10 s but not at the 2 s trace interval. A similar pattern of results to that seen in response to the CS during acquisition was shown drug-free (in the 5 s post-CS) in the extinction tests of conditioned responding. LMA was increased under scopolamine. CONCLUSIONS: The results suggest that nonspecific changes in activity or motivation to respond for the US cannot explain the reduction in trace conditioning as measured by reduced CS responding and in the ISI. Rather, the findings of the present study point to the importance of associative aspects of the task in determining its sensitivity to the effects of scopolamine, suggesting that muscarinic receptors in the hippocampus are important modulators of short-term working memory.

Methylphenidate can reduce selectivity in associative learning in an aversive trace conditioning task.

There are good grounds to expect that methylphenidate (MP) should enhance cognitive function. However, experimental evidence on this point is scant. The present study therefore examined the effects of MP on learning the association between a conditioned stimulus (CS, in this case, noise) and an unconditioned stimulus (UCS, in this case, footshock) in an aversive variant of a trace conditioning procedure. Learning was measured off-the-baseline as conditioned suppression of drinking (both latencies to drink, expressed as suppression ratios, and the amount drunk, expressed as the number of licks, in the presence of the CS). In addition to the measures of discrete cue conditioning, MP effects on contextual conditioning were measured as suppression to apparatus cues and an experimental background stimulus. MP was administered at 1 or 5 mg/kg prior to conditioning sessions. As attention deficit hyperactivity disorder (ADHD) has been characterized as involving a ;wide attentional window' (e.g. Shalev and Tsal, 2003), it was predicted that MP, as the treatment of choice for ADHD, should increase selectivity (narrowing the attentional window). This outcome would show as reduced levels of conditioning (compared to control rats) to less informative trace and contextual cues present during conditioning. Contrary to prediction, both 1 and 5 mg/kg MP increased learning about all the available stimuli, including the less informative trace CS and the background stimulus. These findings are consistent with reduced rather than increased selectivity in learning (because of increased rather than decreased conditioning to weak cues) under MP.

Overshadowing depends on cue and reinforcement sensitivity but not schizotypy.

There is evidence for impaired selective learning mechanisms in individuals high in schizotypy. Overshadowing provides a direct test of selective learning based on cue salience and has previously been reported to be impaired in relation to schizotypy scores. The present study tested for overshadowing using food allergy and Lego construction task variants. Both variants used the same number of conditioned stimulus (CS) cues and the same number of learning trials. CS cues were trained in compound pairs or in isolation and overshadowing was subsequently tested on trials followed by negative versus positive outcomes. Participants also completed the O-LIFE to measure schizotypy and BIS-BAS scales to measure reinforcement sensitivity. Learning was demonstrated for both cue variants; however overshadowing emerged only in the Lego variant and only on the trials followed by the negative outcome. Contrary to expectations, there was no evidence for any relationship between overshadowing and O-LIFE scores. However, there was evidence of a positive relationship between overshadowing and BAS-Drive as well as a negative relationship with BIS-Anxiety, for the trials followed by the positive outcome in the food allergy variant. These results suggest that the development of overshadowing depends on cue and reinforcement sensitivity, but not necessarily on schizotypy.