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The Flinders sensitive (FSL) and Flinders resistant (FRL) line rats have been selectively bred for hyper- and hyposensitivity to the hypothermic effect of cholinergic agonists respectively. In this study, pilocarpine (250 mg/kg) and physostigmine (0.8 mg/kg) doses that are subconvulsant to outbread Sprague-Dawley rats were systemically injected to the FSL and FRL rats and a heterogenous F2 cross. All of the FRL rats developed severe motor limbic seizures in response to pilocarpine, while none of the FSL animals did. The F2 crosses showed intermediate reaction. The FRL rats were also more affected by physostigmine than the other two groups. However, the FSL rats were confirmed to be more sensitive to the hypothermic effects of pilocarpine (20 mg/kg) and physostigmine (0.6 mg/kg). Picrotoxin and kainic acid produced similar responses in the both lines, i.e., induced clonic convulsions in some animals when applied in subthreshold doses (2 and 10 mg/kg, respectively). Thus, the normally cholinergic-insensitive rats are more sensitive to the convulsant effects of high doses of cholinergic agonists, but this increased sensitivity does not extend to noncholinergic convulsants.

The effect of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on voluntary alcohol consumption was examined in two different strains of alcohol-preferring rats, in a continuous-access, two-bottle-choice paradigm. Compared with the vehicle, intraperitoneal injections of L-NAME significantly and dose-dependently (10, 30, and 60 mg/kg) suppressed alcohol intake and preference in both alcohol-preferring (P) and Fawn-Hooded (FH) rats. The effect of the highest dose of L-NAME was nonspecific; it caused general decreases in consumption of alcohol, water, and food. Repeated injection of L-NAME (30 mg/kg) for 4 consecutive days significantly attenuated alcohol intake, but tolerance developed after 3 days of treatment. A single administration of a high dose of L-NAME (60 mg/kg) did not influence the blood alcohol concentrations, which suggests a possible central effect. Furthermore, a moderate dose of 30 mg/kg L-NAME, which selectively inhibited alcohol intake, did not exert a significant effect on telemetrically measured heart rate, core body temperature, and gross motor activity of alcohol naive Fawn-Hooded rats. These results suggest an involvement of nitric oxide in alcohol drinking behavior. Although the true mechanism(s) of action is not yet clear, it can be speculated that L-NAME may exert its action indirectly by modulating neurotransmitters proposed to be involved in alcohol drinking and/or by influencing other neuronal factors, such as neuronal Ca2+ channels, which have been shown to be involved in alcohol drinking behavior.

Neuronal Ca2+ channels have been shown to be involved in both alcohol drinking behavior in rats and nonhuman primates and in the manifestation of alcohol withdrawal symptoms in rodents. Experiments were performed to determine the effect of a single injection of levemopamil, a novel Ca2+ channel antagonist with antiserotonergic [5-hydroxytryptamine2 (5-HT2)] properties, on alcohol preference and alcohol withdrawal symptoms in alcohol-preferring (P) and Wistar rats, respectively. P rats were individually housed and provided free access to food, water, and a solution of 10% (v/v) ethanol. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline, P rats were injected with levemopamil (0, 3.3, 10, 15, and 20 mg/kg) and their food, water, and alcohol intakes measured 24 h later. In a separate experiment, the ability of acute and chronic (12 consecutive days) administrations of levemopamil to suppress alcohol withdrawal symptoms in chronically alcohol-treated rats was studied. In addition, the effects of levemopamil on the level of monoamines in different areas of the brain, as well as its action in alcohol metabolism, were examined. Our findings showed that a single administration of levemopamil (10, 15, and 20 mg/kg) significantly and dose-dependently attenuated alcohol intake and increased water intake in P rats. Both acute and chronic treatment with levemopamil reduced the alcohol withdrawal symptoms, overall seizure scores, and proportion of rats seizing. A single injection of levemopamil produced a clear, but not significant, trend to increase the 5-HT turnover rate in certain brain areas. This drug did not influence the pharmacokinetics of alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)

Male Wistar rats, chronically implanted with cannulas into the anterior hypothalamus, were acutely injected with the calcium channel inhibitors, diltiazem, nicardipine and verapamil, or the choline uptake blocker hemicholinium-3 and tested in the forced swim test. Hemicholinium-3, nicardipine and verapamil markedly increased the duration of active swimming. This antidepressant-like effect did not appear to reflect merely a hyperactive state as the drug-treated rats did not differ from vehicle-injected controls in their open field motility scores. Diltiazem failed to influence rats' performance in either test. Since nicardipine and verapamil, but not diltiazem, share choline uptake property with hemicholinium-3, it seems that this action plays a role in the antidepressant-like effect of all three drugs in the forced swim test.

The effect of injections of norepinephrine (NE)-depleting toxin DSP-4 into the central amygdala (AMY) on apomorphine-induced fighting (AIF) was studied. In addition, the influence of such treatment on related parameters such as spontaneous activity, pain sensitivity and changes in locomotion after (+)3-PPP or apomorphine (1 mg/kg SC each) were verified. Finally, injections of NE or phenylephrine into the AMY five min before AIF were performed. DSP-4 induced marked (-71%) and selective fall in NE within the AMY accompanied by significant increase in aggressive response to 5 mg/kg of apomorphine. DSP-4-treated animals were less active in the open field and more sensitive to pain in a hot plate test. They were also more responsive to locomotor-augmenting action of apomorphine. Significant suppression of AIF was seen after injections of NE and phenylephrine into the AMY. The results suggest that NE input to the AMY plays an inhibitory role in dopamine-related locomotion and aggressivity. Moreover, amygdalar NE appears to be involved in general activity and pain perception modulation.