Karen E. Stevens

Selective α7-nicotinic agonists normalize inhibition of auditory response in DBA mice

Abstract 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 α-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 α-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 α-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 α7 nicotinic receptors, and that their ability to act repeatedly on these receptors may be less affected by desensitization.

Smoking and mental illness.

Patients with mental illness have a higher incidence of smoking than the general population and are the major consumers of tobacco products. This population includes subjects with schizophrenia, manic depression, depression, posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), and several other less common diseases. Smoking cessation treatment in this group of patients is difficult, often leading to profound depression. Several recent findings suggest that increased smoking in the mentally ill may have an underlying biological etiology. The mental illness schizophrenia has been most thoroughly studied in this regard. Nicotine administration normalizes several sensory-processing deficits seen in this disease. Animal models of sensory deficits have been used to identify specific nicotinic receptor subunits that are involved in these brain pathways, indicating that the alpha 7 nicotinic receptor subunit may play a role. Genetic linkage in schizophrenic families also supports a role for the alpha 7 subunit with linkage at the alpha 7 locus on chromosome 15. Bipolar disorder has some phenotypes in common with schizophrenia and also exhibits genetic linkage to the alpha 7 locus, suggesting that these two disorders may share a gene defect. The alpha 7 receptor is decreased in expression in schizophrenia. [(3)H]-Nicotine binding studies in postmortem brain indicate that high-affinity nicotinic receptors may also be affected in schizophrenia.

Smoking and schizophrenia: abnormal nicotinic receptor expression.

Biological and genetic evidence suggests a role for the neuronal nicotinic receptors in the neuropathophysiology of schizophrenia. Nicotine normalizes an auditory evoked potential deficit seen in subjects who suffer from the disease. Nicotinic receptors with both high and low affinity for nicotine are decreased in postmortem brain of schizophrenics compared to control subjects. The chromosomal locus of the human alpha-7 gene (15q14) is linked to the gating deficit with a lod of 5.3, and antagonists of the alpha-7 receptor (alpha-bungarotoxin and methyllycaconitine) induce a loss of gating in rodents. We have cloned the human alpha-7 gene and found it to be partially duplicated proximal to the full-length gene. The duplication is expressed in both the brain and in peripheral blood cells of normal subjects, but is missing in some schizophrenic subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.

Normalizing Effects of Nicotine and a Novel Nicotinic Agonist on Hippocampal Auditory Gating in Two Animal Models

Rapid habituation of the evoked response to repeated auditory stimuli is a physiological manifestation of sensory gating mechanisms that are disturbed in human psychoses. Similar deficits are found in two animal models: fimbria-fornix lesioned Sprague-Dawley rats and DBA/2 mice, an inbred strain with decreased numbers of hippocampal alpha 7 nicotinic receptors. In response to paired auditory stimuli, the hippocampal evoked response of outbred, unlesioned animals is larger to the first than to the second stimulus. Both fimbria-fornix lesioned rats and DBA/2 mice have decreased response to the first stimulus but no further suppression of response to the second stimulus. Parenteral administration of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT418), a newly developed nicotinic agonist, was found to normalize hippocampal auditory evoked responses in both models. The response to the first stimulus was increased, and the response to the second stimulus was suppressed relative to the first. The magnitude and time course of effect were similar to those observed with a 10-fold greater dose of nicotine. Both nicotine and ABT418 were ineffective when a second dose was administered 1 h later, suggesting that both compounds may desensitize the receptor mechanism.

Tropisetron improves deficits in auditory P50 suppression in schizophrenia

Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.

Exposure to a novel environment interferes with the induction of hippocampal primed burst potentiation in the behaving rat

Primed burst (PB) potentiation is a low threshold form of long-term potentiation that is induced by a pattern of electrical stimulation that mimics specific features of hippocampal physiology. In our paradigm, stimulation of the hippocampal commissural afferents composed of a single priming pulse, followed 170 msec later by a burst of four pulses at 200 Hz, induces PB potentiation of the CA1 population spike. We now report that the capacity for patterned stimulation to induce PB potentiation in behaving rats is affected by the animals’ experience with the recording procedures. Specifically, PB potentiation occurred in only 15% of the first recording sessions. With continued stimulations over the course of days, the incidence of PB potentiation increased: Lasting effects occurred in 30% of the second, 75% of the third, and 92% of the fourth through sixth recording sessions. In additional studies, acclimation to the environment, rather than a kindlinglike phenomenon, was identified as the critical precondition for PB potentiation to occur. Thus, our findings indicate that exposure of a rat to a novel environment results in a profound, but temporary, inhibition of hippocampal plasticity. The relationship of this work to studies of stress and hippocampal-dependent learning is discussed.

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.

Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

The α7 nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimers disease, Parkinsons disease, and attention-deficit/hyperactivity disorder. Activation of α7 nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective α7 nAChR positive allosteric modulator, 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942). This compound enhances the choline-evoked rise in intracellular Ca2+ levels in the GH4C1 cell line expressing the cloned human α7 nAChR. JNJ-1930942 does not act on α4β2, α3β4 nAChRs or on the related 5-HT3A channel. Electrophysiological assessment in the GH4C1 cell line shows that JNJ-1930942 increases the peak and net charge response to choline, acetylcholine, and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (PNU-282987). The potentiation is obtained mainly by affecting the receptor desensitization characteristics, leaving activation and deactivation kinetics as well as recovery from desensitization relatively unchanged. Choline efficacy is increased over its full concentration response range, and choline potency is increased more than 10-fold. The potentiating effect is α7 channel-dependent, because it is blocked by the α7 antagonist methyllycaconitine. Moreover, in hippocampal slices, JNJ-1930942 enhances neurotransmission at hippocampal dentate gyrus synapses and facilitates the induction of long-term potentiation of electrically evoked synaptic responses in the dentate gyrus. In vivo, JNJ-1930942 reverses a genetically based auditory gating deficit in DBA/2 mice. JNJ-1930942 will be a useful tool to study the therapeutic potential of α7 nAChR potentiation in central nervous system disorders in which a deficit in α7 nAChR neurotransmission is hypothesized to be involved.

Rats Reared in Social Isolation Show Schizophrenia-Like Changes in Auditory Gating

Central sensory filtering processes can be demonstrated using a paired stimulus paradigm. Normal humans show a diminished vertex-recorded midlatency auditory-evoked potential to the second of paired clicks (0.5 s apart), a phenomenon termed auditory gating. Schizophrenics routinely fail to suppress the response to the second stimulus; thus, they do not gate. Previous animal studies of auditory gating have used psychotomimetic drug administration to induce a schizophrenia-like loss. However, a nonpharmacologic model of deficient gating would be advantageous. Isolation rearing of weanling rats produces impaired prepulse startle inhibition similar to that observed in schizophrenics. The present studied examined the effects of rearing status upon auditory gating. Male Sprague-Dawley rats raised in social isolation (ISO) were compared to socially raised rats (SOC). Across 10 baseline recording sessions, SOC rats showed substantial gating, while ISO rats failed to gate. Abnormal auditory gating is transiently normalized by nicotine, but not haloperidol, in schizophrenics. ISO rats given nicotine bitartrate showed gating in the normal range for 60 min. By contrast, haloperidol failed to normalize gating in ISO rats. Thus, isolation rearing of weanling rats appears to produce a stable schizophrenia-like gating deficiency that shows the same pattern of response to pharmacological interventions.

Selective α7 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 cocaines 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.