5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential.

In vitro, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 exhibited high-affinity binding to the serotonin2C (5HT2C) receptors and stimulated turnover of inositol 1,4,5-triphosphate. Affinity to several of the other 5-HT receptor subtypes and to numerous nonserotonergic receptors was much lower. In rats, both compounds elicited behavioral signs of 5-HT2C receptor agonism but not 5-HT2A receptor agonism. Hypomotility induced in rats by high doses of these compounds was reversed by the 5-HT2C receptor antagonist N-(2-naphthyl)-N'-(3-pyridyl)-urea 1:1 HCI. In addition, these compounds were active in tests used to demonstrate anticompulsive effects: reducing schedule-induced polydipsia in rats (prevented by the 5-HT2C/2B receptor antagonist N-(1-methyl-5'-indolyl)-(3-pyridyl)urea 1:1 HCl, reversing increased scratching induced with 8-hydroxy-dipropylaminotetralin 1:1 HCl in squirrel monkeys (no tolerance developed), decreasing responding in the marble-burying task in mice, and decreasing excessive eating of palatable food in rats. In contrast to these compounds, fluoxetine was much less potent, and in some tasks less efficacious, in reducing excessive behavior in these models. These two 5-HT2C receptor agonists do not show anxiogenic effects in the plus-maze in rats. (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 reduced the olfactory bulbectomy-induced passive avoidance impairment in rats, a result that indicates antidepressant potential. Similarly, in the differential-reinforcement-of-low rate 72-s operant schedule task in rats, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 increased (and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 showed a tendency to increase) total reinforcements received, which is suggestive of antidepressant activity. The electroencephalography defined sleep-waking pattern in rats produced by these two 5-HT2C agonists, as well as fluoxetine, included increased quiet-waking and decreased rapid-eye-movement sleep, which is characteristic of antidepressant drugs. These results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.

Antiaversive effects of 5HT2C receptor agonists and fluoxetine in a model of panic-like anxiety in rats.

Dose-dependent increases in threshold for operant fear/escape responses of rats submitted to aversive stimulation of the dorsolateral periaqueductal gray (dPAG) were recorded following intraperitoneal injection of three chemically unrelated but selective 5HT2C receptor agonists (Ro 60-0175, Org 12962 and Ro 60-0332) and fluoxetine. The decreased sensitivity of rats to the acute panic-like aversion elicited by stimulation of this limbic periventricular region was detected at dosages devoid of impairing effects on the latencies needed for operant brain stimulation interruption. In this paradigm which has been validated as a simulation of acute anxiety with relevance to panic disorder, the selective activation of 5HT2C receptors by Ro 60-0175, Org 12962 or Ro 60-0332 induces effects analogous to those observed following benzodiazepine receptor activation by antipanic agents such as clonazepam or alprazolam or following non-selective and indirect 5HT receptor activation by fluoxetine. Potency and efficacy of 5HT2C receptor agonists were intermediate between those of clonazepam and fluoxetine, indicating authentic antiaversive properties and suggesting antipanic potential for these 5HT2C receptor agonists. In addition, these data suggest that the 5HT2C receptor subtype may play a major role in the therapeutic properties of selective serotonin reuptake inhibitors. It is also speculated that serotonin/benzodiazepine interactions existing in the brain may functionally involve the 5HT2C receptor subtypes and that the anxiogenic action reported under certain circumstances for 5HT mimetics are not mediated by 5HT2C receptor subtypes.

Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan.

The effects of three compounds with alpha-2 adrenoceptor antagonistic properties, mirtazapine (Org 3770; Remeron), mianserin and idazoxan, were measured on hippocampal noradrenergic and serotonergic transmission in freely moving rats by using microdialysis. Dihydroxyphenylacetic acid (DOPAC) was measured as a correlate of noradrenergic presynaptic activity. Infusing 1 microM tetrodotoxin decreased extracellular serotonin (5-HT) and DOPAC by 65 and 40%, respectively. 5-Hydroxytryptophan (25 mg/kg s.c.) increased extracellular 5-HT by 500%, whereas 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (0.5 mg/kg s.c.) decreased 5-HT release by 60%. Prazosin decreased 5-HT release to 60% of base-line in agreement with an alpha-1-mediated control of 5-HT transmission, whereas it increased DOPAC release with 80%. Both mirtazapine (2 and 5 mg/kg s.c.) and idazoxan (1 mg/kg s.c.) caused a rapid increase in DOPAC by up to 80%. Mianserin slowly increased DOPAC, reaching a maximal increase of 30 and 60% at 2 and 5 mg/kg s.c., respectively. Only mirtazapine caused a concurrent increase in 5-HT, reaching up to 80% above base-line within 60 min, whereas mianserin and idazoxan failed to change 5-HT levels significantly. Mirtazapine (5 mg/kg s.c.) only slightly affected DOPAC and homovanillic acid levels in the striatum, hardly affected 5-HT release, but clearly increased 5-hydroxyindole acetic acid. Thus, the antidepressants mirtazapine and mianserin markedly differ in their effects on noradrenergic and serotonergic transmission in vivo as measured with microdialysis in freely moving rats. These differences are explained by their different modulatory effects on noradrenergic transmission.

Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor.

The 5-HT2C receptor gene is unique among the members of the 5-HT receptor family by virtue of its genomic organisation. The human 5-HT2C receptor gene, unlike many other genes for guanine nucleotide binding (G)-proteins, contains three introns which interrupt the coding sequence into four exons. The first two introns are at equivalent positions as compared to the intervening sequences previously found in the 5-HT2(A) receptor gene, suggesting a close evolutionary relationship between both genes. Southern blot analysis shows that the 5-HT2C receptor gene is a single copy gene. Furthermore, we report the functional expression of a complementary DNA for the 5-HT2C receptor, cloned from hippocampal RNA. Membranes prepared from NIH 3T3 cells stably expressing the 5-HT2C receptor cDNA, displayed a single population of high affinity sites for the antagonist [3H]mesulergine (Kd = 2.9 +/- 0.4 nM, Bmax = 44.3 +/- 7.2 pmol/mg protein) as well as for [3H]5-HT (Kd = 9.9 +/- 0.7 nM, Bmax = 13.6 +/- 1.0 pmol/mg protein). Displacement of [3H]mesulergine and [3H]5HT binding by ligands indicated a pharmacological similarity of these binding sites with porcine and rat choroid plexus 5-HT2C receptors. Furthermore, activation of the 5-HT2C receptor with 5-HT results in an increased phospholipase C activity.

Reversal by NGF of cytostatic drug-induced reduction of neurite outgrowth in rat dorsal root ganglia in vitro.

Cytostatic drugs, like cisplatin, vincristine and taxol, when given to cancer patients may cause peripheral neuropathies. We were interested in the potential neuroprotective effects of neurotrophic factors against such neuropathies. To this aim we studied the effects of these cytostatic agents on sensory fibers located in the dorsal root ganglia (DRG) in vitro and studied whether nerve growth factor (NGF) could reverse the cytostatic induced morphological changes on intact DRG (1 DRG/well, n = 10 per dose). Neuritogenesis from DRG was measured with an image analysis system following exposure to different concentrations of cytostatic drugs in the presence of 3 ng NGF/ml and cytosine arabinoside (Ara-C, 10(-6) M). Relative neurite outgrowth in intact DRG in culture was reduced dose-dependently, (a) by vincristine starting at a dose of 0.4 ng/ml for 2 days (-33% as compared to control; P < 0.001, Student's t-test); (b) by taxol 10 ng/ml (-60%; P < 0.001), and (c) by cisplatin 3 micrograms/ml (-47%, P < 0.001). Cisplatin also prevented the migration of satellite cells away from the intact DRG along the extending neurites into the well in contrast to control, vincristine, or taxol. To evaluate the neuroprotective potential of NGF in this in vitro cytostatic neuropathy model, we incubated intact DRG with cytostatic agents in combination with increasing amounts of NGF. Neurite outgrowth from DRG treated with vincristine (0.5 ng/ml)+NGF (3 ng/ml) for 2 days was significantly higher (+87%) than after treatment with vincristine + 1 ng NGF/ml (P < 0.001). Neurite outgrowth from DRG treated with taxol (20 ng/ml)+NGF (3 ng/ml) for 2 days was significantly higher (+228%) than after taxol + 1 ng NGF/ml (P < 0.05). Neuritogenesis from DRG treated with cisplatin (2.5 micrograms/ml)+NGF (3 ng/ml) for 2 days was significantly increased (+105%) compared to treatment with cisplatin + 1 ng NGF/ml (P < 0.001). DRG thus appear to be a very suitable model for studying cytostatic drug-induced neuropathies in vitro and NGF has a clear neuroprotective effect on the vincristine-, taxol-, and cisplatin-induced neuropathies in this in vitro model.

The effect of the potential antipsychotic ORG 5222 on local cerebral glucose utilization in freely moving rats.

The effects of administration of different doses of the potential antipsychotic Org 5222 (0.01 and 0.1 mg/kg i.v.) upon local cerebral glucose utilization (LCGU) in 102 anatomically discrete brain regions of freely moving male Wistar rats were studied with the quantitative autoradiographic [14C]2-deoxyglucose technique. Glucose utilization was significantly changed after treatment with 0.01 and 0.1 mg/kg i.v. Org 5222 in two and four brain areas, respectively. Treatment with 0.01 mg/kg Org 5222 significantly reduced LCGU in the basal thalamus (the ventral posterior medial (VPM) and lateral (VPL) nuclei). After administration of 0.1 mg/kg Org 5222, significant reductions were seen in the basal thalamus (VPL and VPM) and the medio dorsal thalamic nuclei. A highly significant elevation in LCGU was observed in the lateral nucleus of the habenula. The results show that Org 5222 selectively reduced LCGU in thalamic structures and had no or minimal effect on limbic, cortical and nigrostriatal structures, suggesting that Org 5222 may have antipsychotic potential, without inducing cognitive and extrapyramidal side-effects.

Depletion of brain serotonin differently affects behaviors induced by 5HT1A, 5HT1C, and 5HT2 receptor activation in rats.

5-hydroxytryptamine (5HT)-depleted rats were subjected to behavioral experiments in which the response to activation of 5HT1A, 5HT1c, and 5HT2 receptor subtypes was measured. Depletion of 5HT was produced by unilateral intracerebroventricular injection of 5,7-dihydroxytryptamine (100 micrograms/rat) or by systemic injection of p-chlorophenylalanine (150 mg/kg injected intraperitoneally 72, 48, and 24 h before the test). The dose-response curve of the 5HT1A-mediated, 8-hydroxy-2-(di-n-propylamino)tetralin (0.022-0.46 mg/kg)-induced lower lip retraction was not changed after depletion, nor was the dose-response curve of the 5HT2 receptor-mediated (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (0.046-1.0 mg/kg)-induced head shake response. The dose-response curve for penile erections, a 5HT1c receptor-mediated response after mCPP (0.1-1.0 mg/kg), a direct 5HT1c agonist, is shifted to the left after 5HT depletion, whereas the response to indirect activation of the 5HT1c receptor with the 5HT reuptake inhibitors citalopram (2.2-4.6 mg/kg) and paroxetine (0.22-2.2 mg/kg) was inhibited after 5HT depletion. These results suggest that 5HT1c receptors are more subject to denervation supersensitivity than 5HT1A and 5HT2 receptors. This lesion model may be useful to discriminate behaviorally between direct and indirect activation of the 5HT1c receptor.

Antagonism of 8-OH-DPAT-induced behaviour in rats.

Selective activation of the 5-HT1A receptor induces lower lip retraction (LLR) in rats. 8-Hydroxy-dipropylamino tetralin (8-OH-DPAT)-induced LLR could not be antagonised by the 5-HT antagonists methysergide, metergoline or mesulergine. In fact, some 5-HT antagonists induced LLR. However, 8-OH-DPAT-induced LLR could be antagonised by pindolol, spiperone, spiroxatrine and NAN-190, but not by the beta 1-adrenoceptor antagonist metoprolol, the beta 2-adrenoceptor antagonist butoxamine or the dopamine antagonist haloperidol. This antagonism was competitive as the dose-response curve of 8-OH-DPAT was shifted to the right. Pindolol, spiperone, spiroxatrine and NAN-190 all have a high affinity for the 5-HT1A receptor. This indicates that blockade of 8-OH-DPAT-induced LLR is only possible by selective blockade of 5-HT1A receptors. A possible mechanism of action is discussed. The increased defecation induced by 8-OH-DPAT could be antagonised by pindolol and NAN-190. The effect of spiroxatrine and haloperidol on the 8-OH-DPAT-induced increase in defecation was bimodal: an increase after a low and a decrease after a high dose of 8-OH-DPAT. Metoprolol and butoxamine had no effect on the 8-OH-DPAT-induced increase in defecation, thereby excluding an influence of beta-adrenoceptors.

Behavioural pharmacology of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro- 1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrolidine maleate, a compound interacting with dopaminergic and serotonergic receptors.

trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepinol[4,5-c]pyrrolidine maleate (Org 5222) is a new compound with effects on animal behaviour indicating strong antipsychotic potential based on antagonism of dopaminergic and serotonergic effects. The compound inhibits apomorphine-induced climbing behaviour, mouse locomotor activity, rat activity in an open field, shuttle box behaviour in rats, pergolide induced circling in 6-hydroxydopamine(6-OHDA) lesioned rats, serotonin agonist-induced forepaw treading, head shakes and penile erections. The compound is less effective in inducing catalepsy, and antagonising SKF-38393 (tetrahydro- 1-phenyl-1H-3-benzazepine-7,8-diol HCl)-induced circling in 6-OHDA-lesioned rats and it does not induce perioral movements in rats. Based on these data and the neurochemical profile of the compound it was decided that this compound merits clinical investigation in a programme aiming for an effective antipsychotic agent with reduced risks of extrapyramidal side-effects.

Neurochemical studies with the potential antipsychotic compound trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate.

trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c]pyrrolidine maleate (Org 5222) has dopamine D2 antagonistic and negligible anticholinergic properties of the classical neuroleptic haloperidol. In addition it combines the strong antiserotonergic and antihistaminergic properties of chlorpromazine and clozapine with the potent dopamine D-1 antagonistic properties of Sch 23390 (R-(+)-delta-chloro-2,3,4,5-tetrahydro-3-methyl-5- phenyl-1H-3-benazepin-7-ol(Z)-2-buteneoate). This in conjunction to its behavioural properties, warrants clinical testing in psychotic patients.

The effect of antidepressants on aversive periaqueductal gray stimulation in rats.

The selective serotonin (5-HT) uptake inhibitors fluvoxamine and sertraline had anti-aversive effects when administered acutely. Imipramine and clomipramine, which combine noradrenaline (NA) and 5-HT uptake blocking properties, did not have significant effects, whereas the mixed dopamine (DA)/NA uptake blocker nomifensine decreased the thresholds for escape from aversive periaqueductal gray stimulation. These results suggest that indirect 5-HT receptor activation suppresses periaqueductal gray aversion. Conversely, indirect DA and perhaps NA receptor activation appears to enhance periaqueductal gray aversion in rats.

5-HT1C receptors in the serotonergic control of periaqueductal gray induced aversion in rats.

The functional role of brain 5-HT and 5-HT receptor subtypes in periaqueductal gray (PAG) induced aversion has been investigated in rats. Antiaversive effects were found with the serotonin agonists TFMPP, mCPP and DOI but not with RU 24969 which was found to facilitate PAG aversion. The first three serotonin agonists share potent 5-HT1C activity while RU 24969 differs with a high 5-HT1A activity. Proaversive effects were found with the mixed 5-HT1C/5-HT2 antagonists cyproheptadine and ritanserin; this effect was already reported for the mixed 5-HT1C/5-HT2 antagonists metergoline and mianserin and is opposite to the effects of the selective 5-HT2 antagonists ketanserin, pirenperone, trazodone and spiperone. The antiaversive effects of mCPP (1 mg/kg) could be prevented by pretreatment of the animals with mianserin (1 and 10 mg/kg). These results suggest that 5-HT1C receptors play an important role in the serotonergic control of PAG aversion. 5-HT1C receptor activation seems to mediate antiaversive effects whereas acute 5-HT1C receptor blockade appears to facilitate PAG aversion. Functional interactions take place between several receptor types in the in vivo control of PAG aversion, where 5-HT1C receptors appear to play a predominant function.

A large scale, high resolution, automated system for rat sleep staging. I. Methodology and technical aspects.

An automatic rat sleep classification system is described which records and analyses bioelectrical signals from 32 rats over extended periods of time. At present this system is used routinely for the screening of drug effects on sleep. The analysis is based on 3 signals, the parieto-occipital EEG, nuchal EMG and a movement indicator signal. The on-line analysis is done per epoch of 2 sec and involves power spectral analysis of the EEG and rectification and integration of the EMG and movement signals. The automatic sleep staging into 6 stages (active and quiet waking; quiet, deep, pre-REM and REM sleep) is performed off-line. Parameters derived from a discriminant analysis of visually scored tracings of individual rats constitute the basis for the automatic scoring procedure. The movement index is used to discriminate between active and quiet waking, while the use of the EMG level improves the separation of waking and REM sleep. After the construction of hypnograms from these computer scorings a set of parameters can be extracted which characterizes the sleep-waking behavior of each individual rat. These parameters are then used to compare statistically the 2-4 treatment groups which make up each experiment of 32 rats. Experimental validation of the system is reported in an accompanying paper.

Local cerebral glucose uptake in anatomically defined structures of freely moving rats.

Two limitations of the classical [14C]2-deoxyglucose (DG) method are the severe stress to which the restrained animals are exposed, and the difficulties with the anatomical analysis of the autoradiograms. The present study describes modifications which circumvent these limitations. Firstly, rats are provided with two chronic indwelling cannulas to allow blood sampling under unrestrained conditions. Absence of stress is demonstrated by low plasma corticosterone levels in the cannulated rats at the start of the experiment. The second modification concerns the image analysis system. The image of the autoradiogram is superimposed on the image of the identical histologically stained section in order to improve the accuracy of the structure identification. This approach enables the operator to delineate the anatomical brain structure in the histologically stained section and quantify the glucose uptake in the autoradiogram generated from this section. The reproducibility of the present quantitative measuring system is illustrated by glucose uptake measurements in different laminar zones of the various fields in the dorsal hippocampal formation. It is concluded that the present technical improvements of the classically applied [14C]2-deoxyglucose technique provide favourable conditions for the quantitative study on cerebral glucose uptake in normally behaving animals.

Opposite control mediated by central 5-HT1A and non-5-HT1A (5-HT1B or 5-HT1C) receptors on periaqueductal gray aversion.

8-OH-DPAT, a selective 5-HT1A agonist, and mCPP, which has preferential affinity for 5-HT1B and 5-HT1C receptors, were studied for their effects on aversive brain stimulation in rats. Opposite effects were found with these two agonists: D, L-8-hydroxy-N,N-dipropyl-2-aminotetralin HBr (8-OH-DPAT; 0.1-1.0 mg/kg i.p.) dose dependently decreased the threshold for neurostimulation-induced escape behaviour while mCPP (0.1-1.0 mg/kg i.p.) dose dependently increased the threshold. The proaversive effect of 8-OH-DPAT and the antiaversive effect of mCPP suggest that 5-HT1A and non-5-HT1a (5-HT1B or 5-HT1C) receptors play distinct roles in mechanisms of aversion, perhaps at different locations in the CNS.

Effects of serotonin receptor antagonists on PAG stimulation induced aversion: different contributions of 5HT1, 5HT2 and 5HT3 receptors.

The effects of serotonin receptor antagonists with differential selectivity for the various classes of 5HT receptors (5HT1, 5HT2 and 5HT3) were tested for their effects on the response to aversive brain stimulation. Electrical stimulation was administered to the dorsal part of the periaqueductal gray matter (PAG), one of the main cerebral structures subserving negative reinforcement. Stimulation frequency thresholds for escape responses were recorded before and following administration of the compounds. Ketanserin (0.32-32 mg/kg IP), trazodone (1.0-22 mg/kg), pirenperone (0.032-1.0 mg/kg) and spiperone (0.1-0.2 mg/kg) dose-dependently increased stimulation frequency thresholds necessary to induce escape responses. Opposite effects were observed with mianserin (0.01-32 mg/kg) and metergoline (0.032-10 mg/kg) which decreased threshold for escape. ICS 205-930 (0.01-10 mg/kg), did not affect the stimulation frequency threshold for escape. Prazosin (0.1-22 mg/kg) did not specifically affect aversive brain stimulation. Haloperidol (0.02-1.0 mg/kg) increased the frequency threshold for escape responses but with some motoric side effects. These data show that the various types of 5HT receptors differentially contribute to the control of central aversive systems in rats. It is suggested that blockade of 5HT2 receptors suppresses the central aversive system, whereas blockade of some 5HT1 receptors enhances aversion and overcomes the 5HT2-mediated suppression. Blockade of 5HT3 receptors has no effects. Dopamine receptor blockade further contributes to the suppression of the central aversive system. The relevance of these findings to some pathophysiological mechanisms of anxiety and depressive disorders is discussed.

Animal models for anxiety and response to serotonergic drugs.

In examining anxiety and the response of animal models to serotonergic drugs, four aspects should be taken into account: (1) the serotonin receptor is subdivided into at least six receptor subtypes; (2) benzodiazepines have acute anxiety-relieving effects, whereas antidepressants, serotonin-uptake inhibitors, buspirone, and serotonin antagonists have antianxiety effects only after prolonged administration; (3) diagnostic criteria differentiate several distinguishable anxiety disorders that have different responsiveness to serotonin-related drugs, and (4) various types of animal models exist, each responding differently to serotonin-related drugs. Perhaps particular animal models are relevant only for the study of one particular type of anxiety disorder. This differentiated view will be used when discussing the role of 5-hydroxytryptamine (5-HT) receptor subtypes in anxiety disorders and anxiety models. The 5-HT1A receptor is implicated in anxiety by the compounds buspirone and 8-hydroxy-2-(di-n-propyl-aminotetraline) (OHDPAT). The 5-HT1B or the 5-HT1D receptors play a role in the 'defensive burying' anxiety model and probably mediate antidepressant and antianxiety effects of serotonin-uptake inhibitors. The 5-HT1C receptor plays a role in the aversive brain stimulation anxiety model and could play a role in antianxiety effects of mianserin. The 5-HT2 receptor is selectively blocked by ritanserin. In animal 'conflict models' for anxiety, 5-HT-2-receptor antagonists are active, although they are weaker than the benzodiazepines. The 5-HT3-receptor antagonists are reported to be active in social interaction models for anxiety; however, clinical experience in anxiety using these compounds is not yet available.

Ovariectomy and subchronic estradiol-17 beta administration decrease dopamine D1 and D2 receptors in rat striatum.

Ovariectomy and subchronic estradiol-17 beta cause a down-regulation of dopamine D1 and, to a lesser extent, D2 receptors in rat striatum. An intracellular mechanism mediates the DA receptor down-regulation, as various estrogens do not interact with membrane-bound DA receptors in vitro. A common denominator, e.g. enhanced DA turnover, is suggested to mediate the estradiol-induced DA receptor down-regulation. Ovarian factors other than estradiol are additionally proposed to be involved in the regulation of striatal DA receptors.

Effect of metergoline, fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine.

The influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s.c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT1A receptor mediated events in both types of catalepsy.

The pharmacological profile of Org 6906, a potential non-sedative antidepressant that combines monoamine uptake inhibition with alpha 2-adrenolytic activity.

(dl)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-8-amine hydrochloride (Org 6906) is a potential new antidepressant agent, with a neurochemical profile quite different from that of the classical tricyclic antidepressant drugs. The compound was found active in behavioural tests which are considered to be predictive for antidepressant activity, such as the muricidal test in the rat and the acquired immobility model. Neurochemical studies showed that Org 6906 was an inhibitor of the reuptake of monoamines both in vitro and ex-vivo without having appreciable anticholinergic, antihistaminergic or alpha 1-adrenolytic activity. The facilitatory effect on monoaminergic neurotransmission was confirmed by the reversal of hypothermia induced by reserpine. The drug Org 6906 appeared to have selective alpha 2-adrenolytic properties. It facilitated potassium-stimulated release of noradrenaline from slices of cortex, displaced [3H]rauwolscine and [3H]dihydroergocryptine from their binding sites but only weakly blocked alpha 1-adrenoceptors. The alpha 2-adrenolytic properties were also apparent in behavioural interaction models. The compound antagonized the sleep-inducing effects of clonidine in chicks and mice and it antagonized the mydriasis induced by clonidine in the rat. Finally, it was shown that the two enantiomers of Org 6906 contributed almost equally to the relevant neurochemical and behavioural properties.