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Biomedical subjects

Guy A Higgins

Publications and source records attributed to Guy A Higgins.

27 records · Page 2Linked to original sources
PubMed2003

Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands.

In humans, nicotine has been demonstrated to improve both normal and disordered attention, suggesting potential clinical utility for nicotinic ligands. However, attempts to replicate these findings in the rodent have met with some difficulty, thus hampering the search for specific receptor mechanisms underlying these effects. In the present studies, we sought to characterize the effects of nicotine and subtype-selective ligands in a group of aged rats, which show consistent deficits in sustained attention over prolonged sessions of responding in the five-choice serial reaction time task (5-CSRTT). Following the establishment of a replicable performance improvement with nicotine (0.4 mg/kg), we assessed the effects of both SIB 1765F (1-5 mg/kg) and AR-R17779 (20 mg/kg), agonist ligands with selective affinities for the alpha(4)beta(2) and alpha(7) receptor sites, respectively. We then attempted to block this effect of nicotine using the high affinity, competitive nicotinic antagonist DHbetaE (3 mg/kg). Finally, in an attempt to determine whether the psychostimulant profile of nicotinic agonists could be dissociated from their effects on attention, we compared the (R)- and (S)-enantiomers of SIB 1765F in the 5-CSRTT, and in their ability to increase locomotor activity. Reversal of a within-session decline in performance speed and accuracy by nicotine was mimicked by SIB 1765F, but not by AR-R17779, whereas DHbetaE antagonized all of the performance changes induced by nicotine. Finally, the (S)- but not the (R)-enantiomer increased locomotor activity and improved performance in the 5-CSRTT. These results support a critical involvement for the alpha(4)beta(2) nicotinic receptor in mediating the attention-enhancing properties of nicotine.

Aging↗
PubMed2003

Effect of the 5-HT6 receptor antagonists Ro04-6790 and Ro65-7199 on latent inhibition and prepulse inhibition in the rat: comparison to clozapine.

In the present study, we have investigated the effects of two selective 5-HT6 receptor antagonists, Ro04-6790 and Ro65-7199, in three drug-induced models of PPI disruption and on latent inhibition (LI) utilizing a conditioned lick suppression (CLS) procedure. Clozapine was included in each experiment for comparison. Neither Ro04-6790 nor Ro65-7199 (both 30 mg/kg) affected the PPI disruption produced by PCP (1.5 mg/kg s.c.), apomorphine (0.1 mg/kg s.c.), or LSD (0.1 mg/kg s.c.). There was also no interaction between each drug and CS preexposure in the CLS test indicating a failure of each drug to facilitate LI. In contrast, clozapine (12 mg/kg) attenuated an apomorphine and PCP-induced PPI deficit, although the PPI disruption produced by LSD was not significantly affected. At a lower dose of 5 mg/kg, clozapine also facilitated LI. Since each of these tests bear some predictive validity for the detection of antipsychotic drugs, the present studies do not support a therapeutic potential of 5-HT6 receptor antagonists in this regard.

Acetylcholine↗
PubMed2003

Phencyclidine exacerbates attentional deficits in a neurodevelopmental rat model of schizophrenia.

Schizophrenia is characterized by severe abnormalities in cognition, including disordered attention. In the rat, neonatal ventral hippocampal (NVH) lesions induce behavioral abnormalities at adulthood thought to simulate some aspects of the symptomatology of schizophrenia. Here, we compared the effects of NVH and adult ventral hippocampal (AVH) lesions on attentional performance as assessed by the five-choice serial reaction time task (5-CSRTT). NVH-lesioned rats were slower to acquire the task than AVH-lesioned and control animals. When training was complete, NVH- and AVH-lesioned animals exhibited stable but disrupted performance under standard conditions, thus emphasizing an implication of VH in visual attentional processes. Variations in task parameters induced a significantly greater disruption in NVH- and AVH-lesioned groups as compared to controls. NVH-lesioned rats were also hyper-responsive to the disruptive effects of a high dose of phencyclidine (PCP) (3 mg/kg). In contrast, amphetamine (0.4-0.8 mg/kg) had a similar effect in control and VH-lesioned rats. Thus, NVH-lesioned rats were impaired in the acquisition of stable performance in the 5-CSRTT, and were hypersensitive to the cognitive-impairing effects of PCP.

Aging↗
PubMed2003

Transgenic mouse models of Alzheimer's disease: phenotype and application.

Alzheimer's disease (AD) is the most common cause of senile dementia, for which there is presently no disease-based treatment. The identification of genetic factors contributing to this disease, and the intense investigation into the cell biology of amyloid precursor protein (APP) and, to some extent, tau, has led to the development of several transgenic mouse models of this disease. These mice show some of the characteristic AD pathology, such as an age-dependent formation of amyloid plaques consisting of Abeta peptides. However, they usually lack both the tau pathology, i.e. neurofibrillary tangle formation, and the neurodegeneration also associated with AD. Importantly, many of these transgenic lines develop age-dependent deficits in some relevant behavioural tests and thus provide an animal model not only for amyloidosis but also for the cognitive deficits of AD patients. Incorporation of additional disease genes may lead to models that show a more complete disease phenotype. This review attempts to summarize much of this work, and describes how the availability of these models should assist in the understanding of AD aetiology and the identification of effective treatments for this disease. The review also considers the role behavioural testing may have in future AD drug discovery research.

Alzheimer Disease↗
PubMed2002

Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity.

NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia, and pharmacological and genetic approaches have been used to model such dysfunction. We previously have described two mouse lines carrying point mutations in the NMDA receptor glycine binding site, Grin1(D481N) and Grin1(K483Q), which exhibit 5- and 86-fold reductions in receptor glycine affinity, respectively. Grin1(D481N) animals exhibit a relatively mild phenotype compatible with a moderate reduction in NMDA receptor function, whereas Grin1(K483Q) animals die shortly after birth. In this study we have characterized compound heterozygote Grin1(D481N/K483Q) mice, which are viable and exhibited biphasic NMDA receptor glycine affinities compatible with the presence of each of the two mutated alleles. Grin1(D481N/K483Q) mice exhibited a marked NMDA receptor hypofunction revealed by deficits in hippocampal long-term potentiation, which were rescued by the glycine site agonist d-serine, which also facilitated NMDA synaptic currents in mutant, but not in wild-type, mice. Analysis of striatal monoamine levels revealed an apparent dopaminergic and serotonergic hyperfunction. Behaviorally, Grin1(D481N/K483Q) mice were insensitive to acute dizocilpine pretreatment and exhibited increased startle response but normal prepulse inhibition. Most strikingly, mutant mice exhibited a sustained, nonhabituating hyperactivity and increased stereotyped behavior that were resistant to suppression by antipsychotics and the benzodiazepine site agonist Zolpidem. They also displayed a disruption of nest building behavior and were unable to perform a cued learning paradigm in the Morris water maze. We speculate that the severity of NMDA receptor hypofunction in these mice may account for their profound behavioral phenotype and insensitivity to antipsychotics.

Animals↗
PubMed2002

Assessing a vigilance decrement in aged rats: effects of pre-feeding, task manipulation, and psychostimulants.

RATIONALE: In studies assessing sustained attention in humans, performance is often characterised by a decline in function over time. This response pattern, termed the vigilance decrement, is sensitive to manipulations affecting task difficulty, and to reversal with psychostimulant drugs. A valid test of attention in non-human species requires both comparable characteristics of performance, and sensitivity to similar psychoactive drugs. The five-choice serial reaction time task (5-CSRTT) has been described as a test of sustained attention in the rat, however, studies describing vigilance decrements and performance effects of psychostimulants in this task are scarce. OBJECTIVES: We manipulated the standard 5-CSRTT to determine under which conditions a replicable vigilance decrement could be observed, and sought to determine whether this pattern of changes was sensitive to psychostimulant administration. METHODS: One and two-year-old rats performed in five-choice sessions extended to 250 trials. Task difficulty was manipulated by either increasing or decreasing the duration of stimulus presentation, and pre-feeding studies were performed to control for effects of the additional food earned. In the two-year-old group dose-responses were then derived for nicotine (0.1-0.4 mg/kg), amphetamine (0.05-0.4 mg/kg) and caffeine (3-10 mg/kg). RESULTS: Extending five-choice sessions revealed a decline in the performance of two-year-old rats as a function of trial number. Increasing task difficulty induced a response-decrement in one-year old rats; whilst reducing it enhanced the performance of two-year-old rats to that observed in younger subjects. Pre-feeding did not alter the response patterns observed in either group. Nicotine, amphetamine, and caffeine all reversed the performance decrement observed. CONCLUSIONS: These results demonstrate that similar performance characteristics can be observed in both human and rat, serving to validate further the 5-CSRTT as a measure of sustained attention.

Aging↗
PubMed2002

Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety.

The 5-HT2C antagonist SB-242084 was examined in various anxiety tests at doses based on reversal of mCPP-induced hypoactivity (0.1--3 mg/kg ip). In the elevated plus-maze task, SB-242084 exhibited signs of anxiolysis (time spent, distance travelled, and entries into open arms), but this was potentially confounded by its general increase of locomotion; alprazolam selectively affected open-arm parameters. In a Geller--Seifter conflict test, SB-242084 produced a modest, nonsignificant increase in punished responding compared to the significant effect produced by diazepam. None of the treatments significantly affected unpunished responding. In the conditioned emotional response (CER) test, SB-242084 produced an increase in the suppression ratio (SR, smaller than diazepam). Since this 5-HT2C antagonist also increased lever pressing, an additional test was conducted with amphetamine that stimulated lever pressing but, nonetheless, failed to produce any change in SR. In the fear-potentiated startle task, SB-242084 was inactive in comparison to a significant effect of diazepam. The previously described reduction of schedule-induced polydipsia by fluoxetine and 5-HT2C receptor agonist Ro60-0175 was attenuated by SB-242084 pretreatment, however, the latter compound exhibited a potent increase in polydipsia when given alone. The present results demonstrate an anxiolytic potential of SB-242084, as well as an intrinsic response-enhancing property, however, both of these effects are task dependent.

Aminopyridines↗
PubMed2002

Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding.

These studies investigated the effects of antagonists selective for the 5-HT(2A), 5-HT(2B), or 5-HT(2C) receptor subtypes on behaviors elicited or maintained by cocaine. The selective 5-HT(2A) receptor antagonist M100907 (0.5 mg/kg, SC) attenuated the locomotor activity elicited by 10 mg/kg cocaine, whereas the selective 5-HT(2C) receptor antagonist SB242084 (0.5 mg/kg IP) potentiated the locomotor stimulant effect of 10 mg/kg cocaine. The selective 5-HT(2B) antagonist SB215505 (3 mg/kg PO) did not alter cocaine-induced locomotor activity. In a second series of experiments, the effects of M100907 and SB242084 were examined in rats self-administering cocaine intravenously according to a progressive ratio schedule. M100907 (0.5-2 mg/kg) did not alter responding for cocaine at an infusion dose of 0.25 mg. Similarly M100907 (0.5 mg/kg) failed to alter responding for cocaine at infusion doses of 0.0625, 0.125 and 0.25 mg. SB242084 (0.5-1 mg/kg) increased responding for cocaine with the infusion dose set at 0.125 mg. Examination of the effects of SB242084 (0.5 mg/kg) on the cocaine dose response curve revealed significant increases in responding at the lowest doses of 0.0625 and 0.125 but not 0.25 mg. After completion of the self-administration experiments responding was extinguished. M100907 (0.5 mg/kg) attenuated the ability of experimenter administered cocaine (10 mg/kg and 20 mg/kg) to reinstate lever pressing, whereas the priming effect of cocaine (10 mg/kg) was enhanced by SB242084. These results indicate distinct, and in some cases opposite, effects of a 5-HT(2A) compared with a 5-HT(2C) receptor antagonist on various cocaine-mediated behavioral effects.

Aminopyridines↗