Rabbit Nictitating Membrane Response Research Articles

Delayed unpaired extinction as a treatment for hyperarousal of the rabbit nictitating membrane response and its implications for treating PTSD

Treatment for PTSD (Post-traumatic stress disorder) is rarely available immediately after trauma and often delayed for weeks or months after an event. In a rabbit eyeblink conditioning model of PTSD, we have previously shown that presentations of a tone conditioned stimulus (CS) and shock unconditioned stimulus (US) in an explicitly unpaired manner known as unpaired extinction is effective in reducing CS responding and US hyperarousal even if shock intensity is reduced eight-fold and elicits only minimal responding. Here we determined if delayed delivery of unpaired extinction would still be effective in extinguishing hyperarousal. Rabbits were tested for sensitivity to shock before CS-US pairings and after six days of unpaired extinction presented a day, a week or a month after CS-US pairings. Hyperarousal was extinguished a day and a week after conditioning but not after a month suggesting a significant delay in “treatment” can make hyperarousal persist. We next assessed if this persistence of hyperarousal was associative by comparing rabbits given CS-US pairings to those given explicitly unpaired CS and US presentations, measuring hyperarousal a day and a month later, followed by unpaired extinction and hyperarousal assessment. After four weeks, there was an increase in responding for all rabbits but only rabbits receiving CS-US pairings showed a significant increase in associatively-mediated hyperarousal. Importantly, both paired and unpaired groups showed increased levels of responding after unpaired extinction suggesting treatment delayed for too long may no longer be effective and could cause generalized hyperarousal.

Effects of extinction treatments on the reduction of conditioned responding and conditioned hyperarousal in a rabbit model of posttraumatic stress disorder (PTSD).

We have previously characterized a model of posttraumatic stress disorder (PTSD), based on classical conditioning of the rabbit nictitating membrane response (NMR), that focuses on 2 key PTSD-like features: conditioned responses to trauma-associated cues and hyperarousal. In addition to the development of conditioned NMRs (CRs) to a tone conditioned stimulus (CS) associated with a periorbital shock unconditioned stimulus (US), we have observed that rabbits also exhibit a conditioning-specific reflex modification (CRM) of the NMR that manifests as an exaggerated and more complex reflexive NMR to presentations of the US by itself, particularly to intensities that elicited little response prior to conditioning. Previous work has demonstrated that unpaired presentations of the CS and US are successful at extinguishing CRs and CRM simultaneously, even when a significantly weakened version of the US is utilized. In the current study, additional extinction treatments were tested, including continued pairings of the CS with a weakened US and exposure to the training context alone, and these treatments were contrasted with the effects of unpaired extinction with a weakened US and remaining in home cages with no further treatment. Results showed that continued pairings only slightly decreased CRs and CRM, while context exposure had no effect on CRs and marginal effects on reducing CRM. Unpaired extinction was still the most effective treatment for reducing both. Findings are discussed in terms of applications to cognitive-behavioral therapies for treatment of PTSD, such as incorporating mild, innately stressful stimuli into virtual reality therapy.

Subacute fluoxetine enhances conditioned responding and conditioning-specific reflex modification of the rabbit nictitating membrane response

Extensive research on the rabbit nictitating membrane response (NMR) has shown that the NMR reflex can become exaggerated following classical fear conditioning. This learning-related change is referred to as conditioning-specific reflex modification (CRM) and is observed in the absence of the conditioned stimulus. The aim of the current study was to examine the sensitivity of the CRM paradigm to serotonergic manipulation with fluoxetine, a commonly prescribed selective serotonin reuptake inhibitor for anxiety disorders. To assess the effect of fluoxetine on exaggerated reflexive responding indicative of CRM and on conditioned cued fear, rabbits underwent delay NMR conditioning (pairings of tone and periorbital shock) and were tested for CRM, followed by 5 days of daily fluoxetine (0.03, 0.3, or 3.0 mg/kg) or saline injections. CRM was reassessed 1 day and 1 week later, followed by a retention test of conditioned responses (CRs) to the tone. Fluoxetine (3.0 mg/kg) enhanced CRM and retention of conditioned responses, a week after treatment ceased, and this is in agreement with the reports on increased anxiety-like behaviors in other animal models and humans. The CRM paradigm, therefore, may provide important insight into the mechanisms underlying the paradoxical selective serotonin reuptake inhibitor effects.

Dietary Cholesterol Concentration and Duration Degrade Long-Term Memory of Classical Conditioning of the Rabbit's Nictitating Membrane Response.

A rabbit model of Alzheimer's disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease, including learning and memory changes. Although we have shown 2% cholesterol and copper in water can retard learning, other studies show feeding dietary cholesterol before learning can improve acquisition whereas feeding cholesterol after learning can degrade long-term memory. We explored this issue by manipulating cholesterol concentration and duration following classical trace conditioning of the rabbit's nictitating membrane response and assessed conditioned responding after eight weeks on cholesterol. First, rabbits given trace classical conditioning followed by 0.5%, 1%, or 2% cholesterol for eight weeks showed body weight and serum cholesterol levels that were a function of dietary cholesterol. Although all concentrations of cholesterol showed some sign of retarding long-term memory, the level of memory retardation was correlated with serum cholesterol levels. Second, rabbits given trace conditioning followed by different durations of a 2% cholesterol diet combined with different durations of a 0% control diet for 8 weeks showed duration and timing of a 2% cholesterol diet were important in affecting recall. The data support the idea that dietary cholesterol may retard long-term memory.

John A Harvey

John A Harvey died on 25 June 2011, at the age of 80. He was born in New York City, but was raised in Siberia by his grandparents during the first decade of his life. John completed his BA degree in 1955, received his PhD degree from the prestigious doctoral program in Biopsychology in 1959, and began his long and celebrated career as a faculty member, all at the University of Chicago. He moved to the University of Iowa in 1968, and then to Drexel University College of Medicine in the Department of Pharmacology and Physiology in 1988, where he served as Chair from 2006–2008. John's research career is highlighted by many seminal scientific contributions related to the biochemistry of the brain and the development of behavioral pharmacology. While at Chicago, he laid the foundation for decades of investigations in neuropharmacology by seeking to explain how neurotransmitters within the central nervous system governed behavior and behavioral responses to drugs. He launched his career by establishing that monoamine neurotransmitters were organized into fiber tracts that could be identified and selectively destroyed to determine their behavioral functions. Once the brain was damaged, he showed that impaired behavioral functions could be recovered by restoring depleted neurotransmitters or stimulating denervated receptors. Using a model of increased pain sensitivity associated with serotonin depletion, he showed that the precursor 5-HTP could replenish 5-HT to reverse that behavioral deficit. This remained a model for the treatment of neurological damage for years. He championed the transformative idea that medications used to treat psychiatric disorders produced their effects by modifying behavioral functions attributed to monoaminergic pathways. Subsequently, he established that the fenfluramine and amphetamines depleted brain 5-HT to produce neurotoxic effects, initiating investigations that continue in the substance-abuse field. He was among the first to recognize a relationship between brain lesions that destroyed dopaminergic fibers and deficits in feeding and other motivated behaviors. As a lifelong student of the Russian physiologist Ivan Pavlov, John used Pavlovian conditioning of the rabbit nictitating membrane response for the past 25 years to understand how drugs influence learning. John identified the underlying neural circuitry in the rabbit brainstem required for associative learning and then established how drugs specifically altered different components of Pavlovian conditioning. His research established unequivocally that hallucinogenic drugs enhanced learning by activating 5-HT2 receptors, and established key roles for these receptors in learning and cognition. At Drexel University, he established a NIDA program project that used Pavlovian conditioning to study the detrimental influence of prenatal exposure to cocaine on development. He also used Pavlovian conditioning to examine the effects of brain dysfunction related to autism, applying these techniques to a quest for translational biomarkers for this neurodevelopmental disorder. John published over 150 peer-reviewed articles, reviews and book chapters, and his research contributions were recognized by numerous awards. His career achievements in serotonin research were honored by the Irvine H Page Award at the 2006 international meeting of the Serotonin Club. As a member of many professional societies in pharmacology and neuroscience, he contributed a lifetime of active service to the scientific community. Elected a member of the ACNP in 1979 and a Fellow in 1991, he served actively on the Committee on the Use of Animals. He was especially proud of serving the Journal of Pharmacology and Experimental Therapeutics as specific field editor and then editor-in-chief. He was a member of the editorial boards for more than 10 journals. John was widely known and respected for his humor, collegiality and for his intelligence, and was considered by many to be the paramount gentleman. He trained many graduate students and postdoctoral fellows, many of whom developed their own productive and influential careers in biomedical research. John was the beloved husband to Dr Rhoda Harvey, and father to sons Michael (wife Pilar), Andrew (wife Sonya), and his eldest son, David, who predeceased him. He was also a loving grandfather to Oliver and Davia who brought him the greatest joy and pride. With his passing, many who are reading this commentary on John's life and contributions lost a cherished friend and dear colleague.

Incubation of conditioning-specific reflex modification: Implications for post traumatic stress disorder

Incubation of fear has been used to account for the delayed manifestation of symptoms of fear and anxiety including the delayed onset of Post Traumatic Stress Disorder (PTSD). We have shown the utility of classical conditioning-specific modification of the rabbit nictitating membrane response (NMR) as a model of PTSD. This modification includes an exaggeration in the size and a change in the timing of the unconditioned NMR after several days of classical conditioning. To assess the effects of incubation on conditioning-specific modification, we measured changes in responding as a function of the time between classical conditioning and NMR testing. After just one day of classical conditioning resulting in modest levels of learning, increases in response size were an inverted-U shaped function of days of incubation with little if any change occurring one and ten days after training but significant change occurring after six days. The incubation effect persisted for a week. An unpaired control group showed no change in the size of the response confirming the incubation effect was associative. The results bear a striking resemblance to symptoms of PTSD that do not always occur immediately after trauma and become exacerbated over time and then persist. They point to a window when incubation can exacerbate symptoms and speak to the vulnerability of re-experiencing trauma too soon. This could be a serious problem for military or emergency personnel recalled to combat or a disaster site without sufficient time to deal with the effects of their initial experiences.

Unpaired extinction: Implications for treating post-traumatic stress disorder

Extinction of fear is important for treating stress-related conditions particularly post-traumatic stress disorder (PTSD). Although traditional extinction presents the feared stimulus by itself, there is evidence from both clinical and basic research that repeatedly presenting the feared stimulus by itself does not prevent fear from returning. This renewal or relapse can be “thwarted” by unpaired extinction–presentations of the feared stimulus and the event producing the fear. However, no matter how effective standard unpaired extinction may be in the laboratory, repeated presentation of a traumatic event is untenable. To make an unpaired extinction procedure more clinically relevant, we classically conditioned the rabbit nictitating membrane response using electrical stimulation or air puff as the unconditioned stimulus and then during unpaired extinction reduced both the intensity of the unconditioned stimulus and the days of unpaired stimulus presentations. We found unpaired extinction reduced conditioned and exaggerated unconditioned responding (an animal analog of PTSD called conditioning-specific reflex modification) and could be accomplished with a weak unconditioned stimulus as long as extended presentations were used. Surprisingly, brief presentations of a weak unconditioned stimulus or extended presentations of a strong one made the exaggerated responses stronger. One implication is that brief treatment may not just be ineffectual; it may heighten the symptoms of PTSD. Another implication is that using strong stimuli may also heighten those symptoms.

Timing in trace conditioning of the nictitating membrane response of the rabbit (Oryctolagus cuniculus): Scalar, nonscalar, and adaptive features

Using interstimulus intervals (ISIs) of 125, 250, and 500 msec in trace conditioning of the rabbit nictitating membrane response, the offset times and durations of conditioned responses (CRs) were collected along with onset and peak latencies. All measures were proportional to the ISI, but only onset and peak latencies conformed to the criterion for scalar timing. Regarding the CR's possible protective overlap of the unconditioned stimulus (US), CR duration increased with ISI, while the peak's alignment with the US declined. Implications for models of timing and CR adaptiveness are discussed.

Sensory prediction or motor control? Application of marr-albus type models of cerebellar function to classical conditioning.

Marr–Albus adaptive filter models of the cerebellum have been applied successfully to a range of sensory and motor control problems. Here we analyze their properties when applied to classical conditioning of the nictitating membrane response in rabbits. We consider a system-level model of eyeblink conditioning based on the anatomy of the eyeblink circuitry, comprising an adaptive filter model of the cerebellum, a comparator model of the inferior olive and a linear dynamic model of the nictitating membrane plant. To our knowledge, this is the first model that explicitly includes all these principal components, in particular the motor plant that is vital for shaping and timing the behavioral response. Model assumptions and parameters were systematically investigated to disambiguate basic computational capacities of the model from features requiring tuning of properties and parameter values. Without such tuning, the model robustly reproduced a range of behaviors related to sensory prediction, by displaying appropriate trial-level associative learning effects for both single and multiple stimuli, including blocking and conditioned inhibition. In contrast, successful reproduction of the real-time motor behavior depended on appropriate specification of the plant, cerebellum and comparator models. Although some of these properties appear consistent with the system biology, fundamental questions remain about how the biological parameters are chosen if the cerebellar microcircuit applies a common computation to many distinct behavioral tasks. It is possible that the response profiles in classical conditioning of the eyeblink depend upon operant contingencies that have previously prevailed, for example in naturally occurring avoidance movements.

Analysis of long-term cognitive-enhancing effects of bryostatin-1 on the rabbit (Oryctolagus cuniculus) nictitating membrane response

Previous work demonstrated that protein kinase C (PKC) is implicated in learning and memory. This study investigated whether: (i) PKC activated by bryostatin-1 (Bryo) just before or just after sessions of classical conditioning was capable of enhancing classical conditioning of the rabbit nictitating membrane response; (ii) improved behavioral performance matched the time course of PKC activation induced by Bryo; and (iii) vitamin E (Vit E) enhanced the efficacy of Bryo. Paired rabbits received daily trace conditioning with a tone conditioned stimulus and a corneal air puff unconditioned stimulus. Unpaired rabbits received the same stimuli but in an explicitly unpaired manner. After trace conditioning, all rabbits received daily delay conditioning, and then tone intensity testing. Rabbits pretreated with 10 microg/kg Bryo every other day before a relatively simple trace conditioning task showed more conditioned responses (CRs) during the first 10 trials of each trace conditioning session and a higher likelihood of a CR on the first trial of each trace conditioning session than rabbits pretreated with the vehicle control. Rabbits either posttreated daily with 10 microg/kg Bryo or pretreated with Vit E and subjected to a difficult trace conditioning task showed increased CRs relative to the vehicle control. Neither Bryo nor Vit E or their combination altered nonassociative responding or altered sensitivity to the conditioned stimulus or unconditioned stimulus. These findings demonstrate Bryo has long-term enhancing effects on classical conditioning of the rabbit nictitating membrane response.

Conditioning-specific reflex modification of the rabbit's nictitating membrane response and heart rate: Behavioral rules, neural substrates, and potential applications to posttraumatic stress disorder.

Interest in classical conditioning is usually focused on anticipatory responses to a stimulus associated with a significant event, and it is assumed that responses to the event itself are reflexive, involuntary, and relatively invariant. However, there is compelling evidence that both the rabbit nictitating membrane response (NMR) and heart rate response (HR), well-known reflexive reactions to aversive events, can change quite dramatically as a function of learning when measured in the absence of the conditioned stimulus. In the case of NMR conditioning, a simple blink is transformed into a larger and more complex response. For HR conditioning, reflexive heart rate acceleration can actually change to heart rate deceleration. In both cases, the reflex comes to resemble the conditioned response and follows some of the same behavioral laws. This change in response to the aversive event itself or weaker forms of that event is called conditioning-specific reflex modification (CRM). CRM may force us to reevaluate the behavioral and neural consequences of classical conditioning and may have important consequences for the treatment of conditions such as posttraumatic stress disorder.

Classical conditioning of the rabbit's nictitating membrane response is a function of the duration of dietary cholesterol

Modifying dietary cholesterol may improve learning and memory but very high cholesterol can cause pathophysiology and death. Rabbits fed 2% cholesterol for 8, 10 or 12 weeks with 0.12 ppm copper added to distilled water and rabbits fed a normal diet without copper added to distilled water (0 weeks) were given a difficult trace classical conditioning task and an easy delay conditioning task pairing tone with corneal air puff. The majority of cholesterol-fed rabbits survived the deleterious effects of the diet but survival was an inverse function of the diet duration. Compared to controls, the level of classical conditioning and conditioning-specific reflex modification were an inverted "U"-shaped function of diet duration. Highest levels of responding occurred in rabbits on cholesterol for 10 weeks and trace conditioning was negatively correlated with the number of hippocampal β-amyloid-positive neurons. Rabbits on the diet for 12 weeks responded at levels comparable to controls. The data provide support for the idea that dietary cholesterol may facilitate learning and memory but there is an eventual trade off with pathophysiological consequences of the diet.

Cholesterol enhances classical conditioning of the rabbit heart rate response

The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory.

High dietary cholesterol facilitates classical conditioning of the rabbit's nictitating membrane response

Studies have shown that modifying dietary cholesterol may improve learning and that serum cholesterol levels can be positively correlated with cognitive performance. Rabbits fed a 0, 0.5, 1 or 2% cholesterol diet for eight weeks and 0.12 ppm copper added to their drinking water received trace and then delay classical conditioning pairing tone with corneal air puff during which movement of the nictitating membrane (NM) across the eye was monitored. We found that the level of classical conditioning and conditioning-specific reflex modification (CRM) as well as the number of beta amyloid-labeled neurons in the cortex and hippocampus were a function of the concentration of cholesterol in the diet. The data provide support for the idea that dietary cholesterol may facilitate learning and memory.

Time-specific extinction and recovery of the rabbit's (Oryctolagus cuniculus) conditioned nictitating membrane response using mixed interstimulus intervals.

Extinguishing a conditioned response (CR) has entailed separating the conditioned stimulus (CS) from the unconditioned stimulus (US). This research reveals that elimination of the rabbit nictitating membrane response occurred during continuous CS-US pairings. Initial training contained a mixture of 2 CS-US interstimulus intervals (ISIs), 150 ms and 500 ms. The CRs showed double peaks, one for each ISI. When the 150-ms ISI was removed, its CR peak showed 2 hallmarks of extinction: a decline across sessions and spontaneous recovery between sessions. When a further stage of training was introduced with a distinctive CS using the 150-ms ISI, occasional tests of the original, extinguished CS revealed another hallmark of extinction, specifically, strong recovery of the 150-ms peak. These results support both abstract and cerebellar models of conditioning that encode the CS into a cascade of microstimuli, while challenging theories of extinction that rely on changes in CS processing, US representations, and contextual control.

Response linearity determined by recruitment strategy in detailed model of nictitating membrane control

Many models of eyeblink conditioning assume that there is a simple linear relationship between the firing patterns of neurons in the interpositus nucleus and the time course of the conditioned response (CR). However, the complexities of muscle behaviour and plant dynamics call this assumption into question. We investigated the issue by implementing the most detailed model available of the rabbit nictitating membrane response (Bartha and Thompson in Biol Cybern 68:135-143, 1992a and in Biol Cybern 68:145-154, 1992b), in which each motor unit of the retractor bulbi muscle is represented by a Hill-type model, driven by a non-linear activation mechanism designed to reproduce the isometric force measurements of Lennerstrand (J Physiol 236:43-55, 1974). Globe retraction and NM extension are modelled as linked second order systems. We derived versions of the model that used a consistent set of SI units, were based on a physically realisable version of calcium kinetics, and used simulated muscle cross-bridges to produce force. All versions showed similar non-linear responses to two basic control strategies. (1) Rate-coding with no recruitment gave a sigmoidal relation between control signal and amplitude of CR, reflecting the measured relation between isometric muscle force and stimulation frequency. (2) Recruitment of similar strength motor units with no rate coding gave a sublinear relation between control signal and amplitude of CR, reflecting the increase in muscle stiffness produced by recruitment. However, the system response could be linearised by either a suitable combination of rate-coding and recruitment, or by simple recruitment of motor units in order of (exponentially) increasing strength. These plausible control strategies, either alone or in combination, would in effect present the cerebellum with the simplified virtual plant that is assumed in many models of eyeblink conditioning. Future work is therefore needed to determine the extent to which motor neuron firing is in fact linearly related to the nictitating membrane response.

Effects of 4-aminopyridine on classical conditioning of the rabbit (Oryctolagus cuniculus) nictitating membrane response

A large body of data suggests that potassium channels may play an important role in learning and memory. Previous in-vitro research in a number of species including Hermissenda and the rabbit suggests that a 4-aminopyridine-sensitive transient potassium channel may be involved in classical conditioning. We investigated the effects of in-vivo 4-aminopyridine administration (0.5 mg/kg) on classical conditioning of the rabbit nictitating membrane response using a battery of tests designed to assess the associative, sensory, and motor contributors of 4-aminopyridine to responding. 4-Aminopyridine enhanced both classical conditioning and conditioning-specific reflex modification compared with a saline vehicle control, and these effects had several nonassociative components including an increase in the frequency of responding to both the conditioned and the unconditioned stimuli, suggesting a sensitizing effect of the drug. Although 4-aminopyridine can have peripheral effects, it may also modify cerebellar excitability or hippocampal neurotransmitter balance resulting in heightened responsiveness to stimulation.

Stimulus specificity of concurrent recovery in the rabbit nictitating membrane response

Three experiments demonstrated that, following the extinction of an established conditioned stimulus (CS; e.g., tone), the pairing of an orthogonal stimulus from another modality (e.g., light) with the unconditioned stimulus (US) results in strong recovery of responding to the extinguished CS. This recovery occurred to about an equal degree regardless of whether or not initial training contained unambiguous stimulus-reinforcer relationships--that is, consistent CS-US pairings--or some degree of ambiguity, including intramodal discrimination training, partial reinforcement, or even cross-modal discrimination training (tone vs. light). Experiments 1 and 2 demonstrated that this recovery of responding was largely specific to the extinguished CS, but moderate generalization to other stimuli from the same modality did appear. The results are discussed with reference to alternative mechanisms applicable to learning-dependent generalization between otherwise distinct CSs. These models assume that such generalization is mediated by either a shared response, shared reinforcer, shared context, or shared hidden units within a layered neural network. A specific layered network is proposed to explain the present results as well as other types of savings seen previously in conditioning of the rabbit nictitating membrane response.

Temporal properties of cerebellar-dependent memory consolidation.

Classical conditioning of the nictitating membrane response in rabbits is a well defined model of cerebellar-dependent motor memory. This memory undergoes a period of consolidation after the training session, when it is sensitive to reversible inactivations of the cerebellar cortex, but not of the cerebellar nuclei, with the GABA(A) receptor agonist muscimol. Here, the temporal properties of this cerebellar cortex-dependent consolidation were examined using delayed infusions of muscimol in cortical lobule HVI. Cortical infusions delayed by 5 or 45 min after a conditioning session produced significant and very similar impairments of consolidation, but infusions delayed by 90 min produced little or no impairment. Behavioral measures indicate that the muscimol infusions produced significant effects after approximately 30 min and they lasted for a few hours. So, over a time window beginning approximately 1 hr after the end of the training session and closing 1 hr after that, intracortical activity is critical for consolidation of this motor memory.

Conditioning-specific reflex modification of the rabbit (Oryctolagus cuniculus) nictitating membrane response: US intensity effects.

Conditioning-specific reflex modification (CRM) of the rabbit's nictitating membrane response (NMR) describes changes in responding to an unconditioned stimulus (US) when the rabbit is tested in the absence of the conditioned stimulus. Specifically, after at least 3 days of tone-electrical stimulation pairings, responses to the US increase in size, especially at intensities weaker than the training intensity. CRM is similar to classical conditioning in that it is a function of the strength of conditioning, it can be extinguished, and it can be generalized from one stimulus to another. To compare CRM and classical conditioning further, we conducted three experiments to examine the effects of US intensity (1.0, 2.0, and 4.0 mA) on CRM. CRM was weak following conditioning with 1.0 mA and extremely strong following conditioning with 2.0 mA and 4.0 mA. The data suggest that CRM is a function of US intensity and have implications for posttraumatic stress disorder, a disorder potentially modeled by CRM.