Effects of neuroleptic drugs,clonidine and lithium on the expression of conditioned behavioral excitation in rats

Rats with a history of daily (21 days) amphetamine (2.5 mg/kg) treatment showed enhanced activity when under placebo in their amphetamine-associated environment. We found that this conditioned effect was reduced by haloperidol (0.06; 0.125; 0.25 mg/kg), pimozide (0.25; 0.5 mg/kg) and sulpiride (8; 16; 32 mg/kg) but only at doses similar to or, in the case of pimozide, higher than those required to antagonize the unconditioned stimulant effects of amphetamine (2.5 mg/kg). Conversely, we observed that clonidine (7; 15; 30; 60 g/kg) or lithium regimen (between days 15 and 21) leading to lithium plasma levels of 1.3±0.1 mEq/1, abolished amphetamine-conditioned hyperactivity but did not affect the unconditioned stimulation of amphetamine or locomotor activity in control rats. Moreover, we found that hyperactivity induced by the daily anticipation of food delivery shared identical pharmacological sensitivity with the behavioural excitation produced by a conditioning history with amphetamine. In light of the antimanic properties of lithium and clonidine and the ability of this latter drug to reduce noradrenergic transmission, our findings raise the posibility that incentive activity may model noradrenergic-dependent aspects of mania.     

Low doses of corticotropin-releasing factor potentiate amphetamine-induced stereotyped behavior

Corticotropin-releasing factor (CRF) is a 41-amino acid polypeptide that is critically involved in the activation of the hypothalamic-pituitary adrenal axis during stress. In addition, it has been suggested that extrahypothalamic CRF may be important in initiating behavioral responses to stressful events. In the present experiment, we examined the effects of central administration of CRF on amphetamine-induced stereotyped behavior. Amphetamine-induced stereotyped behavior has been considered as a behavioral strategy to cope with excessive arousal. Low doses of CRF (0.02 and 0.1 g), administered into the lateral ventricle (ICV), were shown to potentiate amphetamine (4.0 mg/kg; SC)-induced stereotyped behavior, as measured by the Creese and Iversen rating scale and behavioral observations. These low doses of CRF specifically enhanced the tendency for rats to sniff with their heads down 20 min after injection, and induced licking behavior later during testing. In contrast, the rats treated with a higher dose of CRF (0.5 g, ICV) showed more locomotor activity throughout the test, but did not differ from the saline-treated animals in the intensity of amphetamine-induced stereotyped behavior.     

Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicit feeding in the rat

The effects of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on food intake in non-deprived male rats were investigated. Low doses of 8-OH-DPAT (15–60 g/kg) significantly increased food intake, without affecting drinking, grooming, rearing or locomotion. Microstructural analysis of the elicited feeding behaviour revealed that the rate of eating after 8-OH-DPAT treatment was very similar to that previously reported following 16 h food deprivation. Higher drug doses (250–4,000 g/kg) also elicited feeding and caused locomotor stimulation and serotonin-related stereotyped behaviour (i.e. forepaw padding, headweaving, wet dog shakes, flat body posture). When feeding and stereotypy were observed concurrently, response competition was evident and feeding behaviour was fragmented into numerous short eating bouts. As drug-induced stereotypy declined with time, this fragmented pattern of eating was succeeded by long bouts of eating which were similar to those observed at doses of 15–60 g/kg 8-OH-DPAT. The induction of feeding by a serotonin agonist appears paradoxical, since drugs which enhance brain serotonergic activity usually inhibit feeding.     

d-Ala-met-enkephalin injection into the ventral tegmental area: effect on investigatory and spontaneous motor behaviour in the rat

The mesolimbic dopamine (DA) system, originating in the ventral tegmental area and projecting to limbic forebrain regions, plays a crucial role in mediating several important aspects of behaviour. Proximal to these DA neurons are enkephalin-containing nerve fibers. In an attempt to characterize the behavioural role of enkephalinergic transmission in the VTA, the present experiment examined in detail the investigatory and motor responses to microinfusion of d-ala-met-enkephalin (DALA), a long lasting analogue of enkephalin, into the ventral tegmental area (VTA). Injections into the substantia nigra (SN) and the hippocampus (HPC) were also performed as controls for site specificity. The behavioural apparatus consisted of an eight-hole box monitored by a video camera. Four doses of DALA were injected in the VTA (0.05, 0.1, 1 and 2.5 g/l bilaterally in 1 l volume) and one dose in the SN and HPC (0.1 g/l bilaterally in 1 l volume). The effect of DALA injections in the VTA was characterized by an inverted U-shape dose-effect curve. The low doses (0.05 and 0.1) induced an increase in the frequency of hole visits accompanied by a decrease in the mean duration of visits, whereas the highest doses induced a decrease in hole visit frequency. Low doses of DALA had no effect on strategy or organization of exploration, whereas the high doses produced decreased switching between holes. After low doses of DALA, locomotor activity at the periphery of the testing box was not significantly affected but locomotor activity in the centre was increased. After high doses of DALA, locomotor activity in the center and at the periphery of the box were decreased. Frequency of rearing was either not affected or decreased by DALA treatment. DALA injected in the SN resulted in a small increase in frequency of hole visits and did not affect rearing and locomotor activity. DALA injection in the HPC had no effect on investigatory and spontaneous motor behaviour. The results are discussed in terms of a modulatory role of endogenous enkephalin on mesolimbic dopamine neurons.     

Effects ofd-amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment

Neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA, 50 g on day 1 after birth) caused a marked hyperactivity when the rats were tested as adults. These rats also showed severe DA depletions in striatum and nucleus accumbens. Pretreatment with the noradrenaline (NA) uptake inhibitor desipramine provided protection against NA depletion in frontal cortex and nucleus accumbens. Pretreatment with DNA uptake inhibitors, amfolenic acid or GBR 12909, before 6-OHDA, provided full protection against DA depletion but produced marked NA depletion in frontal cortex. These rats did not demonstrate any degree of hyperactivity. Low doses ofd-amphetamine (0.25 mg/kg SC) or methylphenidate (1 mg/kg SC) reversed the hyperactivity in DA-depleted rats but increased motor activity in vehicle-treated and NA-depleted rats. Higher doses ofd-amphetamine (1 mg/kg) or methylphenidate (4 mg/kg) produced potentiated levels of locomotion but attenuated levels of rearing in DA-depleted animals. The results further suggest the utility of the neonatal DA lesion in rats as a potential animal model for derivation of therapeutic agents that may be efficacious in the treatment of the hyperkinetic syndrome.     

Memory facilitation with posttrial injection of oxotremorine and physostigmine in mice

The immediate posttrial injection of oxotremorine (0.125, 0.250 and 0.500 Mol/kg i.p.) and equimolecular doses of physostigmine can facilitate the retention of a passive avoidance response in mice. Injections given 10 min after training also significantly facilitate retention, but injections given 30 or 120 min after training do not affect retention. These findings suggest an action of oxotremorine and physostigmine on mechanisms involved in memory storage. The enhanced retention produced by oxotremorine and physostigmine was blocked by pretreatment with atropine (2 Mol/kg, 20 min, i.p.) but was not affected by methylatropine (2 Mol/kg, 20min, i.p.). The retention was not modified by posttrial injection of metoxotremorine (0.250 Mol/kg i.p.) or neostigmine (0.250 Mol/kg i.p., quaternary analogs of oxotremorine and physostigmine, respectively. The results suggest a central action of both cholinergic agents attributable to an activation of muscarinic brain receptors.     

Effects of multiple pretreatment with apomorphine and amphetamine on amphetamine-induced locomotor activity and its inhibition by apomorphine

Mice were given a saline preinjection and habituation to the testing environment followed by injection of amphetamine (0.675–5.0 mg/kg IP) and apomorphine (AP, 15–80 g/kg SC) 15 min later. AP produced a dose-dependent inhibition of the amphetamine-induced locomotor activity. A dose of 40 g/kg AP increased approximately threefold the amphetamine dose required to induce the same increase in activity. Repeated administration of AP (30 mg/kg IP once daily for 14 days) resulted in an enhanced response (in the early portion of the time response) to amphetamine challenge, while the ability of subsequent microgram challenge doses of AP to reduce the response were unaffected. Similarly, repeated administration (twice-daily IP injections for 5 days) of amphetamine (5.0 mg/kg) resulted in an enhanced locomotor response to amphetamine challenge and no change in the ability of AP to inhibit the response. These results suggest that repeated administrations of dopamine agonists, although acting through different mechanisms (i.e., indirect versus direct), increase the initial release of neurotransmitter. However, the repeated administration of these agonists does not attenuate the ability of AP to inhibit the release of the neurotransmitter induced by amphetamine. The regulatory functions (i.e., presynaptic receptor control) of release appears to remain intact, but the level of neuronal activity has been increased.     

Cholinergic stimulation of the ventrolateral striatum elicits mouth movements in rats: pharmacological and regional specificity

Cholinomimetic drugs are known to induce changes in perioral behavior in rodents, characterized primarily by purposeless chewing mevements, but little is known about their central sites of action. Using observational methods, the effects of direct microinfusion of a mixture of physostigmine and acetylcholine (PS/Ach, 0, 0.5, 2.5, 5.0 g of each in 0.5 l saline) into the ventrolateral striatum (VLS) were assessed. Cholinergic stimulation of this region produced a dose-dependent induction of mouth movements, characterized by chewing movements, jaw opening and closing, tongue protrusions and jaw tremors. These movements were not directed toward any stimulus. In some rats, cholinergic stimulation of the VLS also induced stereotyped self-biting, although this effect was less prominent and of shorter duration. Induction of mouth movements by cholinergic stimulation of the VLS was blocked by prior administration of atropine, either systemically (50 mg/kg) or directly into the VLS (10 g). Systemic administration of methylatropine (50 mg/kg) did not block the mouth movements. Pretreatment with haloperidol (2.5 g into VLS) had no effect on PS/Ach-induced mouth movements. Infusion of PS/Ach (0, 2.5, 5.0 g) into the dorsolateral or ventromedial striatum did not produce significant changes in oral behavior, although the level of mouth movements was somewhat higher at the medial site. The three sites studied were also differentiated with respect to spontaneous moto behaviors (locomotion and rearing) following direct cholinergic stimulation. These findings are considered as further evidence for the role of the ventrolateral striatum in oral motor behavior.     

The relationship between stereotypy and memory improvement produced by amphetamine

This study examined the possibility that amphetamine-induced stereotypy and facilitation of memory consolidation are both mediated by amphetamine's stimulation of dopaminergic activity in the caudate nucleus. In the first experiment, rats were given pairings of a tone and a shock followed by SC amphetamine (2 mg/kg). The amount of stereotypy and increased locomotor activity produced by the injection were measured immediately. Retention of the tone-shock association was evaluated 48 h later by observing the ability of the tone to suppress drinking. The degree of retention was significantly correlated with the amount of stereotypy but not with the amount of locomotion previously measured. In the second experiment, amphetamine was microinjected into the caudate nucleus (10 g/l) and its ability to produce the same three behavioral effects was examined. These injections produced increased stereotypy and improved retention, but no increase in locomotion. The correlation of memory facilitation with stereotypy and the fact that both were produced by intracaudate amphetamine suggest that they may be mediated by the same neuropharmacological substrate, namely amphetamine-induced release of dopamine in the caudate.     

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

The effects of a single dose of TCDD on the testis were studied in rats. The animals were treated (subcutaneously) once with TCDD doses of 0, 0.5, 1.0, 3.0, 5.0 g/kg body weight. Doses of 3.0 or 5.0 g TCDD/kg reduced the number of spermatids/testis significantly (60% of the controls). Electron microscopic inspection revealed that both doses led to a dissolution on the germinal epithelium. Altered germ cells at all developmental stages occurred in all testes evaluated. Doses of 0.5 or 1.0 g TCDD/kg did not induce any effects in the testis; therefore, under these experimental conditions of single exposure to rats the dose of 1.0 g TCDD/kg can be considered as NOAEL.     

Triazolodiazepines are potent antagonists of platelet activating factor (PAF) in vitro and in vivo

Summary The triazolodiazepines brotizolam, triazolam and alprazolam inhibited PAF-induced human platelet aggregation in vitro (IC₅₀ = 0.54, 7.6 and 13.7 M, respectively) but showed only a weak or no effect against other aggregating agents (ADP, adrenaline, collagen, serotonin, arachidonic acid). In comparison, flunitrazepam and diazepam, two diazepines without the triazole ring, showed IC₅₀-values of 42 and 260 M, respectively. Flunitrazepam does not possess the specificity shown by the other compounds. Brotizolam and triazolam also inhibited PAF-induced human neutrophil aggregation in vitro, with IC₅₀-values 0.21 and 6.6 M, respectively.In anaesthetized guinea pigs, brotizolam (2.5 to 10 mg/kg p.o. or 0.1 to 0.5 mg/kg i.v.) or triazolam (20 to 100 mg/kg p.o.) inhibited dose-dependently the intrathoracic accumulation and aggregation of ¹¹¹Indium labelled platelets induced by an i. v. infusion of PAF (30 ng/kg × min).Brotizolam at doses of 1 to 10 mg/kg p. o. and 0.1 to 0.5 mg/kg i. v. inhibited dose-dependently the reduction in tidal volume (bronchoconstriction), the systemic hypotension and the lethal effect due to i. v. PAF in guinea pigs. Triazolam inhibited these effects of PAF at doses of 50 to 200 mg/kg p.o.PAF-induced systemic hypotension in rats can be reversed by cumulative i. v. doses (0.05 to 1.0 mg/kg) of brotizolam.In conclusion, these results show that triazolodiazepines, like brotizolam and triazolam, are potent inhibitors of PAF-induced effects in vitro and in vivo. Send offprint requests to J. Casals-Stenzel at the above address     

Behavioral differences induced by muscimol selectively injected into pars compacta and pars reticulata of Substantia Nigra

Summary Turning behavior was recorded after injection of the GABA agonist muscimol into the caudal part of rat substantia nigra, pars compacta (SNC) or pars reticulata (SNR). Unilateral injection of muscimol (10–25 ng) into SNC induced ipsilateral body posture. Additional treatment with apomorphine (0.5 mg/kg, s.c.) produced intense ipsilateral turning. This effect was abolished in rats depleted of catecholamines by the combined treatment with reserpine plus -methyltyrosine. The ipsilateral turning was probably not mediated via inhibition of dopaminergic (DA) activity since unilateral SNC injections of the DA agonist apomorphine (2.5–10 g) in contrast produced contralateral turning upon systemic apomorphine administration.Unilateral injection of muscimol into SNR induced strong contralateral turning, resistant to DA receptor blockade. In contrast, the contralateral turning was dose dependently antagonized by apomorphine (0.1–5 mg/kg, s.c.). Locally applied apomorphine (2.5–20 g) into SNR, striatum or nucleus accumbens also antagonized intranigral muscimol, corpus striatum being the most sensitive area. Bilateral intrastriatal apomorphine was most effective, followed by unilateral injection into the ipsilateral striatum. The apomorphine antagonism was attenuated by additional haloperidol treatment, possibly indicating DA-specificity. Systemic amphetamine (2 mg/kg, i.p.) or local injection of the DA agonist ADTN (10–20 g) into SNR, striatum or nucleus accumbens was without inhibitory effect on intranigral muscimol. These results suggest that the interaction between DA and nigral GABA is extremely complex: 1. Differential functional effects of a GABA agonist are found within SNC and SNR; 2. The turning behavior induced by muscimol injected into SNR is antagonized by stimulation of apomorphine sensitive DA receptors but not by those activated by amphetamine or ADTN, and 3. The inhibitory effect of apomorphine is observed following injection into several DA containing structures.     

Effects of morphine on release of acetylcholine in the rat striatum: an in vivo microdialysis study

Summary We examined the effect of morphine on the release of acetylcholine (ACh) in the striatum of freely moving rats using the in vivo microdialysis method. The basal level of ACh was 3.01 ± 0.51 pmol/30 l/15 min in the presence of neostigmine (10 M). Tetrodotoxin (1 M), a selective blocker of voltage-dependent Na⁺ channels, rapidly decreased the release of ACh in the striatal perfusates. Morphine at a dose of 10 mg/kg (i.p.) caused a reduction of ACh release in the striatum at 90–150 min. However, a lower dose of morphine (5 mg/kg, i.p.) did not affect ACh release in the striatum. The reduction following intraperitoneal administration of morphine was abolished by naloxone (1.0 mg/kg).After microinjection of the neurotoxin 6-hydroxydopamine (6 g/3 l, 7 days before) in the substantia nigra, the morphine (10 mg/kg)-induced decrease of ACh was attenuated, and a similar result occurred following reserpine (2 mg/kg, i.p.) 24 h before combined with -methyl-p-tyrosine (300 mg/kg, i. p.) 2.5 h before.These findings indicate that morphine exerts an inhibitory influence on striatal ACh release in freely moving rats and that this inhibitory effect is mediated by the nigro-striatal dopaminergic system.Correspondence to K. Taguchi at the above address     

The influence of low lead doses on the reticulo-endothelial system and leucocytes of mice

The half-life of the indian ink elimination (carbon clearance method) was used as a measure of the RES activity. A significant increase of the RES activity in mice was found already after a single intraperitoneal (i.p.) administration of 20, 50, or 100 g PbAc/kg body weight (b.w.). A significant RES stimulation could also be demonstrated after a single or 10-day oral administration of lead at doses of 10–1,000 g PbAc/kg b.w. No RES stimulation occurred, however, after 30-day oral administration of lead. On determining the reactivity of the RES to 1 g endotoxin/kg b.w. it was found that it was already limited after a single and 10-day oral lead administration. After 30-day oral administration of lead (doses 10–1,000 g PbAc/kg b.w.) the reactivity of the RES was completely suppressed.After a single and 10-day oral administration of lead (doses 10–1,000 g PbAc/kg b.w.) we observed a marked leucocytosis. This effect was most clearly seen after a dose of 100 g PbAc/kg b.w.; the leucocyte counts were increased by up to 50% in comparison with controls. After 30-day oral administration of lead, such a leucocytosis was no longer detectable. In accordance with the findings on the RES, the leucocytosis that is normally induced in the animals by 1 g endotoxin/kg b.w. was significantly reduced or completely suppressed both after single and also after 10 and 30 days' oral administration of lead at doses of 100 and 1,000 g PbAc/kg b.w. These results show that the resistance state of the mouse is impaired already by low doses of lead.     

CCK-8 injected into the nucleus accumbens attenuates the supersensitive locomotor response to apomorphine in 6-OHDA and chronic-neuroleptic treated rats

Postsynaptic dopamine-cholecystokinin (CCK) interactions in the nucleus accumbens were studied in two behavioral preparations of DA receptor supersensitivity: chronic-neuroleptic treated and 6-hydroxydopamine (6-OHDA) denervated rats. Subcutaneous (SC) injections of apomorphine (APO; 0.15 mg/kg) in experiment 1 produced marked hyperlocomotion in rats following 12 days of pretreatment with cis-[Z]-flupenthixol (2 mg/kg; twice per day). Bilateral intra-accumbens (N.Acc.) microinjections of CCK-8 (2 ng and 2 g) reliably reduced APO-stimulated hyperlocomotion. An intermediate CCK dose (20 ng) was without effect. No change in APO responsivity following chronic vehicle treatment was observed and the baseline APO response was not altered by CCK at any dose. Denervation of mesolimbic dopamine (DA) terminals by intra-N.Acc. injections of 6-hydroxydopamine (6-OHDA; 8 g/side) in experiment 2 similarly resulted in intense locomotor hyperactivity after APO stimulation (0.1 mg/kg; SC). Bilateral intra-N.Acc. injections of CCK-8 (1, 10, 100 ng, and 1 g) significantly attenuated the supersensitive locomotor response to APO. As in experiment 1, CCK produced biphasic dose-response effects with strong attenuation that persisted throughout the entire 60-min test at both high (1 g) and low (1 ng) doses. Intermediate CCK doses (10 and 100 ng) produced only shortterm reductions in activity. Hypomotility induced by APO in SHAM-lesioned rats was not effectively reversed by CCK treatments. CCK had no effect on unstimulated baseline locomotor activity in either 6-OHDA or SHAM-lesioned rats. These results provide further evidence that CCK-8 modulates mesolimbic DA activity by functionally opposing the postsynaptic effects of DA in the region of the nucleus accumbens.     

Intrastriatal injection of dl-2-amino-5-phosphonovaleric acid (AP-5) induces sniffing stereotypy that is antagonized by haloperidol and clozapine

dl-2-amino-5-phosphonovaleric acid (AP-5), which blocks glutamatergic transmission at the NMDA-preferring receptor, was injected into the antero-dorsal striatum of rats. AP-5-induced behavioural changes were assessed i) using a stereotypy rating scale and ii) using an experimental chamber designed to quantify sniffing. In both behavioural situations it was shown that AP-5 (10 g/0.5 l) induced continuous intensive sniffing similar to that induced by small doses of systemically administered amphetamine or apomorphine. However, oral stereotypies were not induced by AP-5. Systemically injected clozapine (5 and 10 mg/kg SC) as well as haloperidol (0.1 mg/kg IP) antagonized AP-5-induced sniffing. These results show that besides dopamine receptors, NMDA receptors are involved in the control of sniffing. In behavioural terms, the effect of glutamate mediated by the NMDA receptor in the striatum is opposite to that of dopamine.     

Hemodynamic alterations produced by N,N-di-n-propyldopamine in anesthetized dogs

Summary Intravenous infusion of N,N-di-n-propyldopamine (DPDA) (100–900 g/kg) produced dose-related arterial hypotension which was accompanied by bradycardia at higher doses. Increments in arterial blood pressure induced by carotid artery occlusion were attenuated during administration of DPDA (600 g/kg, i.v.), whereas cardiovascular compensation to postural change remained unaltered. DPDA-induced hypotension and its attenuation of carotid occlusion responses were prevented by pretreatment with sulpiride (0.5 mg/kg, i.v.), indicating involvement of dopamine receptors in these activities.Hemodynamic studies demonstrated that DPDA (600 g/kg, i.v.) lowered mean arterial blood pressure by dilating the systemic vasculature; mean aortic blood flow increased in the presence of bradycardia due to an increment in stroke volume. Left ventricular minute work, stroke work and myocardial oxygen consumption were decreased as a consequence of the hypotension and bradycardia produced by DPDA. The results of other experiments illustrated that propranolol (0.5 mg/kg, i.v.) and nitroglycerin (40 g/kg, i.v.) administered in combination, but not individually, resulted in hemodynamic alterations similar to those of DPDA (600 g/kg, i.v.). However, at equivalent reductions in mean arterial blood pressure, cardiac rate and myocardial oxygen consumption only DPDA increased mean aortic blood flow and lowered left ventricular end-diastolic pressure.The hemodynamic effects produced by DPDA are interpreted to be a reflection of its known ability to inhibit neurogenic release of noradrenaline by stimulation of neuronal dopamine receptors. The composite data suggest that orally effective dopamine receptor agonists may have clinical utility as antihypertensive agents with minimal liability for producing orthostasis. Furthermore, a potential use in ischemic heart disease is suggested by data indicating that DPDA maintained systemic perfusion at reduced levels of myocardial work and oxygen consumption.     

Depletion of brain serotonin by 5,7-dihydroxytryptamine alters the response to amphetamine and the habituation of locomotor activity in rats

Awake Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 g 5,7-dihydroxytryptamine (5,7-DHT) through chronically implanted cannulae. Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 5,7-DHT. In a separate set of animals, liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 80–90% and caudate 5HT by 30–42% as early as 24 h after administration of 5,7-DHT. One or 3 days after lesioning, locomotor and exploratory behavior was characterized with a Behavioral Pattern Monitor (BPM). Relative to controls, lesioned rats exhibited a decreased rate of habituation of both locomotor activity and investigatory holepokes. Although the amount of locomotor activity elicited by amphetamine (1.0 mg/kg) was unchanged by the 5HT depletion, lesioned animals exhibited highly stereotyped patterns of locomotion during the last 30-min test session, in contrast to the relatively random patterns characteristic of control animals given amphetamine. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats.     

In vivo electrophysiological evidence for tonic activation by endogenous noradrenaline of α2-adrenoceptors on 5-hydroxytryptamine terminals in the rat hippocampus

Summary The activation of ₂-adrenergic heteroreceptors was studied by comparing the effectiveness of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of CA₃ dorsal hippocampus pyramidal neurons prior to, and following, the intravenous administration of noradrenergic agents. Desipramine (2 mg/kg), a selective noradrenaline reuptake blocker, reduced the efficacy of the stimulation; this effect was reversed by the ₂-adrenoceptor antagonists yohimbine (0.5 mg/kg) and (-)mianserin (0.5 mg/kg), but not by idazoxan (0.5 mg/kg), an adrenoceptor antagonist with preferential affinity for the imidazoline recognition sites. Low doses of the ₂-adrenoceptor agonist clonidine (2 and 10 g/kg) enhanced the efficacy of the stimulation, while high doses (100 and 400 g/kg) reduced it. These incremental and decremental effects of clonidine were reversed by 0.1 and 1 mg/kg of yohimbine, respectively. The enhancing effect of the low dose of clonidine (10 g/kg) was abolished in rats pretreated with the noradrenaline neurotoxin 6-hydroxydopamine. However, the inhibitory effect of a high dose of clonidine (100 g/kg) was unaltered by this pretreatment. These results indicate that low doses of clonidine preferentially activate ₂-adrenergic autoreceptors on the noradrenaline neurons resulting in a reduction of the tonic inhibitory effect of endogenous noradrenaline on 5-HT neurotransmission, while higher doses of clonidine would decrease 5-HT neurotransmission through the direct activation of ₂-adrenergic heteroreceptors on 5-HT terminals. Furthermore, the selective ₂-adrenergic heteroreceptors antagonist(-)mianserin (0.5 mg/kg) increased by itself the efficacy of 5-HT neurotransmission, an effect not observed with yohimbine and idazoxan. Taken together, these results suggest that, in vivo, the ₂-adrenoceptors on 5-HT terminals of the rat hippocampus are tonically activated by endogenous noradrenaline and modulate 5-HT release. Correspondence to R. Mongeau at the above address     

Effects of naloxone,metenkephalin, and morphine on phencyclidine-induced behavior in the rat

The effects of naloxone, metenkephalin, and morphine were tested on phencyclidine(PCP)-induced stereotyped behaviors, ataxia, and hyperactivity in the rat. Naloxone (8 mg/kg) significantly decreased stereotypy, ataxia, and hyperactivity across all PCP doses tested (2.0, 4.0, and 6.0 mg/kg). Metenkephalin (40 g/kg) and morphine (5 and 10 mg/kg) increased ataxia at the 4.0 and 6.0 mg/kg PCP doses. Stereotypy was altered by the opiates in a dose-dependent manner; enhanced by metenkephalin (40 g/kg) at 2.0 mg/kg and inhibited by metenkephalin (40 g/kg) and morphine (10 mg/kg) at 4.0 and 6.0 mg/kg PCP. Locomotor activity was increased by morphine (5 mg/kg) at 2 mg/kg PCP. These results suggest an involvement of central opiate receptor mechanisms in the mediation of PCP-induced behaviors in the rat.