Releaser D-fenfluramine Research Articles

Enhanced Behavioral Response to Serotonin-Related Agonists in Postweaning Protein Malnourished Mice

We investigated whether postweaning protein malnutrition (PM) affects serotonergic systems. Mice were fed a PM diet or normal protein (control) diet from weaning (21 d of age). Twenty days later, we tested for behavioral effects of the selective serotonin (5-HT)(1A) receptor agonist 8-hydroxy-N,N-dipropyl-2-aminoteralin (8-OH-DPAT) and the 5-HT releaser d-fenfluramine. The number of head weaving responses induced by 8-OH-DPAT or d-fenfluramine in the PM mice was significantly increased compared with the control diet group. The effects of 8-OH-DPAT and d-fenfluramine were blocked by pretreatment with the selective 5-HT(1A) receptor antagonist WAY-100635 (0.01 mg/kg). However, postpubertal (56 d of age) mice fed with the PM diet did not show an enhancement of the 8-OH-DPAT-induced head weaving response. These results indicate the occurence of a supersensitivity of postsynaptic 5-HT(1A) receptor in the postweaning PM group. Moreover, they highlight the postweaning stage as a vulnerable period to malnutrition-induced alterations in central serotonergic systems.

Mechanisms mediating the ability of caffeine to influence MDMA (‘Ecstasy’)‐induced hyperthermia in rats

Caffeine exacerbates the hyperthermia associated with an acute exposure to 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') in rats. The present study investigated the mechanisms mediating this interaction. Adult male Sprague-Dawley rats were treated with caffeine (10 mg x kg(-1); i.p.) and MDMA (15 mg x kg(-1); i.p.) alone and in combination. Core body temperatures were monitored before and after drug administration. Central catecholamine depletion blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine provoked a hyperthermic response when the catecholamine releaser d-amphetamine (1 mg x kg(-1)) was combined with the 5-HT releaser D-fenfluramine (5 mg x kg(-1)) or the non-selective dopamine receptor agonist apomorphine (1 mg x kg(-1)) was combined with the 5-HT(2) receptor agonist DOI (2 mg x kg(-1)) but not following either agents alone. Pretreatment with the dopamine D(1) receptor antagonist Schering (SCH) 23390 (1 mg x kg(-1)), the 5-HT(2) receptor antagonist ketanserin (5 mg x kg(-1)) or alpha(1)-adreno- receptor antagonist prazosin (0.2 mg x kg(-1)) blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Co-administration of a combination of MDMA with the PDE-4 inhibitor rolipram (0.025 mg x kg(-1)) and the adenosine A(1/2) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg x kg(-1)) or the A(2A) receptor antagonist SCH 58261 (2 mg x kg(-1)) but not the A(1) receptor antagonist DPCPX (10 mg x kg(-1)) exacerbated MDMA-induced hyperthermia. A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A(2A) receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.

Depletion of 5-HT Disrupts Prepulse Inhibition in Rats: Dependence on the Magnitude of Depletion, and Reversal by a 5-HT Precursor

The 5-HT1A agonist 8-OH-DPAT has been reported to disrupt prepulse inhibition (PPI) of the acoustic startle reflex after local administration into the raphe nuclei. Because it is likely that 8-OH-DPAT disrupted PPI by activation of somatodendritic inhibitory receptors, and thereby, via a decrease in 5-HT neurotransmission, we tested whether chronic, drug-induced, depletions of 5-HT have similar effects. Rats were drug-treated for three consecutive days and tested in a short PPI paradigm on day 4, and retested 2 h later, after acute saline or drug administration. Repeated treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine methyl ester (PCPA; 160 mg/kg) produced a small, but significant, attenuation of PPI, and a large decrease in extracellular 5-HT levels in the hippocampus, as measured in independent microdialysis experiments. An even larger depletion of 5-HT was obtained by substituting the 3rd PCPA administration with the 5-HT releaser d-fenfluramine (10 mg/kg); this combined treatment nearly abolished PPI in the majority of animals. The involvement of 5-HT in the latter effects was confirmed by the finding that low doses of the 5-HT precursor 5-hydroxy-l-tryptophan reinstated PPI during retest. These data, together with recently published studies, provide strong evidence that pharmacologically-induced depletion of 5-HT disrupts PPI.

Manipulation of operant responding for an ethanol-paired conditioned stimulus in the rat by pharmacological alteration of the serotonergic system.

It is becoming increasingly clear that environmental stimuli play a critical role in the maintenance of drug taking behaviour. This has led to investigations into the neural mechanisms by which environmental stimuli can come to control behaviour using paradigms such as conditioned reinforcement. The majority of this work has involved the use of food-paired conditioned stimulus rodent paradigms. Relatively few studies have attempted to investigate the neuropharmacology of behaviour maintained by presentation of a stimulus paired with ethanol drinking. Several lines of research support an important role for brain serotonin (5-HT) neurotransmitter systems in the control of alcohol drinking behaviour. The aim of the present study was, initially, to establish a procedure in which rats respond for an ethanol-paired conditioned stimulus, and second, to study the effects of a range of serotonergic compounds previously shown to be effective in reducing oral ethanol self-administration, on responding for this conditioned stimulus. Results showed that the 5-HT releaser d-fenfluramine, the selective serotonin reuptake inhibitor fluoxetine, the 5-HT1A receptor agonist 8-hydroxy-2[di-n-propylamino]tetralin, the partial 5-HT1A receptor agonist buspirone, and the 5-HT1B/5-HT2C receptor agonist 1-(3-trifluoromethylphenyl)piperazine, but not the 5-HT2A/5-HT2C receptor agonist 1-(2,5-dimethoxy-4-iodophenylaminopropane)-2, selectively reduced responding on a lever leading to presentation of an ethanol paired conditioned stimulus. In addition the non-specific D1/D2 dopamine receptor antagonist haloperidol was active in this paradigm. Results are consistent with involvement of the dopaminergic and 5-HT systems, in particular activation of 5-HT1A and 5-HT1B receptor subtypes, in mediation of the conditioned or secondary reinforcing properties of ethanol.

Serotonergic Facilitation of Acetylcholine Release In Vivo from Rat Dorsal Hippocampus via Serotonin 5‐HT3 Receptors

The serotonin (5-HT) releaser d-fenfluramine and its active metabolite d-norfenfluramine, or the 5-HT-uptake inhibitor citalopram, by increasing synaptic 5-HT availability, facilitated in vivo release of acetylcholine (ACh) from dorsal hippocampi of freely moving rats as determined by the microdialysis technique. The effects of d-norfenfluramine (7.5 mg/kg i.p.) and citalopram (10 microM, applied by reverse dialysis) were prevented by a 14-day chemical lesion of the raphe nuclei, suggesting mediation by the 5-HT system in the cholinergic action of the drugs. The increase in extracellular ACh content induced by d-norfenfluramine (5 mg/kg i.p.) was antagonized by the 5-HT3 receptor antagonists tropisetron (0.5 mg/kg i.p.) and DAU 6215 (60 micrograms/kg i.p.), but not by the mixed 5-HT1 and 5-HT2 receptor antagonist metergoline (2 mg/kg s.c.). In accordance with an involvement of the 5-HT3 receptor in the ACh facilitation induced by d-norfenfluramine is the finding that the selective 5-HT3 receptor agonist 2-methylserotonin (250 micrograms i.c.v., or 10 microM applied by reverse dialysis) raised ACh release. The effect of the intracerebroventricular drug was prevented by the 5-HT3 antagonists DAU 6215 (60 micrograms/kg i.p.) and ondansetron (60 micrograms/kg s.c.). These antagonists by themselves did not modify the basal ACh release, indicating that 5-HT does not tonically activate the 5-HT3 receptors involved. In conclusion, the overall regulatory control exerted by 5-HT in vivo is to facilitate hippocampal ACh release. This is mediated by 5-HT3 receptors probably located in the dorsal hippocampi.

Repeated cocaine exposure inhibits the adrenocorticotropic hormone response to the serotonin releaser d-fenfluramine and the 5-HT 1A agonist, 8-OH-DPAT

The influence of cocaine exposure on serotonergic neurons and postsynaptic 5-HT 1A receptor-mediated responses was evaluated by measuring neuroendocrine responses to a serotonin (5-HT) releaser or a 5-HT 1A agonist. Male rats received cocaine (15 mg/kg, i.p.) or saline twice daily for 7 days. Forty-two hr after the final cocaine injection, the 5-HT releaser d-fenfluramine (0, 0.2, 0.6, 2, or 5 mg/kg, i.p.) or the 5-HT 1A agonist, 8-OH-DPAT (0, 10, 50, 200 or 500 μg/kg, s.c.) were administered. Blood samples were then collected for analysis of plasma ACTH, prolactin, and renin concentrations. The ACTH responses to d-fenfluramine and 8-OH-DPAT were inhibited in cocaine pretreated rats. However, the prolactin responses to d-fenfluramine and 8-OH-DPAT were not significantly modified by cocaine exposure. Additionally, the renin response to d-fenfluramine was unaltered by repeated cocaine administration, while 8-OH-DPAT did not alter renin secretion in either pretreatment group. In contrast to published reports which show that cocaine exposure produces supersensitive 5-HT 2A and/or 5-HT 2C receptor-mediated responses, the present data suggest that repeated cocaine exposure produces subsensitivity to at least some postsynaptic 5-HT 1A receptors. Cocaine-induced deficits in the ACTH response to 5-HT releasers may reflect 5-HT 1A receptor subsensitivity, but presynaptic deficits cannot be excluded. Examination of the ACTH response to 5-HT 1A agonists may represent a valuable approach to deermine deficits in 5-HT function in human cocaine abusers.

Selective reduction by serotonergic agents of hypertonic saline consumption in rats: evidence for possible 5-HT1C receptor mediation

Previously, it has been shown that, in small doses, putative 5-HT1A receptor agonists selectively increase ingestion of hypertonic saline without affecting either water or isotonic saline intake. Evidence was obtained in the present series of experiments for selective reduction in hypertonic saline following the administration of a variety of serotonergic directly- and indirectly-acting agonists. Water, isotonic saline (0.9%), or hypertonic saline (1.8%) were made available to separate groups of water-deprived rats. The results indicated some selectivity with the 5-HT-uptake inhibitor and releaser d-fenfluramine and the 5-HT uptake inhibitor fluoxetine, and with the 5-HT agonists mCPP [1-3-chlorophenyl)piperazine] and MK 212 [6-chloro-2-(1-piperazinyl)pyrazine]. In each case, hypertonic intake was significantly suppressed. Distinct from these compounds were TFMPP [1-(3-(trifluoromethyl)phenyl)piperazine], RU 24969 [5-methoxy-3-(1,2,3,6-tetrahydropyridinyl)1H-indole], and quipazine. This second group either reduced fluid intake indiscriminately or reduced water and isotonic saline drinking. Selective reduction in the intake of hypertonic saline did not occur. Finally, peripheral-administration of 5-HT or the 5-HT1B agonist CGS 12066B [7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo) (1,2-a) 1:2 maleate], had no significant effect on fluid intake in any fluid condition. The results are discussed in terms of a possible serotonergic mechanism which may underlie inhibition of hypertonic salt drinking, and which involves mediation through a subtype of the 5-HT1 receptor.