Depression frequently coexists with dementia, although in many cases the depression is not recognized clinically. Depression represents a major additional burden in dementia, not only for the patients but also for families, caregivers, and, economically, society as a whole. However, depression in patients with dementia does respond to treatment, and appropriate therapy can significantly improve the well-being of these patients. Depression in patients with dementia is currently treated with a variety of standard antidepressive agents (tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), but none is free from significant side effects. Moreover, the use of these drugs is often complicated by a number of age-related factors or effects on the cholinergic neurotransmitter system. Consequently, an antidementia treatment with concomitant antidepressive properties and an acceptable benefit/risk ratio would represent an attractive therapeutic option. The pathogenesis of depression in patients with dementia is not well understood, but may be related to increased intracellular calcium ions in the CNS, the so-called "calcium hypothesis." This hypothesis may explain why some calcium antagonists exert psychotropic effects, including putative antidepressant activity. Animal models and clinical data provide support for the use of calcium channel antagonists for the treatment of depression, with the potential for good tolerability. The latter aspect is especially important for elderly patients with dementia. Although antidepressive effects have been seen with a number of calcium channel antagonists, the dihydropyridine derivative nimodipine shows particular potential for clinical use, perhaps because nimodipine is one of the most lipophilic of these drugs and therefore achieves high concentrations in the CNS, and because of the unique biochemical properties of the dihydropyridine compounds compared with other L type calcium channel blockers. Nimodipine also increases somatostatin levels in CSF, one of the cardinal biochemical deficits in Alzheimer's disease. Data obtained incidentally from the use of nimodipine in the treatment of elderly demented patients clearly demonstrate significant antidepressant activity by the drug in this patient group. Formal clinical evaluation is therefore recommended to establish more clearly the therapeutic benefits offered by nimodipine in patients who suffer from both dementia and depression.

The effects of acute and repeated treatment with the 5-HT1A receptor ligand ipsapirone on hippocampal excitatory synaptic transmission and in an ultrasonic vocalization anxiety test were investigated in the rat. Synaptic responses in the CA1 region of the dorsal hippocampus of alert, freely behaving male Wistar rats were reduced after acute injection of ipsapirone (1 or 2 mg/kg, i.p.). This effect was prevented by pretreatment with the 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide trihydrochloride, 0.25 or 0.5 mg/kg, i.p.) but not by the 5-HT-depleting agent para-chlorophenylalanine (300 mg/kg per day for 3 days, i.p.). WAY-100635 (0.1-0.3 mg/kg, i.p.) also blocked the acute anti-aversive effects of ipsapirone (3 mg/kg, i.p.) in the anxiety test. Repeated administration of ipsapirone (1 or 2 mg/kg per day for 7-8 days, i.p.) produced a gradual reduction in baseline synaptic transmission which was transiently reversed by WAY-100635 (0.25 mg/kg, i.p.). Ipsapirone (1 mg/kg per day for 7 days) produced a gradual and sustained reduction in the duration of vocalizations in the anxiety test which paralleled the reduction in baseline synaptic responses in the same animals. The data indicate that with repeated administration of ipsapirone, a prolongation and enhancement of the 5-HT1A receptor-mediated reduction in hippocampal excitatory synaptic transmission occurs. This delayed effect may contribute to the sustained anxiolytic and/or antidepressant effect of ipsapirone.

Several lines of evidence suggest that L-type calcium (Ca2+) channels play a role in excessive ethanol (EtOH) intake. In accordance with this, a considerable amount of antagonists for these ion channels has been found to suppress EtOH intake and preference in various animal models of alcoholism. The aim of the present study was to examine antialcohol effects of L-type Ca2+ channel antagonists in alcohol-preferring AA rats. These rats, a Wistar line selectively bred for a high 10% v/v EtOH preference in a free-choice situation, have thus far not been subjected to systematic investigations with Ca2+ channel antagonists. Therefore, effects on EtOH preference and intake, as well as on food and total fluid intake, were evaluated for the 1,4-dihydropyridine (DHP) derivatives nimodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine, as well as for the phenylalkylamine verapamil and the benzothiazepine diltiazem, utilizing a limited access, free-choice procedure. All DHPs were found to be highly effective in reducing both EtOH intake and preference, without affecting total fluid intake. Irrespective of route of application (IP or PO), the effective dose ranges were found to be very similar across compounds (10-30 mg/kg). Nevertheless, because food intake was also reduced, the effects were not completely selective. For nimodipine, the (-)-enantiomer seemed to be more effective as its (+)-enantiomer, possibly reflecting stereoselectivity at central binding sites. Compared to the DHPs, verapamil produced a similar profile of activity, but diltiazem was found to be ineffective. These results confirm and extend previous findings with L-type Ca2+ channel antagonists obtained in other models of alcoholism and suggest that this class of compounds offers an interesting approach for the pharmacotherapy of alcoholism.

Previous studies have shown that injection of 5-hydroxytryptamine (serotonin) receptor agonists in the dorsal raphe nucleus (DRN) to stimulate somatodendritic 5-HT1A autoreceptors or in the hippocampus to stimulate postsynaptic 5-HT1A receptors, induces anxiolytic-like effects in the rat. The mechanisms triggered by the latter treatment were investigated by measuring both the electrical activity of serotonergic DRN neurons and the anxiolytic response in rats receiving injections with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) or ipsapirone into the dorsal hippocampus. Anxiety-related behavior was estimated by recording the time of ultrasonic vocalization (USV) due to electric foot shocks under standardized conditions. Intrahippocampal application of 8-OH-DPAT or ipsapirone produced a dose-dependent inhibition of the firing of serotonergic DRN neurons and of the shock-induced USV response. However, the range of efficient doses of 8-OH-DPAT via the intrahippocampal route (1-10 micrograms/rat) was larger than that using the i.v. route of injection (0.15-2.5 micrograms/rat). Furthermore, maximal inhibition of the firing of DRN serotonergic neurons occurred earlier when 8-OH-DPAT was injected i.v. (within 1-2 min) than when it was injected into the dorsal hippocampus (within 5 min). Interestingly, the injection of 8-OH-DPAT into the striatum, where 5-HT1A receptors are hardly detectable, or a lateral ventricle, also yielded dose-dependent reduction in both the firing rate of serotonergic DRN neurons and the USV response. Finally, local lesion with ibotenic acid to eliminate postsynaptic 5-HT1A receptors did not alter the inhibitory effects of intrahippocampal application of 8-OH-DPAT on the firing of serotonergic DRN neurons and the USV response. These data indicated that postsynaptic 5-HT1A receptors were not responsible for the inhibitory effects of 8-OH-DPAT and ipsapirone injected in forebrain areas on the electrical activity of serotonergic neurons and the USV response in rats. As shown by the autoradiographic labeling by [3H]8-OH-DPAT at distance from its injection site in the dorsal hippocampus, the diffusion of 5-HT1A receptor agonists (from injected areas in the forebrain to the DRN where they directly inhibit the electrical activity of serotonergic neurons) more likely accounted for their anxiolytic-like effects.

The present study compared the 5-HT1A receptor ligands 8-OH-DPAT and ipsapirone with diazpepam and imipramine in the shock induced ultrasonic vocalization anxiety test and the forced swimming depression test in the rat. Acutely, 8-OH-DPAT induced anxiolytic and antidepressive effects (ED50: 0.12 and 1.4 mg/kg, i.p., respectively), whereas ipsapirone induced anxiolytic (ED50: 0.6 mg/kg) and moderate antidepressive effects (33% at 3-10 mg/kg). Virtually no tolerance developed for the anxiolytic effects after 2 weeks of treatment with 0.03-1 mg/kg 8-OH-DPAT or 0.1-10 mg/kg ipsapirone (i.p., b.i.d.), with 10 mg/kg/day ipsapirone (s.c., mini-pumps), or with 1.5 mug/rat/hr 8-OH-DPAT (local infusion in the dorsal raphe nucleus, mini-pumps). However, some tolerance developed for the antidepressive effects of 8-OH-DPAT (ED50: 0.6,1.4, 2.5 and >3 mg/kg, after 2 weeks of pretreatment with vehicle, 0.3, 1, and 3 mg/kg 8-OH-DPAT, respectively, i.p., b.i.d.). In the case of ipsapirone, the dose-effect curve in the forced swimming test was shifted to the left after 2 weeks of pretreatment with ipsapirone (0.3-10 mg/kg, i.p., b.i.d.). Acutely, diazepam induced an anxiolytic effect (ED50: 3.6 mg/kg, i.p.), but failed to induce an antidepressive effect; whereas imipramine induced an antidepressive effect (ED50: 20.5 mg/kg) and a moderate anxiolytic effect (max. efficacy: 47% at 30 mg/kg). Upon repeated administration (2 weeks), diazepam (5 mg/kg) showed tolerance for its anxiolytic effects and weak antidepressive effects emerged, whereas imipramine (20 mg/kg) showed weak sensitization for both effects. It is concluded that (a) with all compounds, tolerance, as well as sensitization can be observed, depending on the behavioral test, the dose and the type of compound; and (b) compared with the other compounds tested, relatively low doses of 5-HT1A drugs offer the most attractive profile of mixed anxiolytic/antidepressive activity. (C) 1993 Wiley-Liss, Inc.

Rats were trained to discriminate 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, 1.25 mg/kg i.p.), a selective and nonselective 5-hydroxytryptamine1A (5-HT, serotonin) receptor agonist, respectively, from saline in a two-lever procedure. The selective 5-HT1A receptor agonist ipsapirone substituted completely for 8-OH-DPAT (ED50, 1.52 mg/kg) and 5-OMe-DMT substituted partially for 8-OH-DPAT, whereas 8-OH-DPAT (ED50, 0.07 mg/kg) and ipsapirone (ED50, 4.15 mg/kg) substituted completely for 5-OMe-DMT. These results suggest that the discriminative stimulus properties of both 8-OH-DPAT and 5-OMe-DMT are 5-HT1A receptor mediated, although 5-OMe-DMT may involve an additional interaction with other 5-HT receptor subtypes. 5-OMe-DMT substituted for 8-OH-DPAT after application in the lateral ventricle (ED50, 3.0 micrograms/rat) and the dorsal raphe nucleus (DRN, 1.1 micrograms/rat). After application in the DRN (ED50 range, 1.4-5.0 micrograms/rat) and the median raphe nucleus (2.3 micrograms/rat), and after bilateral application into the CA-4 region of the dorsal hippocampus (4.1 micrograms/rat), 8-OH-DPAT also produced responding on the 8-OH-DPAT lever. Ipsapirone also substituted for 8-OH-DPAT after application into the DRN and the hippocampus (ED50S, 38 and 62 micrograms/rat, respectively). The 5-HT1A mixed agonist-antagonist (1-(2-methoxyphenyl) 4-[4-(2-pthalimido)butyl]piperazine, i.p. NAN-190) attenuated the discriminative stimulus effects of 8-OH-DPAT injected i.p. (0.1 mg/kg), into the DRN (10 micrograms) or into the hippocampus (2 x 10 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

In the rat forced swimming test, systemic application of the serotonin 1A (5-HT1A) receptor agonist 8-OH-DPAT reduced immobility (ID50 0.17–1.37 mg/kg, depending on route of application and application schedule). Intracerebroventricular (i.c.v.) or local application into the dorsal raphe nucleus (DRN), a brain area rich in presynaptic 5-HT1A receptors, resulted in a parallel shift of the dose-response curve to the left (ID50 5.1 and 3.9 μg/rat, respectively). Systemic application of the 5-HT1A receptor partial agonist ipsapirone resulted in a U-shaped dose-response curve (maximal effect about 30% immobility reduction at 3–10 mg/kg). Local application of ipsapirone in the DRN reduced immobility (maximal effect 40% at 60 μg/rat). However, 8-OH-DPAT and ipsapirone were still effective after depletion of brain 5-HT by means of 5,7-DHT (150 μg, i.e. v.) or pCPA (either 2 ± 150 mg/kg or ± 350 mg/kg, i.p.) Additionally, in non-lesioned rats: (1) the putative (postsynaptic) 5-HT1A antagonist NAN-190, but not spiperone, haloperidol, prazosin or 1-PP, was able to block the anti-immobility effects of 8-OH-DPAT in a behaviorally specific manner; (2) local application of 8-OH-DPAT and ipsapirone in the lateral septum (a brain area rich in postsynaptic 5-HT1A receptors) reduced immobility (8-OH-DPAT: ID50 11.4 μg/rat; ipsapirone: maximal effect at 30 μg/rat 38%); and (3) pretreatment with ipsapirone resulted in an attenuation of the effect of 8-OH-DPAT when both compounds were administered either systemically or in the lateral septum but not when both compounds were microinjected into the DRN. It is hypothesized that the anti-immobility effects of 5-HT1A receptor agonists are mediated by pre- and postsynaptic 5-HT1A receptors and that they closely reflect the intrinsic activity of these compounds at these receptors.

1. Preclinical and clinical studies suggest that 5-HT1A receptor agonists are a new class of mixed anxiolytics/antidepressants with, possibly, impulsivity reducing properties. 2. The anxiolytic effects of 5-HT1A receptor agonists result predominantly from an interaction with presynaptic 5-HT1A receptors (resulting in a decrease of serotonergic transmission), whereas the antidepressive and, possibly, the impulse control enhancing effects, result predominantly from an interaction with postsynaptic 5-HT1A receptors. 3. These proposed mechanism(s) of action fit well with the generally held view that anxiety is the result of a hypersensitive 5-HT system; whereas impulsivity and depression is the result of a hyposensitive 5-HT system. 4. However, it appears very likely that activation of pre- and postsynaptic 5-HT1A receptors is additionally involved in the antidepressive and impulse control enhancing effects, on the one hand, and in the anxiolytic effects of these compounds, on the other hand. 5. These latter, seemingly paradoxical, findings can be explained by assuming that (1) the presynaptic mechanism reflects an anxiolytic component in the animal models of impulsivity and depression, (2) antagonism of postsynaptic 5-HT1A receptors by these compounds contributes to their anxiolytic effects, (3) postsynaptic 5-HT1A and 5-HT2 receptors have functionally opposing effects or, alternatively, that (4) downregulation of postsynaptic 5-HT2 receptors contributes to the therapeutic effects of these compounds.

A putative animal model of anxiety based on shock-induced ultrasonic vocalization was pharmacologically validated in young adult rats. Suppression of shock-induced ultrasonic vocalization was obtained with diazepam, chlordiazepoxide, meprobamate and pentobarbital; the serotonin (5-HT)1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], buspirone, ipsapirone, gepirone and tandospirone; the nonselective 5-HT receptor agonists TFMPP [1-(3-trifluoromethylphenyl)piperazin], mCPP [1-(3-chlorophenyl)piperazin] and DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane); the NMDA antagonists PCP (phencyclidine) and MK-801; the alpha 2-adrenoceptor antagonists idazoxane, yohimbine and 1-PP (1-pyrimidinylpiperazine); and the atypical neuroleptic clozapine. The alpha 2-adrenoceptor agonist clonidine, the 5-HT2/5-HT1C antagonist ritanserin, the 5-HT3 antagonists ondansetron and ICS-205,930, and the 5-HT reuptake inhibitor fluoxetine did not, or only partially, reduce ultrasonic vocalization. Tricyclic and tetracyclic, as well as some atypical antidepressants and a monoamineoxidase (MAO) inhibitor, showed no ultrasonic vocalization reducing effects, or reduced ultrasonic vocalization only at high doses. An opiate, an antimuscarinic, (pro)convulsants and typical neuroleptics did not reduce ultrasonic vocalization. The present findings suggest that the ultrasonic vocalization model specifically measures anxiolytic effects. Because ultrasonic vocalization responding develops within five days, remains stable for at least three months and gives highly reproducible results, the test appears suitable for rapid and repeated testing of new anxiolytics in the same animals.

In rats, the 5-HT1A receptor full agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT1A receptor partial agonists ipsapirone and buspirone dose dependently and completely inhibited shock-induced ultrasonic vocalization after systemic injection and after microinjection into the dorsal raphe nucleus, a brain region rich in somatodendritic 5-HT1A receptors. As compared with injection into the dorsal raphe nucleus, ipsapirone and 8-OH-DPAT were significantly less potent after microinjection into the lateral ventricle or the median raphe nucleus. Depletion of brain 5-HT (5-hydroxytryptamine) by means of 5,7-dihydroxytryptamine or parachlorophenylalanine inhibited ultrasonic vocalization. In lesioned rats, however, ipsapirone (i.p. or dorsal raphe nucleus) and 8-OH-DPAT (dorsal raphe nucleus) retained their ability to inhibit ultrasonic vocalization and, in nonlesioned rats, bilateral injection of ipsapirone, buspirone and 8-OH-DPAT into the dorsal hippocampus and the amygdala - two brain regions rich in postsynaptic 5-HT1A receptors - also inhibited ultrasonic vocalization. In a Geller-Seifter conflict test, i.p. and local injection of 8-OH-DPAT in the dorsal raphe nucleus and the hippocampus selectively enhanced punished responding. It is suggested that both presynaptic and (possibly to a lesser extent) postsynaptic 5-HT1A receptors are involved in the anxiolytic effects of ipsapirone, buspirone, and 8-OH-DPAT.

Ipsapirone, a 5-HT1A receptor agonist, is a psychoactive compound with anxiolytic and antidepressive properties. Concerning the mechanism of action of ipsapirone, most studies point towards an interaction with the central serotonergic system. For characterization of the anxiolytic properties of ipsapirone, the ultrasonic vocalization test, a rat model based on conditioned anxiety, was used. In this test ipsapirone time and dose dependently inhibited the shock induced ultrasonic vocalization of rats after systemic application of ipsapirone, indicating its potent anxiolytic properties. To gain further insight into the mechanism underlying the anxiolytic activity of ipsapirone, the effects of this compound on the central serotonergic system of rats were characterized. Extracellular single unit recordings, measuring the firing rate of serotonergic dorsal raphe neurons in anaesthetized rats, showed that ipsapirone dose and time dependently suppressed neuronal firing. In the hippocampus, one of the projection areas of the serotonergic dorsal raphe neurons, systemic application of ipsapirone resulted in a dose- and time-dependent reduction in serotonergic neurotransmission, measured as a reduced serotonin output in microdialysis experiments with freely moving rats. The time- and dose-effect curves reflecting the anxiolytic, electrophysiological, and biochemical effects correlated well with each other for different doses of ipsapirone. It is concluded that ipsapirone exhibits its anxiolytic effects, at least partially, by stimulating presynaptic somatodendritic 5-HT1A receptors in the brain stem raphe nuclei (i.e., the dorsal raphe), resulting in attenuation of presynaptic cell firing and subsequent inhibition of serotonergic neurotransmission in the limbic system (i.e., the hippocampus).

Acute stimulation of 5-HT1A receptors has been reported to diminish some 5-HT2 receptor-mediated responses in the rat, but there is controversy as to whether repeated stimulation of 5-HT1A receptors leads to identical changes. In this study, we tested the influence of repeated treatment with the 5-HT1A receptor agonist ipsapirone (0.5 g/l in drinking water for 21 days) on some 5-HT2 receptor-mediated responses elicited by the acute injection of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These responses included hyperglycemia, corticosterone release, and head shakes; cortical 5-HT2 receptor number and DOI-induced prolactin release (a 5-HT1C/5-HT2 receptor-mediated event) were also analyzed. In a first series of experiments, ipsapirone administration for 1, 8, 15, and 20 days reduced the duration fo shock-induced ultrasonic vocalization. Ipsapirone administration for 21 days reduced fluid intake and decreased body weight, but did not affect baseline plasma glucose, corticosterone, and prolactin levels or cortical 5-HT2 receptor number. The increases in plasma glucose levels elicited by acute injection of either DOI (0.1-1 mg/kg i.v.) or clonidine (an alpha 2-adrenoceptor agonist; 0.05 mg/kg i.v.) were reduced in ipsapirone-pretreated rats. The maximal effects of DOI and clonidine on plasma corticosterone or prolactin levels were not affected by ipsapirone pretreatment. Ipsapirone decreased the area under the corticosterone curve in both DOI- and clonidine-treated rats. Lastly, the head-shake response to DOI (0.5-2 mg/kg s.c.) was similar in vehicle- and ipsapirone-pretreated rats. These data indicate that a 3-week treatment with anxiolytic doses of the 5-HT1A receptor agonist ipsapirone does not desensitize 5-HT2 receptors.

Central Institute of Mental Health, Unit Neurobiology of Functional Psychoses P. O. Box 12 21 20, D-6800 Mannheim 1, F. R. G.

For a systematic study of the influence of age and gender on symptomatology and early course of schizophrenia, we collected a representative sample of 392 first hospital admissions for schizophrenia (broad definition) from a population of 1.5 million. By using several operational definitions we assessed ‘true onset’ in a semistructured interview ‘IRAOS’. We were able to demonstrate that the mean age at onset is 3-4 years higher in females than in males with the lifetime risk being exactly equal. In males the rates of onset show a steep increase starting from school age and reach a peak in the age group 15-24, followed by a monotonous decrease. Females reach a lower first peak with a clear delay between 20 and 29. After the decrease a second smaller peak is observed consistently in females in the age group 45-49 and over. We hypothesized that the effect of dopaminol on the dopaminergic system enhances the vulnerability threshold, which is lowered again during menopause. We tested the hypothesis experimentally with animal models: estradiol treatment caused a significant reduction of both dopamine-agonist and -antagonist induced behavior showing a maximum in neonatal rats. The higher age at onset and the second peak after menopause in females may therefore be due to effects of estrogens. A comparison of early symptoms in the two sexes revealed only few significant differences, which are more likely to be attributed to illness behavior than to the disease. The same is true for the comparison over three age groups, which in negative symptoms showed no differences, whereas solely personality development accounted for the gender difference in positive symptoms. Patterns of early course of the psychosis also are surprisingly similar in the two sexes and over the three age groups. Unexpected is the prolonged course and the predominance of negative symptoms in the early states of schizophrenia in females compared to males.

We found in a representative sample of 392 first hospital admissions for schizophrenia a higher mean age at onset in females by 3.2 to 3.9 years, whereas the lifetime risk was equal for both sexes. In males the rates of onset show a steep increase reaching the maximum value in the age group 15-24 years, followed then by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease a second smaller peak is observed consistently in females within the age group 45-49 years and over. After having excluded alternative explanations for this gender differences (for example, diagnosis artefacts, sociocultural factors), we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold for schizophrenia, which is lowered again during the menopause. Alternatively we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of schizophrenia in males. We tested these hypotheses in animal models by investigating the effects of the gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. Testosterone showed no clear influence on the tested dopamine-mediated behaviour. Oestradiol caused a significant reduction on both dopamine-agonist and dopamine-antagonist induced behaviour. These effects were stronger in neonatal animals. Since oestradiol caused a 2.8-fold reduction of dopamine receptor affinity for sulpiride, we assumed that the behavioural changes caused by oestradiol were accounted for by a down-regulation of the dopaminergic system.(ABSTRACT TRUNCATED AT 250 WORDS)