| 1 | Neuropsychopharmacology 2000 Dec 23: 654-66 |
|---|---|
| PMID | 11063921 |
| Title | Birth insult alters dopamine-mediated behavior in a precocial species, the guinea pig. Implications for schizophrenia. |
| Abstract | schizophrenia is associated with increased birth complications, suggesting that birth complications might alter CNS dopaminergic activity later in life. In rats, Caesarean section (C-section) birth can produce long term changes in dopaminergic biochemistry and behavior. However rat brain is somewhat immature compared to human brain at birth. The current study tested if mild birth complications also alter dopamine-mediated function in a species with a more mature CNS at birth, the guinea pig. As adults, guinea PIGS born by C-section showed increased amphetamine-induced locomotion and disruption of prepulse inhibition (PPI) of acoustic startle, compared to vaginally born controls. Guinea PIGS born by C-section with 1 min of added global anoxia showed reduced amphetamine-induced locomotion and disrupted PPI, while a C-section plus 2 min anoxia group showed no change in amphetamine-induced locomotion but increased amphetamine-induced startle. No group differences in effects of amphetamine or apomorphine on PPI were observed. Taken with previous findings, these results indicate that mild birth complications can cause long term changes in dopamine-mediated behavior in both guinea pig and rat, two species spanning the level of human brain maturity at birth. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Behav. Brain Res. 2004 Dec 155: 217-22 |
| PMID | 15364480 |
| Title | Prepulse inhibition of the acoustic startle reflex in pigs and its disruption by d-amphetamine. |
| Abstract | Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating. The dopamine receptor agonist-mediated disruption of PPI in rats is widely used as a model of the sensorimotor gating deficiencies demonstrated in schizophrenia patients. As a possible tool for validation of a pig model of psychosis, we wished to verify the existence of PPI in landrace PIGS and investigate the potential disruption of PPI by d-amphetamine (AMPH) in these animals. PPI of the acoustic startle reflex and its potential disruption by AMPH were investigated using three doses 0.5-1.5mg/kg with a paradigm including two levels of prepulses (82 and 88dB) and a prepulse (PP) interval of 60 and 120ms. We found an average PPI of the startle reflex of 25.6% and both of the investigated PP intensities and PP intervals were equally effective in this PP-inhibitive paradigm. AMPH significantly disrupted PPI and, in spite of only the 0.5mg/kg dose proved statistically significant, the results indicate this to be dose-related. We have demonstrated the phenomenon of PPI of the startle reflex in landrace PIGS and its disruption by d-amphetamine. Studies of sensorimotor gating defects could be a valuable additional tool in assessing pig models of neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Int J Psychophysiol 2004 May 52: 267-75 |
| PMID | 15094249 |
| Title | Scalp recordings of mid-latency AEP and auditory gating in the Göttingen minipig: a new animal model in information processing research. |
| Abstract | Early central information processing, measured in humans by the gating of the middle latency auditory evoked potential (AEP) P50 and the effect of attention on AEP N100, is affected in schizophrenia. Exploring the possibility of using miniature PIGS in longitudinal studies of chronic neuropsychiatric disorders, we present a method for recording seven channel surface middle latency AEP in the awake animal. The AEP and the AEP gating measured in a paired stimulus paradigm similar to the P50 gating paradigm used in humans, were recorded in six adult male miniPIGS in two sessions. The AEP had a stable N40/P60/N120/P200 configuration and in the gating paradigm the difference between stimulus one (S1) and two (S2) P60 and N120 amplitudes were significant. Mean AEP P60 gating ratio (S2/S1) at the posterior central electrode was 0.66 (std 0.29) range 0.21-1.08 and corresponding N120 was 0.60 (std 0.19) range 0.28-0.76. The method presented is feasible for scalp recordings of middle latency evoked potentials in the awake animal, but further studies of interval sensitivity and the effect of arousal manipulation are needed to assess the equivalence of the pig components to those of the human at similar latencies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Behav. Brain Res. 2004 May 151: 295-301 |
| PMID | 15084445 |
| Title | Pre-pulse inhibition of the acoustic startle eye-blink in the Göttingen minipig. |
| Abstract | Pre-pulse inhibition (PPI) of the startle response is a measure of sensorimotor gating which has been frequently shown to be deficient in schizophrenic patients. In humans it is typically measured as the attenuation of the startle eye-blink reflex EMG when a startle eliciting noise is preceded by a weak white noise pre-pulse (PP), the interval between the PP and the startle noise stimulus (SNS) determining the degree of inhibition. Aiming at developing a new animal model of schizophrenia, we have investigated the acoustic startle eye-blink and PPI in 10 Göttingen miniPIGS. The stimuli and the block design of the stimulation were similar to paradigms used in human research. Initially the startle habituation across trials and blocks, secondarily the PPI at PP to SNS intervals of 30, 60, 120, 220, 520, 1020 and 2020 ms was investigated. One pig out of ten did not have a startle response, and three other PIGS did not have a startle response of a sufficient magnitude to demonstrate the PPI seen in the other six PIGS at the expected PP intervals of 60, 120, and 220 ms. Maximal inhibition was seen at the 220 ms interval (mean PPI 58.6%, range -18.4 to 94.6%, N = 9). Most of the results in the PIGS are in accordance with findings in studies of the human startle eye-blink EMG and this initial study promotes further studies and the use of the PPI measure in the validation of minipig models of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Behav. Brain Res. 2004 May 151: 295-301 |
| PMID | 15084445 |
| Title | Pre-pulse inhibition of the acoustic startle eye-blink in the Göttingen minipig. |
| Abstract | Pre-pulse inhibition (PPI) of the startle response is a measure of sensorimotor gating which has been frequently shown to be deficient in schizophrenic patients. In humans it is typically measured as the attenuation of the startle eye-blink reflex EMG when a startle eliciting noise is preceded by a weak white noise pre-pulse (PP), the interval between the PP and the startle noise stimulus (SNS) determining the degree of inhibition. Aiming at developing a new animal model of schizophrenia, we have investigated the acoustic startle eye-blink and PPI in 10 Göttingen miniPIGS. The stimuli and the block design of the stimulation were similar to paradigms used in human research. Initially the startle habituation across trials and blocks, secondarily the PPI at PP to SNS intervals of 30, 60, 120, 220, 520, 1020 and 2020 ms was investigated. One pig out of ten did not have a startle response, and three other PIGS did not have a startle response of a sufficient magnitude to demonstrate the PPI seen in the other six PIGS at the expected PP intervals of 60, 120, and 220 ms. Maximal inhibition was seen at the 220 ms interval (mean PPI 58.6%, range -18.4 to 94.6%, N = 9). Most of the results in the PIGS are in accordance with findings in studies of the human startle eye-blink EMG and this initial study promotes further studies and the use of the PPI measure in the validation of minipig models of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Eur. J. Pharmacol. 2008 Dec 600: 87-92 |
| PMID | 18930726 |
| Title | The tachykinin NK3 receptor agonist senktide induces locomotor activity in male Mongolian gerbils. |
| Abstract | The tachykinin family of receptors has been of strong interest recently due to the potential of the tachykinin NK(3) receptor antagonism in treatment of schizophrenia. However, critical differences in the tachykinin NK(3) receptor between rats, mice and humans make rats and mice less acceptable species for testing tachykinin NK(3) receptor antagonism. This has led to testing of tachykinin NK(3) receptor activity in gerbils and guinea PIGS. As these species are much less common laboratory animals than rats and mice, there is a relative paucity of in vivo testing models for tachykinin NK(3) receptor activation. In the present study, locomotor activity induced by the tachykinin NK(3) receptor agonist senktide was characterized. Injection of senktide i.c.v. was found to dose-dependently induce hyperlocomotion from a dose of 0.06 nmol to the maximal dose tested, 0.6 nmol. Locomotion induced by 0.1 nmol of senktide could be blocked by injection of the tachykinin NK(3) receptor antagonists SB222200 (10 and 30 mg/kg i.p.) and talnetant (SB223412; 10 and 30 mg/kg i.p.), as well as by osanetant (SR142801; 10 and 30 mg/kg i.p.) when administered in a vehicle containing vitamin E and glycofurol. Senktide-induced activity was also reversed by the antipsychotics haloperidol (0.3 and 1 mg/kg p.o.) and risperidone (1 mg/kg p.o.), but not by the serotonin 5HT(2a/c) receptor antagonist MDL100907 (tested at 0.1, 0.3 and 1 mg/kg p.o.). Hyperlocomotion induced by 0.03 nmol of senktide was potentiated by antagonism of the tachykinin NK(1) receptor with aprepitant (1, 3 and 10 mg/kg, p.o.). Thus, hyperlocomotion induced by senktide in gerbils is a tachykinin NK(3) receptor-mediated behavior that is appropriate for use in testing tachykinin NK(3) receptor activity of novel compounds. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Chem. Res. Toxicol. 2008 Apr 21: 869-73 |
| PMID | 18380445 |
| Title | Testing the hypothesis that vitamin C deficiency is a risk factor for clozapine-induced agranulocytosis using guinea pigs and ODS rats. |
| Abstract | The use of clozapine is limited by a relatively high incidence of drug-induced agranulocytosis. Clozapine is oxidized by bone marrow cells to a reactive nitrenium ion. Although many idiosyncratic drug reactions are immune-mediated, the fact that patients with a history of clozapine-induced agranulocytosis do not immediately develop agranulocytosis on rechallenge suggests that some other factor may be responsible for the idiosyncratic nature of this reaction. The reactive nitrenium ion is very rapidly reduced back to clozapine by vitamin C, and many schizophrenic patients are vitamin C deficient. We set out to test the hypothesis that vitamin C deficiency is a major risk factor for clozapine-induced agranulocytosis using a vitamin C deficient guinea pig model. Although the vitamin C deficient guinea PIGS did not develop agranulocytosis, the amount of clozapine covalent binding in these animals was less than we had previously observed in samples from rats and humans. Therefore, we studied ODS rats that also cannot synthesize vitamin C. Vitamin C deficient ODS rats also did not develop agranulocytosis, and furthermore, although covalent binding in the bone marrow was greater than that in the guinea pig, it was not increased in the vitamin C deficient ODS rats relative to ODS rats that had adequate vitamin C in their diet. Therefore, it is very unlikely that vitamin C deficiency is a major risk factor for clozapine-induced agranulocytosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Neuropsychopharmacology 2008 Jun 33: 1642-52 |
| PMID | 17728699 |
| Title | In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): potential therapeutic utility in the treatment of schizophrenia. |
| Abstract | Neurokinin-3 (NK3) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK3 receptors on monoaminergic neurotransmission, has led to the hypothesis that NK3 receptor antagonists may have therapeutic efficacy in the treatment of psychiatric disorders. Here we describe the in vitro and in vivo characterization of the highly selective NK3 receptor antagonist talnetant (SB-223412). Talnetant has high affinity for recombinant human NK3 receptors (pKi 8.7) and demonstrates selectivity over other neurokinin receptors (pKi NK2 = 6.6 and NK1<4). In native tissue-binding studies, talnetant displayed high affinity for the guinea pig NK3 receptor (pKi 8.5). Functionally, talnetant competitively antagonized neurokinin B (NKB)-induced responses at the human recombinant receptor in both calcium and phosphoinositol second messenger assay systems (pA2 of 8.1 and 7.7, respectively). In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pKB = 7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pKB = 7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK3 receptors. Talnetant (3-30 mg/kg i.p.) significantly attenuated senktide-induced 'wet dog shake' behaviors in the guinea pig in a dose-dependent manner. Microdialysis studies demonstrated that acute administration of talnetant (30 mg/kg i.p.) produced significant increases in extracellular dopamine and norepinephrine in the medial prefrontal cortex and attenuated haloperidol-induced increases in nucleus accumbens dopamine levels in the freely moving guinea PIGS. Taken together, these data demonstrate that talnetant is a selective, competitive, brain-penetrant NK3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Eur. J. Pharmacol. 2010 Feb 627: 106-14 |
| PMID | 19879867 |
| Title | In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics. |
| Abstract | Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea PIGS. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | J. Nucl. Med. 2011 Sep 52: 1449-56 |
| PMID | 21828113 |
| Title | 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements. |
| Abstract | Small-molecule ?(7) nicotinic acetylcholine receptor (?(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled ?(7)nAChR PET tracer would be important for in vivo quantification of ?(7)nAChR binding in humans and to measure ?(7)nAChR occupancy of ?(7)nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of (11)C-NS14492 as a selective ?(7)nAChR PET radioligand. The high-affinity ?(7)nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using (11)C-methyl triflate. Female Danish Landrace PIGS were studied at baseline and after intravenous administration of blocking doses of either the ?(7)nAChR partial agonist SSR180711 or the unlabeled NS14492. (11)C-NS14492 was given as an intravenous bolus injection, and the PIGS were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; (11)C-NS14492 regional distribution volumes were calculated, and ?(7)nAChR occupancy was determined using an occupancy plot. (11)C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with ?(7)nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of (11)C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to ?(7)nAChR in vivo. We report here that (11)C-NS14492 is the first, to our knowledge, PET radioligand for ?(7)nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of ?(7)nAChR binding in the human brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Nucl. Med. Biol. 2016 Apr 43: 455-462 |
| PMID | 27209485 |
| Title | Synthesis and evaluation of (18)F-labeled 5-HT2A receptor agonists as PET ligands. |
| Abstract | The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand. Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/?mol. PET studies in Danish landrace PIGS revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [(18)F]2 and [(18)F]3 showed very low brain uptake. None of the investigated (18)F-labeled Cimbi-36 derivatives [(18)F]1, [(18)F]2 and [(18)F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |