Acute and chronic effects of three benzodiazepines in the social interaction anxiety test in mice

The effects on active social interaction of acute and chronic dosage with diazepam (1 mg/kg), desmethyldiazepam (2 mg/kg),and chlor-desmethyldiazepam (0.125 mg/kg) were studied in pairs of mice. The mice were tested under either high or low levels of illumination. In all cases acute drug treatment significantly reduced social interaction, but this was not seen with chronic treatment (9 days). Two of the drugs, diazepam and desmethyldiazepam, showed an anxiolytic action, i.e., these drugs resulted in significantly less variation in social interaction with the change in light levels, compared with vehicle-injected controls.     

Antidepressant-like effects of the acute and chronic administration of nicotine in the rat forced swimming test and its interaction with fluoxetine [correction of flouxetine

An antidepressant action of nicotine (NIC) has recently been suggested. Flouxetine, a selective serotonin reuptake inhibitor, is currently the most widely used antidepressant. In the present study, we analyzed the effects of the administration of NIC, fluoxetine (FLX), and the combination of both drugs given acutely, subchronically, and chronically as well as 7 days after chronic administration of these drugs on the forced swim test. Results showed that NIC induced a significant reduction of the time in immobility during the forced swim test (antidepressant effect), with a concomitant increase in swimming activity (serotonergic activation), after acute administration. These effects remain the same after subchronic and chronic administration. FLX failed to induce any effect after acute administration but did induce a significant decrease of immobility and an increase of swimming after subchronic administration. The effect of the chronic administration was significantly larger compared to subchronic administration. The combination of both drugs induced a larger effect than that observed after a single administration but only after subchronic treatment. No effect was observed after the end of the 7-day treatments. Data suggest that NIC has an antidepressant action that is expressed faster than FLX but remains the same later. Thus, cholinergic-serotonergic interactions could play an important role in the treatment of depression.     

Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats

RATIONALE: Most smokers report smoking has an anxiolytic effect, which may contribute to nicotine dependence. OBJECTIVE: To examine effects in the social interaction test (SI) of anxiety after 4 weeks' self-administered nicotine (15 infusions of 0.03 mg/kg, totalling 0.45 mg/kg per day), and after 24 and 72 h of withdrawal. The effect of exposure to the operant chamber on withdrawal responses was also examined. METHODS: Animals were trained to self-administer saline or nicotine and after 4 weeks they were tested in SI after their daily self-administration session. Animals were retested after 24 and 72 h withdrawal, when they were either taken directly from the home cage or were tested 5 min after a 30-min exposure to the operant chamber. RESULTS: Compared with the saline control group, the animals that had been self-administering nicotine for 4 weeks showed decreased social interaction with no decrease in locomotor activity, indicating a significant anxiogenic effect of the nicotine infusions. There was no change in social interaction after 24 and 72 h withdrawal from chronic nicotine, regardless of whether or not the rats were exposed to the operant chamber just prior to being tested. CONCLUSIONS: Nicotine self-administration is not maintained because of its anxiolytic effect, but despite, or because of, its anxiogenic effect. There was no evidence of an anxiogenic response after either 24 or 72 h of withdrawal and thus increased anxiety on withdrawal from nicotine does not seem to contribute to nicotine self-administration.     

Long-term changes in social interaction and reward following repeated MDMA administration to adolescent rats without accompanying serotonergic neurotoxicity

RATIONALE: MDMA is a popular drug of abuse in adolescents which causes serotonergic neurotoxicity in adult but not young rodents. However, few studies have examined the long-term behavioural consequence of MDMA and it is unclear whether such changes occur in the absence of neurotoxicity. OBJECTIVES: The present study examined whether treatment of young rats with MDMA produced long-term behavioural alterations without accompanying serotonergic neurotoxicity. METHOD: Male Lister hooded rats ( n=36, postnatal day (PND) 39) received MDMA (7.5 mg/kg i.p., twice daily for 3 days) or saline (l ml/kg i.p.) and the acute effect on open field behaviour and body temperature was monitored. Following drug withdrawal, social interaction in pre-treatment- and weight-matched rat pairs, cortical [(3)H]paroxetine binding and hippocampal and frontal cortical serotonin and dopamine levels (PND 53, n=12) and conditioned place preference (PND 70, n=24) to cocaine (5 mg/kg IP) were analysed. RESULTS: MDMA elicited the expected immediate serotonin syndrome with significant hyperlocomotion, decreased rearing and hypothermia. Twelve to 29 days after the last MDMA injection social interaction was significantly attenuated (by 41%) and the sub-threshold conditioned place preference to cocaine was significantly enhanced compared with that in saline controls, although no significant side preference to cocaine occurred in the latter. MDMA pre-treatment did not alter 5-HT levels or cortical [(3)H]paroxetine binding. CONCLUSION: MDMA administration to adolescent rats reduced social interaction and enhanced the sub-threshold rewarding effect of cocaine at adulthood, despite an absence of accompanying serotonergic and dopaminergic neurotoxicity.     

Mice performance on the staircase test following acute ethanol administration

This study examined the effect of acute ethanol administration as compared to diazepam on the number of rearing events and the number of steps ascended in the mouse staircase test, an animal model sensitive to benzodiazepines. Acute ethanol administration, similar to acute diazepam administration, reduces rearing (at doses that do not reduce climbing) in the staircase test. This effect of acute ethanol administration is insensitive to the benzodiazepine antagonist flumazenil and is not consistently counteracted by the partial inverse agonist Ro15-4513. It seems that the mouse staircase test is an efficient paradigm for studying agents active at the gamma-aminobutyric acid (GABA(A)) receptor complex, including ethanol.     

Diazepam withdrawal responses measured in the social interaction test of anxiety and their reversal by baclofen

After 21 days of treatment with diazepam (0.5 or 2 mg/kg/day) rats were tolerant to the effects of diazepam to increase social interaction in the low light unfamiliar test condition of the social interaction test of anxiety. When they were tested 24 h after the last of 21 injections they showed significant decreases in social interaction, indicating an anxiogenic withdrawal response. However, the social interaction scores of rats tested 48 h after withdrawal from diazepam treatment were no longer different from those of the control group. The decreased social interaction, indicating increased anxiety, detected 24 h after withdrawal of diazepam (21 daily injections of 0.5 or 2 mg/kg), could be reversed by the usual daily diazepam dose (0.5 or 2 mg/kg, respectively) or by baclofen (0.5 or 1 mg/kg). Baclofen (2 mg/kg) was sedative in both control treated and diazepam-dependent rats, but was ineffective at reversing the decrease in social interaction seen after diazepam withdrawal. Possible sites of action mediating these effects of baclofen are discussed, and it is suggested that either post-synaptic GABA_B sites in the hippocampus are involved or that the reversal of the decreased social interaction detected on withdrawal of diazepam treatment is due to a baclofen-mediated inhibition of 5-HT release in the hippocampus.     

Flumazenil prevents the development of chlordiazepoxide withdrawal in rats tested in the social interaction test of anxiety

Rats were chronically treated with chlordiazepoxide (CDP 10 mg/kg/day) or vehicle for 27 days. Twenty-four hours after their last dose, they received flumazenil (4 mg/kg) or vehicle and were tested in the social interaction test, in a low-light, familiar arena. CDP withdrawal significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. This was completely reversed by flumazenil. A second group received CDP for 27 days and, in addition, received a single dose of flumazenil (4 mg/kg) 6 days before testing. Flumazenil prevented the development of the anxiogenic withdrawal response in these rats.     

Paradoxical changes in spinal cord reflexes following the acute administration of acrylamide

Acrylamide (ACR) produces a central-peripheral distal axonopathy when administered chronically. This is characterized functionally by decreases in the monosynaptic reflex (MSR) and dorsal root potential (DRP) and alterations in the characteristics of the dorsal root reflex (DRR). Acute administration of ACR inhibits the oxidative enzyme complex NADH-tetrazolium reductase and slows retrograde axoplasmic transport. This study was carried out to determine if the spinal cord reflexes are also affected following acute administration of ACR. Dose-response studies revealed a dose-dependent increase in both the MSR and DRR. A single injection of 50 mg/kg ACR caused an increase in both the MSR and DRR within 15 min and continued for over 3 h. These data are paradoxical since chronic administration of ACR results in decreased function. Two possible mechanisms are proposed. First, calcium ion regulation may be involved in both the acute and chronic effects of ACR on spinal cord reflexes. Second, a depolarization of the neurons is occurring just prior to cell injury or death.     

Anticholinergic sensitivity following chronic nicotine administration as measured by radial-arm maze performance in rats

Chronic nicotine administration in rats has been previously found to improve choice accuracy performance of rats in the radial-arm maze. A nicotine-induced choice accuracy improvement was also seen in the current study. Rats were trained to asymptotic levels of choice accuracy performance on a working memory paradigm in an 8-arm radial maze. During and after 3 weeks of chronic nicotine treatment, rats were tested for sensitivity to acute doses of the nicotinic and muscarinic receptor antagonists, mecamylamine and scopolamine. During the first week of administration, nicotine-treated rats were supersensitive to the sedation caused by mecamylamine. This suggests that nicotine may not have been acting as a simple nicotinic agonist, since in this case, the opposite effect, an attenuated effect of mecamylamine in the nicotine-treated group, would have been expected. Three to 4 weeks after withdrawal from chronic nicotine administration, the treated rats were more sensitive to the choice accuracy deficits caused by the muscarinic blocker scopolamine (0.16 mg/kg) and the nicotinic blocker mecamylamine (10 mg/kg). This supersensitivity may have been due to a lasting change caused by chronic nicotine in the cholinergic bases of memory function.     

Prostaglandins in rat placenta following acute and chronic administration of morphine.

The objective of the present study was to obtain information on prostaglandin (PG) biosynthesis in placenta following narcotic administration. PG biosynthetic capacity was determined in whole rat placenta homogenates in the presence of Na arachidonate, by evaluating net production of PGs assayed against PGE1 on rat stomach strips. An enhanced prostaglandin-like activity is shown in homogenates of placenta from rats treated subcutaneously with 10 mg/kg of morphine. This increase was prevented by naloxone pre-treatment. Continual morphine administration during gestation, results in a normalization of placental biosynthetic capacity thus suggesting the development of a tolerance to the narcotic effect.     

Changes in brain tryptophan and tyrosine following acute and chronic morphine administration

Morphine increased brain concentrations of tryptophan and tyrosine 1–2 hr after administration in a dose-dependent manner in male rats. Concentrations of these amino acids in blood serum decreased 30–45 min post-injection and then rose towards control values. The rise in brain amino acids was antagonized by pretreatment with naloxone. In addicted rats there was only a slight increase in brain tryptophan and no increase in tyrosine. Thirty minutes after naloxone-precipitated withdrawal, tryptophan and tyrosine concentrations were elevated in brain, in contrast to the decline in these amino acids seen after naloxone administration in acutely morphinized rats.These results support the hypothesis that the elevated turnover of brain monoamines induced by morphine administration is related to increased availability of precursor amino acids in morphinized animals.     

Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine

  Rationale: The elevated plus-maze provides a test situation in which distinctive states of anxiety are elicited on trials 1 and 2 and the dorsal hippocampus has previously been shown to mediate the anxiogenic effects of (–)-nicotine in the social interaction test. Objective: To determine the effects of a wide dose range of (–)-nicotine on trial 1 and 2 in the plus-maze after systemic administration and whether the dorsal hippocampus is a site mediating the anxiogenic effect of nicotine. Methods: (–)-Nicotine (0.001, 0.005, 0.01, 0.05, 0.1, 0.5 and 1 mg/kg) was injected IP 30 min before testing for 5 min in the plus-maze. Rats receiving dorsal hippocampal infusions received bilateral infusions of 0.5 μl of artificial CSF or (–)-nicotine (0.1, 1, 4 or 8 μg). The needle was left in place for 50 s after injection and testing took place 3 min later. Rats tested on trial 1 were naive to the plus-maze, those tested on trial 2 had received a previous 5-min undrugged exposure to the maze 48 h earlier. Results: Low doses of (–)-nicotine (0.001, 0.005, 0.01, 0.05 and 0.1 mg/kg, IP) were without effect on either trial, but higher doses (0.5 and 1 mg/kg, IP) had anxiogenic effects on both trials, as shown by decreases in percentage time spent and percentage entries onto the open arms. Infusion of (–)-nicotine (0.1, 1, 4 and 8 μg) bilaterally into the dorsal hippocampus was without effect on trial 1, but 1 μg had an anxiolytic effect on trial 2, shown by an increased percentage time spent on the open arms. Conclusions: The results on both trials in the plus-maze after systemic administration of nicotine add to previous reports from the social interaction test that high doses of nicotine have anxiogenic effects. However, the effects of nicotine in the dorsal hippocampus are different in all three anxiety tests (anxiogenic in social interaction, ineffective on trial 1, anxiolytic on trial 2) showing that nicotinic cholinergic control in this brain region may vary depending on the state and/or type of anxiety generated by the test. The brain region(s) underlying the anxiogenic effects of IP nicotine on both trials in the plus-maze remain to be identified. Received: 16 August 1998 / Final version: 10 December 1998     

Effects of social anxiety and social evaluation on beer consumption and social interaction

In an experimental "party" situation socially anxious subjects and subjects who received negative social evaluations drank less beer and had lower blood alcohol concentrations than did subjects who were not socially anxious or who received positive evaluations.     

Cyproheptadine resembles clozapine in vivo following both acute and chronic administration in rats

Cyproheptadine is a cheap, widely available anti-allergy drug with a broad receptor binding profile which resembles that of clozapine. In rats discriminating clozapine from vehicle cyproheptadine mimicked clozapine very closely. Acutely it induced full generalization in the absence of response suppression, as observed with clozapine. Chronic administration of clozapine and cyproheptadine induced tolerance and cross-tolerance respectively to the clozapine stimulus. This was characterized by circa 3.5-fold parallel shifts to the right in the clozapine generalization curves. Such tolerance and cross-tolerance was spontaneously reversible, suggesting that it was pharmacodynamic, and that clozapine and cyproheptadine induce similar neuroadaptations when administered chronically. Administration of chlordiazepoxide at a very high dose induced no cross-tolerance to the clozapine stimulus showing the pharmacological specificity of tolerance. The clozapine stimulus is a compound cue involving actions at various receptors, and various clozapine-like antipsychotic (APD) drugs generalize fully to it. These data demonstrate that in vivo cyproheptadine resembles clozapine both acutely and chronically. Our findings, in conjunction with other actions of cyproheptadine -- induction of weight gain, alleviation of clozapine withdrawal, anxiolytic actions, alleviation of 'typical' APD-induced motoric side effects, and some preliminary clinical findings -- suggest that further study of cyproheptadine in conjunction with a 'typical' APD for the possible treatment of schizophrenia is merited at both pre-clinical and clinical levels.     

Homovanillic acid in caudate and pre-frontal cortex following acute and chronic neuroleptic administration

Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex after single and repeated doses of several types of neuroleptic drugs. Twice daily administration of low or high doses of haloperidol, fluphenazine, or (-) sulpiride resulted in greater tolerance to the initial HVA increase in caudate compared to prefrontal cortex.     

Synergistic interaction between nicotine and social rewards in adolescent male rats

Rationale  Smoking typically begins during adolescence and is largely reinforced by social cues. During adolescence in rats, sensitivity to both social cues and drugs of abuse is enhanced. Objectives  We have previously demonstrated in adolescent male rats that a low dose of cocaine interacts with social reward to produce an enhanced conditioned place preference (CPP) relative to either reward given alone. The present study further examined the nature of drug–social reward interactions using nicotine. Methods  Dose–effect functions for nicotine-CPP were established using two different routes of administration (vehicle, 0.1, 0.3, and 0.6 mg/kg, SC and vehicle, 0.01, 0.03, and 0.06 mg/kg, IV). The effects of nicotine on social reward-CPP and social play behavior were next examined using parameters presumed to be sub-threshold for establishing social reward- and nicotine-CPP. Results  Dose-dependent nicotine-CPP was observed using both routes of administration. Two pairings of the initially non-preferred side of the apparatus with either SC nicotine or another adolescent rat failed to produce CPP when examined alone, but together produced a robust CPP despite nicotine reducing social play. This interaction effect was not observed with the IV nicotine. A final experiment demonstrated that the enhancement of CPP with the combination of rewards was not due to additive effects of weak, sub-threshold conditioning. Conclusions  These findings suggest that nicotine and social rewards interact synergistically in adolescent rats resulting in a greater, perhaps qualitatively different, reward than either reward given alone. Understanding drug–social reward interactions may provide new directions for development of preventions and interventions of adolescent smoking. Funding sources: This work was supported by grants R01DA11064, R21DA023123, and F31DA023746 from the National Institute on Drug Abuse (NIDA). The content is solely the responsibility of the authors and does not necessarily represent the official view of NIDA or the National Institutes of Health.