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Brief N-methyl-D-aspartate (NMDA) receptor blockade in neonatal rats has been reported to increase neuronal apoptosis. We replicated this finding using MK-801 (0.5 mg/kg) administered twice on postnatal day 7, and then studied the long-term consequences. In adulthood, treated rats showed reduced volume and neuronal number within the hippocampus, and altered hippocampal NMDA receptor (NR1 subunit) expression. Synaptophysin mRNA was decreased in the thalamus (laterodorsal nucleus). Adult MK-801-treated females had prepulse inhibition deficits and increased locomotor activity. The data show that a transient and limited glutamatergic intervention during development can have chronic behavioural, structural and molecular effects. The effects are reminiscent of alterations reported in schizophrenia and, as such, are consistent with hypotheses advocating a role for NMDA receptor hypofunction, and aberrant apoptosis, in the neurodevelopmental pathogenesis of the disorder.

The spontaneously hypertensive rat (SHR) has been proposed as an animal model of attention deficit hyperactivity disorder (ADHD). It is hyperactive in a variety of behavioural paradigms and has a sustained attention deficit. This study investigated whether the SHR would exhibit impaired acquisition and performance of a differential low rate (DRL) schedule of reinforcement because of increased impulsivity, compared with the Wistar–Kyoto (WKY) rat, its normotensive progenitor. In addition, the performance of both strains was compared with Sprague–Dawley (CD) rats. SHR rats were not impaired in the acquisition of this test compared with WKY or CD rats. Indeed, WKY rats took significantly longer to acquire this task than either SHR or CD rats. The WKY rats performed poorly compared with the other strains in those parts of training that required high response rates (e.g. FR-1), but better where low rates of responding were required (e.g. DRL-30s and DRL-60s). The rank order of efficiency when performance was measured under DRL-60s was WKY>SHR>CD. However, the pattern of responding at DRL-60s suggested poor schedule control for the WKY rats. Therefore, the performance of SHR in the DRL test does not appear to represent a valid model of ADHD. Further, our findings with the WKY rat suggest that this strain is a poor behavioural control for the SHR.

Some of the major practical and theoretical issues that are associated with gene-targeting studies in mice are discussed. The availability of sufficient space to house the extensive breeding colonies associated with studies in gene-manipulated mice is an important logistical consideration that requires consideration at an early stage. A practical example is discussed which illustrates some of these issues. Problems associated with disease control and methods of maintaining the health status of valuable colonies are also outlined. Differences in the behavioural phenotype of inbred mouse strains pose important issues for study design and selection of host mouse lines. The results from studies exploring variations in the behavioural phenotype of six common inbred strains are briefly outlined. The impact of phenotypic variation on behavioural studies is considered and the implications for experimental design are discussed.

Detailed characterisation of six inbred strains of mice commonly used in transgenic and knockout research was carried out using a battery of behavioural tests (SHIRPA) followed by discriminant analysis of the data. In the primary observation screen, DBA/2 mice were relatively irritable and vocalised during handling. C57BL/6 were hyperactive as measured by transfer arousal, arena activity and touch-escape tests. By contrast, C3H were markedly hypoactive, had significantly enhanced grip strength and were also significantly impaired on the visual placing task. In the elevated plus-maze, BALB/c mice showed the highest level of open arm entries and time spent in the open arms, indicating the lowest level of anxiety. There was a clear dissociation of strains on exploratory activity, as measured in the holeboard test and spontaneous locomotor activity (LMA). DBA/2 mice were hyperactive in LMA but demonstrated relatively low levels of holeboard exploration. None of the six strains learnt the water maze spatial learning task particularly well. C57BL/6 and 129/Sv demonstrated most ability and C3H showed no evidence of having acquired the task. The SHIRPA screening battery and discriminant analysis of the data have enabled us to determine the relevant contribution of a number of behavioural measurements to the marked differences in phenotype of mouse strains. These data confirm the importance of carrying out a comprehensive profile in order to accurately characterise the phenotype of gene-targeted and transgenic mice.

The localization of orexin neuropeptides in the lateral hypothalamus has focused interest on their role in ingestion. The orexigenic neurones in the lateral hypothalamus, however, project widely in the brain, and thus the physiological role of orexins is likely to be complex. Here we describe an investigation of the action of orexin A in modulating the arousal state of rats by using a combination of tissue localization and electrophysiological and behavioral techniques. We show that the brain region receiving the densest innervation from orexinergic nerves is the locus coeruleus, a key modulator of attentional state, where application of orexin A increases cell firing of intrinsic noradrenergic neurones. Orexin A increases arousal and locomotor activity and modulates neuroendocrine function. The data suggest that orexin A plays an important role in orchestrating the sleep-wake cycle.

The effects of the corticotropin-releasing factor (CRF) receptor antagonists, α-helical CRF-(9–41), [ d -Phe 12 ,Nle 21,38 ,CαMeLeu 37 ]humanCRF-(12–41) ( d -PheCRF-(12–41)) and astressin ([cyclo(30–33){ d -Phe 12 ,Nle 21,38 ,Glu 30 ,Lys 33 ]humanCRF-(12–41) upon hypophagic and motor activation response to human/ratCRF (h/rCRF) were investigated. All three antagonists (100 μg intracerebroventricular (i.c.v.)) blocked the effects of h/rCRF (1 μg i.c.v.) upon food intake and body weight change in food-deprived rats. In contrast, α-helical CRF-(9–41) and astressin (both at 100 μg i.c.v., but not lower doses), but not d -PheCRF-(12–41) (up to 100 μg i.c.v.), blocked h/rCRF (0.3 μg i.c.v.)-induced motor activation in rats in a familiar environment. The ability of d -PheCRF-(12–41) to block CRF-induced hypophagia, but not motor activation, suggests a selective action of this antagonist upon the behavioural effects of centrally administered h/rCRF.

The present study determined the behavioural effects of the corticotropin releasing factor (CRF)-related peptides, human/rat CRF (h/rCRF), ovine CRF (oCRF), sauvagine (SAUV), urotensin I (UT) and the recently discovered neuropeptide, rat urocortin (rUCN). All of the peptides dose-dependently increased motor activity in a familiar environment and reduced feeding in hungry rats. There was no apparent relationship between potency/affinity at CRF2 receptors and effects in these two tests. In a comparison of h/rCRF and rUCN upon discrete spontaneous behaviours, both peptides (3.0 microg i.c.v.) increased activity and grooming, induced a fore-paw tremor and reduced the incidence of motionlessness. However, h/rCRF reduced motionlessness to a greater extent and was a more potent inducer of defaecation, weight loss, oral movements and fore-paw tremor than rUCN. In the elevated X maze, both h/rCRF and rUCN (1.0 microg i.c.v.) had anxiogenic-like effects upon behaviour. In contrast, h/rCRF (1.0 microg i.c.v.), but not rUCN (1.0-10 microg i.c.v.) increased the startle response to an acoustic stimulus. In summary, all the CRF-related peptides increased motor activity and reduced feeding in rats in a similar manner and both rUCN and h/rCRF induced anxiogenesis. However, there were some behavioural differences between rUCN and h/rCRF which require further study. Further pharmacological investigation of the role of CRF receptor subtypes requires the use of subtype selective antagonists.

This study compared the effects of receptor-selective peptide and nonpeptide opioid agonists administered intramuscularly to squirrel monkeys responding under a fixed-interval 3-min schedule of stimulus termination. The mu opioid receptor agonist morphine (0.1-3.0 mg/kg) increased response rate at low doses and decreased it and quarter-life at higher doses. [D-Ala2,N-Me-Phe4,Gly-ol]Enkephalin (DAMGO; 0.3-3.0 mg/kg) reduced quarter-life at the highest dose. The kappa dose. The kappa opioid receptor agonist U50,488H (0.1-1.0 mg/kg) elevated response rate transiently and dose-dependently decreased quarter-life. Dynorphin A(1-13) (0.3-10 mg/kg), a purported endogenous ligand of the kappa opioid receptor, decreased response rate slightly but significantly at 3.0 mg/kg and had no effect on quarter-life. Thus, the behavior of squirrel monkeys was affected by systemically administered peptide as well as by nonpeptide opioid drugs. The two alkaloids were much more effective than the two peptides, presumably because of greater ability to penetrate the blood-brain barrier. Quarter-life was often a more sensitive measure of drug effects than was response rate.

Naloxone-filled (1.0 mg/kg per h) or sham pumps were implanted subcutancously (s.c.) in rats on day 0 and removed on day 7. Spontaneous locomotor activity was lower in naloxone-infused rats on day 3 only. Cumulative dose-response curves to D-amphetamine were constructed in separate groups on day 6 or day 8 (0.0–6.4 mg/kg s.c.). On day 6, naloxone infusion attenuated the gross movement response to D-amphetamine, but not the fine movement response. There were no differences in the response of naloxone- or sham-infused rats to D-amphetamine on day 8. Therefore, withdrawal from continuous naloxone infusion had no influence upon spontaneous or D-amphetamine-stimulated activity.