Roman Stefanski

Metrifonate improves spatial navigation and avoidance behavior in scopolamine-treated, medial septum-lesioned and aged rats

We investigated the effects of acute p.o. pretraining treatment with an indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation and passive avoidance behavior. Metrifonate (10-100 mg/kg, orally, p.o.) did not improve the water maze or passive avoidance performance of young intact rats. However, in young rats metrifonate over a broad dosage range (10-100 mg/kg, p.o.) was able to alleviate the adverse effects of scopolamine (a muscarinic acetylcholine receptor antagonist; 0.4 and 2.0 mg/kg in water maze and passive avoidance study, respectively) and medial septum-lesioning on spatial reference and working memory and passive avoidance performance. In old (23-month-old) rats, a defect of water maze and passive avoidance behavior was observed. In old rats, metrifonate improved spatial reference memory function in the water maze and also passive avoidance at 10-30 mg/kg, but the 3 mg/kg dose was ineffective. Very old (27-month-old) rats had a more severe impairment of water maze performance than old rats, and metrifonate 3-30 mg/kg did not improve their spatial navigation. These results show that metrifonate may over a wide range of doses stimulate cognitive functioning, but during advanced aging neurobiological defects develop that may mask some of the therapeutic effects of metrifonate in rats.

Effects of combined block of α1-adrenoceptors and NMDA receptors on spatial and passive avoidance behavior in rats

The present study was designed to investigate the interactions between alpha 1-adrenoceptors and NMDA receptors in modulating spatial navigation and passive avoidance behavior in rats. Pretraining treatment with prazosin, and alpha 1-adrenoceptor antagonist, at 2 mg/kg i.p., impaired acquisition performance in a water maze navigation test and had no effect on passive avoidance behavior. Posttraining and pretest injections of prazosin had no effect on water maze or passive avoidance behavior. Pretraining treatment with ((+/-))-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive NMDA receptor antagonist, does dependently (3 and 10 mg/kg) impaired passive avoidance and water maze behavior. Posttraining treatment with CPP had no effect on water maze and passive avoidance behavior. A pretraining combination of subthreshold doses of CPP (1 mg/kg) and prazosin (1 mg/kg) impaired water maze behavior. A combination of subthreshold doses of CPP (3 mg/kg) and prazosin (1 mg/kg) injected posttraining or pretest had no marked effect on water maze or passive avoidance performance. A control experiment showed that CPP 3 mg/kg or CPP 1 mg/kg and prazosin 1 mg/kg injected pretraining had no effect on cue navigation to a clearly visible platform, but CPP 10 mg/kg markedly impaired performance. The present results indicate that alpha 1-adrenoceptors and NMDA receptors may synergistically regulate acquisition of spatial navigation performance. Therefore, it would be interesting to study the effects of combined stimulation of alpha 1-adrenoceptors and NMDA receptors on age-related memory defects.

Restraint stress-induced changes in saccharin preference: The effect of antideprressive treatment and diazepam

The effect of antidepressive treatment and of diazepam on saccharin preference has been studied in a model of acute restraint stress-induced saccharin preference deficit. It has been shown that 1-hr stressor produces short-term, and significant decrease of saccharin preference in a two-bottle test, measured at 24-hr periods of time. Single doses of desipramine and citalopram (10 mg/kg, IP) given prior to stress session significantly attenuated the deficit in saccharin preference. Less strong, but similar effects appeared after postshock antidepressant administration. On the other hand, electroconvulsive shock treatment rather enhanced the depressive influence of the stressor, while diazepam (1 mg/kg, IP) antagonized the suppression of saccharin preference, especially when the drug was given immediately after restraint stress. It is concluded that the acute immobilization-induced decrease in saccharin preference most probably reflects changes in brain emotional processes. The role of disturbances in central motivational mechanisms and its contribution to the effects of antidepressive drugs remains to be established.

Competitive NMDA receptor antagonist, CGP 40116, substitutes for the discriminative stimulus effects of ethanol

A drug discrimination procedure was used to compare the ability of competitive (CGP 37849, D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate; CGP 40116, D-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate) and non-competitive (dizocilpine) NMDA receptor antagonists to substitute for ethanol in rats trained to discriminate between a 1.0 g/kg dose of ethanol (i.p.) and saline. Dizocilpine (0.1-0.3 mg/kg) substituted partially for ethanol at doses that markedly reduced the rate of responding. CGP 37849 (1.25-5.0 mg/kg) substituted partially for ethanol and suppressed the response rate. CGP 40116 (0.5-2.5 mg/kg), and active D-stereoisomer of CGP 37849, completely substituted (88%) for ethanol, and caused only moderate suppression of the response rate.

Discriminative stimulus effects of ethanol: Lack of antagonism with N-methyl-d-aspartate and d-cycloserine

Several drug discrimination studies reported that both competitive and uncompetitive NMDA receptor antagonists substituted for ethanol stimulus in rats. In the present study we examined if compounds that act as agonists at the NMDA receptor complex, D-cycloserine (a partial agonist at the glycine positive modulatory site) and N-methyl-D-aspartate (an agonist at the glutamate binding site), could antagonize the discriminative stimulus effects of ethanol. Rats were trained to discriminate between IP administered 1.0 g/kg of ethanol (10% v/v) and saline under a sweetened milk-reinforced fixed ratio 10 (FR10) schedule of reinforcement. When the animals met the discriminative criteria, antagonism tests were conducted with D-cycloserine (0.3-10.0 mg/kg, IP) and N-methyl-D-aspartate (15.0-60.0 mg/kg, IP). Neither D-cycloserine nor N-methyl-D-aspartate antagonized the ethanol-mediated discriminative stimulus effects. In addition, D-cycloserine (3.0-300.0 mg/kg, IP) did not substitute for ethanol. These results indicate that at least certain agonists at the NMDA receptor complex do not attenuate the ethanol interoceptive cue in the rat.

5 -HT1A Receptor agonist (8-OH-DPAT) and 5-HT2 receptor agonist (DOI) disrupt the non-cognitive performance of rats in a working memory task

The present study investigated the role of 5-HT1A and 5-HT2 receptors in the execution of a working memory task (delayed non-matching to position, DNMTP) by assessing the influence of 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT 2 receptor agonist) on the performance of rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT) and their controls. Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid levels were reduced in examined brain areas (especially in the hippocampus where there was a 90 percent reduction). Noradrenaline concentrations were also decreased (mostly on the same side of the injection) by about 20 percent. 5,7-DHT lesioned rats did not significantly differ from their controls in performance in the DNMTP task. At the 30 μg/kg dose, 8-OH-DPAT did not affect the DNMTP-performance of rats, but at the higher dose (100 μg/kg) it reduced the probability of responding to the sample lever. DOI (100 and 300 μg/kg) also interfered with the non-cognitive performance of rats. Since neither of these agonists affected significantly the choice accuracy, they do not appear to influence the working memory per se. The 5,7-DHT lesioned rats did not differ from their controls in response to these agonists. These results suggest that the combination of 5-HT1A receptor stimulation by 8-OH-DPAT and 5-HT2 receptor stimulation by DOI can interfere with the non-cognitive performance of rats in the DNMTP task. The results further indicate that the effect of 8-OH-DPAT may be mediated through post-synaptic rather than pre-synaptic 5-HT1A receptors.

Studies on the role of 5-HT3 receptors in the mediation of the ethanol interoceptive cue

The drug discrimination test was used to evaluate the role of 5-HT3 receptors in the mediation of the stimulus properties of ethanol in rats trained to discriminate between ethanol (1.0 g/kg, 10% v/v, i.p.) and saline vehicle. Rats trained to discriminate between a lower dose of ethanol (0.5 g/kg i.p.) failed to attain discrimination criteria after 20 weeks (100 sessions) of training. None of the doses of 5-HT3 receptor antagonists (0.001, 0.01, 0.1, 1.0, 10.0 mg/kg of tropisetron or ondansetron) administered i.p. 30 min before ethanol, antagonized the discriminative stimulus properties of ethanol. Furthermore, none of the centrally (1, 10, 35 micrograms per rat) or i.p. (0.1, 1.0, 2.5, 5.0, 10.0 mg/kg) administered doses of 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide, could replace the ethanol discriminative cue. These results suggest that 5-HT3 receptors are not primarily involved in the mediation of the stimulus properties of ethanol.

Studies on the role of nicotinic acetylcholine receptors in the discriminative and aversive stimulus properties of ethanol in the rat

The role of the nicotinic acetylcholine receptor (nAChR) in the discriminative and aversive stimulus effects of ethanol was studied in rats. In the operant drug discrimination procedure the rats were trained to discriminate between 1.0 g/kg ethanol and saline under the FR10 schedule of sweetened milk reinforcement. Neither the nAChR agonist, nicotine (0.1-0.6 mg/kg) nor the nAChR antagonist, mecamylamine (3.0-6.0 mg/kg) substituted for the ethanol stimulus. Moreover, mecamylamine (0.5-6.0 mg/kg) did not antagonise the ethanol stimulus. The cross-familiarisation conditioned taste aversion procedure was used as an alternative method to study stimulus resemblance between ethanol and nicotine. Six daily injections of nicotine (0.6 mg/kg) significantly decreased a subsequent ethanol-induced taste aversion conditioning. The aversive stimulus effects of ethanol were investigated with the conditioned taste aversion (CTA) paradigm. Mecamylamine (1.0-3.0 mg/kg) did not attenuate an ethanol-induced CTA. These results suggest that: (1) nAChRs are not primarily involved in the discriminative stimulus effects of ethanol when studied with the operant drug discrimination test; (2) nAChRs are not critically involved in the ethanol-induced CTA.

Discriminative Stimulus Properties of Ethanol in the Rat: Differential Effects of Selective and Nonselective Benzodiazepine Receptor Agonists

Rats were trained to discriminate between ethanol (1.0 g/kg; 10% v/v) and saline under a fixed ratio 10 schedule of sweetened milk reinforcement. Both diazepam [nonselective, full benzodiazepine (BZ) receptors agonist] and bretazenil (nonselective, partial BZ receptor agonist) produced dose-dependent ethanol-appropriate responding (>75%). Neither diazepam nor bretazenil affected the response rate at the doses producing maximal generalisation from ethanol. In contrast, zolpidem (full BZ1 receptor agonist) and abecarnil (full BZ1/full or partial BZ2 receptor agonist) produced only moderate (<50%) ethanol-appropriate responding when tested up to doses that markedly decreased the overall response rate. These results suggest that: 1) there are no major differences between full and partial, nonselective BZ receptor agonists in their ability to substitute for 1.0 g/kg dose of ethanol; 2) stimulation of BZ1 receptors alone is not sufficient to produce ethanol-like discriminative stimulus effects in the rat.

Serotonin 5-HT2 Receptor Antagonists

SummaryThis review highlights recent pharmacological and clinical advances in the understanding of the potential use of serotonin 5-HT2 receptor antagonists as treatments for a number of psychiatric disorders, namely anxiety, depression and schizophrenia.5-HT2 receptor antagonists have not yet been clearly demonstrated to be effective in humans as treatments for anxiety. Some preliminary clinical trials suggest that the 5-HT2 receptor antagonist ritanserin may have a beneficial effect in patients with generalised anxiety disorder, but the evidence is far from compelling.Upregulation of central 5-HT2 receptors and an accompanying increase in phosphoinositide turnover appear to be predisposing biological factors in depression. A functional interaction between 5-HT1A and 5-HT2 receptors may be of particular importance, since 5-HT2 receptor antagonism can ultimately result in a facilitation of 5-HT1A receptor-mediated neurotransmission and this may be beneficial for the treatment of depression. Ritanserin appears to be more effective than placebo in alleviating the depressive symptoms of dysthymia. Nefazodone is a new antidepressant that combines 5-HT2 receptor blockade with serotonin reuptake inhibition. Comparisons with imipramine favour nefazodone in terms of tolerability and suggest that both drugs are equally clinical effective.In schizophrenia, 5-HT2A receptor function appears to be altered. Modulation of dopaminergic function via 5-HT2A receptors may provide a viable mechanism for enhancing the effect of antipsychotics. Risperidone, the first post-clozapine agent that has 5-HT2A and dopamine D2 receptor antagonist actions, is at least as effective as haloperidol and perphenazine in reducing acute psychotic symptoms. Its major clinical advantages are a greater efficacy in controlling the secondary negative symptoms and a lower incidence of extrapyramidal symptoms (EPS). The efficacy of ritanserin in alleviating both positive and negative symptoms in acutely psychotic patients seems to support the hypothesis that potent 5-HT2A receptor antagonism alone may contribute to the therapeutic action of several clinically effective antipsychotics that have reduced liability to induce EPS.