Biomedical subjects
Publications and source records attributed to S Ahlenius.
Rats were trained to perform an aversely motivated discriminative task in a shuttle-box. The conditioned avoidance response was selectively suppressed by 8-OH-DPAT in a dose-dependent manner (25-100 micrograms.kg-1). There were no statistically significant deficits in discriminative performance. The present results suggest antipsychotic-like properties of 8-OH-DPAT.
Bilateral transection of the dorsal penile nerve in male rats was followed by reduction of the amount of intromissions in relation to the frequency of mounts and abolishment of the capacity to ejaculate. Treatment with 8-OH-DPAT (0.25 mg.kg-1 -20 min SC) essentially normalized the behavior of the operated animals which showed a normal proportion of mounts to intromissions and which all ejaculated at almost all testing occasions. It was speculated that treatment with 8-OH-DPAT makes central neural mechanisms more responsive to genital stimulation thereby facilitating the development of full penile erection, vaginal insertion and intromission.
The present results show that the effects on striatal dopamine (DA) turnover of a single dose of the DA receptor antagonists haloperidol or raclopride in the rat, are dependent on the activity level of the animal during treatment. Thus, animals tested for treadmill locomotion 30 and 60 min. after injection display an increased striatal DA turnover at 90 or 120 min. (raclopride and haloperidol, respectively) compared with control animals which were administered the same dose of the DA antagonist, but which did not have the treadmill tests. The relevance of these findings with respect to individual differences in clinical response and occurrence of side effects as well as the reported difficulties in obtaining good correlations between plasma levels and clinical response with DA-receptor blocking antipsychotic drugs are discussed.
In order to study the effects of castration of brain dopamine (DA) receptor sensitivity, the effects of apomorphine on locomotor activity and striatal DA synthesis, as assessed by the dihydroxyphenylalanine (DOPA) accumulation after NSD-1015 treatment, were examined in normal and castrated male Sprague-Dawley rats pretreated with reserpine (5 mg/kg-18 hrs). There was an enhanced locomotor response to apomorphine (0.05-0.1 mg/kg) in castrated animals, as compared to sham operated controls. Furthermore, the increase in DOPA accumulation produced by the reserpine treatment was antagonized to a greater extent by apomorphine in the castrated animals. These results indicate an enhanced DA receptor sensitivity at both pre- and post-synaptic sites.
Two ergot derivatives, lisuride and quinpirole, were examined for their ability to antagonize hyperbaric oxygen-induced (5 ATA O2) convulsions in mice. Significant protection was obtained by lisuride (25-400 micrograms.kg-1, i.p.) and quinpirole (100-200 micrograms.kg-1, i.p.). The efficacy was found to be about 50% of the protection obtained by diazepam (4 mg.kg-1, i.p.). Both lisuride and quinpirole significantly reduced rectal temperature at all doses administered. In separate experiments, at normal atmospheric conditions, all drugs to some extent reduced estimated respiratory minute volume. Taking these effects into account, lisuride is considerably more active as an anticonvulsant than quinpirole.
In vivo catecholamine and 5-HT synthesis during sexual activity and treadmill locomotion was estimated in male rats by measuring the accumulation of DOPA and 5-HTP after inhibition of cerebral aromatic amino acid decarboxylase by means of NSD-1015 (100 mg.kg-1 i.p.). An increase in catecholamine as well as 5-HT synthesis during sexual activity was observed in both the neostriatum and the nucleus accumbens. An increase in catecholamine synthesis during treadmill locomotion was found in the neostriatum only. No significant changes in monoamine synthesis were found in the septal area or in the anterior hypothalamus.
Recent neuroanatomical tracer studies have demonstrated the topography of 'limbic' (A10) projections into the striatum of the rat (see Introduction). The target areas include the nucleus accumbens and the ventromedial part of the neostriatum, whereas the dorsolateral part of the neostriatum does not receive such afferents. Taking this topography into account, the present results show that local application of cis-flupenthixol (10-40 micrograms/side) into the nucleus accumbens or the ventromedial, but not the dorsolateral, neostriatum produces suppression of exploratory locomotor activity in the rat. trans-Flupenthixol (40 micrograms/side) was completely ineffective when locally applied into the nucleus accumbens. Measurements of the concentrations of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) at the site of injection, and in neighboring areas at different times after cis-flupenthixol administration, indicated that there was little or no diffusion of the drug from the injection sites. Much higher concentrations of DOPAC and HVA in a given area were found after systemic administration of cis-flupenthixol as compared with local application of the drug to the same area.
In the present report we have investigated the effects of apomorphine, (-)3-PPP, L-DOPA and haloperidol on the elicitation of convulsions induced in mice by exposure to oxygen at high pressure (HBO) (5 ata O2). It was found that the administration of apomorphine (0.025-0.1 mg X kg-1 s.c.), (-)3-PPP (4 mg X kg-1 i.p.) L-DOPA (200-400 mg X kg-1 i.p.) as well as haloperidol (0.25-2.0 mg X kg-1 i.p.) produced a significant protection against HBO-induced convulsions. Haloperidol was the only drug to produce a dose-dependent decrease in respiration, and this effect does probably explain the anticonvulsant effects observed. The low doses at which apomorphine was effective, and the effects produced by (-)3-PPP, indicate an effect mediated via DA autoreceptors. Alternatively, and more likely taking the effects of L-DOPA into account, the DA receptors involved are sensitive enough to disclose postsynaptic agonist properties of apomorphine and (-)3-PPP at the doses employed.
The administration of the putative 5-hydroxytryptamine1 (5-HT1) agonist 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) (0.0625-1.0 mg X kg-1) suppresses lordosis behaviour induced in ovariectomized female rats by daily treatment for 3-5 days with estradiol benzoate (1.25 micrograms/rat). A similar suppressive effect on the lordosis behaviour can be obtained by administration of the dopamine/serotonin agonist, lisuride (0.1-0.4 mg X kg-1), or after the administration of the dopamine (DA) agonists, apomorphine (0.2-0.8 mg X kg-1) or quinpirole (0.75-2.50 mg X kg-1). The suppressive effects on the lordosis behaviour by 8-OH-DPAT cannot be antagonized by the DA receptor antagonist haloperidol (0.2 mg X kg-1) neither with methiotepin (0.5 mg X kg-1), which is assumed to be a non-selective 5-HT receptor blocking agent, nor with pirenperone (0.25 mg X kg-1) which is assumed to be a 5-HT2 receptor blocking agent. However, a partial blockade of the lordosis suppressive effects of 8-OH-DPAT was obtained by treatment with (-)-pindolol, which is thought to be a partial 5-HT1 blocking agent, suggesting that 8-OH-DPAT exerts its suppressive effects on the lordosis behaviour through the 5-HT system. Haloperidol causes a complete blockade of the suppressive effects of apomorphine and quinpirole suggesting that these drugs exert their inhibitory effects on the lordosis behaviour by activating the DA system.(ABSTRACT TRUNCATED AT 250 WORDS)
In the present experiments we have investigated the duration of haloperidol-induced effects in rats tested repeatedly, and in rats tested on a single occasion after drug administration. The behavioral test situations used include treadmill locomotion (speed 4 m/min), inclined grid catalepsy, two-way conditioned avoidance behavior and open field spontaneous locomotor activity. It was found that the duration of haloperidol-induced effects on treadmill locomotion, spontaneous locomotor activity, catalepsy and a conditioned avoidance response (doses: 0.32, 0.32, 1.25 and 0.2 mg/kg IP, respectively) was about 2 hr or less in animals observed once only ("independent procedure"). With the possible exception for locomotor activity, the duration of haloperidol-induced effects was considerably prolonged, up to 8 hr depending on the test situation, in animals observed repeatedly after the administration of haloperidol in the same doses ("dependent procedure"). The enhanced duration by the dependent procedure is probably not caused by handling stress since the enhanced duration of haloperidol-induced effects in some of the behavioral tests were only noted in animals tested repeatedly in one particular test, and not in animals given the repeated pretests in another situation. Furthermore, it was not possible to relate the enhanced duration of haloperidol-induced effects by repeated testing to changes in striatal DA metabolism as evaluated by measurements of DOPAC, HVA and DA. It was found that the treadmill test 2-4 hr after haloperidol (0.12-0.32 mg/kg IP), at certain doses and time intervals produced an increase in DA turnover [(DOPAC + HVA)/DA], but this increase was the same in both procedures (dependent and independent).(ABSTRACT TRUNCATED AT 250 WORDS)
Raclopride, a new potential antipsychotic agent blocking central dopamine (D2) receptors, was found to suppress exploratory locomotor activity, treadmill locomotion and conditioned avoidance response in rats. The threshold dose for effects in these test situations was about 0.5 mg/kg intraperitoneally. A considerably higher dose, 16 mg/kg intraperitoneally, was needed to produce maximal catalepsy. Maximal effects were obtained within 1-2 hrs and the duration of the effect was 2-8 hrs, depending on the test situation. The behavioural profile of raclopride is different from the classic antipsychotic haloperidol, blocking central dopamine (DA) receptors, as well as from the partial DA agonist preclamol, which inhibits central DA neurotransmission by activating DA autoreceptors. Thus, although similar to haloperidol in other respects, comparatively high doses of raclopride are needed to produce catalepsy, indicating less propensity to produce severe extrapyramidal side effects. Raclopride and preclamol are about equipotent in suppressing exploratory locomotor activity. However, raclopride is more potent than preclamol in suppressing treadmill locomotion, conditioned avoidance behaviour and catalepsy.
The organization of afferent and efferent connections of the interpeduncular nucleus (IP) has been examined in correlation with its subnuclear parcellation by using anterograde and retrograde tracing techniques. Based on Nissl, myelin, and acetylcholinesterase staining five paired and three unpaired IP subnuclei are distinguished. The unpaired division includes the rostral subnucleus (IP-R), the apical subnucleus (IP-A), and the central subnucleus (IP-C). The subnuclei represented bilaterally are the paramedian dorsal medial (IP-DM) and intermediate subnuclei (IP-I) and the laterally placed rostral lateral (IP-RL), dorsal lateral (IP-DL), and lateral subnuclei (IP-L). Immunohistochemical techniques showed cell bodies and fibers and terminals immunoreactive for substance P, leu-enkephalin, met-enkephalin, or serotonin to be differentially distributed over the different IP subnuclei. Substance P-positive perikarya were found in IP-R, enkephalin neurons in IP-R, IP-A, and the caudodorsal part of IP-C, and serotonin-containing cell bodies in IP-A and the caudal part of IP-L. Efferent IP projections were studied both by injecting tritiated leucine in IP and by injecting HRP or WGA-HRP in the presumed termination areas. The results indicate that the major outflow of IP is directed caudal-ward to the median and dorsal raphe nuclei and the caudal part of the central gray substance, i.e., the dorsal tegmental region. The projection appears to terminate mainly in the raphe nuclei, around the ventral and dorsal tegmental nuclei of Gudden, and in the dorsolateral tegmental nucleus. The descending projection to the dorsal tegmental region originates in virtually all IP subnuclei, but the main contribution comes from IP-R and the lateral subnuclei IP-RL, IP-DL, and IP-L. Sparser projections to the dorsal tegmental region originate in IP-C and IP-I, whereas the contribution of IP-A is only minimal. The projections from IP-R are mainly ipsilateral and those from IP-DM are mainly contralateral. IP fibers to the median and dorsal raphe nuclei originate predominantly in IP-R and IP-DM, and to a lesser extent in IP-C, IP-I, IP-RL, and IP-DL. A much smaller contingent of IP fibers ascends to diencephalic and telencephalic regions. A relatively minor projection, stemming from IP-RL and IP-DL, reaches the lateral part of the mediodorsal nucleus, the nucleus gelatinosus, and some midline thalamic nuclei. These IP fibers follow either the habenulo-interpeduncular pathway or the mammillothalamic tract.(ABSTRACT TRUNCATED AT 400 WORDS)
The administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), inhibited the lordosis induced by estradiol benzoate or estradiol benzoate plus progesterone in ovariectomized rats. There was no facilitation of lordosis by 8-OH-DPAT in animals pretreated with a threshold dose of estradiol benzoate. The results are consistent with the view that 8-OH-DPAT is an agonist at 5-HT receptors and provide further support for an inhibition role of central 5-HT in the mediation of lordosis behavior.
The effects of two proposed dopaminergic autoreceptor agonists, (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and the azepine derivative B-HT 920, on spontaneous locomotor activity, treadmill locomotion, and catalepsy in the rat have been compared with the effects produced by the postsynaptic dopamine (DA) receptor blocking agent haloperidol. It was found that the threshold dose for suppression of exploratory locomotor activity was 0.5, 0.005 and 0.2 mg/kg for (-)3-PPP, B-HT 920 and haloperidol, respectively. The corresponding doses for suppression of treadmill locomotion were 8.0, 5.12 and 0.2 mg/kg, respectively. Furthermore, (-)3-PPP and B-HT 920, in contrast to haloperidol, did not produce any catalepsy. Thus, using exploratory locomotor activity as an index of limbic forebrain DA functions and treadmill locomotion and catalepsy as indices of extrapyramidal DA functions, the DA autoreceptor agonists, in contrast to the postsynaptic antagonist, show a difference in the doses required to produce these effects. The designation of the behavioral functions as "limbic" or extrapyramidal is supported by the finding that scopolamine, 0.8 mg/kg, antagonized the haloperidol-induced suppression (0.2 mg/kg) of treadmill locomotion, but not the suppression of exploratory locomotor activity.
Both lisuride and 8-OH-DPAT dose dependently antagonized the 5-HTP-induced inhibition of male rat sexual behavior. The increase in the number of intromissions and/or the ejaculation latency produced by 5-HTP, 25 mg/kg i.p. (-60 min) in combination with the peripheral 5-HTP decarboxylase inhibitor benserazide, 25 mg/kg i.p. (-90 min), were antagonized by lisuride, 0.05-0.1 mg/kg i.p. (-15 min) and by 8-OH-DPAT, 0.025-0.05 mg/kg i.p. (-15 min). Thus, in this model lisuride and 8-OH-DPAT behave as 5-HT antagonists.
Oxotremorine (0.1-0.8 mg/kg IP), but not arecoline (12-48 mg/kg IP), or pilocarpine (5-20 mg/kg IP), reduced both the number of intromissions to ejaculation and the ejaculation latency in methscopolamine-pretreated male rats. The effects of oxotremorine, (0.4 mg/kg IP) were completely antagonized by the administration of scopolamine (0.4 mg/kg IP). Methscopolamine (3-12 mg/kg IP), or scopolamine (0.2-0.4 mg/kg IP) did not by themselves produce any statistically significant effects on male rat sexual behavior.
It was found that PCPA (4 X 50-100 mg/kg) decreased the respiratory response to tone pulses (acoustic reaction), and this effect was antagonized by the administration of 5-HTP (25 mg/kg), after inhibition of extracerebral aromatic amino acid decarboxylase by means of benserazide (25 mg/kg). A further increase in the dose of 5-HTP, 50-100 mg/kg, in animals not treated with PCPA did not significantly affect the acoustic reaction. The putative 5-HT agonist 8-OH-DPAT produced a decrease in the acoustic reaction (but also at higher doses some desynchronization of respiration with tone). The administration of d-amphetamine, 0.5-2.0 mg/kg, resulted in an increase in the acoustic reaction. Thus, in the present experiment, using a simple sensory-motor response, 8-OH-DPAT behaves as a 5-HT antagonist and the results provide further support for mixed 5-HT receptor agonist/antagonist properties of this compound.
The injection of (-)3-PPP into the nucleus accumbens, 10 microgram/side, produced a suppression of exploratory locomotor activity without affecting treadmill locomotion. Furthermore, the suppression of exploratory locomotor activity produced by (-)3-PPP was antagonized by the administration of haloperidol, 25-50 micrograms/kg i.p.