Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats.

Gestational stress (GS) produces profound behavioural impairments in the offspring and may permanently programme hypothalamic-pituitary-adrenal (HPA) axis function. We investigated whether or not GS produced changes in the maternal behaviour of rat dams, and measured depression-like behaviour in the dam, which might contribute to effects in the progeny. We used the Porsolt test, which measures immobility in a forced-swim task, and models depression in rodents, while monitoring maternal care (arched-back nursing, licking/grooming, nesting/grouping pups). Pregnant rats underwent daily restraint stress (1 h/day, days 10-20 of gestation), or were left undisturbed (control). On post-parturition days 3 and 4, dams were placed into a swim tank, and time spent immobile was measured. GS significantly elevated immobility scores by approximately 25% above control values on the second test day. Maternal behaviours, in particular arched-back nursing and nesting/grouping pups, were reduced in GS dams over post-natal days 1-10. Adult offspring showed increased immobility in the Porsolt test, and also hypersecreted ACTH and CORT in response to an acute stress challenge. These data show that GS can alter maternal behaviour in mothers, and this might contribute to alterations in the offspring. GS may be an important factor in maternal post-natal depression, which may in turn detrimentally effect the offspring because depressed mothers do not sufficiently care for their offspring.

Modulation of 5-HT4 receptor function in the rat isolated ileum by fluoxetine: the involvement of endogenous 5-hydroxytryptamine.

The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 microM. Fluoxetine (10 microM) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 microM) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg-1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis.

Thyroid hormones, brain function and cognition: a brief review.

In addition to their role in cellular metabolic activity, thyroid hormones (THs), also regulate neural development; the central nervous system is particularly dependent on TH for normal maturation and function. Specifically, there appears to be extensive inter-reliance between TH and acetylcholine (Ach), nerve growth factor and hippocampal function. These associations led us to investigate the possible effects of thyroxine (L-T4) on performance of a spatial learning task, where cholinergic activity and hippocampal function are known to be important. Groups of rats (n=20) received saline (controls) or L-T4 at 2.5 or 5mg/kg daily for 4 days as a sub-chronic treatment, or 0, 5 or 10mg/kg doses administered every third day for 28 days prior to testing as a chronic regimen. Rats were assessed in a water maze for their ability to find a submerged or visible platform. Forty minutes prior to water maze testing, half the animals in each group received 1mg/kg scopolamine to elicit a cognitive deficit. Following testing, rats were decapitated, blood samples taken, and the frontal cortex and hippocampus were dissected out for acetylcholinesterase (AChE) assay. The results showed that L-T4 treatment, administered both sub-chronically and chronically, significantly enhanced the ability of rats to learn a spatial memory task, compared with controls. Moreover, both short-term and long-term L-T4 treatment reduced the cognitive-impairing effects of scopolamine. Improvements in performance were shown to occur alongside significantly increased cholinergic activity in frontal cortex and in the hippocampus of treated animals. These findings demonstrate an augmentative effect of L-T4 upon cognitive function, possibly mediated by an enhancement of cholinergic activity. The results support previous findings of a relationship between L-T4 and acetylcholine, and underscore possible mechanisms by which disorders of thyroid function may be associated with cognitive decline.

Anxiolytic profile of ropinirole in the rat, mouse and common marmoset.

RATIONALE: Some features of Parkinson's disease are exacerbated by stress and anxiety and it is important to understand the effects of dopamine receptor agonists on measures of anxiety. The aim of this study was to assess the effects of the dopamine D2/D3 receptor agonist ropinirole in models of anxiety and depression in the rat, mouse and marmoset. RESULTS: In the rat elevated plus-maze test, ropinirole (0.01-1 mg/kg, i.p.) produced an inverted-U dose-response curve in the percentage time spent in the open arms. Compared with vehicle, ropinirole (0.1 mg/kg) had a significant anxiolytic-like effect, which was similar to that observed with 1.5 mg/kg diazepam. This effect was found at doses that did not affect motor behaviour or induce stereotypy. In the mouse black and white box test of anxiety, ropinirole (0.1-10 mg/kg, i.p.) increased both the rearing time and number of line crosses in the white section. This effect reached statistical significance for both measures at a dose of 0.1 mg/kg and suggests an anxiolytic-like action of the compound. By contrast, the dopamine agonist bromocriptine (0.1-10 mg/kg, i.p.) did not produce significant changes in these behaviours. In the marmoset human threat test, ropinirole (0.01-10 microg/kg, s.c.) reduced the number of postures at all doses tested and this reached statistical significance at 10 microg/kg. Ropinirole did not compromise the effect of amitriptyline in the Porsolt test of depression and in itself produced antidepressant-like effects. CONCLUSIONS: These data demonstrate that systemic administration of ropinirole produces anxiolytic-like effects in three separate models in the mouse, rat and marmoset. This may predict an action of ropinirole in man that would provide a superior profile of action over other presently available anti-parkinsonian agents.

Manipulation of operant responding for an ethanol-paired conditioned stimulus in the rat by pharmacological alteration of the serotonergic system.

It is becoming increasingly clear that environmental stimuli play a critical role in the maintenance of drug taking behaviour. This has led to investigations into the neural mechanisms by which environmental stimuli can come to control behaviour using paradigms such as conditioned reinforcement. The majority of this work has involved the use of food-paired conditioned stimulus rodent paradigms. Relatively few studies have attempted to investigate the neuropharmacology of behaviour maintained by presentation of a stimulus paired with ethanol drinking. Several lines of research support an important role for brain serotonin (5-HT) neurotransmitter systems in the control of alcohol drinking behaviour. The aim of the present study was, initially, to establish a procedure in which rats respond for an ethanol-paired conditioned stimulus, and second, to study the effects of a range of serotonergic compounds previously shown to be effective in reducing oral ethanol self-administration, on responding for this conditioned stimulus. Results showed that the 5-HT releaser d-fenfluramine, the selective serotonin reuptake inhibitor fluoxetine, the 5-HT1A receptor agonist 8-hydroxy-2[di-n-propylamino]tetralin, the partial 5-HT1A receptor agonist buspirone, and the 5-HT1B/5-HT2C receptor agonist 1-(3-trifluoromethylphenyl)piperazine, but not the 5-HT2A/5-HT2C receptor agonist 1-(2,5-dimethoxy-4-iodophenylaminopropane)-2, selectively reduced responding on a lever leading to presentation of an ethanol paired conditioned stimulus. In addition the non-specific D1/D2 dopamine receptor antagonist haloperidol was active in this paradigm. Results are consistent with involvement of the dopaminergic and 5-HT systems, in particular activation of 5-HT1A and 5-HT1B receptor subtypes, in mediation of the conditioned or secondary reinforcing properties of ethanol.

Changes in hippocampal theta following intrahippocampal corticotropin-releasing hormone (CRH) infusions in the rat.

Hippocampal theta activity is a large amplitude, sinusoidal wave that occurs during attentive immobility and exploratory behaviour in the rat, and it is thought to be involved in memory formation. Recent reports suggest that corticotropin-releasing hormone (CRH) has pro-mnemonic effects in rodents. Because memory-enhancing substances/manipulations generally alter either theta frequencies or amplitudes, these variables were monitored in urethane-anaesthetised rats following intrahippocampal infusions of CRH. Adult male, Lister hooded rats were implanted with a hippocampal recording electrode and a guide cannula, both aimed at the dentate gyrus. When CRH was infused into the hippocampus, the main change in the hippocampal EEG was a slow onset increase in the amplitude of spontaneous theta and, paradoxically, a significant decrease in the amount of time spent displaying theta. These data suggest that CRH has the ability to modulate ongoing hippocampal theta, but, considering the slow effect, the involvement of hippocampal CRH receptors is suspect. Regardless of locus, the described electrophysiological changes suggest that hippocampal cholinergic systems may play a role in the memory-enhancing effects of CRH.

The dopamine D3/D2 receptor agonist 7-OH-DPAT induces cognitive impairment in the marmoset.

Previous work has shown that dopaminergic systems are involved in cognitive function in the common marmoset. The present study investigated the role of dopamine D3 receptors in cognitive performance in the marmoset. The effects of the putative dopamine D3 receptor agonist, 7-OH-DPAT, on performance of a same-day reversal visual object discrimination task were assessed using a miniature Wisconsin General Test Apparatus (WGTA). Within the same test session marmosets acquired a two-choice object discrimination initial task and a reversal task to criterion. 7-OH-DPAT (6-10 microg/kg) significantly impaired reversal task performance only, without affecting acquisition of the initial task. A higher dose of 25 microg/kg 7-OH-DPAT impaired initial task acquisition as well as reversal task acquisition, possibly as a consequence of a nonspecific influence on motor function. The dopamine D2 receptor antagonist (-)sulpiride (5-10 microg/kg) and the alpha2-receptor antagonist yohimbine (50 microg/kg) failed to attenuate the effects of 7-OH-DPAT (6 microg/kg) in this task. In contrast, the dopamine D2/D3 receptor antagonist raclopride (50 microg/kg) significantly attenuated the 7-OH-DPAT-induced impairment of reversal task performance. These results suggest that activation of dopamine D3 receptors produces a selective impairment of aspects of cognitive function in the marmoset.

Effects of SCH23390 and raclopride on anxiety-like behavior in rats tested in the black-white box.

Dopamine (DA) systems are activated by stress, and this response has as a corollary the induction of stress-related behaviors such as anxiety. In mice, D2 receptor blockade produces an apparent anxiogenic effect, although locomotor impairments might have been present. We investigated the effects of D1 and D2 antagonists on a variety of anxiety-like behaviors induced by the black-white box in rats and carefully screened for any locomotor deficits. Adult male Lister hooded rats were injected with either the D1 antagonist SCH23390 (0. 0.1. or 0.25 mg/kg i.p.) or the D2 antagonist raclopride (0, 0.05, or 0.10 mg/kg i.p.) 20 min prior to being placed into the white chamber of the black-white box (n = 8-10/group). Rats were videotaped and the tapes were scored for latency to exit the white chamber, latency to reenter the white chamber, time spent in the white chamber, intercompartmental crossing, and locomotor activity. ANOVA revealed no effect of the D1 antagonist SCH23390 on any behavioral measure. However, the raclopride-treated rats left the white area sooner than control rats (p < 0.01). Raclopride-treated rats also exhibited delayed reentry times to the white chamber compared to control rats (p < 0.01) and spent significantly less time in the white chamber (p < 0.05). Neither SCH23390 nor raclopride affected locomotor activity in a manner that confounded these behaviors. These results confirm that D2 receptor blockade enhances anxiety in rats tested in the black-white box.

An investigation into the effects of 5-HT agonists and receptor antagonists on ethanol self-administration in the rat.

Pharmacological manipulation leading to altered 5-HT function has been widely demonstrated to reduce ethanol intake in free choice tests. The aim of the present study was to examine the effects of a range of compounds known to influence 5-HT neurotransmission, including selective 5-HT receptor agonists and antagonists, on ethanol ingestion and maintained behaviour in an operant self-administration paradigm. Female Sprague-Dawley rats were trained to respond for 8% ethanol (v/v) in a 60-min test by a previously described technique. The number of responses and ethanol reinforcers (dipper deliveries), ethanol consumption (g/kg of body weight), and locomotor activity (LMA) were measured following administration of 5-HT agonists (5-HT, d-fenfluramine, fluoxetine, buspirone, TFMPP, and DOI) and antagonists (metergoline, ritanserin, and ondansetron) 30 min prior to testing. d-Fenfluramine, fluoxetine, buspirone, TFMPP, and DOI all produced a reduction in ethanol ingestion and maintained behaviour at doses that failed to reduce LMA. Conversely, metergoline and ritanserin only reduced ethanol self-administration at doses that concomitantly reduced LMA. 5-HT and ondansetron were without effect on any measure. These results demonstrate that, under the present experimental conditions, activation of central 5-HT1A, 5-HT1B, and 5-HT2 receptors reduced ethanol intake and reinforced behaviour in an operant paradigm.

Regulation of hippocampal theta activity by corticosterone: opposing functions of mineralocorticoid and glucocorticoid receptors.

Recently, we reported that intrahippocampal cholinergic blockade increased corticosterone (CORT) and adrenocorticotrophin (ACTH) secretion induced by restraint stress. These data suggested to us that CORT may modify hippocampal cholinergic function as part of the negative-feedback control of hypothalamic-pituitary-adrenal (HPA) axis activity. Hippocampal cholinergic theta is a rhythmic, sinusoidal waveform that occurs in alert, immobile rats presented with threatening stimuli and is reliably expressed in urethanized rats. We reasoned that if hippocampal cholinergic systems regulate HPA axis activity, perhaps CORT acts to modulate theta activity. In the present study we have examined the effects of blocking mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) on theta activity in urethane-anesthetized rats. Adult male, Lister hooded rats (n=15) were anesthetized with urethane, and a theta recording electrode was positioned in the hippocampus adjacent to an infusion cannula. A bipolar stimulating electrode was placed in the dorsomedial posterior hypothalamus (DMPH) to activate theta. Baseline recordings of DMPH-stimulated activity (0.1-0.5 mA) were obtained. Rats were then administered either the MR antagonist spironolactone or the GR antagonist RU 38486 (150 ng), and DMPH-stimulated activities were monitored for 45 min. Changes in theta frequency (Hz) and amplitude (mV; energy at peak theta frequency) were analyzed using analysis of variance (ANOVA) followed by Bonferroni t-tests. Neither drug affected hippocampal theta frequencies elicited by DMPH stimulation. However, GR blockade produced marked increases in theta amplitudes of approximately 100% above predrug levels. Alternatively, MR blockade produced exactly the opposite response, as amplitude values fell to approximately 50% of predrug levels. Hippocampal cholinergic theta activity is modulated by CORT acting through MR and GR, and the rapidity of the response suggests a nongenomic mechanism. These data raise the possibility that hippocampal cholinergic systems, and theta activity, are involved in CORT-mediated negative-feedback control of the HPA axis.

The influence of postweaning housing conditions on drug-induced conditioned taste aversion.

Postweaning social isolation can influence the sensitivity of rats to several effects of drugs of abuse. The present study investigated the influence of postweaning housing conditions on the sensitivity of rats to the aversive effects of a number of psychoactive agents using a conditioned taste aversion (CTA) test procedure. Development of a CTA was assessed by pairing administration of the drug with the consumption of a 0.05% (weight/volume) saccharin solution in water-deprived (18 h) rats in a 20 min drinking period. Saccharin consumption was then measured in 20 min test sessions over the next 4 consecutive days. Consumption of saccharin solution was significantly reduced in both isolated and enriched rats following administration of d-amphetamine (2 mg/kg), cocaine (30 mg/kg), morphine (10 mg/kg), nicotine (1.0 mg/kg), caffeine (20 mg/kg), alcohol (1.5 g/kg), and LiCl (0.15 M, 4 ml/kg). There was no significant effect of housing conditions on the CTA induced by cocaine, nicotine, alcohol, or LiCl; however, isolation-reared rats were found to be less sensitive to the aversive effects of d-amphetamine, morphine, and caffeine in this paradigm. These results suggest that rearing rats in social isolation induces an attenuation in sensitivity to the aversive effects of some psychoactive agents.

The effects of intrahippocampal scopolamine infusions on anxiety in rats as measured by the black-white box test.

Hippocampal cholinergic projections mediate attention to arousing stimuli as demonstrated by behavioral, electrophysiological, and endocrine studies. We recently reported that peripheral injections of the cholinergic antagonist scopolamine (SCOP) increased anxiety-like behaviour (ALB) in rats and we sought to investigate if this response might be hippocampally mediated. Adult male, Lister Hooded rats were implanted bilaterally with hippocampal cannulae 3 weeks prior to testing. On the test day, rats were injected with vehicle (VEH; artificial CSF at 3 microl), 15 or 30 microg SCOP, 20 min prior to being placed into the white chamber of the black-white box (n = 10/group). Rats were scored for latencies to exit and reenter the white chamber, total time spent in the white chamber, intercompartmental crossings, and activity. SCOP at 30 microg significantly reduced time to exit the white arena, while both doses of SCOP elevated latencies to reenter the white chamber. There were no effects of SCOP on intercompartmental crossing, time spent in the white chamber, or on activity levels. Loss of hippocampal cholinergic function impairs processing of threatening stimuli that manifests itself as increased ALB.

The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test.

1. The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. 2. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. 3. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(-)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. 4. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. 5. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse.

Effect of aversive stimulation on 5-hydroxytryptamine and dopamine metabolism in the rat brain.

The neurochemical consequences of aversive behavior based on novelty, rat social interaction, have been assessed in various rat brain regions utilizing high-performance liquid chromatography coupled with an electrochemical detector (HPLC-ECD) technique. The present studies indicated that compared to animals from the home cage, those exposed to the high-light aversive unfamiliar test condition, had significantly increased levels of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT), in the tested brain regions including amygdala, entorhinal cortex, frontal cortex, temporal cortex, tuberculum olfactorium, hippocampus, nucleus accumbens, and striatum. The levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the metabolites of dopamine (DA), were increased in tuberculum olfactorium, nucleus accumbens, and striatum. When compared to the low-light familiar test condition (LF), the levels, following exposure to the highlight unfamiliar situation, of 5-HIAA were significantly increased in the amygdala, entorhinal cortex, tuberculum olfactorium, hippocampus, and nucleus accumbens, while the 5-HIAA levels remained unchanged in the frontal cortex, temporal cortex, and striatum. The DOPAC and HVA levels were also increased by the HU situation in the amygdala, tuberculum olfactorium, and nucleus accumbens. An increase was also found for the levels of DA in the amygdala. Such effects were prevented by diazepam or the 5-HT3 receptor antagonist ondansetron. It is concluded that the aversive test condition of the social interaction test (HU) increases 5-HT and DA turnover throughout the rat brain. Such effects might be related to the sensitivity to novel anxiolytic drug of the social interaction test.

Bidirectional effects of dopamine D2 receptor antagonists on responding for a conditioned reinforcer.

In general, the administration of dopamine (DA) antagonists has been shown to result in the attenuation of reward processes. Recently, however, it has been suggested that low doses of DA antagonists can enhance the incentive value of a primary reinforcer. The present study examined the effect of DA receptor antagonists on responding for a conditioned stimulus (CS) and compared their effects to that produced by d-amphetamine. For 12 days, food-deprived rats were trained to associate a CS with a food reward. In the test phase, the CS was presented following a response on one of two levers (CR), whereas responding on the other lever (NCR) had no consequence. Low doses of d-amphetamine (0.5 mg/kg), sulpiride (4 mg/kg), pimozide (0.025 mg/kg), and raclopride (0.05 mg/kg) selectively enhanced responding on CR. A low dose of haloperidol (0.01 mg/kg) led to a nonspecific increase in lever responding. Treatment with larger doses of these compounds as well as with the D1 antagonist SCH23390 attenuated responding on CR. Both CR and NCR responding were reduced following administration of higher doses of d-amphetamine. Results indicate that responding for a conditioned reinforcer is potentiated following administration of low doses of D2 receptor antagonists, suggesting that D2 receptor blockade can facilitate incentive motivation.

Hippocampal cholinergic blockade enhances hypothalamic-pituitary-adrenal responses to stress.

We examined the role of the hippocampal cholinergic system, which is known to mediate processes related to fear and anxiety, in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Bilateral intra-hippocampal injections (30 microg per side) of the muscarinic antagonist Scopolamine augmented adrenocorticotropin and corticosterone responses to restraint without altering basal HPA activity compared to vehicle-treated animals. These results suggest that the hippocampal cholinergic system regulates stress-induced HPA activity and may serve to coordinate behavioral and neuroendocrine responses to stress.

Post-weaning housing conditions influence the behavioural effects of cocaine and d-amphetamine.

Post-weaning social isolation can induce profound and long lasting effects on an animal's behaviour. The present study investigated the influence of post-weaning housing conditions on the sensitivity of rats to the behavioural effects of d-amphetamine and cocaine. The locomotor stimulant effects of both drugs were compared following acute and chronic administration. The influence of post-weaning housing conditions on the effects of d-amphetamine and cocaine on responding for food and for a conditioned reinforcer were also examined. Isolated rats showed enhanced locomotor activity on exposure to a novel environment. This difference was further exaggerated following administration of d-amphetamine (0.5 mg/kg) and cocaine (5 mg/kg). Isolated, but not enriched, rats exhibited sensitisation to the locomotor activating effects of repeated administration of a dose of 0.5 mg/kg d-amphetamine, whilst both groups sensitised equally to a dose of 1.0 mg/kg d-amphetamine. Rearing conditions did not affect sensitisation to cocaine (5, 10 mg/kg). Isolated rats exhibited a higher rate of responding for a conditioned stimulus and for food on a progressive ratio schedule of reinforcement, both of which were enhanced to a greater extent in isolates following administration of cocaine (5 mg/kg) and d-amphetamine (0.5 mg/kg). These results suggest that isolation rearing induces an enhancement in sensitivity to both the locomotor stimulant and reinforcing properties of amphetamine and cocaine.

Cognitive dysfunctions induced by scopolamine are reduced by systemic or intrahippocampal mineralocorticoid receptor blockade.

Central cholinergic blockade with scopolamine (SCOP) produces profound cognitive impairments in human and animal subjects. We hypothesized that cognitive deficits induced by cholinergic blockade originate partly from its ability to enhance reactivity to the environment, an effect that would be ameliorated by prior mineralocorticoid receptor (MR) blockade, because MR antagonists reduce reactivity to novelty. In the present study, we investigated whether or not systemic or intrahippocampal infusions of the MR antagonist spironolactone (SPIRO) would affect SCOP-induced cognitive impairments in a water maze task. Adult male Lister hooded rats (350-450 g) served as subjects. In Experiment 1, rats were administered SPIRO (0 or 100 mg/kg i.p.) followed 10 min later by SCOP (0, 0.5, or 2.0 mg/kg i.p.; n = 10/group). In Experiment 2, groups of rats implanted with hippocampal cannulae received central infusions of SPIRO (50 ng/microliter; 3 microliters in total) 10 min prior to SCOP injection (2.0 mg/kg i.p.; n = 6/group). Behavioural testing started 15 min after SCOP administration and consisted of a simple water maze task in which animals were required to locate a submerged platform using spatial cues. The testing regime consisted of two phases: a) acquisition, and b) retention, 24 h later. Peripheral, but not central, injections of SPIRO enhanced water maze performance during acquisition in SCOP-treated rats, as shown by shorter latencies and shorter distances travelled to locate the hidden platform. Both peripheral and central SPIRO administration reduced the long-term retention deficits in performance in the SCOP-treated animals. These data are in general agreement with a growing body of research suggesting that corticosteroid hormones interact with central cholinergic systems to affect both physiological and behavioural responses. MR blockade may reduce an animal's reactivity to the environment and enable it to selectively filter out extraneous stimuli that it would otherwise react to, thus impairing performance.

Hippocampal mineralocorticoid, but not glucocorticoid, receptors modulate anxiety-like behavior in rats.

Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by negative-feedback mechanisms in the form of cytosolic and nuclear steroid receptors, sensitive to levels of circulating corticosterone (CORT). There are two types of steroid binding sites found in the brain: (i) mineralocorticoid receptors (MR); and (ii) glucocorticoid receptors (GR). The hippocampus expresses the highest density of both MR and GR relative to other brain regions, and has long been recognized as a principal component controlling HPA axis inhibition. Because hippocampal cholinergic blockade produced anxiety-like behaviour, and affected HPA axis function, we explored if the induction of anxiety might be attributable to changes in CORT. CORT also produced anxiety, although in a qualitatively unique manner than that produced by cholinergic blockade. In the present study, we have examined if CORT-induced anxiety occurs through an interaction with hippocampal MR or GR. Adult, male Lister Hooded rats were implanted bilaterally with hippocampal cannulae, and received infusions of either the MR antagonist, spironolactone (150 ng), or the GR antagonist, RU38486 (150 ng), either 10 min or 3 h prior to being tested in the Black-White box. MR blockade, 10 min prior to testing, led to a pronounced anxiolytic effect as revealed by the increased amount of time spent in the white compartment, and increased amount of intercompartmental exploration. There was no effect of MR blockade 3 h prior to testing, and GR antagonism produced no effects at either pretreatment time. These data are the first to show that hippocampal MR are directly involved in anxiety; moreover, the time course of the effect demonstrates that a non-genomic mechanism probably underlies this response. Stress may be an important predisposing factor in the development and expression of anxiety.

Strain differences in ethanol preference and reinforced behaviour: a comparison of two-bottle choice and operant self-administration paradigms.

An animal's volitional consumption of ethanol may be influenced by both genetic and environmental factors. In addition, genetic control of ethanol intake may depend on the test paradigm used. In the present study, performance for, and intake of ethanol in a limited access oral operant paradigm, and preference for ethanol in a two-bottle free choice test in the home-cage were compared in female rats of the heterogeneous Sprague Dawley (SD) and inbred Lewis strains. A smaller proportion of SD rats reached criterion on the self-administration task (four of 10 SD vs eight of 10 Lewis), but those SD rats that did achieve criterion maintained higher levels of responding and greater ethanol intake, relative to the Lewis strain, in the operant self-administration paradigm. Additionally, SD but not Lewis rats exhibited increased locomotor activity and an increase in performance for ethanol compared with water. In marked contrast, Lewis rats exhibited a greater preference for 10% ethanol over water in the two-bottle choice test compared with the SD strain, which preferred water to ethanol. These results suggest that both genotype and test paradigm are involved in the extent to which ethanol serves as a positive reinforcer and that unlike two-bottle choice preference tests, self-administration studies are more highly predictive of the reinforcing properties of ethanol.