The nitric oxide synthesis inhibitor L-NAME produces anxiogenic-like effects in the rat elevated plus-maze test, but not in the social interaction test.

The effects of the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME) were investigated in two animal models of anxiety: the elevated plus-maze and the social interaction test. In the elevated plus-maze, L-NAME (12.5-50 mg/kg) had an anxiogenic-like profile as indicated by dose-dependent reductions in the time spent on the open arms, open arm entries, the percentage of open arm entries and head dips, but there was no significant effect on the number of stretch attend postures. In contrast, L-NAME (12.5-50 mg/kg) failed to modify time spent in social interaction but did reduce a measure of vertical activity. The differential effects of L-NAME in the two anxiety paradigms are discussed.

Social interaction: responses to chlordiazepoxide and the loss of isolation-reared effects with paired-housing.

This study investigated the action of chlordiazepoxide (CDP), on the social interaction (SI) of adult rats maintained in one of three housing conditions: (i) group-reared, (ii) isolated from weaning or (iii) paired during adulthood after initial isolation at weaning (pair-housed former isolates; PHFIs). Group-reared rats and PHFIs rats were housed in pairs starting 21 days prior to the first experiment. For these two groups, CDP (2.5 and 5.0 mg/kg) increased SI in unfamiliar, but not familiar (cagemate) pairings. In rats isolated throughout, SI was markedly increased and this was unaffected by CDP. Isolated rats also exhibited increased motor activity (MA) during SI tests, and the MA of both isolates and PHFIs was reduced by CDP. Finally, levels of aggression were very low except in isolates, where a relatively modest increase in aggression was reversed by either pairing or CDP. To summarise, isolation-induced increases in SI and aggression were reversed by pairing, but pairing only attenuated isolation-induced increases in MA. Although CDP reduced the elevated aggression and MA of isolated rats, it had no effect on their elevated SI scores. These data question the permanence of anxiety-related, isolation-induced behavioural changes and stand in contrast to the irreversible anxiogenic profile reported for isolation-reared rats in the elevated X-test.

Effects of chlordiazepoxide, nicotine and d-amphetamine in the rat potentiated startle model of anxiety.

The effects of acute administration of chlordiazepoxide (2.5 and 5.0mg/kg, i.p.), nicotine (0.05, 0.1 and 0.4mg/kg, s.c.) and d- amphetamine (0.5 and 1.0mg/kg, i.p.) on rat potentiated startle were investigated. Chlordiazepoxide, 2.5 and 5.0mg/kg, attenuated potentiation of startle, indicating an anxiolytic profile, although the effect of the higher dose was less marked and was accompanied by a reduction in overall startle response, probably reflecting drug-induced sedation. Nicotine at doses of 0.05 and 0.4mg/kg had no significant effects in this test. However, 0.1mg/kg nicotine eliminated potentiation of startle (in two separate experiments), an action comparable to that of 2.5mg/kg chlordiazepoxide. d-Amphetamine at doses of 0.5 and 1.0mg/kg did not significantly influence potentiation of startle. The results suggest that nicotine has an anxiolytic profile in the potentiated startle paradigm which is not due to its psychostimulant properties.

Role of amygdaloid nuclei in the anxiolytic effects of benzodiazepines in rats.

Previous work has implicated the amygdala, especially the central and basolateral nuclei, in the anxiolytic effects of benzodiazepines in animal models of anxiety. However there are contradictory findings on the relative importance of each nucleus. The experiments reported here show that midazolam (1.0µg) injected bilaterally into the basolateral nucleus significantly increased open arm activity on the elevated plus-maze. In contrast midazolam (1.0µg) had no effect when injected into the central nucleus. These results suggest that the basolateral nucleus is one substrate mediating anxiolytic effects. However, a brief review of the literature supports the suggestion that both nuclei can be involved, but findings will depend upon the particular paradigm used.

Aversive environmental stimuli as a factor in the psychostimulant response to nicotine.

Saline-treated rats tested on an elevated open platform were less active (p less than 0.01) than those tested on an enclosed platform of the same dimensions. Acute nicotine (0.05, 0.1 and 0.4 mg/kg SC) increased the activity (p less than 0.01) of rats tested on the open platform but had no effect on activity measured on the enclosed platform. When injected chronically, the highest dose tested increased the activity of rats tested on both platforms, whereas the two lower doses continued to exert selective effects on the activity of rats tested on the open platform. d-Amphetamine (0.1 to 0.5 mg/kg SC) and cocaine (5 and 15 mg/kg IP) evoked dose-dependent increases in activity which were independent of the test environment used. It is concluded that nicotine appeared to be a more effective psychostimulant in the rats tested on the open platform because, at doses lower than those needed to evoke general psychostimulation, it attenuated the reduction in activity caused by exposure to the more aversive environment.

The role of hippocampal 5-HT in the effects of nicotine on habituation to an X-maze.

Neither the chronic administration (40 daily subcutaneous injections) of nicotine (0.4 mg/kg) nor its withdrawal (3 days) influenced avoidance of the more aversive open runways of an elevated X-maze in rats which had been habituated to the apparatus. Lesions of the serotonergic fibres innervating the hippocampus increased total activity (P less than 0.05). However, analysis of covariance indicated that reduced 5-hydroxytryptamine secretion in the hippocampus was probably not the mechanism by which nicotine stimulated total activity in these rats.

Effect of lithium administration on rat brain 5-hydroxyindole levels in a possible animal model for mania.

The effect of short term administration of lithium on the hyperactivity induced by a mixture of d-amphetamine (DEX) and chlordiazepoxide (CDZP) have been examined in the rat and an attempt made to relate this action to changes in brain concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). The DEX-CDZP mixture caused a large increase in Y-maze entries (P less than 0.001). Lithium (2 or 4 mEq/kg) attenuated the increase in entries (P less than 0.001) and activity cage locomotion (P less than 0.01) without significantly affecting these parameters in saline-treated rats. However, the increased 5-HT concentration (P less than 0.05) found in the midbrain after the DEX-CDZP mixture was not modified by prior administration of lithium. In control rats lithium had no effect on the level of 5-HT in the cerebellum, cerebral cortex, midbrain or striatum. Levels of 5-hydroxyindoleacetic acid (5-HIAA) in all four brain regions were unaffected by both the DEX-CDZP mixture or pretreatment with lithium. The possible action of the DEX-CDZP mixture on central 5-HT systems and the suitability of the hyperactivity induced by the drug mixture as a model for mania is discussed.

Behavioural and adrenocortical responses to nicotine measured in rats with selective lesions of the 5-hydroxytryptaminergic fibres innervating the hippocampus.

The effects of acute and subchronic (7) injections of nicotine (0.4 mg kg-1, s.c.) and of selective lesions of the 5-hydroxytryptaminergic (5-HTergic) pathways innervating the hippocampus on the spontaneous behaviour of rats in an elevated X-maze composed of two open and two enclosed runways have been examined. Subchronic, but not acute, nicotine increased total spontaneous activity. Neither acute nor subchronic nicotine altered the ratio of open:closed runway entries. Destruction of the 5-HTergic pathways innervating the hippocampus with 5,7-dihydroxytryptamine caused a reduction in the ratio of open:enclosed runway entries. Acute, but not subchronic, nicotine caused a significant increase in plasma corticosterone. The lesion had no effects on the plasma levels of this hormone. No significant interactions between the lesion and the responses to nicotine were observed. The data failed to provide any evidence that hippocampal 5-HTergic systems may be implicated in the effects of nicotine on the spontaneous behaviour of the rat.

Studies on the possible role of brain 5-HT systems and adrenocortical activity in behavioural responses to nicotine and diazepam in an elevated X-maze.

Subchronic (6 days) but not acute injections of nicotine (0.4 mg/kg SC) increased spontaneous activity (P less than 0.01) in an elevated X-maze composed of two open and two enclosed runways. Neither acute nor subchronic nicotine altered significantly the ratio of open:enclosed runway entries (O/E ratio). Diazepam (5 mg/kg PO) had no significant effects on spontaneous activity but increased the O/E ratio (P less than 0.05). Acute nicotine increased (P less than 0.01) whereas subchronic nicotine caused a small decrease (P less than 0.05) in the plasma corticosterone concentration. Both acute and subchronic diazepam decreased the levels of the hormone (P less than 0.01 and P less than 0.05, respectively) although the reduction elicited by chronic diazepam was less than that caused by acute diazepam (P less than 0.05). In the experiments with diazepam the plasma corticosterone concentration correlated negatively with the O/E ratio (r = -0.58; P less than 0.05), whereas in the experiments with nicotine plasma corticosterone correlated negatively (r = -0.46; P less than 0.05) with enclosed runway entries. Nicotine injections were associated with a regionally-selective reduction in the 5-hydroxyindole acetic acid (5-HIAA) concentration in the hippocampus (P less than 0.05) and a reduction in hippocampal 5-hydroxytryptamine (5-HT) which approached statistical significance. Chronic, but not acute, diazepam increased (P less than 0.01) hypothalamic 5-HT. The changes in 5-HT and 5-HIAA did not appear to be directly related to the behavioural or adrenocortical responses to either of the drugs.