α7 Nicotinic Receptor Subunits Are Not Necessary for Hippocampal-Dependent Learning or Sensorimotor Gating: A Behavioral Characterization of Acra7-Deficient Mice

The α7 nicotinic acetylcholine receptor (nAChR) subunit is abundantly expressed in the hippocampus and contributes to hippocampal cholinergic synaptic transmission suggesting that it may contribute to learning and memory. There is also evidence for an association between levels of α7 nAChR and in sensorimotor gating impairments. To examine the role of α7 nAChRs in learning and memory and sensorimotor gating, Acra7 homozygous mutant mice and their wild-type littermates were tested in a Pavlovian conditioned fear test, for spatial learning in the Morris water task, and in the prepulse inhibition paradigm. Exploratory activity, motor coordination, and startle habituation were also evaluated. Acra7 mutant mice displayed the same levels of contextual and auditory-cue condition fear as wild-type mice. Similarly, there were no differences in spatial learning performance between mutant and wild-type mice. Finally, Acra7 mutant and wild-type mice displayed similar levels of prepulse inhibition. Other behavioral responses in Acra7 mutant mice were also normal, except for an anxiety-related behavior in the open-field test. The results of this study show that the absence of α7 nAChRs has little impact on normal, base-line behavioral responses. Future studies will examine the contribution of α7 nAChR to the enhancement of learning and sensorimotor gating following nicotine treatments.     

Nicotinic acetylcholine receptors of the ventral tegmental area are involved in mediating morphine-state-dependent learning

In the present study, the possible role of nicotinic acetylcholine (nACh) receptors of the ventral tegmental area (VTA) on morphine-state-dependent learning was studied in adult male Wistar rats. As a model of memory, a step-through type passive avoidance task was used. All animals were bilaterally implanted with chronic cannulae in the VTA, trained using a 1 mA foot shock, and tested 24 h after training to measure step-through latency. Post-training subcutaneous (s.c.) injection of morphine (0.5–5 mg/kg) dose-dependently reduced the step-through latency, showing morphine-induced amnesia. Amnesia induced by post-training morphine was significantly reversed by pre-test administration of morphine (2.5–5 mg/kg, s.c.) and induced morphine-state-dependent learning. Pre-test injection of nicotine (0.25–1 μg/rat) into the VTA plus an ineffective dose of morphine (0.5 mg/kg) significantly restored the memory retrieval. It should be noted that pre-test intra-VTA injection of the same doses of nicotine (0.25–1 μg/rat) alone cannot affect memory retention. Furthermore, pre-test intra-VTA injection of the nicotinic acetylcholine receptor antagonist, mecamylamine (1–3 μg/rat) 5 min before the administration of morphine (5 mg/kg, s.c.) dose-dependently inhibited morphine-state-dependent learning. Pre-test injection of the higher dose of mecamylamine (3 μg/rat) into the VTA by itself decreased the step-through latency and induced amnesia. On the other hand, mecamylamine (0.5 and 1 μg/rat, intra-VTA) reversed the effect of nicotine on morphine response. The results indicate that nACh receptors in the VTA participate in the modulation of morphine-induced recovery of memory, on the test day.     

Impairment of spatial learning and hippocampal synaptic potentiation in c-kit mutant rats

The c-kit receptor tyrosine kinase encoded by the white-spotting (W) gene is highly expressed in rat hippocampal CA1–CA4 regions. We found an impaired spatial learning and memory in homozygous c-kit (Ws/Ws) mutant rats that have a 12-base deletion in the tyrosine kinase domain of the c-kit gene and a very low kinase activity. Electrophysiological studies in hippocampal slices revealed that the long-term potentiation (LTP) induced by the tetanic stimulation (100 Hz, 1 sec) in the mossy fiber (MF)–CA3 pathway, but not in the Schaffer collaterals/commissural–CA1 pathway, was significantly reduced in c-kit mutants compared with wild-type (+/+) rats. The paired-pulse facilitation (PPF) was measured before the tetanus and after the establishment of the LTP in each slice. The initial PPF in the MF–CA3 pathway positively correlated with the amplitude of the LTP in the wild-type rats but not in the c-kit mutant rats. Furthermore, they failed to show the normal characteristics observed in the MF–CA3 pathway of +/+ rats; that is, the negative correlation between the initial PPF and the changes in PPF measured after the LTP. These findings suggest an involvement of SCF/c-kit signaling in hippocampal synaptic potentiation and spatial learning and memory.     

Varenicline ameliorates ethanol-induced deficits in learning in C57BL/6 mice

Ethanol is a frequently abused drug that impairs cognitive processes such as learning. Varenicline, an α4β2 nicotinic receptor partial agonist and α7 nicotinic receptor full agonist prescribed for smoking cessation, has been shown to decrease ethanol consumption. The current study investigated whether varenicline could ameliorate ethanol-induced deficits in learning and whether varenicline alters blood alcohol concentration in C57BL/6 mice. Conditioning consisted of two auditory conditioned stimulus (CS; 30 s, 85 dB white noise)—foot shock unconditioned stimulus (US; 2 s, 0.57 mA) pairings. For all studies, saline or ethanol (1.0, 1.5, 2.0 g/kg i.p.) was administered 15 min before training, and saline or varenicline (0.05, 0.1, 0.2 mg/kg i.p.) was administered 60 min before either training or testing. For blood alcohol analysis, saline or varenicline (0.1 mg/kg) was administered 60 min before collection, and saline or ethanol (1.0, 1.5, 2.0 g/kg) was administered 15 min before collection. Varenicline dose-dependently ameliorated ethanol-induced conditioning deficits for all three doses of ethanol when administered before training but not when administered 24 h later, before testing. In addition, varenicline did not alter blood alcohol concentration. The smoking cessation aid varenicline may have therapeutic uses for treating ethanol-associated disruptions in cognitive processes.     

Learning of a hippocampal-dependent conditioning task changes the binding properties of AMPA receptors in rabbit hippocampus.

The N-methyl-D-asparate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtypes of glutamate receptors have been shown to play critical roles in various forms of synaptic plasticity (i.e., learning and memory, long-term potentiation). We previously demonstrated that the binding of [3H]AMPA to the AMPA subtype of glutamate receptors was selectively increased in hippocampus following classical conditioning of the rabbit nictitating membrane response in a delay paradigm. We report here that the same effect was observed in a variant of this learning paradigm that requires the participation of the hippocampus, i.e., trace conditioning of the rabbit nictitating membrane. The binding of [3H]TCP (N-[1-(2-thienyl)cyclo-hexyl]-3,4-piperidine) to the NMDA receptor remained unchanged in all the experimental groups tested. Paired presentations of conditioned and unconditioned stimuli resulted in an increased binding of [3H]AMPA, an agonist of the AMPA receptors, in several hippocampal subfields while the binding of an antagonist, [3H]CNQX (6-nitro-7-cyanoquinoxaline-2,3-dione), was decreased. The results suggest that the learning-induced changes in binding of the ligands to the AMPA receptor reflect changes in affinity of the receptor rather than in the number of sites. These results support the hypothesis that changes in hippocampal glutamate receptors are a corollary of synaptic plasticity in certain forms of learning.     

Ethanol state-dependent memory: involvement of dorsal hippocampal muscarinic and nicotinic receptors

In the present study, the effects of bilateral injections of cholinergic agents into the hippocampal CA1 regions (intra-CA1) on ethanol state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intraperitoneal injection (i.p.) of ethanol (0.25, 0.5 and 1 g/kg) dose dependently induced impairment of memory retention. Pre-test administration of ethanol (0.5 and 1 g/kg, i.p.) induced state-dependent retrieval of the memory acquired under pre-training ethanol (1 g/kg, i.p.) influence. Pre-test intra-CA1 injection of physostigmine (2.5 and 5 μg/mouse, intra-CA1) or nicotine (0.3 and 0.5 μg/mouse, intra-CA1) improved pre-training ethanol (1 g/kg)-induced retrieval impairment. Moreover, pre-test administration of physostigmine (2.5 and 5 μg/mouse, intra-CA1) or nicotine (0.3 and 0.5 μg/mouse, intra-CA1) with an ineffective dose of ethanol (0.25 g/kg) significantly restored the retrieval and induced ethanol state-dependent memory. Pre-test intra-CA1 injection of the muscarinic receptor antagonist, atropine (4 and 8 μg/mouse, intra-CA1) or the nicotinic receptor antagonist, mecamylamine (2 and 4 μg/mouse, intra-CA1) 5 min before the administration of ethanol (1 g/kg, i.p.) dose dependently inhibited ethanol state-dependent memory. Pre-test intra-CA1 administration of physostigmine (0.5, 2.5 and 5 μg/mouse), atropine (2, 4 and 8 μg/mouse), nicotine (0.1, 0.3 and 0.5 μg/mouse) or mecamylamine (1, 2 and 4 μg/mouse) alone cannot affect memory retention. These findings implicate the involvement of a dorsal hippocampal cholinergic mechanism in ethanol state-dependent memory and also it can be concluded that there may be a cross-state dependency between ethanol and acetylcholine.     

Nicotine vs. ethanol discrimination: Extinction and spontaneous recovery of responding

Studies regarding extinction and spontaneous recovery of the discriminative stimulus effects of drugs are limited. Eight rats were initially trained to discriminate nicotine (0.4 mg/kg) vs. ethanol (800 mg/kg). For four rats, itraperitaneal (IP) administrations of nicotine fifteen minutes prior to fifteen-minute training sessions served as a discriminative stimulus (S^D) for predicting food-reinforced lever pressing (VI-1 min). On other sessions ethanol functioned in predicting nonreinforcement (S^Δ). The stimulus roles of the drugs were counterbalanced for the remaining four rats. S^Δ and S^D sessions alternated quasi-randomly with two daily sessions at 1000 and 1400 hours. Discriminative control was not disrupted following ten extinction sessions under a non-drug/saline condition, but was disrupted following extinction sessions under the original training drugs. Instances of spontaneous recovery (SR) occurred throughout extinction under the drug condtions. There was no evidence for SR two weeks following extinction, but partial recovery four weeks following the final extinction phase. Contextual status (context renewal) had neither a restorative or disruptive impact on extiguished or discriminated responding, respectively. Theser results support and extend the limited number of other studies by demonstrating extinction and spontaneous recovery of responding discriminated bytwo distinct drugs. Some theoretical interpretations regarding history effects and training in the context of drug discrimination are entertained.     

Nicotinic modulation of tone-evoked responses in auditory cortex reflects the strength of prior auditory learning

Nicotinic acetylcholine receptors (nAChRs) contribute to sensory-cognitive function, as demonstrated by evidence that nAChR activation enhances, and nAChR blockade impairs, neural processing of sensory stimuli and sensory-cognitive behavior. To better understand the relationship between nAChR function and behavior, here we compare the strength of nAChR-mediated physiology in individual animals to their prior auditory behavioral performance. Adult rats were trained on an auditory-cued, active avoidance task over 4 days and classified as “good,” “intermediate” or “poor” performers based on their initial rate of learning and eventual level of performance. Animals were then anesthetized, and tone-evoked local field potentials (LFPs) recorded in layer 4 of auditory cortex (ACx) before and after a test dose of nicotine (0.7 mg/kg, s.c.) or saline. In “good” performers, nicotine enhanced LFP amplitude and decreased response threshold to characteristic frequency (CF) stimuli, yet had opposite effects (decreased amplitude, increased threshold) on responses to spectrally distant stimuli; i.e., cortical receptive fields became more selective for CF stimuli. In contrast, nicotine had little effect on LFP amplitude in “intermediate” or “poor” performing animals. Nicotine did, however, reduce LFP onset latency in all three groups, indicating that all received an effective dose of the drug. Our findings suggest that nicotinic regulation of cortical receptive fields may be a distinguishing feature of the best-performing animals, and may facilitate sensory-related learning by enhancing receptive field selectivity.     

Reduced K+ Channel Inactivation, Spike Broadening, and After-Hyperpolarization in Kvβ1.1-Deficient Mice with Impaired Learning

A-type K⁺ channels are known to regulate neuronal firing, but their role in repetitive firing and learning in mammals is not well characterized. To determine the contribution of the auxiliary K⁺ channel subunit Kvβ1.1 to A-type K⁺ currents and to study the physiological role of A-type K⁺ channels in repetitive firing and learning, we deleted the Kvβ1.1 gene in mice. The loss of Kvβ1.1 resulted in a reduced K⁺ current inactivation in hippocampal CA1 pyramidal neurons. Furthermore, in the mutant neurons, frequency-dependent spike broadening and the slow afterhyperpolarization (sAHP) were reduced. This suggests that Kvβ1.1-dependent A-type K⁺ channels contribute to frequency-dependent spike broadening and may regulate the sAHP by controlling Ca²⁺ influx during action potentials. The Kvβ1.1-deficient mice showed normal synaptic plasticity but were impaired in the learning of a water maze test and in the social transmission of food preference task, indicating that the Kvβ1.1 subunit contributes to certain types of learning and memory.     

Deficits in acquisition and extinction of conditioned responses in mGluR7 knockout mice

Metabotropic glutamate receptor 7 (mGluR7) is expressed in brain regions implicated in emotional learning and working memory, and previous behavioral experiments indicated contributions of mGluR7 to various complex behaviors. In the present study, we investigated the specific effects of mGluR7 deletion on a variety of conditioning paradigms that model crucial neurocognitive and psychopathological behavioral phenomena. Null-mutant mGluR7^−/− mice displayed defects during scheduled appetitive conditioning, acquisition and extinction of appetitive odor conditioning, extinction of response suppression-based conditioned emotional responding (CER), acquisition of discriminative CER, and contextual fear conditioning. mGluR7^−/− animals were slower to acquire the association between a conditioned stimulus and a positive or negative reinforcer, but eventually reached similar performance levels to their wildtype littermates. Notably, extinction learning of conditioned responses was slower in mGluR7^−/− compared to wildtype animals. The observed delays in the acquisition of complicated stimulus associations across conditioning procedures may suggest a critical role for mGluR7 in neurocognitive functions and psychopathology.     

Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats

A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the β-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [³H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [³H]NE release. The compound (800–2400 μg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with ¹⁴C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod performance, or in tests of general locomotor activity. Furthermore, latencies to select a lever in the DSDT were not affected. These results suggest that PF-68 induced deficits in learning and memory without confounding peripheral motor, sensory, or motivational effects at the tested doses. Furthermore, none of the doses induced a conditioned taste aversion to a novel 0.1% saccharin solution indicating a lack of nausea or gastrointestinal malaise induced by the compound. The data indicate that increases in neuronal plasma membrane order may have significant effects on neurotransmitter function as well as learning and memory processes. Furthermore, compounds such as PF-68 may also offer novel tools for studying the role of neuronal PMO in mnemonic processes and changes in PMO resulting from age-related disorders such as AD.     

Differential effects of beta-adrenergic receptor blockade in basolateral amygdala or insular cortex on incidental and associative taste learning

The importance of central β-adrenergic system has been essentially investigated in aversive/emotional learning tasks. However, recent data suggest that the β-adrenergic system is also required for incidental taste learning. In the present study we evaluated in rats whether β-adrenergic receptor activity is required for taste habituation, an incidental taste learning, and also for conditioned taste aversion (CTA) learning, an associative learning. To address this issue, a low dose of the β-adrenergic antagonist propranolol was infused before learning in either the basolateral amygdala (BLA) or the insular cortex (IC), two forebrain areas reported to play a key role in taste memory formation. Incidental taste learning was assessed using a single presentation of the sweet taste saccharin 0.1%, which is sufficient to increase saccharin consumption (relative to water baseline) during a second presentation. CTA was assessed by pairing the first saccharin 0.1% presentation with a delayed gastric malaise, thus causing a decrease in saccharin consumption (relative to water baseline) during a second presentation. Propranolol infusion in BLA (1 μg/0.2μl) or IC (2.5 μg/0.5 μl) before the first taste exposure impaired incidental taste learning but did not affect CTA. These results highlight the important role played by the β-adrenergic receptor activation in cortical and amygdaloid structures during taste learning. Moreover, they are the first to suggest that incidental learning is more sensitive to blockade of noradrenergic system than associative learning.     

Evidence of a role for multiple memory systems in behavioral extinction

The acquisition of learned behavior involves multiple memory systems, and hippocampal system damage impairs cognitive learning while leaving stimulus-response habit learning intact. In view of evidence that extinction also involves new learning, the present experiments examined whether multiple memory systems theory may be applicable to the neural bases of extinction. Adult Long-Evans rats were trained to run in a straight-alley maze for food reward. Twenty-four hours later, rats matched for runway latencies during acquisition received extinction training. In a response extinction condition conducive to habit learning, rats performed a runway approach response to an empty food cup. In a latent extinction condition conducive to cognitive learning, rats were placed at an empty food cup without performing a runway approach response. Prior to daily extinction training, neural activity of the dorsal hippocampus was reversibly inactivated via infusion of bupivacaine (0.75%, 0.5 microl/side). Control rats receiving saline infusions displayed extinction behavior in both the response and latent training conditions. In contrast, rats receiving bupivacaine extinguished normally in the response condition, but did not display latent extinction. The findings (1) confirm that learning underlying extinction of the same overt behavior can occur with or without explicit performance of the previously acquired response, (2) indicate that extinction learning produced by response and latent training procedures can be neuroanatomically dissociated, and (3) suggest that similarly to initial task acquisition, the hippocampus may critically mediate extinction in situations requiring the use of cognitive learning, such as when performance of a previously acquired response habit is prevented.     

Hippocampal theta (3-8Hz) activity during classical eyeblink conditioning in rabbits

In 1978, Berry and Thompson showed that the amount of theta (3–8 Hz) activity in the spontaneous hippocampal EEG predicted learning rate in subsequent eyeblink conditioning in rabbits. More recently, the absence of theta activity during the training trial has been shown to have a detrimental effect on learning rate. Here, we aimed to further explore the relationship between theta activity and classical eyeblink conditioning by determining how the relative power of hippocampal theta activity [theta/(theta + delta) ratio] changes during both unpaired control and paired training phases. We found that animals with a higher hippocampal theta ratio immediately before conditioning learned faster and also that in these animals the theta ratio was higher throughout both experimental phases. In fact, while the hippocampal theta ratio remained stable in the fast learners as a function of training, it decreased in the slow learners already during unpaired training. In addition, the presence of hippocampal theta activity enhanced the hippocampal model of the conditioned response (CR) and seemed to be beneficial for CR performance in terms of peak latency during conditioning, but did not have any effect when the animals showed asymptotic learning. Together with earlier findings, these results imply that the behavioral state in which hippocampal theta activity is absent is detrimental for learning, and that the behavioral state in which hippocampal theta activity dominates is beneficial for learning, at least before a well-learned state is achieved.     

Acute Ethanol Administration Impairs Spatial Performance While Facilitating Nonspatial Performance in Rats

Acute ethanol administration produces learning and memory impairments similar to those found following lesions to the hippocampal system in rats. For example, both ethanol and hippocampal lesions impair performance on spatial learning and memory tasks while sparing performance on many nonspatial learning and memory tasks. Lesions to the hippocampal system can also alter the nature of the information that the animal uses to guide its behavior, from using spatial information to using individual cues. In the present experiment, rats were trained, while sober, to navigate on an eight-arm radial arm maze to a specific arm for food reward. During training, the rewarded arm was always in the same specific location and contained well-defined cues. After the rat learned the task, a memory test was conducted under different doses of ethanol (0.0 g/kg [saline control], 1.0, 1.5, or 2.0 g/kg, intraperitoneal). On the test day the maze was rotated so that the cued arm was 90 degrees to the right of its original position. During testing, intact rats showed a significant bias to approach the place where they had been previously rewarded, even though the cue was no longer located there. Acute ethanol administration dose dependently reduced approaches to the rewarded place. However, ethanol administration did not result in increases in random choices; rather, it resulted in a dose-dependent increase in approaches to the cued arm, now in a new location. These results extend previous research showing that acute ethanol administration and lesions to the hippocampal system produce similar effects on learning and memory in rats.     

Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala

Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly correlated with behavioral changes induced by nicotine. Here, we study the effect of chronic oral administration of nicotine on the long-term synaptic potentiation in the amygdala, a key structure for emotional memory. We find that oral administration of nicotine for 7 d produces a significant enhancement of LTP in the amygdala. This facilitation is pathway specific: Nicotine selectively facilitates LTP in the cortical-lateral amygdala pathway, but not the thalamic-lateral and the lateral-basolateral synaptic pathway. The synaptic facilitation induced by a 7-d exposure to nicotine is long-lasting, it persists for 72 h after cessation of nicotine but decays 8 d after its cessation. In contrast, a shorter exposure of nicotine (24 h) induces only a short-lasting facilitation of synaptic plasticity that dissipates 24 and 72 h after cessation of nicotine. The facilitation of LTP in the amygdala after exposure to nicotine is mediated by removal of GABAergic inhibition, is dependent on the activation NMDA receptors, and can be prevented by blocking either α7 or β2 nACh receptors. Our results indicate that chronic exposure to nicotine can promote the induction of long-lasting modifications of synapses in a specific pathway in the amygdala.These changes in synaptic plasticity may contribute to the complex neural adaptations and behaviors caused by nicotine.     

Long-lasting teratogenic effects of nicotine on cognition: gender specificity and role of AMPA receptor function

Nicotine, the main psychoactive ingredient in tobacco, readily crosses the placental barrier to cause growth and neurobehavioral abnormalities in the offspring. The current study was designed to assess whether nicotinic action causes long lasting teratogenic effects and synaptic dysfunctions. Pregnant Sprague-Dawley rats were infused with nicotine via osmotic minipumps at a dose of 6 mg/kg/day corresponding to the dose receiving during heavy smoking. A battery of behavioral tests and electrophysiological experiments were performed during specific postnatal periods. A spectrum of developmental and behavioral modifications in adolescent, young-adult and aged animals resulted after prenatal nicotine exposure. The potentially teratogenic effect of nicotine was clearly demonstrated in both genders by changes in developmental reflexes, exploratory and novelty seeking behavior, as well as a higher level of anxiety, and changes in individual and group responses in learning and memory. Most of the behavioral abnormalities were transitional with advancing age (6 months), although cognitive deficits measured by a two-way active avoidance task were long-lasting for male rats. Electrophysiological studies show decreased excitatory postsynaptic responses (mEPSCs) mediated by AMPA receptors in the hippocampus. These results suggest that teratogenic effect of nicotine on cognition is age and gender-specific, long-lasting and associated with AMPA receptor function.     

Memories of reward and nonreward regulate the extinction and reacquisition of both excitatory and inhibitory associations

The memories of the unconditioned stimulus (US) and its absence (No US), symbolized as S^R and S^N, respectively, may be retrieved on US or No US trials giving rise to four types of associations, S^R → US, S^R → No US, S^N → US, and S^N → No US. Here, following acquisition under partial reward (PRF), rats were shifted either to different schedules of PRF (Experiment 1) or extinction (Experiments 1 and 2). Inhibitory S^R → No US associations formed in acquisition survived extinction and shifts to one, but not another type of PRF schedule (Experiments 1 and 2). Excitatory S^R → US associations also survived extinction (Experiment 2). These findings, as well as the acquisition findings of Experiment 2, are consistent with the sequential model but not with the only other two theories said to be able to explain PRF findings, the frustration hypothesis of Amsel and the attention hypothesis of Mackintosh [see Haselgrove, M., Aydin, A., & Pearce, J. M. (2004). A partial reinforcement extinction effect despite equal rates of reinforcement during Pavlovian conditioning. Journal of Experimental Psychology: Animal Behavior Processes, 30, 240–250]. Also, the reacquisition findings obtained here are inconsistent with two views applied to several learning phenomena, the rule-learning view and the position-item view.     

Hormonal dissociation of limbic lesion effects on shuttle box avoidance in rats.

Rats with septal or hippocampal lesions, relative to normal rats, showed facilitated acquisition of a shuttle box avoidance response. The rats with septal lesions were also highly resistant to extinction compared with normal rats. When the same lesion effects were examined in hypophysectiomized rats, the animals with septal lesions continued to show facilitated performance, and those rats with hippocampal lesions performed no differently than nonoperated control animals. These findings are consistent with the hypothesis that the facilitated avoidance performance found in rats with hippocampal lesions is attributable to lesion-induced changes in hypophyseal activity, but similar changes induced by septal lesions are not.