Jerzy Vetulani

A possible common mechanism of action of antidepressant treatments

SummaryThe response of the norepinephrine (NE) sensitive cyclic AMP generating system in slices of the rat limbic forebrain after both the acute and chronic administration of the tricyclic antidepressants desipramine (DMI) and iprindole as well as electroconvulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after the administration of a single dose or short term treatment with DMI and iprindole. However, the administration of the antidepressants on a clinically more relevant time basis markedly reduced the sensitivity of the cyclic AMP generating system to NE. This change in sensitivity was not related to the levels of the drugs in brain. The response of cyclic AMP to NE was also reduced by ECT, but the onset of this action was shorter than that observed with the antidepressants. ECT also antagonized the enhanced response of cyclic AMP to NE following destruction of central adrenergic nerve terminals with 6-hydroxydopamine. It thus appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.

ADAPTIVE MECHANISMS OF THE NORADRENERGIC CYCLIC AMP GENERATING SYSTEM IN THE LIMBIC FOREBRAIN OF THE RAT: ADAPTATION TO PERSISTENT CHANGES IN THE AVAILABILITY OF NOREPINEPHRINE (NE)

Abstract— The noradrenergic cyclic AMP generating system in slices of the limbic forebrain of rats displays characteristics which are compatible with those of a central NE receptor. The cyclic AMP response to a Kmax concentration of NE (concentration of NE which elicits maximal increase in the level of cyclic AMP) is significantly enhanced in slices from reserpinized animals, although the Ka value of NE (concentration of NE eliciting half‐maximum response) was not significantly changed. Chemosympathectomy with 6‐hydroxydopamine (6‐OHDA) significantly enhanced the activity of the system to NE and isoproterenol but not to adenosine and reduced the Ka value for NE. The changes in the reactivity of the cyclic AMP generating system following 6‐OHDA administration appear to be related to a decrease in the availability of NE and not to that of other neurotransmitters as protection by desipramine (DMI) of noradrenergic neurons against the neurotoxic action of 6‐OHDA prevented the development of supersensitivity to NE. Conversely, and independent of the actual concentration of NE in brain tissue, a persistent increase in the availability of NE caused by prolonged MAO inhibition lead to a marked decrease in the reactivity of the cyclic AMP generating system. The results provide further evidence for a regulatory mechanism in the CNS involving the noradrenergic receptor that adapts its sensitivity to NE in a manner inversely related to the degree of its stimulation by the catecholamine.

The noradrenergic cyclic AMP generating system in the limbic forebrain: Pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics

The cyclic AMP generating system in slices of the rat limbic forebrain was investigated. In consists of: (u) A noradrenergic system which responds to norepinephrine (NE) and isoproterenol. Though the rise of the nucleotide elicited by isoproterenol is more rapid than that caused by NE, the maximal effect is less than half of that induced by NE; (2) an adenosine-dependent system. The noradrenergic cyclic AMP generating system in the limbic forebrain displays a number of properties of a central NE receptor: it develops supersensitivity to NE and isoproterenol following prolonged deprivation of NE at postsynaptic sites (chronic treatment with reserpine or chemosympathectomy with 6-hydroxydopamine). When noradrenergic terminals are protected from 6-hydroxydopamine by desmethylimipramine, the responses to NE are not enhanced. Responses to NE are blocked by both propranolol and phentolamine, while responses to isoproterenol are blocked by propranolol but not by phentolamine. The adenosine-dependent system does not develop supersensitivity after central chemosympathectomy and is not blocked by either alpha- or beta-antagonists. While not altering the basal level of the nucleotide, clinically effective antipsychotic drugs caused a dose-dependent inhibition of the limbic noradrenergic cyclic AMP response with clozapine and pimozide being particularly potent (IC50 0.06 and 0.08 muM, respectively). Antipsychotic drugs do, however, not affect cyclic AMP responses elicited by adenosine. The results are compatible with the view that the central NE receptor is closely related to or may be an integral part of an adenylate cyclase system and that its blockade in the limbic forebrain by antipsychotic drugs may contribute to their therapeutic action.

The mechanism of 1,2,3,4‐tetrahydroisoquinolines neuroprotection: the importance of free radicals scavenging properties and inhibition of glutamate‐induced excitotoxicity

1‐Methyl‐1,2,3,4‐tetrahydroisoquinoline (1MeTIQ), unlike several other tetrahydroisoquinolines, displays neuroprotective properties. To elucidate this action we compared the effects of 1MeTIQ with 1,2,3,4‐tetrahydroisoquinoline (TIQ), a compound sharing many activities with 1MeTIQ (among them reducing free radicals formed during dopamine catabolism), but offering no clear neuroprotection. We found that the compounds similarly inhibit free‐radical generation in an abiotic system, as well as indices of neurotoxicity (caspase‐3 activity and lactate dehydrogenase release) induced by glutamate in mouse embryonic primary cell cultures (a preparation resistant to NMDA toxicity). However, in granular cell cultures obtained from 7‐day‐old rats, 1MeTIQ prevented the glutamate‐induced cell death and 45Ca2+ influx, whereas TIQ did not. This suggested a specific action of 1MeTIQ on NMDA receptors, which was confirmed by the inhibition of [3H]MK‐801 binding by 1MeTIQ. Finally, we demonstrated in an in vivo microdialysis experiment that 1MeTIQ prevents kainate‐induced release of excitatory amino acids from the rat frontal cortex. Our results indicate that 1MeTIQ, in contrast to TIQ, offers a unique and complex mechanism of neuroprotection in which antagonism to the glutamatergic system may play a very important role. The results suggest the potential of 1MeTIQ as a therapeutic agent in various neurodegenarative illnesses of the central nervous system.

A possible physiological role for cerebral tetrahydroisoquinolines.

Tetrahydroisoquinolines present in the mammalian brain, 1,2,3,4-tetrahydroisoquinoline (TIQ) and salsolinol, suspected to cause neurodegeneration leading to Parkinsons disease, were investigated to find their possible physiological role. To this aim their behavioral and receptor effects induced after a single dose were tested in mice and rats. Both compounds do not affect significantly the basal locomotor activity, very effectively block hyperactivity induced by apomorphine (rats) and amphetamine (mice), only partially block hyperactivity induced by scopolamine, do not affect locomotor stimulation induced by cocaine, and strongly augment the running fit induced by morphine (mice). They do not produce extrapyramidal symptoms and do not potentiate haloperidol-induced catalepsy (rats). TIQ and salsolinol do not displace antagonists of several receptors (including D1 and D2) from their binding sites, but displace the agonists of α2-adrenoreceptors, [3H] clonidine and of dopamine receptors, [3H] apomorphine. The results indicate that salsolinol and TIQ act as specific antagonists of agonistic conformation of dopamine receptors, and owing to that may play a role of endogenous feed-back regulators of the dopaminergic system. Those properties make tetrahydroisoquinolines potential antidopaminergic drugs devoid of extrapyramidal effects, with possible application in substance addiction disorder as anti-craving agents.

Analysis of the difference in the behavioral effects of apomorphine in C57BL/6 and DBA/2 mice

The influence of pimozide on the effects of apomorphine on locomotor activity and stereotypy was studied in two inbred strains of mice. In C57BL/6 mice, in which apomorphine did not produce stereotypy of gnawing, the biphasic effect of apomorphine on locomotor activity (hypomotility followed by hypermotility) was unaffected by pimozide. In DBA/2 mice, in which high doses of apomorphine produce hypomotility and compulsive gnawing, both these effects (but not hypomotility produced by low doses of apomorphine) were counteracted by pimozide. The results are consistent with the assumption that both strains of mice have separate inhibitory and stimulatory dopamine receptors mediating locomotor activity. In addition, DBA/2 but not C57BL/6 mice have dopamine receptors which mediate stereotypy and are sensitive to pimozide.

Dopamine receptors in the striatum and limbic system of various strains of mice: relation to differences in responses to apomorphine.

Dopamine receptors, defined as [3H]spiroperidol binding sites, had similar population parameters in the limbic forebrain of C57BL/6, Albino Swiss and DBA/2 mice, but the parameters of the striatal populations were different: not only the densities differed among themselves, but the KD value of the striatal dopamine receptors of DBA/2 mice was significantly higher than that in the two remaining strains. Behavioral responses of Albino Swiss mice to apomorphine: biphasic effect of apomorphine on locomotor activity and stereotypy characterized by high motility, frequent rearing and sharp, not very frequent bites, were similar to those described earlier for C57BL/6 mice, and differed from those reported for DBA/2 mice. The results suggest that the difference in responding to apomorphine in various strains of mice may be related to differences in their striatal dopamine receptors.

Different effects of 3-chlorophenylpiperazine on locomotor activity and acquisition of conditioned avoidance response in different strains of mice.

SummaryMice of C57BL/6 (C57), Balb/c (BALB), and CD-1 (CD) strains were injected with 3-chlorophenylpiperazine (CPP), 1–10 mg/kg ip, and their exploratory and basal locomotor activities and acquisition of conditioned avoidance response in a shuttle-box were tested. In C57 mice CPP did not affect either locomotor activity or shuttle-box performance. In BALB mice CPP inhibited both basal and exploratory activities (the latter only in higher doses) and facilitated the acquisition of conditioned avoidance response. In CD mice CPP did not affect exploration, but inhibited basal locomotor activity and facilitated the shuttle-box performance. It is concluded that there exist large interstrain differences in responsiveness of mice to CPP, and that the drug may facilitate acquisition of conditioned avoidance response through a strain-specific, serotonin-independent mechanism.

Nimodipine on Shuttle-box Avoidance Learning in Mice: No Impairment But Slight Improvement

The dihydropyridine calcium channel antagonist nimodipine was tested in mice of CD-1, C57BL/6, and DBA/2 strains subjected to shuttle-box avoidance training. In contrast with some findings of other authors showing impairment of shuttle-box avoidance learning by low doses of the drug in rats, nimodipine given IP before each training session at doses of 0.25, 0.5, 1, 2.5, or 5 mg/kg never impaired avoidance acquisition in mice. On the contrary, one dose of nimodipine (1 mg/kg) significantly improved avoidance acquisition in mice of the DBA/2 strain. The drug failed to impair avoidance performance in DBA/2 mice even if given acutely in the middle (third session) or at the end (fifth session) of the training period. The results contradict studies showing cognitive impairment induced by calcium channel blockers, and may provide some limited evidence in support of improved cognitive function in normal animals, although this effect is much less evident than in aged or brain-damaged subjects.

Facilitation of shuttle-box avoidance behaviour in mice treated with nifedipine in combination with amphetamine

The dihydropyridine calcium channel antagonist nifedipine, tested in mice of CD-1, C57BL/6 and DBA/2 strains, at doses of 2.5, 5 and 10 mg/kg IP, had no significant effect on shuttle-box avoidance acquisition. Nifedipine also failed to affect performance retention in CD-1 mice subjected to a one-trial passive avoidance task (step-through). While ineffective alone, nifedipine strongly enhanced the shuttle-box avoidance facilitating action of amphetamine (1 and 2 mg/kg IP) in low performing CD-1 mice. The results indicate that although calcium channel blockers do not affect learning in avoidance paradigms in normal animals, they can interfere with the effects of other centrally acting drugs. Calcium antagonists might interfere with neuronal changes induced by amphetamine, but at present it is difficult to explain the strong avoidance facilitation produced by combinations of nifedipine and amphetamine. A possibility that the action of nifedipine on cerebral circulation is involved in the amphetamine-nifedipine interaction cannot be excluded.