Conditioned Avoidance Paradigm Research Articles

Rewarding Approach Behaviour Attenuates the Return of Pain-Related Avoidance After Successful Extinction with Response Prevention

After successful exposure treatment for chronic pain, pain-related fear and avoidance may return, i.e., relapse may occur. This return of fear and avoidance may be modulated by various post-treatment factors. In this study, we aimed to investigate two potential factors that may affect return of fear and avoidance, i.e. cognitive load and rewarding approach behaviour. In an operant pain-related avoidance conditioning paradigm, healthy pain-free volunteers first learned to fear and avoid an arm-reaching movement that was often paired with painful electrocutaneous stimulation (T1), by performing alternative movements that were less often (T2) or never (T3) paired with pain. During extinction with response prevention, participants were only allowed to perform T1, and pain was omitted. To model relapse, two unexpected painful stimuli were presented (i.e., reinstatement manipulation), after which participants could freely choose among the three arm-reaching movements again. During test, the Low Load group performed an additional easy digit task, whereas the High Load group performed a more cognitively demanding digit task. The Reward group performed the demanding digit task, whilst being rewarded to perform T1. Results showed that pain-related fear and avoidance returned, irrespective of cognitive load imposed. When participants were rewarded to approach T1, however, the return of avoidance, but not fear, was attenuated. Our findings suggest that engaging in rewarding activities may facilitate the maintenance of treatment outcomes, and provide additional support to the growing body of literature indicating a divergent relationship between fear and avoidance. PerspectiveResults of this experiment suggest that engaging in rewarding activities may optimize exposure treatment for chronic pain, by dampening the return of pain-related avoidance – though not of pain-related fear – after extinction.

Nicotine limits avoidance conditioning with opioids without interfering with the ability to discriminate an opioid-interoceptive state

Approximately 90 % of individuals undergoing treatment for opioid use disorder (OUD) report comorbid use of nicotine. As such, further investigation into underlying mechanisms contributing to the extreme comorbidity between nicotine and opioid use are warranted. Nicotine administration significantly escalates self-administration of opioids and this increase in motivational efficacy persists despite contingent punishment of opioid consumption. Additionally, both systemic and intra-insular administration of nicotine produces a rightward shift in the dose-response function in both morphine-induced conditioned place preference and taste avoidance paradigms, particularly at higher doses (5–20 mg/kg). Two possible interpretations arise from these outcomes. One is that nicotine may specifically affect learning about the malaise-inducing effects of morphine thus facilitating acceptance of higher doses of morphine. Another interpretation is that it more generally reduces sensitivity to the interoceptive effects of morphine such that higher doses are needed to produce comparable effects in nicotine-treated, relative to control, rats. To further address these possibilities, we asked whether nicotine administration interfered with the ability to discriminate the morphine interoceptive state, irrespective of its hedonic evaluation, at a dose that is impacted by nicotine in avoidance conditioning paradigms. First, we demonstrated that systemic nicotine pretreatment significantly attenuates taste avoidance induced by a low dose of morphine (3 mg/kg). Next, we used an occasion setting paradigm with this same dose of morphine to test whether systemic nicotine pretreatment interferes with the ability to discriminate between saline- and morphine-induced interoceptive states. Within this task, nicotine had no effect on the ability to effectively discriminate between the interoceptive effects of morphine and saline. Collectively, these data suggest that nicotine may be specifically altering the overall hedonic assessment of morphine perhaps by interfering with learning about its deleterious consequences.

Performance of the intracerebroventricularly injected streptozotocin Alzheimer’s disease model in a translationally relevant, aged and experienced rat population

The intracerebroventricularly (icv) injected streptozotocin (STZ) induced brain state is a widely used model of sporadic Alzheimer-disease (AD). However, data have been generated in young, naive albino rats. We postulate that the translationally most relevant animal population of an AD model should be that of aged rats with substantial learning history. The objective of the study was thus to probe the model in old rats with knowledge in various cognitive domains. Long-Evans rats of 23 and 10 months age with acquired knowledge in five-choice serial reaction time task (5-CSRTT), a cooperation task, Morris water-maze (MWM) and “pot-jumping” exercise were treated with 3 × 1.5 mg/kg icv. STZ and their performance were followed for 3 months in the above and additional behavioral assays. Both STZ-treated age groups showed significant impairment in the MWM (spatial learning) and novel object recognition test (recognition memory) but not in passive avoidance and fear conditioning paradigms (fear memory). In young STZ treated rats, significant differences were also found in the 5CSRTT (attention) and pot jumping test (procedural learning) while in old rats a significant increase in hippocampal phospho-tau/tau protein ratio was observed. No significant difference was found in the cooperation (social cognition) and pairwise discrimination (visual memory) assays and hippocampal β-amyloid levels. STZ treated old animals showed impulsivity-like behavior in several tests. Our results partly coincide with partly deviate from those published on young, albino, unexperienced rats. Beside the age, strain and experience level of the animals differences can also be attributed to the increased dose of STZ, and the applied food restriction regime. The observed cognitive and non-cognitive activity pattern of icv. STZ in aged experienced rats call for more extensive studies with the STZ model to further strengthen and specify its translational validity.

Remote, online assessment of avoidance learning

Avoidance is an adaptive response to actual or perceived threat. However, persistent avoidance despite low likelihood of threat can become maladaptive and prevent effective psychological treatment. To examine behavioural avoidance, in-person, lab-based threat learning paradigms are typically used with relatively small sample sizes. However, such methods pose issues when in-person testing is difficult. The aim of the current study was therefore to adapt a validated lab-based threat and avoidance conditioning paradigm into an online avoidance learning task to investigate threat expectancy and avoidance remotely during the COVID-19 pandemic. An online fear and avoidance learning task was developed and administered to 119 participants who differed in the opportunity to avoid a safe stimulus. Fear and avoidance conditioning were successful and the opportunity to avoid a known safe stimulus increased threat expectancy and fear for the experimental group, relative to the control group. Such remote delivery paradigms may therefore be useful when evaluating changes in fear and avoidance

Pain and avoidance: The potential benefits of imagining your best possible self

Positive affect is hypothesized to improve safety learning taking place during extinction (i.e., the core mechanism of exposure treatment), therefore improving the maintenance of treatment outcomes. We investigated whether positive affect during extinction attenuates the subsequent return of pain-related avoidance and fear. In an operant pain-related avoidance conditioning paradigm, sixty healthy volunteers performed arm-reaching movements using a robotic arm. During acquisition, they learned to avoid an easy but painful movement (T1) by choosing more effortful movements that were sometimes (T2) or never (T3) painful. Then, the Positive affect group wrote about and imagined their best possible self, which is known to induce positive affect, whereas the Control group wrote about and imagined a typical day. During extinction with response prevention (RPE), participants were only allowed to perform T1, which was no longer paired with pain. Next, two painful stimuli were presented when participants were not moving (i.e., reinstatement manipulation). During test, all movements were available, and we examined whether fear and avoidance of the previously painful movements would re-emerge. Pain-related avoidance returned in both groups, but the two groups did not differ herein. The Positive affect group reported increased positive affect, though not more than the Control group. Nevertheless, they generalized the learned safety of T1 to the other movements during RPE, whereas they also retrospectively rated the pain as less intense and less unpleasant. These results add to the literature of positive affect as a resilience factor.

The effect of social anxiety on the acquisition and extinction of low-cost avoidance

Excessive avoidance and safety behaviours are a hallmark feature of social anxiety disorder. However, the conditioning and extinction of avoidance behaviour in social anxiety is understudied. Here, we examined the effect of individual differences in social anxiety on low-cost operant avoidance conditioning and extinction in 80 female participants. We employed an avoidance conditioning and extinction paradigm and measured skin conductance response, threat expectancy ratings and avoidance behaviour throughout the task. Findings demonstrated that elevated levels of social anxiety predicted the generalisation of conditioned avoidance responses across to safety cues during avoidance conditioning. When the opportunity to avoid was returned after the threat extinction phase, elevated social anxiety was associated with increased avoidance behaviour to threat cues. The results suggest that compromised extinction of avoidance behaviour is a characteristic of social anxiety and supports the strategy of minimising avoidance and safety behaviours during exposure therapy for the treatment of social anxiety disorder. Future research should utilise the avoidance conditioning and extinction paradigm as a laboratory model for clinical research to investigate how, and under what circumstances, the extinction of avoidance and safety behaviours can be improved for individuals high in social anxiety.

Sensation seeking and neuroticism in fear conditioning and extinction: The role of avoidance behaviour

Maladaptive avoidance behaviour, a key symptom of anxiety-related disorders, prevents extinction learning and maintains anxiety. Individual personality traits likely influence avoidance propensity: high sensation-seeking may decrease avoidance, thereby increasing extinction, and neuroticism may have the reverse effect. However, research on this is scarce. Using a naturalistic conditioned avoidance paradigm, 163 women underwent differential fear acquisition to a conditioned stimulus (CSplus). Next, during extinction, participants could either choose a risky shortcut, anticipating shock signalled by CSplus, or a time-consuming avoidance option (lengthy detour). Across participants, increased skin conductance (SCR) acquisition learning predicted subsequent instrumental avoidance. Avoidance, in turn, predicted elevated post-extinction SCR and shock-expectancy, i.e., ‘protection-from-extinction’. Mediation analyses revealed that sensation seeking decreased protection-from-extinction—both for shock-expectancy and SCR—via attenuating avoidance. Neither sensation seeking nor neuroticism were related to acquisition learning and neuroticism was neither related to avoidance nor extinction. Transcranial direct current stimulation administered before extinction did not influence present results. Results highlight the important role of elevated avoidance propensity in fear maintenance. Results moreover provide evidence for reduced sensation-seeking and increased acquisition learning to be avoidance-driving mechanisms. Since approach-avoidance conflicts are faced by anxiety patients on a daily basis, strengthening sensation-seeking-congruent attitudes and approach behaviours may optimize individualized treatment.

Negative reinforcement rate and persistent avoidance following response-prevention extinction

Persistent avoidance may be influenced by prior negative reinforcement rate (i.e., how effective the response is at controlling threat). In clinical settings, the effectiveness of extinction-based methods for treating anxiety-related avoidance may be impacted by prior reinforcement rate. Here, we conducted a laboratory-based treatment study to investigate the persistence of avoidance following response-prevention extinction (RPE) when prior avoidance had been differentially effective at cancelling shock. Participants in three negative reinforcement rate groups (100%, 50%, and 0%) completed a validated avoidance conditioning paradigm involving Pavlovian fear extinction, RPE, and re-extinction phases. It was hypothesised that partially reinforced avoidance would lead to diminished resistance to fear extinction following response prevention, compared to continuously- or never-reinforced avoidance. Persistent avoidance was related to prior negative reinforcement rate, with higher rates more resistant to extinction. These findings illustrate the role of reinforcement rate in the persistence of avoidance and may aid understanding of treatment relapse.

Once an Avoider Always an Avoider? Return of Pain-Related Avoidance After Extinction With Response Prevention

In exposure for chronic pain, avoidance is often forbidden (extinction with response prevention; RPE) to prevent misattributions of safety. Although exposure is an effective treatment, relapse is common. Little is known about the underlying mechanisms of return of pain-related avoidance. We hypothesized that pain-related avoidance would recover when becoming available again after RPE and after unexpected pain episodes (“reinstatement”), especially when restricting avoidance during RPE (compared to instructing not to use it). In an operant pain-related avoidance conditioning paradigm, healthy volunteers used a robotic arm to perform various arm reaching movements differing in pain-effort trade-off. During acquisition, participants learned to avoid pain by performing more effortful movements. During RPE they only performed the formerly pain-associated movement under extinction, and were either forbidden (Restricted group) or merely instructed (Instructed group) not to perform other movements. One day later, we tested spontaneous recovery and reinstatement of pain-related fear and avoidance with availability of all movements. Results showed that pain-related fear and avoidance re-emerge after RPE, though not to pretreatment levels. The reinstatement manipulation had no additional effect. No group differences were observed. We discuss findings in the context of learning processes in (chronic) pain disability and relapse prevention in chronic pain treatment.Perspective: Using experimental models of relapse, we investigated the return of pain-related avoidance behavior after extinction with response prevention. Findings are potentially informative for clinicians performing exposure treatment with chronic pain patients.

The validity of human avoidance paradigms

Excessive avoidance towards innocuous cues is a central diagnostic criterion across anxiety-related disorders. Relevant laboratory paradigms typically include instrumental learning procedures, where the presentation of an aversive cue (e.g., a shock) can be prevented by executing an experimenter-defined response (e.g., a button press) during the presentation of a warning cue (e.g., a square). Despite the popularity of these paradigms, there is no evaluation of how well the experimental findings of conditioned avoidance extend to maladaptive avoidance, or whether findings from animal studies could be informative for human studies. Here, we present a validation of the conditioned avoidance paradigm. We show that although this procedure meets the majority of the tested validity criteria (i.e. face, construct, predictive, and diagnostic validity), it also faces a number of challenges, including the non-consideration of individual differences in learning or the use of procedures that cannot be easily translated to clinical settings. For meeting these challenges, we suggest extensions of the paradigm including the test of individual differences by using ambiguous stimuli as well as the use of virtual reality procedures. Our main conclusion is that despite the significant knowledge provided in conditioned avoidance paradigms, their expansion will allow reaching more theoretical and clinical insights.

MK212, a 5-hydroxytryptamine 2C receptor agonist, inhibits conditioned avoidance responses independent of blocking endogenous dopamine release in rats

Although it is widely accepted that 5-hydroxytryptamine (5-HT) 2C receptor agonists produce antipsychotic effects by reducing endogenous dopamine release from presynaptic neurons, no direct evidence supports this. The aim of the present study was to investigate whether the antipsychotic effects induced by 5-HT2C receptor agonists are dependent on the inhibition of endogenous dopamine release. We developed a novel conditioned avoidance response paradigm to test this hypothesis. In this assay, rats in which dopamine was depleted by reserpine failed to show conditioned avoidance responses, and the acute administration of quinpirole reversed the disruption of avoidance responses induced by reserpine. This suggests that animals successfully showed conditioned avoidance responses independent of endogenous dopamine release under these experimental conditions. Our results revealed that MK212 (0.5 mg/kg) reduced avoidance responses triggered by quinpirole in dopamine-depleted rats. Therefore, 5-HT2C receptor agonists can inhibit conditioned avoidance responses independent of blocking endogenous dopamine release. Furthermore, the 5-HT2C receptor agonist, MK212, decreased the extracellular concentration of glutamate in the nucleus accumbens, indicating that this mechanism may be critical for the antipsychotic effects of 5-HT2C receptor agonists.

Sleep deprivation impairs cognitive performance in zebrafish: A matter of fact?

The zebrafish (Danio rerio) has become a valuable model organism for behavioral studies examining learning and memory. Its diurnal circadian rhythm and characterized sleep-like state make it comparable to mammals, features that have contributed to establishing this small vertebrate as a translational model for sleep research. Despite sleep being an evolutionarily conserved behavior, its mechanisms and functions are still debated. Sleep deprivation is commonly associated with decreased attention, reduced responsiveness to external stimuli, altered locomotor activity and impaired performance on cognitive tasks. In the current study, we examined the effects of partial and total sleep deprivation on zebrafish learning performance in an active avoidance conditioning paradigm. In addition, we examined the effects of two drugs known to alter sleep (alcohol and melatonin) on learning performance in sleep deprived animals. Our results suggest that although partial sleep deprivation did not alter learning performance, total sleep deprivation was found to significantly impair behavioral responses to the electric shock as well as avoidance learning. However, when sleep deprived fish were treated with alcohol the night before the learning task, learning performance was similar to the control group. In contrast, melatonin treatment did not alter learning performance in sleep deprived animals. We conclude that the zebrafish is a sensitive tool for investigating the effects of sleep deprivation on cognitive performance and may be a useful model for dissecting the mechanisms underlying learning and memory.

Neurobehavioral impairments produced by developmental lead exposure persisted for generations in zebrafish (Danio rerio)

The zebrafish has become a useful animal model for studying the effects of environmental contaminants on neurobehavioral development due to its ease of breeding, high number of eggs per female, short generation times, and a well-established avoidance conditioning paradigm. Using avoidance conditioning as the behavioral paradigm, the present study investigated the effects of embryonic exposure to lead (Pb) on learning in adult zebrafish and the third (F3) generation of those fish. In Experiment 1, adult zebrafish that were developmentally exposed to 0.0, 0.1, 1.0 or 10.0μM Pb (2–24h post fertilization) as embryos were trained and tested for avoidance responses. The results showed that adult zebrafish hatched from embryos exposed to 0.0 or 0.1μM Pb learned avoidance responses during training and displayed significantly increased avoidance responses during testing, while those hatched from embryos exposed to 1.0 or 10.0μM Pb displayed no significant increases in avoidance responses from training to testing. In Experiment 2, the F3 generation of zebrafish that were developmentally exposed to an identical exposure regimen as in Experiment 1 were trained and tested for avoidance responses. The results showed that the F3 generation of zebrafish developmentally exposed as embryos to 0.0 or 0.1μM Pb learned avoidance responses during training and displayed significantly increased avoidance responses during testing, while the F3 generation of zebrafish developmentally exposed as embryos to 1.0 or 10.0μM Pb displayed no significant changes in avoidance responses from training to testing. Thus, developmental Pb exposure produced learning impairments that persisted for at least three generations, demonstrating trans-generational effects of embryonic exposure to Pb.

Characterisation of Lu AF33241: A novel, brain-penetrant, dual inhibitor of phosphodiesterase (PDE) 2A and PDE10A

Here, we present a preliminary pharmacological characterisation of Lu AF33241, a novel, brain penetrant phosphodiesterase inhibitor of (PDE) 2A and 10A tool compound, in in vitro/in vivo assays indicative of PDE2A and/or PDE10A inhibition, and in vivo models/assays relevant to cognitive processing and antipsychotic-like activity. An assay was also included to investigate potential effects on motor activity. The in vitro selectivity of Lu AF33241 was determined against a panel of PDE enzymes. Lu AF33241 potently inhibited both full-length recombinant hPDE2A (Ki=4.2nM) and hPDE10A (Ki=42nM). The compound moderately inhibited both hPDE1C (Ki=1200nM), hPDE7B (Ki=890nM), and hPDE11A (Ki=1800nM). Lu AF33241 displayed a Ki above 5000nM against all other tested members of the PDE family. Albeit within a narrow dose range, Lu AF33241 attenuated sub-chronic phencyclidine-induced deficits in novel object recognition (3 and 10mg/kg), displayed antipsychotic-like activity in the conditioned avoidance response paradigm (10mg/kg), and did not induce catalepsy within a dose-range of 2–6mg/kg. Further catalepsy studies are needed to investigate a predictive safety window. Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool compound that may serve to further the understanding of the roles played by these enzymes in various CNS disorders.

Waking up to the alarm: sleep, clocks, and making memory (s)tick.

Waking up to the alarm: sleep, clocks, and making memory (s)tick.

The Neural Foundations of Reaction and Action in Aversive Motivation.

Much of the early research in aversive learning concerned motivation and reinforcement in avoidance conditioning and related paradigms. When the field transitioned toward the focus on Pavlovian threat conditioning in isolation, this paved the way for the clear understanding of the psychological principles and neural and molecular mechanisms responsible for this type of learning and memory that has unfolded over recent decades. Currently, avoidance conditioning is being revisited, and with what has been learned about associative aversive learning, rapid progress is being made. We review, below, the literature on the neural substrates critical for learning in instrumental active avoidance tasks and conditioned aversive motivation.

In vitro and in vivo characterisation of Lu AF64280, a novel, brain penetrant phosphodiesterase (PDE) 2A inhibitor: potential relevance to cognitive deficits in schizophrenia

Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3',5'-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus (p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions.

Newly Identified Characteristic of Taste Avoidance Conditioning with High Voltage as an Unconditional Stimulus in &lt;i&gt;Lymnaea Stagnalis&lt;/i&gt;

Based on the newly established taste avoidance conditioning paradigm, Lymnaea can learn the temporal sequence of sucrose application and subsequent applied high voltage with small current resulting in significant suppression of feeding response to sucrose. The most efficient condition to acquire the long-term memory (LTM) is obtained by 15 paired presentations of a conditional stimulus (CS) and an unconditional stimulus (US). This repetition number for LTM acquisition is different among the taste avoidance conditioning employed as US, such as KCl, mechanical tapping and electrical high voltage, however the behavioral modification is thought to activate the same neuronal circuit via RPeD11 which is the inter neuron to control the whole-body withdrawal response. All of these USs are thought to be recognized as a noxious stimulus sensing at RPeD11.

High voltage with little current as an unconditional stimulus for taste avoidance conditioning in Lymnaea stagnalis

A new and better taste avoidance conditioning paradigm for Lymnaea has been developed that replaces the previously used tactile unconditional stimulus (US) with an brief electrical stimulus (1000V, 80μA), while continuing to use a sucrose application to the lips as the conditional stimulus (CS). With 15 paired CS–US presentations on a single day, we were able to elicit both short-term memory (STM) and long-term memory (LTM). The LTM persisted for at least one week. While STM was elicited with 5, 8, or 10 paired presentations of the CS–US on a single day, LTM was not. The new US used here was more consistent than the previously used US, and this stimulus consistency may explain why 15 paired CS–US presentations now result in LTM formation.

The Muscarinic Acetylcholine Receptor Agonist BuTAC Mediates Antipsychotic-Like Effects via the M4 Subtype

The generation of muscarinic acetylcholine receptor (mAChR) subtype-selective compounds has been challenging, requiring use of nonpharmacological approaches, such as genetically engineered animals, to deepen our understanding of the potential that members of the muscarinic receptor subtype family hold as therapeutic drug targets. The muscarinic receptor agonist 'BuTAC' was previously shown to exhibit efficacy in animal models of psychosis, although the particular receptor subtype(s) responsible for such activity was unclear. Here, we evaluate the in vitro functional agonist and antagonist activity of BuTAC using an assay that provides a direct measure of G protein activation. In addition, we employ the conditioned avoidance response paradigm, an in vivo model predictive of antipsychotic activity, and mouse genetic deletion models to investigate which presynaptic mAChR subtype mediates the antipsychotic-like effects of BuTAC. Our results show that, in vitro, BuTAC acts as a full agonist at the M2AChR and a partial agonist at the M1 and M4 receptors, with full antagonist activity at M3- and M5AChRs. In the mouse conditioned avoidance response (CAR) assay, BuTAC exhibits an atypical antipsychotic-like profile by selectively decreasing avoidance responses at doses that do not induce escape failures. CAR results using M2(-/-), M4(-/-), and M2/M4 (M2/M4(-/-)) mice found that the effects of BuTAC were near completely lost in M2/M4(-/-) double-knockout mice and potency of BuTAC was right-shifted in M4(-/-) as compared with wild-type and M2(-/-) mice. The M2/M4(-/-) mice showed no altered sensitivity to the antipsychotic effects of either haloperidol or clozapine, suggesting that these compounds mediate their actions in CAR via a non-mAChR-mediated mechanism. These data support a role for the M4AChR subtype in mediating the antipsychotic-like activity of BuTAC and implicate M4AChR agonism as a potential novel therapeutic mechanism for ameliorating symptoms associated with schizophrenia.