Biomedical subjects

I Lucki

Publications and source records attributed to I Lucki.

At least 73 records · Page 4Linked to original sources

PubMed1993

Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists and d-amphetamine.

The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 microgram/side of the dopamine receptor agonists SKF 38393 (D1) and quinpirole (D2) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonist d-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

Effect of chronic treatments with tandospirone and imipramine on serotonin-mediated behavioral responses and monoamine receptors.

The effects of acute and chronic treatment of rats with the tricyclic antidepressant imipramine, the 5-HT1A receptor partial agonist tandospirone, or its metabolite 1-PP were compared on behavioral responses produced by the activation of 5-HT receptors and on brain monoamine receptors. The behaviors examined were the 5-HT behavioral syndrome elicited by the 5-HT1A receptor agonist 8-OH-DPAT and the head shake response produced by the 5-HT2 receptor agonist DOB. Drug treatments were administered either by subcutaneous infusion from implanted minipumps or by repeated injection and the effects of chronic drug treatment were assessed when the drug was present and absent at the time of testing. The infusion of tandospirone blocked elicitation of the 5-HT behavioral syndrome when tested after 1 or 14 days of drug treatment (drug present) and 24 hr after the drug was withdrawn (drug absent). When administered by injection, tandospirone blocked the production of the 5-HT syndrome 1 hr (drug present), but not 24 hr (drug absent), following either 1 day or 14 days of drug treatment. Chronic infusion of imipramine did not alter the 5-HT syndrome. Chronic, but not acute, injections of imipramine blocked the 5-HT syndrome when tested 1 hr but not 24 hr, after the final injection. Treatment with 1-PP did not alter the 5-HT syndrome. The head shake response was attenuated by acute and chronic injection of tandospirone either 1 or 24 hr after treatment, although chronic infusion of tandospirone did not alter this behavior. Head shaking was attenuated by the infusion and injection of imipramine after acute treatment, chronic treatment, or following drug withdrawal. Chronic injection of 1-PP also inhibited the head shake response 24 hr after injection, although 1-PP was ineffective at all other times and when given by infusion. The density of hippocampal 5-HT1A receptors was unaltered by the chronic drug treatments. 5-HT2 receptor density in frontal cortex was reduced by the chronic infusion of either tandospirone, imipramine, and 1-PP, but only by chronic injections of imipramine. The density of cortical beta-adrenergic receptors was reduced following chronic imipramine injections or infusion. The results suggest that both tandospirone and imipramine may regulate 5-HT-mediated responses and 5-HT2 receptor density, which may contribute to their efficacy as antidepressants, although their effects were dependent upon the method of administration and may involve different neuropharmacological mechanisms.

Analysis of Variance↗

PubMed1993

Antidepressant-like activity of compounds with varying efficacy at 5-HT1A receptors.

Three novel compounds (WY-48,723, WY-50,324, WY-47,846 [zalospirone]), with high affinity but varying efficacy for the 5-HT1A receptor, were examined for producing the 5-HT behavioral syndrome and for potential antidepressant activity in the forced swimming test (FST). WY-50,324 was more potent than WY-48,723 at producing the 5-HT syndrome, but unlike WY-48,723, it produced only some of the behaviors of the 5-HT syndrome and its profile resembles that of a partial agonist. WY-48,723 appeared to be a full agonist because it produced behavioral effects similar to those of 8-OH-DPAT. The syndrome produced by these compounds was antagonized by pretreatment with pindolol. Zalospirone did not produce the syndrome but it antagonized the syndrome produced by 8-OH-DPAT. WY-48,723 and WY-50,324 reduced immobility time in the FST. These effects were similar to those produced by the tricyclic antidepressant desipramine and the 5-HT1A agonist 8-OH-DPAT. Zalospirone did not reduce immobility time, but increased it, which made it difficult to evaluate in this screen. These results suggest that the full agonist WY-48,723 and the partial agonist WY-50,324 may both possess antidepressant activity. Antidepressant-like activity appears to be a characteristic of compounds with a medium to high efficacy for activating 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

The presence of a serotonin uptake inhibitor alters pharmacological manipulations of serotonin release.

The present study investigated the effects of the presence of the serotonin uptake inhibitor citalopram in the perfusion medium on pharmacological manipulations which increased and decreased striatal serotonin release using in vivo microdialysis. A high performance liquid chromatography detection system equipped with a microbore column was used which reduced the detection limit to 0.5 fmol serotonin/5 microliters sample and enabled basal striatal serotonin release to be measured without the addition of a serotonin uptake inhibitor to the perfusion medium. Although serotonin uptake inhibitors have frequently been used to enhance the serotonin content of dialysate samples, the effects of the presence of serotonin uptake inhibitors on pharmacological manipulations which increased and decreased the release of serotonin have not yet been characterized. Serotonin release was reduced by the systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Although 5-HT release was reduced by 8-OH-DPAT after the addition of citalopram, the 5-HT1A receptor agonist did not reduce absolute levels of extracellular serotonin below basal values of serotonin measured in the absence of citalopram. In addition, citalopram dramatically prevented the four-fold increase in the release of serotonin produced by the systemic administration of the serotonin-releasing agent fenfluramine. The blockade of fenfluramine's effects by citalopram supports the hypothesis that transport of fenfluramine into serotonergic neurons is necessary to increase serotonin release. This study demonstrates that the use of an HPLC detection system equipped with a microbore column can reliably measure basal serotonin release using in vivo microdialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

Somatostatin receptors in the nucleus accumbens selectively mediate the stimulatory effect of somatostatin on locomotor activity in rats.

Multiple somatostatin (SRIF) receptor subtypes, which mediate distinct biological actions of SRIF, are expressed in the rat central nervous system. In the present study, we examined the effects of local injections of SRIF and the SRIF analogs MK 678 and CGP 23996 into the anterior nucleus accumbens on locomotor activity. The binding of [125I]Tyr11-SRIF to membranes from rat nucleus accumbens was potently and monophasically inhibited by SRIF. MK 678 inhibited only 58% of specific [125I]Tyr11-SRIF binding, indicating that the nucleus accumbens expresses both SRIF1 (MK 678-sensitive) and SRIF2 (MK 678-insensitive) receptors. The inhibition of [125I]Tyr11-SRIF binding by CGP 23996 was best fit by a two-site model, and analysis indicated an approximately 100-fold selectivity of this peptide for SRIF receptor subtypes. Intra-accumbens injections of SRIF (3.2-100 ng/side) produced significant increases in locomotor activity with a maximal 212% increase relative to saline control. This effect was mediated by SRIF1 receptors, as MK 678 (1-320 ng/side) produced a dose-dependent significant increase in locomotor activity with a maximal 228% increase relative to saline control, comparable to that attained with 3 to 10 micrograms of d-amphetamine. In contrast, CGP 23996 did not affect locomotor activity at doses of 3.2 to 1000 ng/side. The retroenantiomer hexapeptide analog L363-572, which is 70-fold less potent than MK 678 to inhibit radioligand binding to SRIF1 receptors, did not affect locomotor activity at doses up to 100 ng/side. These results indicate that SRIF1 receptors mediate the locomotor-activating effects of SRIF in the nucleus accumbens of the rat.

Animals↗

PubMed1993

Serotonergic involvement in haloperidol-induced catalepsy.

The ability of serotonin (5-HT)-selective compounds to reverse catalepsy due to blockade of dopamine (DA) receptors was examined in rats treated with the antipsychotic haloperidol (HAL). The 5-HT-releasing drug fenfluramine significantly reversed HAL-induced catalepsy. The 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin and buspirone potently and dose-dependently reversed HAL-induced catalepsy. The effect of 8-hydroxy-2-(di-n-propylamino)tetralin was blocked by pretreatment with the 5-HT1A/1B receptor antagonist pindolol, but not the 5-HT2 receptor antagonist ketanserin. The 5-HT1C/2 receptor agonist 2,5-dimethoxy-4-bromoamphetamine also completely reversed HAL-induced catalepsy, an effect blocked by ketanserin, but not pindolol. Neither antagonist alone had any effect. The 5-HT1B/1C receptor agonist trifluoromethylphenylpiperazine only partially reversed HAL-induced catalepsy, and the effect was not dose dependent. The 5-HT1C/2 receptor antagonist mianserin reversed HAL-induced catalepsy on its own; therefore, its ability to block the effect of trifluoromethylphenylpiperazine could not be tested. The nature of the disruption of HAL-induced catalepsy was examined by measuring the ability of increasing doses of HAL to surmount the effects of the serotonergic agonists. The mixed DA-D1/D2 receptor agonist apomorphine shifted the dose-effect curve for HAL to the right in a parallel manner, indicative of a competitive interaction between HAL and apomorphine at the D2 receptor. In contrast, the 5-HT receptor agonists flattened the dose-effect curve for HAL, suggestive of noncompetitive interactions. These data suggest that the 5-HT receptor agonists are not reversing HAL-induced catalepsy by indirectly increasing DA release. Rather, the agonists reverse HAL-induced catalepsy through interactions at their specific 5-HT receptor subtypes. Thus, the 5-HT receptor agonists may provide novel approaches for the development of drugs which can reverse or prevent the extrapyramidal side effects associated with antipsychotic treatment.

Animals↗

PubMed1992

Effects of chronic treatment with selective agonists on the subtypes of dopamine receptors.

The effects of chronic administration of selective dopaminergic agonists on D1 and D2 receptor density, affinity and function were measured in Sprague-Dawley rats. Animals received daily injections (i.p.) of the D1-selective agonist SKF-38393 (10 mg/kg), the D2-selective agonist quinpirole (1 mg/kg), SKF-38393 plus quinpirole, or saline for 14 days. Quantitative autoradiographic analysis revealed that the density of D2 receptors was decreased following chronic treatment with quinpirole alone or in combination with SKF-38393 whereas SKF-38393 by itself had no effect on this receptor. In contrast, the density of D1 receptors was increased following treatment with SKF-38393. Although quinpirole by itself had no effect on D1 receptors, co-administration with SKF-38393 attenuated the up-regulation of D1 receptors produced by SKF-38393 in the caudate-putamen and nucleus accumbens but not in the substantia nigra. The up-regulation of D1 receptors in response to chronic SKF-38393 may be attributed to the partial agonist properties of SKF-38393 which may not provide sufficient D1 receptor stimulation to down-regulate the receptor. Quinpirole-induced hypothermia and SKF-38393-induced hyperthermia were measured before and after chronic agonist treatments to examine the effects of these treatments on thermoregulatory functions mediated by each receptor subtype. Treatment with quinpirole or quinpirole plus SKF-38393 resulted in desensitization of quinpirole-induced hypothermia, whereas treatment with SKF-38393 alone had no effect. All of the chronic treatments produced sensitization of SKF-38393-induced hyperthermia. Since not all treatments result in an increase in the density of D1 receptors, up-regulation of D1 receptors is not the sole mechanism for this sensitization.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Discriminative stimulus properties of the benzodiazepine receptor antagonist flumazenil.

Rats were trained to discriminate the stimulus properties of the benzodiazepine (BZ) receptor antagonist flumazenil using a conditioned taste aversion procedure. On drug trials, fluid-restricted rats were injected with flumazenil (32 mg/kg), given access to a 0.25% saccharin solution for 30 min, and injected with LiCl (1.8 mEq/kg IP). On saline trials, injections of saline bracketed the period of saccharin consumption. Acquisition of the discriminated taste aversion, as measured by differential effects on drinking between saline and drug trials, developed after only five pairings of flumazenil with the LiCl injections. Flumazenil did not alter saccharin consumption in unconditioned controls (N = 9) that never received LiCl. The discrimination was also measured by flumazenil's ability to reduce the preference for saccharin over tap water using two-bottle choice tests. Flumazenil demonstrated dose-dependent generalization upon decreasing the training dose as low as 1 mg/kg. Two other BZ receptor antagonists of different chemical structure, CGS 8216 and ZK 93426, substituted completely for the flumazenil stimulus. Partial generalization was exhibited to the partial inverse agonists FG 7142 and beta-CCE, while the full inverse agonists DMCM and PTZ failed to substitute for the flumazenil stimulus. The BZ receptor agonists diazepam and alprazolam failed to substitute for the flumazenil stimulus, although partial generalization was shown with CDP. The results suggest that the BZ receptor antagonist flumazenil may produce intrinsic discriminative stimulus effects that are independent from those of BZ receptor agonists or inverse agonists.

Analysis of Variance↗

PubMed1992

Desensitization of 5-HT1A autoreceptors by chronic administration of 8-OH-DPAT.

The function of 5-HT1A autoreceptors was examined by measuring the ability of the 5-HT1A receptor agonist 8-OH-DPAT to reduce 5-HT release in the striatum using in vivo microdialysis. 8-OH-DPAT reduced the release of 5-HT in the striatum. Chronic treatment with 8-OH-DPAT (1.0 mg/kg s.c.) for 7 days, but not 1 day, attenuated the effect of an acute challenge dose of 8-OH-DPAT. The results of the present study indicate that in vivo microdialysis can be used to study the effects of activation of 5-HT1A autoreceptors on 5-HT release and the regulation of 5-HT release by chronic administration of psychoactive drugs.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

5-HT1 receptors and behavior.

The activation of different subtypes of the 5-HT1 receptor can be associated with specific behavioral responses. The present review discusses different categories of behavioral studies that have examined functional distinctions among 5-HT1 receptors. These include: 1) behavioral responses elicited by selective 5-HT receptor agonists; 2) drug discrimination experiments; 3) studies of sensorimotor reactivity and motivated behavior; and 4) behavioral models of clinical psychotherapeutic effects.

Animals↗

PubMed1992

Brain serotonin2 and serotonin1A receptors are altered in the congenitally hyperammonemic sparse fur mouse.

In previous studies we documented an increase in the levels of the serotonin metabolite, 5-hydroxyindoleacetic acid, in the congenitally hyperammonemic sparse fur mouse. To extend these findings, brain serotonin receptors were studied in these animals. Radioligand binding assays were performed using [3H]ketanserin to label serotonin2 sites and 8-[3H]hydroxy(di-n-propylamino)tetralin to label serotonin1A sites in cortical membrane homogenates. The capacity (Bmax) for [3H]ketanserin binding was significantly lower (-21%; p less than 0.05) in sparse fur animals than in control animals; there was no change in affinity (KD). In contrast, the capacity for 8-[3H]hydroxy(di-n-propylamino)tetralin binding was significantly greater (26%; p less than 0.05) in sparse fur compared with control animals. No difference in affinity was observed. Using two behavioral assays, the functional responsiveness of these serotonin receptors was compared in sparse fur and control animals. Head twitch activity elicited by administration of the serotonin agonist quipazine was studied as a behavior mediated by serotonin2 receptors. Compared with controls, sparse fur mice demonstrated a significantly decreased head twitch response (p less than 0.005). Hypothermia elicited by administration of 8-hydroxy(di-n-propylamino)tetralin was studied as a physiologic response mediated by serotonin1A receptors. Although there were not overall group differences in the dose-response data, there was a significant increase in the hypothermia induced by 8-hydroxy(di-n-propylamino)tetralin in sparse fur compared with control mice (p less than 0.02) at the highest dose. These data provide further support for a link between hyperammonemia and alterations in the serotonin system.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

Neurochemical changes associated with the persistence of spontaneous oral dyskinesia in rats following chronic reserpine treatment.

Rats treated chronically with reserpine develop spontaneous oral dyskinesia. The present study examined the development of the oral dyskinesia during the course of reserpine treatment, and its persistence after termination of treatment. Rats were injected with either reserpine (1 mg/kg, s.c.) or vehicle once daily for 4 days and then every other day for 6 weeks. Oral dyskinesia developed rapidly, reaching a maximal level after 3 days. It persisted at a maximal level for up to 20 days after termination of reserpine treatment, and continued to persist above control level for at least 60 days. The reserpine-treated rats also exhibited stereotypy in response to acute injection of the D1-selective agonist SKF-38393 (10 mg/kg), which was not observed in control rats. In contrast to the oral dyskinesia, this altered sensitivity to SKF-38393 returned to normal within 20 days after terminating the reserpine treatment, suggesting that these two behavioral responses involve different neural mechanisms. Quantitative autoradiographic measurement of dopamine receptor subtypes revealed that both D1 and D2 receptors were increased in the caudate-putamen (Cpu) and nucleus accumbens. Only the increase in D2 receptor density in the CPu correlated with the persistence of the oral dyskinesia; both changes persisted following termination of the reserpine treatment, and their magnitude was less at 60 days than at 1 and 20 days post-treatment. These results may have important implications for tardive dyskinesia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1991

Altered behavioral responses mediated by serotonin receptors in the genetically dystonic (dt) rat.

The genetically dystonic (dt) rat is an animal model of dystonia that displays sustained abnormal movements that include: torticollis, clasping of the hindlimbs, rigidity of the limbs, and contortions of the trunk. Since serotonin (5-HT) has been shown to be involved in some animal models of movement disorders, the functional responsiveness of the 5-HT system in dt rats and phenotypical normal littermates was examined by administering 5-HT agonists selective for different receptor subtypes and observing behavioral responses associated with the activation of specific 5-HT receptor subtypes. The dt rats were 6-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT) to produce the 5-HT behavioral syndrome. The dt rats demonstrated a diminished head-shaking response following administration of the 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB). However, the dt rats also displayed significantly fewer head shakes following mechanical stimulation of the aural pinnae. The inability of the dt rats to demonstrate head-shaking behavior following stimulation of 5-HT2 receptors is probably due to the dt rat's difficulty in producing the motor responses involved in this behavioral response and do not reflect alterations in 5-HT2 receptor sensitivity. These results suggest that the 5-HT system, particularly 5-HT1A receptors, may have an integral role in the abnormal movements displayed by the genetically dystonic rat and movement disorders in general.

Animals↗

PubMed1991

Behavioral studies of serotonin receptor agonists as antidepressant drugs.

Recent developments in the pharmacology of antidepressant drugs have focused on compounds that enhance the neurotransmission of serotonin (5-hydroxytryptamine; 5-HT), such as 5-HT uptake inhibitors. In addition, the 5-HT1A receptor partial agonist buspirone and other similarly structured compounds termed azapirones are also candidates for antidepressant therapy. The author reviews results from clinical and preclinical studies that support the efficacy of 5-HT1A receptor agonists as antidepressants. Initial clinical trials and animal behavior studies that predict clinical activity of antidepressant drugs have reported evidence favoring the antidepressant-like activity of 5-HT1A receptor partial agonists. Animal behavior studies have also examined the potential neurochemical mechanisms underlying the antidepressant effects of buspirone and related compounds. Evidence is reviewed that the antidepressant activity may be due to the activation of postsynaptic 5-HT1A receptors, although 5-HT1A receptor agonists also activate somatodendritic autoreceptors which diminish the release of 5-HT. Evidence does not support the involvement of a common metabolite 1-PP in the antidepressant activity of 5-HT1A receptor-selective azapirones. Few studies have examined the effects of chronic administration of 5-HT1A receptor agonists and their potential interaction with other receptors, such as 5-HT2 receptors.

Animals↗

PubMed1991

Behavioral and neurochemical effects of chronic administration of reserpine and SKF-38393 in rats.

Alterations in the density of dopamine receptor subtypes and behaviors mediated by the D1-selective agonist SKF-38393 were examined in rats treated chronically with reserpine, SKF-38393 or the combination of these drugs. Animals received either vehicle or reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with [3H]SCH-23390 and D2 receptors labeled with [3H]spiroperidol revealed that chronic administration of reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic drug treatments also altered behavioral responses. Chronic administration of SKF-38393 alone produced sensitization of the oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of SKF-38393 in rats treated with reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of reserpine alone produced a spontaneous oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist spiroperidol. These findings are discussed in terms of their relevance to Parkinson's disease and tardive dyskinesia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1990

Destruction of the nucleus raphe obscurus and potentiation of serotonin-mediated behaviors following administration of the neurotoxin 3-acetylpyridine.

Systemic administration of the neurotoxin 3-acetylpyridine (3-AP) to rats produced spontaneous episodes of spasmodic movement involving the trunk and limbs including torticollis, contortions of the trunk and rigid extension of the limbs. Because the neurotransmitter serotonin (5-HT) has been implicated in various human involuntary movement disorders, the functional and anatomical integrity of the 5-HT system in rats treated with 3-AP were examined. 5-HT-containing neurons in the brain stem were studied using immunohistochemical labeling with antiserum to 5-HT. Cells in the nucleus raphe obscurus were found to be altered following 3-AP treatment as shown by a decrease in 5-HT immunoreactivity as compared to control rats. No changes in 5-HT immunoreactivity were observed in any other region containing 5-HT cell bodies. Behaviorally, rats treated with 3-AP were 2.5-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.33-3.3 mg/kg) to produce the 5-HT syndrome. Similarly, 3-AP-treated rats were 2-fold more sensitive to the selective 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 0-1.0 mg/kg) at producing the head shake response. Although these behaviors associated with brain stem 5-HT receptors were potentiated by 3-AP, the hypothermic effect of 8-OH-DPAT which involves ascending mesencephalic 5-HT neurons was unchanged following 3-AP treatment. Treatment with 3-AP did not produce significant alterations of 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) content in any brain region studied. Quantitative autoradiographic analysis of the density of 5-HT1A receptors labeled with [3H]8-OH-DPAT revealed that these sites were unchanged in regions of the brain (frontal cortex, hippocampus and brain stem) and in the spinal cord. Similarly, few changes in the density of 5-HT2 receptors measured with [3H]ketanserin were observed in various brain regions. These results suggest that neurons from the nucleus raphe obscurus are involved in the elicitation of 5-HT-mediated behavioral responses by 5-HT1A and 5-HT2 receptor agonists that are though to be mediated through brain stem and spinal cord mechanisms. In addition, because of the close neuroanatomical relationship of the nucleus raphe obscurus with various brain regions known to be involved in motor control, the destruction of this region by 3-AP may contribute to the spasmodic motor behaviors observed following 3-AP treatment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

Increased sensitivity to benzodiazepine antagonists in rats following chronic treatment with a low dose of diazepam.

The effects of benzodiazepine (BZ) antagonists on operant behavior were examined in rats chronically administered a low dose of diazepam (DZ). The low maintenance dose of DZ (5 mg/kg twice daily) was selected as more closely associated with its anxiolytic effects than the higher treatment doses previously used to study BZ dependence. Food-restricted rats were trained to press a lever for food reinforcement under a FR20 schedule of reinforcement prior to the start of DZ administration. Acute administration of DZ caused a dose-dependent reduction of response rates, with 5 mg/kg causing a 50% decrease. Rats treated chronically with DZ became tolerant to its rate-suppressant effects as shown by a 5-fold increase in the dose of DZ required to reduce FR20 response rates by 50%. The BZ antagonist flumazenil (formerly Ro 15-1788; 10-56 mg/kg) suppressed rates of responding in rats treated chronically with DZ. The suppression of operant responding was obtained when flumazenil was given up to 3 h, but not 18 h, after the last treatment with DZ. In contrast, only the highest dose of flumazenil (56 mg/kg) caused reductions of operant responding when given to rats treated with saline. The BZ antagonist CGS 8216 (3.3-33 mg/kg IP), given 10 min prior to the session, was similarly more potent and effective at suppressing operant responding in rats treated chronically with DZ than saline. This procedure may provide a model for the clinical problem of physical dependence to chronically-administered low, anxiolytic doses of BZ tranquilizers.

Animals↗

PubMed1990

Antidepressant-like activity of 5-HT1A agonists measured with the forced swim test.

This study examined the abilities of 5-hydroxytryptamine (5-HT) agonists with varying selectivity for different subtypes of 5-HT receptors to produce antidepressant-like behavioral effects in the forced swim test in rats. The 5-HT1A agonists 8-OH-DPAT (0.125-1.0 mg/kg, SC) and tandospirone (SM-3997) (5-20 mg/kg, SC) both produced dose-related decreases in immobility time following subchronic treatment in rats. These effects were similar to those of the tricyclic antidepressants imipramine (5-15 mg/kg) and desipramine (5-15 mg/kg). In addition, the 5-HT1A agonists, buspirone (20 mg/kg), gepirone (20 mg/kg) and ipsapirone (10 and 20 mg/kg) demonstrated antidepressant-like effects. Other groups of rats treated subchronically with each of the 5-HT1A agonists or antidepressants showed no increase in locomotor activity, so that general changes in activity could not account for the reduction of immobility time in the forced swim test. 5-HT agonists selective for other receptor subtypes, such as the 5-HT1B/1C agonist m-CPP (5 mg/kg) and the 5-HT2/1C agonist DOB (1 mg/kg), were not effective in this behavioral test. The benzodiazepine diazepam (5 mg/kg) also failed to reduce immobility time, suggesting that anxiolytic properties of 5-HT1A agonists did not mediate this behavioral effect. A common metabolite of some of the 5-HT1A agonists, 1-PP, was ineffective in reducing immobility time. The stimulant d-amphetamine (2 mg/kg) significantly reduced immobility time but also significantly increased locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗