Abstract
The effects of both acute and chronic treatment with a number of antidepressant drugs on various biochemical and behavioural aspects of central serotonergic (5-HT) processes was studied in rats and mice.
Chronic treatment with the relatively selective 5-HT uptake inhibitor chlorimipramine produced a significant reduction in rat brain levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA). No change in brain 5-HIAA levels was found in rats treated chronically with desipramine, and neither chlorimipramine or desipramine significantly altered brain concentrations of 5-HT.
A single 5 mg/kg dose of the new tetracyclic antidepressant mianserin produced a marked blockade of the operant behavioural depressant effect due to administration of 25mg/kg L-5-hydroxytryptophan (L-5-HTP) to rats. This antagonistic effect was potentiated 1 hour after the final dose of a chronic mianserin treatment schedule, but at 48 hours following the last mianserin dose no significant effect on the L-5-HTP-mediated syndrome was apparent. In contrast, a single dose of the selective 5-HT uptake inhibitor fluoxetine enhanced the operant behavioural depressant effect of 12.5mg/kg L-5-HTP. At both 1 and 48 hours following termination of chronic fluoxetine treatment, operant behavioural depression was still markedly enhanced, although slightly less in the 1 hour, and further reduced in the 48 hour test sessions.
The characteristic 'head twitch' syndrome produced by L-5-HTP plus the monoamine oxidase (MAO) inhibitor isocarboxazid in mice, was blocked by single 5mg/kg doses of the antidepressants mianserin, nomifensine, amitryiptyline and trazadone, suggesting central 5-HT receptor antagonistic activities for these drugs. Single 5mg/kg doses of fluoxetine and chlorimipramine were without noticeable effect on head twitch behaviour in the particular experiments performed, while the MAO inhibitor pargyline greatly potentiated head twitch behaviour. Chronic treatment with these various antidepressants produced an enhanced blockade for mianserin, a similar degree of blockade for amitriptyline, but no significant effects on head twitch behaviour for fluoxetine, chlorimipramine, nomifensine or pargyline. These results suggest a number of differences from the acute effects of these drugs on central 5-HT systems after chronic treatment, which may be significant to their mechanisms of antidepressant activity.
Chronic treatment with mianserin followed by 72 hours withdrawal was observed to increase the specific binding of (3H)5-HT to rat brain membrane preparations, although this effect fell just short of statistical significance in the experiment performed.
A relatively new 'animal model of depression', the amphetamine withdrawal syndrome in rats, was briefly investigated. No alteration was detected in the binding characteristics of (3H)5-HT to rat brain membranes following withdrawal from chronic amphetamine treatment. Concurrent administration of chronic fluoxetine or mianserin were both found to worsen rather than alleviate operant behavioural depression following amphetamine withdrawal. This paradoxical effect, most obvious for fluoxetine, was shown to be probably related to a metabolic drug interaction, as fluoxetine produced a large increase in brain amphetamine concentrations.
A single 25mg/kg dose of L-5-HTP, produced a partial reversal in operant behavioural depression measured at 12 hours following chronic amphetamine withdrawal, although this effect appeared to be short-lasting and requires more detailed investigation.