The effects of antidepressant drugs on central 5-HT receptor activity were studied in rats and mice. Antidepressant drugs were evaluated for their ability to displace 3H-5-HT and 3H-d-LSD from membrane binding sites in the dorsal neocortex of rats in vitro and for their ability to block 5-HTP and d-LSD induced behavioral effects in mice. The degree of blockade of head-twitches in mice produced by the antidepressants was highly correlated with their affinity for 3H-d-LSD binding sites. A number of antidepressant drugs such as amitriptyline, nortriptyline, mianserine, doxepine, nomifensine and dibenzepine appear to possess marked 5-HT receptor blocking activity at some type of 5-HT receptors in brain. New antidepressant drugs such as zimelidine, which specifically inhibit 5-HT reuptake and do not block 5-HT receptor sites, may after chronic treatment also reduce the functional activity of 5-HT systems by producing adaptive changes in postsynaptic 5-HT mechanisms. Thus, a new indoleamine hypothesis of depression is presented: the therapeutic action of antidepressant drugs may in part be due to a reduced functional acitivity of some central 5-HT systems.

Alaproclate, a new specific 5-HT uptake inhibitor, was examined for its action on several receptors in the brain, for its action on the NA, DA and 5-HT uptake mechanisms in vivo and for its action on brain biogenic amine content. Alaproclate was practically devoid of action on a number of receptors as examined in binding studies in vitro: 5-HT, histamine-H1, alpha 1, -alpha 2-adrenergic and dopamine D2 receptors. Alaproclate had also a weak affinity for 3H-norzimeldine binding sites in contrast to imipramine. Unlike the tricyclic antidepressants alaproclate had a negligible action on muscarinic receptors and failed to block muscarinic induced stimulation in vivo. Contrary to clomipramine alaproclate failed to block NA uptake in vivo. Alaproclate was found to display a regional selectivity in blocking 5-HT uptake in vivo (measured with the H 75/12-method). The compound was most potent in the hippocampus and hypothalamus followed by striatum and cerebral cortex with a low potency in the spinal cord. The results are discussed in relation to a previously presented carrier site model for serotonin reuptake.

Zimelidine (ZIM) and its main active metabolite norzimelidine (NZIM) have been shown to preferentially inhibit 5‐hydroxytryptamine (5‐HT) neuronal uptake both in vitro and in vivo while having much less effect on noradrenaline (NA) uptake. ZIM in vivo blocked the 5‐HT uptake mechanism in the cerebral cortex, hippocampus, striatum, hypothalamus and spinal cord, thus indicating effects on both the ascending and descending 5‐HT pathways. ZIM is devoid of a 5‐HT releasing action, MAO‐inhibitory properties and effects on dopamine (DA) uptake. ZIM failed to reduce NA turnover even in high doses, but markedly reduced 5‐HT turnover in very low doses in the rat. ZIM also enhanced 5‐HT mediated behaviours in mice in doses related to the inhibition of 5‐HT uptake. In contrast to amitriptyline (AMI) and mianserin (MIAN), ZIM only in extremely high doses displayed a 5‐HT receptor blocking action in vitro and failed to block 5‐HT mediated behaviour. ZIM was practically devoid of action on histamine H1 and H2 receptors, and had also a neglible action on noradrenergic α1‐ and α2‐receptors, and on β‐receptors. Unlike the tricyclic antidepressants (TAD's) ZIM had a negligible action on muscarinic receptors and failed to affect cholinergic induced activity. Long‐term treatment with ZIM did not result in any attenuation of the 5‐HT uptake blocking potency or the reduction of 5‐HT turnover. This long‐term treatment slightly reduced the number of β‐receptors in the brain. However, repeated ZIM‐treatment induced a new 5‐HT receptor binding site characterized by a low affinity and with a high number of binding sites and decreased the number of high affinity 5‐HT receptor binding sites. Unlike the TAD's zimelidine failed to block the action of reserpine. Metabolic and behavioural interaction studies in mice showed that ZIM was devoid of any significant interactions with ethanol, barbiturates and benzodiazepines. It is concluded that ZIM markedly differs front both the TAD's and new antidepressants such as mianserin and nomifensine. ZIM seems preferentially to effect the presynaptic 5‐HT reuptake mechanism while having a negligible action on noradrenergic, 5‐HT, acetylcholine and histamine receptors in the brain.

The effects of the specific 5-HT uptake inhibitors alaproclate and zimelidine, the 5-HT releasing compound p-chloroamphetamine (PCA) and the specific NA uptake inhibitor desipramine on pain sensitivity were examined in male rats using the hot-plate and tail-flick methods. The effects of alaproclate and zimelidine on 5-HT uptake mechanisms in the hypothalamus and spinal cord were also studied. Alaproclate, zimelidine, PCA and desipramine produced hypoalgesia in the hot-plate but not in the tail-flick test. Naloxone (1 mg/kg) failed to block the hypoalgesia produced by alaproclate and PCA in the hot-plate test. Zimelidine but not desipramine pretreatment blocked the analgetic action of PCA in the hot-plate test. Alaproclate significantly enhanced morphine analgesia in the hot-plate test but did not affect morphine analgesia in the tail-flick test. In contrast, zimelidine tended to enhance and significantly prolonged morphine analgesia in the tail-flick test but did not affect morphine analgesia in the hot-plate test. Zimelidine inhibited 5-HT uptake with equal potency in the hypothalamus and spinal cord, while alaproclate produced a greater inhibition of 5-HT uptake in the hypothalamus. These findings show test-specific effects after enhancement of central 5-HT neurotransmission. It is suggested that various aspects of pain sensitivity and morphine analgesia may involve different 5-HT pathways in the brain and spinal cord. Moreover, 5-HT pathways in the forebrain may mediate analgesia of a non-opiate type.

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