Early social isolation, but not maternal separation, affects behavioral sensitization to amphetamine in male and female adult rats.

Early life stressful manipulations, such as maternal separation (MS) or social isolation (SI), can influence the neurobiological development of rats and alter the response of adult animals to drugs of abuse. The present study examined the acute and sensitized behavioral responses (locomotor activity (LMA) and stereotypy) induced by amphetamine after MS or SI in male and female rats. In addition, the hypothesis that the combination of SI and MS could lead to additional effects on the behavioral response to amphetamine was tested. After the repetitive, intermittent administration of 1.5 mg/kg D-amphetamine over five consecutive days, the behavioral expression of sensitization to a challenge injection was assessed following a 2-day withdrawal period. In both sexes, MS and SI did not alter the acute locomotor activating effects of amphetamine as measured in the open-field environment after the first administration of the drug. Whereas SI altered the expression of sensitization to amphetamine in both sexes, MS did not affect it. Finally, in none of the behavioral variables measured did MS and SI interact to further modify the behavioral profile of the animals. The present results suggest that a postweaning manipulation of the environment (SI) is more effective than a preweaning manipulation (MS) in modifying the expression of sensitization to amphetamine.

Dissociation between the effects of pre-weaning and/or post-weaning social isolation on prepulse inhibition and latent inhibition in adult Sprague--Dawley rats.

Human attentional impairments can be modelled in the rat using the prepulse inhibition (PPI) or the latent inhibition (LI) paradigm. The present study investigated the consequences of a combination of pre-weaning maternal separation (MS) and post-weaning social isolation (SI) on both PPI and LI in male and female Sprague--Dawley rats tested as adults. We report here a double dissociation between the effects of MS (repeated 4 h daily separations) and SI on PPI and LI: MS did not modify PPI, but enhanced LI. In contrast, SI disrupted PPI, the deficits being restricted to male rats, but left LI intact. There were no additive effects of MS and SI on PPI or LI. While MS improved avoidance learning, SI impaired it. Although both PPI and LI assess processes of selective attention, our results support the contention, already stated in the literature, that they involve differing neuro-psychological mechanisms. Furthermore, the fact that only males exhibited PPI deficits following SI has implications for the well-known differential vulnerability of human males to certain psychiatric disorders (e.g. schizophrenia). Finally, the combination of MS and SI could represent a relevant animal model for some aspects of schizophrenia, since both PPI and LI were altered.

Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome.

Rearing rats in isolation has been shown to be a relevant paradigm for studying early life stress and understanding the genesis of depression and related affective disorders. Recent studies from our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging conditions. Accordingly, the present series of experiments assessed the contribution of each condition to the expression of the prepulse inhibition of the acoustic startle, food hoarding and spontaneous locomotor activity. In addition, ex vivo neurochemical changes in the brains of isolated and grouped rats reared either in sawdust-lined or in grid-floor cages were determined by measuring dopamine and serotonin as well as their major metabolites in a "psychosis circuit" that includes mainly the hippocampus and selected hippocampal efferent pathways projecting towards the anterior cingulate and infralimbic cortices, nucleus accumbens, dorsolateral caudate nucleus, amygdala and entorhinal cortex. The results of the present study demonstrate that rearing rats in isolation (i) produces a syndrome of generalized locomotor hyperactivity; (ii) increases the startle response; (iii) impairs prepulse inhibition; (iv) tends to increase food hoarding behavior; (v) increases basal dopamine turnover in the amygdaloid complex; (vi) decreases basal dopamine turnover in the infralimbic part of the medial prefrontal cortex; and (vii) decreases basal turnover of serotonin in the nucleus accumbens. In the entorhinal cortex, dopamine neurotransmission seemed to be more sensitive to the caging conditions since a decreased basal turnover of dopamine was observed in grid-reared animals. Plasma corticosterone levels were also increased in grid-reared animals compared with rats reared in sawdust cages. Finally, isolates reared on grids showed a significant positive correlation between plasma corticosterone levels and dopamine in the left nucleus accumbens.Altogether, these results support the contention that there is a link between social isolation, attention deficit, spontaneous locomotor hyperactivity and reduced dopamine turnover in the medial prefrontal cortex. Furthermore, our data demonstrate that rearing rats in grid-floor cages represents a form of chronic mild stress associated with increased corticosterone levels, decreased basal turnover of entorhinal dopamine and increased dopamine activity in the left nucleus accumbens. Finally, a significant and selective decrease in the basal turnover of serotonin in the nucleus accumbens of isolated rats may be linked to the isolation-induced locomotor hyperactivity.

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.

Strain differences in the isolation-induced effects on prepulse inhibition of the acoustic startle response and on locomotor activity.

The authors investigated the effects of isolation rearing on acoustic startle response, prepulse inhibition (PPI), its modification by apomorphine, and locomotor activity in 3 rat strains: Wistar (WS), Sprague-Dawley (SD), and Lister hooded (LH). SD and LH, but not WS, showed isolation-induced PPI deficits. In 2 consecutive PPI tests, only SD isolates showed significant PPI deficits. An isolation rearing effect in LH was significant only in the 1st PPI test. Apomorphine dose-dependently (0.0-0.5 mg/kg) disrupted PPI, but sensitivity to the drug differed, with WS and SD rats being more sensitive to lower doses (0.01-0.05 mg/kg) than LH rats (0.5 mg/kg). Isolates, irrespective of strain, did not differ from grouped rats in their response to the apomorphine challenge. Only WS and LH isolates demonstrated significantly increased locomotor activity. Strain differences in the different parameters measured did not predict isolation-induced effects on PPI.

Circadian time does not modify the prepulse inhibition response or its attenuation by apomorphine.

The present study investigated the influence of circadian time (experimental testing during the light or dark phase of the light:dark cycle) on the acoustic startle response (ASR), prepulse inhibition (PPI), and apomorphine-induced PPI deficits in Wistar rats housed under a reversed light:dark cycle (lights off at 0700 h and on at 1900 h). There was no significant difference in the startle response amplitude or PPI response of animals tested during the light phase compared with those tested during the dark phase. Similarly, the response to apomorphine (0.01-0.05 mg/kg subcutaneously) was not modulated by circadian time. Thus, under the conditions adopted in the present study, ASR, PPI, and apomorphine-induced PPI deficits remained stable across the circadian cycle. Such findings may be of importance for other investigators using the PPI paradigm to study brain plasticity mechanisms and pharmacological manipulations of apomorphine-induced PPI deficits in rats housed under normal or reversed light:dark cycle conditions.

Isolation rearing-induced disruption of prepulse inhibition: further evidence for fragility of the response.

The present study investigated isolation-induced disruptions of prepulse inhibition (PPI), and effects on locomotor activity as a function of home caging condition (sawdust vs grid-floor) in the Wistar rat. Isolates reared in grid-floor cages did not show a disruption of PPI. However, when isolates were reared in sawdust cages, a PPI deficit was evident. In an open field environment, isolates demonstrated significantly increased spontaneous locomotor activity compared to their group-housed counterparts, irrespective of the caging condition employed. Grouped animals reared in grid-floor cages, however, showed reduced activity compared to grouped animals reared in sawdust cages. Although d-amphetamine treatment appeared to enhance locomotor activity selectively in isolates, particularly in those reared in grid-floor cages, this result could be explained by the existing pre-drug activity levels. With respect to PPI, not only were isolation-induced deficits in the Wistar rat difficult to detect in a variable prepulse intensity PPI procedure, but when apparent, the deficits were of a fragile nature. The findings suggest that caging condition may be a critical methodological factor in experiments investigating isolation-induced PPI deficits. Indeed, our results may indicate that rearing animals in grid-floor cages represents a form of chronic mild stress, which can interfere with normal sensorimotor gating mechanisms, in addition to other behaviours.

Selective effects of 8-OH-DPAT on social competition in the rat.

Previous research has demonstrated that dominant-subordinate relationships measured in small groups of rats competing for access to palatable food or fluids can be disrupted by both anxiolytic and anxiogenic drugs, and it has been proposed as a possible animal model of anxiety. The present study investigated the effects of the selective 5-HT1A agonist 8-OH-DPAT on the rank order of triads of rats measured in terms of access to sweetened milk. The effect of 8-OH-DPAT on locomotor activity and intake of sweetened milk was also determined. 8-OH-DPAT (25 and 37.5 micrograms/kg) significantly increased the subordinate animals position in the social hierarchy without effect on the individual intakes of sweetened milk or locomotor activity. The same doses administered to dominant animals had no effect on any of the parameters measured. The 8-OH-DPAT-induced increase in social competition in subordinate rats was dissociable from effects on feeding behavior and locomotor activity. The results from this study provide further evidence that social competition in groups of rats may represent a model that can be used to detect drugs acting via receptor mechanisms believed to be implicated in anxiety.

Acute and chronic arecoline: effects on a scopolamine-induced deficit in complex maze learning.

These studies tested the effect of arecoline, a nonselective muscarinic agonist, administered either acutely or by chronic peripheral infusion via osmotic minipumps, on a scopolamine-induced deficit in a Stone (14 unit) T-maze task in rats. Scopolamine alone (0.125-1.0 mg/kg, IP) dose-dependently impaired maze acquisition, increasing maze run-times and to a lesser extent, the number of errors committed. Neither acute administration of arecoline (5.0 and 10.0 mg/kg, IP), when tested against a deficit induced by scopolamine (0.25 mg/kg, IP), nor chronic arecoline administration (30 and 50 mg/kg per 24 h), when tested against a deficit induced by scopolamine (0.5 mg/kg), were able to ameliorate the decrements in maze performance. In fact, the higher dose of arecoline (50 mg/kg per 24 h) infused over 10 days potentiated the scopolamine-induced deficit, with respect to latency. These data indicate that dose selection is of great importance when employing arecoline in tests of learning and memory and that the influence of the method of administration of arecoline on the behavioural outcome warrants further study.

Aged Stone maze-impaired rats exhibit reduced striatal muscarinic receptor densities.

Muscarinic receptor densities, measured by saturation radioligand binding using the muscarinic antagonist [3H]QNB, were compared in the striatum, frontal cortex and hippocampus between two populations of young (3 month) and aged (12-20 month) Hooded Lister rats which had previously been tested in a complex maze task. Aged rats were impaired in their performance of a Stone (14-unit T-maze) task and were less spontaneously active than young rats. Muscarinic receptor numbers were significantly decreased in the striatum of aged rats, whilst numbers in the hippocampus and frontal cortex and receptor affinities in all three areas were unaltered. These results indicate that the age-associated depletion of striatal muscarinic receptors may contribute to deficits in cognitive processing and/or motor behaviour which underlie impairments in the performance of complex spatial tasks.

Ondansetron fails to attenuate a scopolamine-induced deficit in a Stone maze task.

The 5-HT3 receptor antagonist ondansetron has previously been reported to improve cognition in the mouse, rat and marmoset in a variety of behavioural paradigms. The present study used the Stone maze to test the effect of ondansetron on the deficit caused by scopolamine in the performance of a highly complex spatial memory task in the rat. Ondansetron administered over a large dose range (1.0 ng kg-1-1.0 micrograms kg-1, i.p., b.d.) for a period of 10-15 days failed to attenuate the scopolamine deficit. Indeed at one dose level ondansetron (100 ng kg-1, i.p., b.d.) administered in combination with scopolamine (0.5 mg kg-1, i.p.) significantly potentiated the deficit, compared with the performance of rats receiving scopolamine alone.

Effects of cholecystokinin tetrapeptide and sulfated cholecystokinin octapeptide in rat models of anxiety.

The effects of the acutely administered cholecystokinin (CCK) agonists CCK tetrapeptide (BOC-CCK-4) and sulfated CCK octapeptide (CCK-8S) were examined in four animal models of anxiety in rats. In the elevated plus maze, BOC-CCK-4 reduced the time spent in the open arms and the number of entries into the open arms. BOC-CCK-4 but not the anorectic acting CCK-8S increased the suppression of feeding in a conflict paradigm based on novelty suppressed feeding in hungry rats. In the two-compartment black-and-white box, BOC-CCK-4 decreased the time spent and locomotor activity in the white compartment. In the ultrasound vocalization test, using rat pups separated from the mother, BOC-CCK-4 increased the number of distress calls. No evidence was found for inducing anxiety-like behaviour by CCK-8S.

Initiation and maintenance of oral ethanol self-administration in female Sprague-Dawley rats.

Group-housed female Sprague-Dawley rats were trained to self-administer 5% ethanol (v/v) in a large self-administration chamber (100 x 40 x 40 cm) following three different initiation methods. The procedures were 1) an ethanol injection procedure, 2) a sucrose substitution procedure, and 3) a prandial drinking technique. Only the prandial drinking method served to maintain responding for ethanol in the absence of water deprivation or sweetening of the alcohol solution. Rats trained using this technique showed a large preference for 5% ethanol over water and a significant increase in locomotor activity while responding for 5% ethanol but not while responding for water. When the concentration of ethanol was increased from 1% to 32%, the amount of ethanol ingested increased up to a maximum of 1.233 +/- 0.3 g/kg of 32% ethanol, and response rates and number of ethanol deliveries followed an inverted U-shaped curve. Appreciable blood ethanol levels were detected immediately following self-administration of 8% ethanol. These results show that, in female Sprague-Dawley rats under the experimental conditions described, the prandial drinking technique was the most effective in inducing stable oral ethanol self-administration and suggest that under these conditions and in these subjects ethanol was acting as a positive reinforcer.

Angiotensin converting enzyme inhibitors as potential cognitive enhancing agents.

Anecdotal reports of a mood-elevating effect in patients and improvements in the performance of memory tests in the clinic has led to investigations into the nootropic actions of angiotensin converting enzyme (ACE) inhibitors. A cognitive enhancing action for the ACE inhibitors has been demonstrated in a number of animals models of memory function. Neurochemical studies in animals have shown that angiotensin II acting via an angiotensin II receptor can inhibit the release of 3HAch from entorhinal cortex slices. Thus the ability of ACE inhibitors to facilitate cognitive processes may be related to reduced availability of angiotensin II. Lack of specificity of ACE inhibitors may be a limiting factor in the development of such compounds as cognitive enhancers. However, the recent development of selective antagonists for subtypes of the angiotensin II receptor may represent a novel approach for the treatment of cognitive disorders with an underlying cholinergic disturbance.

The effect of the 5-HT3 receptor antagonist, RS-42358-197, in animal models of anxiety.

The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H- benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.

The effects of 5-HT3 receptor antagonists in models of dependency and withdrawal.

Pharmacological manipulations to enhance 5-HT synthesis and release have been reported to reduce alcohol intake. However, recent evidence indicates that 5-HT3 receptor antagonists may also exert a similar effect in a number of species. This report reviews the existing data which implicates a central role for 5-HT3 receptors in the control of psychoactive substance abuse.

Profile of action of a novel 5-hydroxytryptamine1A receptor ligand E-4424 to inhibit aversive behavior in the mouse, rat and marmoset.

E-4424 (2-(4-[4-(4-chloro-1-pyrazolyl)butyl]-1-piperazinyl)pyrimidine) was shown to be a 5-hydroxytryptamine1A receptor ligand in radioligand binding assays and in an in vitro guinea pig ileum preparation had both 5-hydroxytryptamine1A antagonist and agonist effects. The antagonist/agonist ratio of E-4424 was greater than in the case of buspirone and ipsapirone. E-4424 was compared to diazepam, buspirone and ipsapirone to inhibit the behavioral response to an aversive situation in the mouse black and white test box, the rat social interaction test and a marmoset human threat test. The acute administration of E-4424 (0.0001-0.5 mg/kg, i.p.) to the mouse decreased aversion to the white area of the test box and was as effective as diazepam (0.125-1.0 mg/kg, i.p.) and much more potent than buspirone (0.25-1.0 mg/kg, i.p.) or ipsapirone (0.5-5.0 mg/kg, i.p.). E-4424 was also effective in enhancing rat social interaction and reducing anxiety-related behaviors in the marmoset and was again more potent than diazepam, buspirone or ipsapirone. Withdrawal from a 14-day administration of diazepam, cocaine, nicotine or alcohol exacerbated the response to the aversive situation in the mouse test. This was not observed after withdrawal from a chronic treatment with E-4424, buspirone or ipsapirone. However, E-4424 administered during drug withdrawal prevented the response caused by withdrawal from cocaine, alcohol, nicotine and diazepam: buspirone was ineffective and ipsapirone only attenuated that syndrome after alcohol withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset.

The cognitive-enhancing potential of the 5-hydroxytryptamine (5-HT) selective 5-HT3 receptor antagonist, ondansetron, was investigated in a model of cognitive impairment induced by the muscarinic receptor antagonist, scopolamine. For this purpose, marmosets were trained in an object discrimination task utilizing the Wisconsin General Test Apparatus. Administration of scopolamine (0.01-0.04 mg/kg, SC) caused a dose-dependent impairment in the acquisition of the object discrimination task in that marmosets required more trials to reach criterion, made more errors, and took longer to choose the objects. Administration of arecoline (0.06-0.1 mg/kg, SC) or 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol- 1-yl)methyl]-4H-carbazol-4-one,HCl.2H2O (ondansetron) (0.1-1 micrograms/kg, SC) prevented the scopolamine-induced impairment in task acquisition in that the performance of marmosets was indistinguishable from that of saline-treated animals and was significantly better than that following scopolamine/saline. From these studies, we conclude that ondansetron prevents impairment in the cognitive performance of marmosets induced by administration of scopolamine.

Behavioural effects of anxiogenic agents in the common marmoset.

The effects of the anxiogenic agents FG7142, caffeine, pentylenetetrazole, and amphetamine were assessed in two anxiety situations in the marmoset, first in an "anxiogenic" test based on the animal's response to a human observer standing in front of the home cage and second in a low-anxiety situation where animals behaviour was videotaped in the absence of the observer. In response to the human observer, the anxiolytic agent diazepam (0.1-2.5 mg/kg, SC) was shown to reduce the intensity of behaviours such as postures, while increasing time spent on the cage front. In this test, with the exception of amphetamine, which only modified responding at stereotypic doses, the anxiogenic agents failed to modify marmoset behaviour. In contrast, in the low-anxiety filming protocol the anxiogenic agents consistently reduced measures of locomotor activity while increasing the amount of time animals spent in the nest box. It is suggested that the low-anxiety protocol may be useful to evaluate drug-induced anxiogenesis and in studies of withdrawal from chronic anxiolytic treatment or drugs of abuse.

The distribution of 5-HT3 recognition sites in the marmoset brain.

The distribution of the binding of [3H]GR65630 (0.2 nM) to putative 5-HT3 recognition sites in the brain of the common marmoset was assessed using autoradiography. Specific binding was heterogeneously distributed with the highest densities found in discrete nuclei of the lower medulla (nucleus tractus solitarii, dorsal motor nucleus of the vagus nerve, nucleus of spinal trigeminal nerve tract and the area postrema). In forebrain areas, relatively high binding densities were located in the medial habenula nucleus and the hippocampus (CA3, CA4 and fascia dentata). Low levels of specific binding in the rest of the forebrain hindered quantification.