Transcranial focal electrical stimulation via tripolar concentric ring electrodes does not modify the short- and long-term memory formation in rats evaluated in the novel object recognition test.

Noninvasive transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCREs) has been under development as an alternative/complementary therapy for seizure control. Transcranial focal electrical stimulation has shown efficacy in attenuating penicillin-, pilocarpine-, and pentylenetetrazole-induced acute seizures in rat models. This study evaluated the effects of TFS via TCREs on the memory formation of healthy rats as a safety test of TFS. Short- and long-term memory formation was tested after the application of TFS using the novel object recognition (NOR) test. The following independent groups were used: naïve, control (without TFS), and TFS (treated). The naïve, control, and stimulated groups spent more time investigating the new object than the familiar one during the test phase. Transcranial focal electrical stimulation via TCREs given once does not modify the short- and long-term memory formation in rats in the NOR test. Results provide an important step towards a better understanding for the safe usage of TFS via TCREs.

Endogenous opiates mediate radiogenic behavioral change.

Exposure of C57BL/6J mice to ionizing radiation caused stereotypical locomotor hyperactivity similar to that produced by morphine. Naloxone administration prevented this radiation-induced behavioral activation. These results support the hypothesis that endorphins are involved in some aspects of radiogenic behavioral change.

Altered hippocampal circuit function in C3H alpha7 null mutant heterozygous mice.

The alpha7 subtype of nicotinic receptor is highly expressed in the hippocampus where it is purported to modulate release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The alpha7 receptor-mediated release of GABA is thought to contribute to hippocampal inhibition (gating) of response to repetitive auditory stimulation. This hypothesis is supported by observations of hippocampal auditory gating deficits in mouse strains with low levels of hippocampal alpha7 receptors compared to strains with high levels of hippocampal alpha7 receptors. The difficulty with comparisons between mouse strains, however, is that different strains have different genetic backgrounds. Thus, the observed interstrain differences in hippocampal auditory gating might result from factors other than interstrain variations in the density of hippocampal alpha7 receptors. To address this issue, hippocampal binding of the alpha7 receptor-selective antagonist alpha-bungarotoxin as well as hippocampal auditory gating characteristics were compared in C3H wild type and C3H alpha7 receptor null mutant heterozygous mice. The C3H alpha7 heterozygous mice exhibited significant reductions in hippocampal alpha7 receptor levels and abnormal hippocampal auditory gating compared to the C3H wild type mice. In addition, a general increase in CA3 pyramidal neuron responsivity was observed in the heterozygous mice compared to the wild type mice. These data suggest that decreasing hippocampal alpha7 receptor density results in a profound alteration in hippocampal circuit function.

The 5-HT(1A) receptor active compounds (R)-8-OH-DPAT and (S)-UH-301 modulate auditory evoked EEG responses in rats.

Schizophrenics commonly demonstrate abnormalities in central filtering capability following repetitive sensory stimuli. Such sensory inhibition deficits can be mirrored in rodents following administration of psycho-stimulatory drugs. In the present study, male Sprague-Dawley rats were implanted with brain surface electrodes to record auditory evoked EEG potentials in a paired-stimulus paradigm, using 87 dB clicks delivered 0.5 s apart. Amphetamine (1.83 mg/kg, i.p.) produced the expected loss of sensory inhibition, as defined by an increase in the ratio between test (T) and conditioning (C) amplitudes at N40, a mid-latency peak of the evoked potentials. Also, the 5-HT(1A) agonist (R)-8-OH-DPAT caused a significant increase in the TC ratio at the highest dose studied (0.5 mg/kg s.c.), while the 5-HT(1A) antagonist (S)-UH-301 did not significantly affect the TC ratio at any dose studied (0.1-5 mg/kg s.c.). When administered with amphetamine, a lower dose of 8-OH-DPAT (0.1 mg/kg) and the highest dose of UH-301 tested (5 mg/kg, s.c.) were able to reverse the amphetamine-induced increase in TC ratio. The findings suggest that 5-HT(1A) signaling is involved in sensory inhibition and support the evaluation of 5-HT(1A) receptor active compounds in conditions with central filtering deficits, such as schizophrenia.

Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation.

Impaired gating of the auditory evoked P50 potential is one of the most pharmacologically well-characterized features of schizophrenia. This deficit is most commonly modeled in rodents by implanted electrode recordings from the hippocampus of the rodent analog of the P50, the P20-N40. The validity and effectiveness of this tool, however, has not been systematically reviewed. Here, we summarize findings from studies that have examined the effects of pharmacologic modulation on gating of the rodent hippocampal P20-N40 and the human P50. We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges. Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings. We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied. Overall, this review supports continued use of hippocampal P20-N40 gating as a translational tool for schizophrenia research.

Selective alpha 7 nicotinic receptor stimulation normalizes chronic cocaine-induced loss of hippocampal sensory inhibition in C3H mice.

BACKGROUND: A physiological alteration associated with schizophrenic and manic psychoses is diminished inhibition of the electrophysiological response to repeated auditory stimuli. This deficit also occurs in cocaine addicts. Studies in animals show that such inhibition is decreased by noradrenergic receptor stimulation and that the inhibition is enhanced by nicotinic cholinergic receptor stimulation. METHODS: C3H mice were treated for 7 days with cocaine. They were then prepared for electrophysiological recording. After the effects of cocaine treatment were observed, they were treated with nicotine agonists. RESULTS: Chronic cocaine administration markedly diminished inhibition of the hippocampal-evoked response to repeated auditory stimuli. The loss of inhibition was reversed by acute treatment with either nicotine or the selective alpha 7 nicotinic agonist 3-(2,4)-dimethoxybenzylidine anabaseine (DMXB; GTS21). The effects of nicotine showed tachyphylaxis, whereas those of DMXB did not. CONCLUSIONS: This reversal of cocaine's effect by nicotinic agonists is consistent with previous pharmacological studies of the inhibition of auditory response. Additionally, the ability of nicotinic agonists to reverse a physiological defect associated with psychosis may have therapeutic implications for the neuropsychiatric sequelae of cocaine addiction in humans.

Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice.

BACKGROUND: Abnormal sensory inhibition is observed in the majority of schizophrenic patients. DBA/2 mice spontaneously exhibit a similar deficit in sensory inhibition and thus provide a model for drug development targeted to this physiologic abnormality. The impaired sensory inhibition is characterized by diminished response of the hippocampal evoked potential to the second of closely paired auditory stimuli (500-m/sec interstimulus interval). Subnormal levels of hippocampal alpha7 nicotinic cholinergic receptors are associated with the deficient sensory inhibition in both DBA/2 mice and people with schizophrenia. METHODS: Our study examined the inhibition of the P20-N40 auditory evoked potential in DBA/2 mice after intragastric administration of DMXB-A (3-2,4-dimethoxybenzylidine anabaseine), an alpha7 nicotinic receptor partial agonist. After presentation of auditory stimuli, electroencephalographic responses were recorded and measured to monitor the effects of the DMXB-A, alone and in combination with selective nicotinic antagonists. RESULTS: Gastric administration of DMXB-A (10 mg/kg) improved sensory inhibition in DBA/2 mice. This improvement was blocked by alpha-bungarotoxin, but not mecamylamine, indicating that DMXB-A exerts its effects through the alpha7 nicotinic receptor. CONCLUSIONS: Intragastrically administered DMXB-A improves deficient sensory inhibition in DBA/2 mice through stimulation of alpha7 nicotinic receptors. These studies agree with results from previous studies with subcutaneously administered DMXB-A.

Nicotinic agonists and psychosis.

Schizophrenia patients have insufficient inhibitory processing of identical paired auditory stimuli. This deficient "auditory gating" is thought to have physiological relevance, and its severity correlates with certain measures of both positive and negative symptoms. Schizophrenia patients also represent the heaviest smoking population subgroup. Because smoking temporarily normalizes their auditory gating deficit, this may represent a form of self-medication. Although this deficit is unresponsive to treatment with typical antipsychotic drugs, it does respond to the atypical antipsychotic clozapine. The normalization of this deficit by smoking may account for some of the intense drive to smoke that is experienced by schizophrenia patients. However, the normalizing effect of nicotine is transient and is not observed with repeated administration. Auditory gating is modulated by the alpha7 nicotinic receptor subtype, a rapidly desensitizing low-affinity nicotinic receptor. Agents that selectively activate the alpha7 receptor represent a novel class of therapeutic agents for use in the treatment of schizophrenia. Whether selective alpha7 agonists will have beneficial effects on symptoms other than the auditory gating deficit has not yet been established. The first developed alpha7-selective agonist, 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A), normalizes auditory gating in three distinct animal models of the deficit. DMXB-A is a prototype for this potential new drug class, but proof-of-concept for this type of pharmacotherapy will not be available until the completion of planned clinical trials assessing DMXB-A's effects in schizophrenia patients. Additional avenues to the potential normalization of auditory gating deficits are also discussed, focusing on the novel efficacy of clozapine and the potential utility of allosteric modulators of nicotinic receptors.

Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains.

One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of alpha-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal alpha-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal alpha-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane alpha-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal alpha-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that alpha-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.

Kainic acid lesions in adult rats as a model of schizophrenia: changes in auditory information processing.

Previous studies have suggested that intracerebroventricular kainic acid injections alter brain anatomy and neurochemistry in a manner similar to what is observed in schizophrenic patients. Disturbances in sensory information processing are one of the major symptoms of schizophrenia. Thus, the present experiments were designed to evaluate the hypothesis that hippocampal damage, induced by administration of kainic acid, would alter the processing of auditory stimuli in a paired-click paradigm. Adult male Sprague-Dawley rats were implanted for surface recording of auditory evoked potentials. At the time of electrode implantation, the rats also received bilateral injections of either kainic acid or the vehicle solution. In vehicle-treated rats, the midlatency N40 component of the auditory evoked potential was diminished in amplitude by approximately 60% in response to the second of a pair of clicks delivered 0.5 s apart. By contrast, no reduction of the N40 wave evoked by the second click was observed in kainate-treated rats. Further, administration of haloperidol, a prototypical neuroleptic agent, did not improve this auditory processing dysfunction in kainate-treated animals. Loss of auditory filtering in the paired-click paradigm and a lack of response to haloperidol in this test are typically observed in schizophrenic humans. Thus, the present results demonstrate that kainate-lesioned rats possess a functional schizophrenia-like abnormality, further reinforcing the utility of this model system for studying the basic neurobiology of schizophrenia-induced sensory processing deficits.

Hippocampal and cortical sensory gating in rats: effects of quinpirole microinjections in nucleus accumbens core and shell.

Sensory processing disturbances, as measured in the P50/sensory gating paradigm, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In this paradigm, the response to the second of paired-click stimuli is attenuated by an inhibitory effect of the first stimulus. Sensory gating has been observed in most healthy human subjects and normal laboratory rats. Because mesolimbic dopamine has been implicated in other filtering disturbances such as prepulse inhibition of the acoustic startle response and given the fact that amphetamine and apomorphine have been shown to disrupt gating, this study was performed to investigate the role of mesolimbic dopamine in sensory gating. The dopamine D2 receptor agonist quinpirole (10 microg/0.5 microl) was injected bilaterally in nucleus accumbens core and shell and effects on cortical and hippocampal sensory gating were investigated. Also, effects of the dopamine D2 receptor antagonist haloperidol (0.1 mg/kg, subcutaneously) as pretreatment were studied. First, quinpirole significantly reduced both the amplitude to the first click and gating as measured in the cortex and in the hippocampus. There was a tendency for the quinpirole effects on hippocampal gating to be more pronounced in rats injected in the shell. Secondly, haloperidol did not antagonize effects of quinpirole on hippocampal parameters, whereas haloperidol pretreatment fully antagonized quinpirole effects on cortical parameters. In conclusion, gating can be significantly reduced when a dopamine agonist is specifically targeted at mesolimbic dopamine D2 receptors. However, an important consideration is that the dopaminergic effects in the present study on gating are predominantly mediated by the effects on the amplitude to the first click. This has also been suggested for systemic amphetamine injections in rats and schizophrenic patients. This casts doubt on whether dopamine receptor activation affects the putative inhibitory process between the first and the second stimulus.

Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia.

Many investigators have proposed that biological endophenotypes might facilitate the genetic analysis of schizophrenia. A deficit in the inhibition of the P50 evoked response to repeated auditory stimuli has been characterized as a neurobiological deficit in schizophrenia. This deficit is linked to a candidate gene locus, the locus of the alpha7-nicotinic cholinergic receptor subunit gene on chromosome 15q14. Supportive evidence has been found by other investigators, including: 1) linkage of schizophrenia to the same locus; 2) linkage of bipolar disorder to the locus; and 3) replication of the existence of this neurobiological deficit and its relation to broader neuropsychological deficits in schizophrenia. It is certain that there are many genetic factors in schizophrenia and bipolar disorder; what is needed is a complete and precise description of the contribution of each individual factor to the pathophysiology of these illnesses.

Nicotinic cholinergic normalization of amphetamine-induced loss of auditory gating in freely moving rats.

The impairment in normal sensory processing which is usually observed in schizophrenics has been demonstrated using a paired-stimulus paradigm. Normal individuals show a diminished midlatency evoked potential response to the second of a pair of clicks given at a 0.5-s interval. This phenomenon is termed auditory "gating". Schizophrenics routinely fail to suppress their response to the second click in this paradigm; thus, they do not gate. Heavy tobacco use is common among schizophrenics and it has recently been shown that nicotine causes a transient normalization of auditory gating in these individuals. Our laboratory has been utilizing animal models to investigate the sensory deficit observed in schizophrenia. In the present study, rats were administered amphetamine to produce a schizophrenia-like loss of auditory gating. They were then given nicotine, which resulted in a dose-dependent normalization of the amphetamine-induced loss of gating. This effect was blocked by concurrent central administration of d-tubocurarine. Neither nicotine nor d-tubocurarine had any effect on auditory gating when administered alone. These data are in agreement with the human studies showing normalization of auditory gating with nicotine administration and suggest a possible role for the nicotinic cholinergic receptor in the modulation of auditory gating in the rat model.

Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice.

Abnormal sensory inhibition is a measurable indicator of a sensory processing deficit which is observed in schizophrenia, and other disorders, and which may be heritable. This deficit has also been observed in certain inbred mouse strains where the intensity of the deficit has been correlated with reduction in the number of hippocampal alpha-bungarotoxin-sensitive nicotinic receptors. Nicotine and certain nicotinic agonists produce brief periods of normal sensory inhibition in these mice. Similarly, nicotine also transiently normalizes sensory inhibition in schizophrenics. The present study assessed the effects of a novel nicotinic partial agonist (GTS-21), selective for the alpha-bungarotoxin site, on sensory inhibition in DBA mice, a strain with no sensory inhibition under routine experimental conditions. GTS-21 produced a dose-dependent normalization of sensory inhibition which was blocked by alpha-bungarotoxin but not mecamylamine. In contrast to other nicotinic agonists, normalization of sensory inhibition by GTS-21 and two related anabaseine compounds, DMAB-anabaseine and DMAC-anabaseine, was observed when administered a second time to the animal, after a 40-min delay. Our results indicated that the anabaseine compounds increase sensory inhibition through alpha7 nicotinic receptors, and that their ability to act repeatedly on these receptors may be less affected by desensitization.

Morphine tolerance offers protection from radiogenic performance deficits.

When rats are exposed to a sufficiently large dose of ionizing radiation they exhibit lethargy, hypokinesia, and deficits in performance. These and other behavioral changes parallel those often observed in this species after a large dose of morphine. Since the release of endogenous opiates has been implicated in some stress reactions, we sought to determine if they might play a part in radiogenic behavioral deficits. Rats were trained to criterion on a signaled avoidance task. Some subjects were then implanted with a pellet containing 75 mg of morphine. Other animals received placebo implants. Over a number of days, morphine tolerance was evaluated by measurement of body temperature changes. Prior to 2500 rad 60Co exposure or sham irradiation, morphine (or placebo) pellets were removed. Twenty-four hours later rats were retested to assess their performance on the avoidance task. Morphine-tolerant subjects performed significantly better than the irradiated placebo-implanted group and no differently than morphine-tolerant/sham-irradiated animals. Morphine tolerance seems to provide a degree of behavioral radiation resistance. These data are consistent with the hypothesis that endogenous opiate hyperexcretion may play some part in the behavioral deficits often observed after irradiation.

BAM-18: analgesia, hyperalgesia and locomotor effects.

BAM-18, a proenkephalin A-derived opioid peptide, is widely distributed throughout rat CNS and displays high affinity for both mu and kappa opioid receptors. In the present study, BAM-18 was tested in two analgesia paradigms, tail-flick and hot-plate. Injections were centrally administered through a chronically implanted unilateral cannula in the lateral ventricle. In the tail-flick, low doses of BAM-18 (5 micrograms) produced a hyperalgesia while high doses of BAM-18 (50 micrograms) produced an analgesic response. Naloxone (10 mg/kg, s.c.) reversed the BAM-18-induced analgesia and unmasked a persistent hyperalgesia. Morphine-induced (1 microgram) analgesia was completely reversed by 5 micrograms BAM-18. In the hot-plate test, high doses of BAM-18 produced analgesia, with no hyperalgesia observed at any dose. Naloxone reversed the BAM-18-induced analgesia. The locomotor effects of BAM-18 did not differ from those of morphine except in effective dose (50 micrograms vs. 5 micrograms, respectively). Opioid and non-opioid effects of BAM-18 are discussed and compared with other endogenous peptides.

Hippocampal mu-receptors mediate opioid reinforcement in the CA3 region.

Dependence on reinforcing chemicals is manifested when drug-seeking and drug-taking behaviors come to dominate the response repertoire. Clinical observations suggest that the craving and compulsive drug-seeking that characterize drug dependence are aroused by memories of the reinforcing drug experience. If so, a brain structure intimately associated with memory--the hippocampus--would be a plausible substrate for drug reinforcement effects. We report here that drug-naive rats rapidly learn to self-administer the opioid peptide dynorphin A in the CA3 region of hippocampus, and that this behavior is blocked by co-administration of the non-selective opiate antagonist naloxone. Subsequent studies demonstrated that coadministration of mu-, but not kappa- or delta-opioid antagonists also blocked self-administration behavior. We conclude that mu-receptors in the CA3 region of hippocampus may be important target sites for opioid dependence.

Dopaminergic and noradrenergic modulation of amphetamine-induced changes in auditory gating.

Dopaminergic and noradrenergic mediation of central sensory gating were assessed in Sprague-Dawley rats using a condition-test paradigm in which auditory evoked potentials were recorded. In this paradigm, unmedicated rats 'gate', i.e. suppress the response to the second of a pair of clicks delivered at a 0.5 s interval. Amphetamine-treated rats fail to gate; in this respect, they resemble schizophrenic humans. Previous studies had indicated noradrenergic involvement in the mediation of auditory gating in rats. In this study, we used selective antagonists to assess the contribution of alpha- and beta-adrenergic receptors, and dopamine D1- and D2-receptors, to amphetamine-induced alterations in gating. Both the alpha-antagonist, phentolamine, and the beta-antagonist, timolol, normalized gating by potentiating amphetamine-induced decreases in the amplitude of the test response. SCH 23390, a D1-receptor antagonist, also normalized gating, but by elevating the amphetamine-reduced amplitude of the conditioning response. Sulpiride did not significantly alter amphetamine-induced changes in gating. Thus, both noradrenergic alpha- and beta-receptors and dopamine D1-receptors appear to modulate gating. However, their dissimilar means of normalizing gating suggests that noradrenergic and dopaminergic drugs act via different mechanisms and possibly different neuroanatomical loci.

Inhibition of nitric oxide synthase prevents alpha 7 nicotinic receptor-mediated restoration of inhibitory auditory gating in rat hippocampus.

The hippocampus rapidly inhibits its response to repetitive auditory stimulation, an example of an auditory sensory gating mechanism involved in human psychopathology. The neuronal basis of this inhibitory gating mechanism has been investigated in rats. Activation of the alpha 7 nicotinic receptor is required. alpha 7 nicotinic receptor activation also releases nitric oxide in the hippocampus and blockade of nitric oxide synthase reduces inhibitory gating of auditory response. There has not been a direct demonstration that blockade of nitric oxide synthase specifically prevents alpha 7 nicotinic receptor activation of the inhibition of auditory response. Therefore, the goal of the present study was to determine whether this functional effect of alpha 7 receptor activation requires release of nitric oxide. Lesions of the fimbria-fornix disrupt auditory gating by preventing cholinergic stimulation of the hippocampus. Following recovery from this surgery, rats were administered 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A; 10 mg/kg, sc), an agonist at the alpha 7 receptor. DMXB-A restored auditory gating in the fimbria-fornix-lesioned rats, indicating that activation of the alpha 7 nicotinic receptor alone is sufficient to restore auditory gating following lesions of the fimbria-fornix. However, intracerebroventricular infusion of N(omega)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, blocked the DMXB-A-mediated restoration of auditory gating; infusion of the inactive D-enantiomer did not. Restoration of auditory gating by DMXB-A in the fimbria-fornix-lesioned rats was blocked by intracerebroventricular infusion of alpha-bungarotoxin, but not by mecamylamine or dihydro-beta-erythroidine. Together, these data support the hypothesis that nitric oxide mediates alpha 7 nicotinic receptor activation of gating of auditory response in rat hippocampus.

Modulation of hippocampal primed burst potentiation by anesthesia.

This study demonstrates that the anesthetics urethane and pentobarbital differentially affect a low threshold form of long-lasting synaptic plasticity, termed primed burst (PB) potentiation, in the CA1 area of rat hippocampus. PB potentiation was generated by the delivery of a 5-pulse patterned stimulus train, consisting of one priming pulse followed 170 ms later by a burst of 4 pulses at 200 Hz. PB potentiation could not be reliably generated in urethane-anesthetized rats unless stimulus currents were raised to 150% of baseline levels during the stimulus train. In pentobarbital-anesthetized rats, PB potentiation could always be evoked at baseline stimulus intensities. Differences between the anesthetics which could contribute to their varying effects upon PB potentiation are discussed.