Medial versus lateral parabrachial nucleus lesions in the rat: effects on cholecystokinin- and D-fenfluramine-induced anorexia

The two major components of the pontine parabrachial nucleus (PBN), the medial (gustatory) and lateral (visceral) subdivisions, have been implicated in a variety of ingestive behaviors. The present study examined the influence of bilateral ibotenic acid lesions of the medial or lateral PBN on the anorectic effects of two systemically administered drug treatments. In Experiment 1, 24-h food-deprived rats where injected with sulfated cholecystokinin (26-33) (CCK; 0, 4.0, or 8.0 microg/kg) and then given 60 min access to food. In Experiment 2, the influence of D-fenfluramine (DFEN; 0, 0.5, 1.0, or 2.0 mg/kg) on deprivation-induced feeding was examined in the same rats using the same behavioral procedure as in Experiment 1. Lesions of the lateral PBN abolished CCK-, but not DFEN-induced anorexia whereas lesions of the medial PBN augmented DFEN-, but had no influence on CCK-induced anorexia. The results suggest that the satiating effects of CCK and DFEN are mediated through different mechanisms involving, respectively, visceral and orosensory processing.     

Medial versus lateral parabrachial nucleus lesions in the rat: effects on cholecystokinin- and -fenfluramine-induced anorexia

The two major components of the pontine parabrachial nucleus (PBN), the medial (gustatory) and lateral (visceral) subdivisions, have been implicated in a variety of ingestive behaviors. The present study examined the influence of bilateral ibotenic acid lesions of the medial or lateral PBN on the anorectic effects of two systemically administered drug treatments. In Experiment 1, 24-h food-deprived rats where injected with sulfated cholecystokinin_26-33 (CCK; 0, 4.0, or 8.0 μg/kg) and then given 60 min access to food. In Experiment 2, the influence of -fenfluramine (DFEN; 0, 0.5, 1.0, or 2.0 mg/kg) on deprivation-induced feeding was examined in the same rats using the same behavioral procedure as in Experiment 1. Lesions of the lateral PBN abolished CCK-, but not DFEN-induced anorexia whereas lesions of the medial PBN augmented DFEN-, but had no influence on CCK-induced anorexia. The results suggest that the satiating effects of CCK and DFEN are mediated through different mechanisms involving, respectively, visceral and orosensory processing.     

Modulation of dopamine release by striatal 5-HT2C receptors

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.     

Clozapine and haloperidol differentially alter the constitutive activity of central serotonin2C receptors in vivo.

BACKGROUND: Central serotonin2C (5-HT2C) receptors are known to play a role in the mechanism of action of the antipsychotic drugs (APDs) clozapine and haloperidol. However, evidence for the involvement of the constitutive activity of 5-HT2C receptors in the dopamine (DA)ergic effects of APDs is lacking in vivo. METHODS: Using in vivo microdialysis in halothane-anesthetized rats, we assessed the ability of selective 5-HT2C compounds to modulate the release of DA induced by haloperidol and clozapine in the nucleus accumbens and striatum. RESULTS: Both APDs induced a dose-dependent increase in accumbal and striatal DA extracellular levels. The effect of .01 mg/kg haloperidol was potentiated by the 5-HT2C inverse agonist SB 206553 (5 mg/kg) but unaltered by the 5-HT2C antagonists SB 243213 and SB 242084 (1 mg/kg). Conversely, the effect of 1 mg/kg clozapine, a dose able to reverse the decrease in DA outflow induced by the 5-HT2C agonist Ro 60-0175 (3 mg/kg), was unaffected by SB 206553 but blocked by SB 243213 (1 mg/kg) and SB 242084 (.3 and 1 mg/kg). CONCLUSIONS: These results show that clozapine and haloperidol differentially alter the constitutive activity of 5-HT2C receptors and suggest that clozapine behaves as a 5-HT2C inverse agonist in vivo.     

Reversal of dexfenfluramine-induced anorexia and c-Fos/c-Jun expression by lesion in the lateral parabrachial nucleus

The external subdivision of the lateral parabrachial nucleus (LPBE) shows strong Fos-like immunoreactivity (FLI) following anorectic doses of the indirect serotonin agonist dexfenfluramine (DFEN). In an effort to determine the contribution of the LPBE to DFEN-induced anorexia, bilateral ibotenate lesions were made in the LPBE, and the effects of the lesion on DFEN-induced anorexia and FLI as well as c-June-like immunoreactivity (JLI) were examined. It was found that LPBE lesion significantly attenuated DFEN anorexia: in a 1-h food intake test following 24-h food deprivation, DFEN (2 mg/kg) suppressed food intake by 60% in intact rats but only 34% in rats with LPBE lesions. In addition to this behavioral change, LPBE lesion completely abolished DFEN-induced FLI and JLI in the lateral subdivision of the central nucleus of the amygdala (CeL) and laterodorsal subdivision of the bed nucleus of stria terminalis (BSTLD), both of which showed strong FLI and JLI in intact rats. DFEN-induced FLI and JLI in other brain regions were not affected by LPBE lesion, including the ventromedial and lateral hypothalamus, caudate-putamen, and the nucleus of the solitary tract (NST). The parallel loss of DFEN-induced anorexia and FLI/JLI following LPBE lesion raises the novel possibility that LPBE-CeL/BSTLD pathway may be involved in DFEN anorexia.     

Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice

DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] displays a high affinity for the rat 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi 7.3, 7.4 and 7.8, respectively) and acts as an agonist. DOI (0.5-4 mg/kg, i.p. 30 min pre-test) increased the number of punished passages in the mouse four plates test (FPT). The anti-punishment action of DOI (1 mg/kg, i.p. 30 min pre-test) was abolished by prior treatment with the selective 5-HT2A receptor antagonist SR 46949B (0.1 and 1 mg/kg, i.p. 45 min pre-test) but not by the selective 5-HT2C receptor antagonist RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor the selective 5-HT2C/2B receptor antagonist SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). An anxiolytic-like action was also observed for DOI (1 mg/kg) in the elevated plus maze (EPM). The anxiolytic-like action of DOI (1 mg/kg, i.p. 30 min pre-test) was antagonised by pre-treatment with SR 46949B (0.125 and 0.5 mg/kg, i.p. 45 min pre-test) but not by RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). In conclusion, DOI produced an anxiolytic-like profile in the mouse FPT and EPM. These effects are likely to be 5-HT2A receptor mediated.     

Medial versus lateral parabrachial nucleus lesions in the rat: effects on mercaptoacetate-induced feeding and conditioned taste aversion

The two experiments of the present study examined the influence of bilateral electrophysiologically-guided ibotenic acid lesions of the medial (gustatory) and lateral (viscerosensory) subdivisions of the parabrachial nucleus (PBN) on lipoprivic feeding and on the acquisition of a conditioned taste aversion. In Experiment 1, mercaptoacetate (0, 400, 600, or 800 micromol/kg) failed to enhance food intake in normal rats maintained and tested on standard laboratory chow. In the same procedure, rats with lesions of the medial or lateral PBN consumed less food during baseline but nonetheless were sensitive to the orexigenic action of mercaptoacetate. In Experiment 2, both types of PBN lesions prevented acquisition of a conditioned taste aversion induced by the oral self administration of lithium chloride. The results suggest that PBN neurons essential for conditioned taste aversion are not involved in the mercaptoacetate-induced feeding of rats maintained and tested on standard laboratory chow.     

Serotonin (1A) receptor involvement in acute 3,4-methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat

The current study assessed whether various co-administered serotonin (5-HT) receptor antagonists could prevent some of the acute behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") in rats. In the social interaction test, MDMA (5 mg/kg) significantly increased the duration of total social interaction between two conspecifics meeting for the first time. Microanalysis showed that MDMA increased adjacent lying and approach behaviours while reducing anogenital sniffing. MDMA (5 mg/kg) also caused elements of the serotonin syndrome including low body posture and piloerection. In the emergence test, MDMA significantly increased hide time and emergence latency indicating increased anxiety-like behavior. Pretreatment with the 5HT 1A receptor antagonist, WAY 100635 (1 mg/kg), prevented MDMA-induced increases in social interaction and markers of the serotonin syndrome while the 5-HT 1B receptor antagonist GR 55562 (1 mg/kg) and 5-HT 2A receptor antagonist ketanserin (1 mg/kg) were ineffective. The 5-HT 2B/2C receptor antagonist, SB 206553 (2 mg/kg), prevented MDMA-induced prosocial effects but caused pronounced thigmotaxis (hyperactivity at the periphery of the testing chamber). The anxiogenic effect of MDMA on the emergence test was not prevented by pretreatment with any of the 5-HT receptor antagonists tested. These results indicate that prosocial effect of MDMA may involve 5-HT 1A and possibly 5-HT 2B/2C receptors. In contrast, MDMA-induced generalised anxiety, as measured by the emergence test, seems unlikely to involve the 5-HT 1A, 5-HT 1B or 5-HT 2A, 5-HT 2B or 5-HT 2C receptors.     

Role of 5-hT2C receptors in the hypophagic effect of m-CPP, ORG 37684 and CP-94,253 in the rat

Compounds that stimulate 5-HT2C and/or 5-HT1B receptors induce hypophagia, but the relative role of these receptors in the control of feeding behaviour remains to be unequivocally demonstrated. The objectives of the present study were: (a) comparison of the hypophagic effect of the mixed 5-HT2C/1B receptor agonist, m-CPP, with that of ORG 37684 and CP-94,253, a relatively selective 5-HT2C and 5-HT1B receptor agonist, respectively; (b) verification of the contribution of 5-HT2C receptors to the hypophagic effect of these compounds by antagonism experiments; and (c) to test whether cotreatment with ORG 37684 and CP-94,253 leads to a more pronounced reduction of food intake as compared with treatment with either compound alone. Food intake was measured in a free feeding experimental protocol employing female Wistar rats. m-CPP was more potent in suppressing food intake than ORG 37684 and CP-94,253 (ED50 values for the first hour of access: 0.45, 1.84 and 3.48 mg/kg ip, respectively). The 5-HT2C receptor antagonists, metergoline and SB 242.084, completely reversed the hypophagic effect of ORG 37684, but not that of CP-94,253 and m-CPP. The hypophagic effect of ORG 37684 was potentiated by a low (inactive) dose of CP-94,253 (ED50: 4.95 and 2.44 mg/kg ip after vehicle and CP-94,253 pretreatment, respectively) and vice versa (ED50 values: 4.02 and 0.62 mg/kg ip). It is concluded that the hypophagic effect of ORG 37684-but not that of m-CPP and CP-94,253--is exclusively mediated by activation of 5-HT2C receptors. The results further indicate that simultaneous activation of 5-HT2C and 5-HT1B receptors underlies the higher potency of m-CPP in reducing food intake, as compared with other, more selective, compounds.     

Differential effects of 5-HT(2A) and 5-HT(2C) receptor blockade on strategy-switching

Recent experiments indicate that blockade of serotonin (5-HT) 2A and 2C receptors have differential effects on reversal learning. The present experiments investigated the effects of the 5-HT(2A) receptor antagonist, ketanserin and 5-HT(2C) receptor antagonist, SB242084 on acquisition and strategy-switching in a visual cue-response paradigm. Long-Evans rats were trained in a cross-maze to enter an arm based on color (visual cue version) or a specific turn response (response version). Systemic treatment with ketanserin did not affect initial learning of a visual cue or response discrimination, but ketanserin at 0.5 mg/kg significantly enhanced a switch between visual cue and response strategies. Ketanserin facilitated strategy-switching by inhibiting responses to a previously relevant strategy without affecting choices to never-reinforced strategies. Treatment with SB242084 (0.5, 1.0 or 2.0 mg/kg) did not affect acquisition of a visual cue or response discrimination. SB242084 treatment also did not affect strategy-switching. The present findings suggest that blockade of 5-HT(2A), but not 5-HT(2C), receptors enhance strategy switching.     

MPTP-induced deficits in motor activity: Neuroprotective effects of the spintrapping agent, α-phenyl-tert-butyl-nitrone (PBN)

Summary In Experiment 1, groups of mice were administered either saline or MPTP (2 × 30mg/kg, s.c., separated by a 24-hr interval) 30min after being injected either PBN (15, 50 or 150mg/kg, s.c., low, medium and high doses, respectively) or L-Deprenyl (0.25 or 10.0mg/kg, s.c., low and high doses, respectively), the reference compound used, or saline. Tests of spontaneous motor activity 14 days later indicated that the MPTP-induced hypokinesia for locomotion and rearing was alleviated by prior administration with PBN (50 or 150mg/kg) or L-Deprenyl (10.0mg/kg); lower doses of PBN (15mg/kg) and L-Deprenyl (0.25mg/kg) did not affect the MPTP-induced deficits. Dopamine (DA) concentrations in the striatum confirmed a more severe loss of DA in the MPTP, PBN(15) + MPTP and Deprenyl(0.25) + MPTP groups than in the control group. Significant protection of DA was observed in the PBN(50) + MPTP, PBN(150) + MPTP and Deprenyl(10) + MPTP groups that did not exhibit an hypokinetic behaviour. In Experiment 2, the effects of repeated treatment with PBN (50mg/kg, s.c. over 12 days), post-MPTP, were studied in aged (15-month-old) and young (3-month-old) mice. Subchronic administration of PBN increased substantially the motor activity of old and young mice that had received MPTP. Aged control (saline) mice showed an activity deficit compared to young control mice; this deficit was abolished by repeated PBN treatment. The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.     

Effects of mu-CPP and mesulergine on dietary choices in deprived rats: possible mechanisms of their action

Although it has been well established that compounds that stimulate 5-HT(2C) and/or 5-HT(1B) receptors induce hypophagia by promoting satiety process, the relative role of these receptor subtypes in dietary choices remains to be fully determined. m-CPP is considered a useful probe of 5-HT(2C) receptor function in vivo and its administration reduces food intake and appetite in humans and rats. Conversely, the non-selective 5-HT(2C) receptor antagonist mesulergine elicits feeding in rats. Food intake and dietary choices were measured in a food-deprivation experimental protocol employing male Wistar rats. Animals were given access for a 4-h period to a pair of isocaloric diets. These two diets were enriched in protein or carbohydrate proportions, respectively, but fat content was held constant. The mixed 5-HT(2C/1B) receptor agonist, m-CPP, led to a dose-dependent hypophagia, due to substantial reduction in carbohydrate consumption while protein intake was spared (0.62, 1.25 and 2.50 mg/kg i.p., respectively). The non-selective 5-HT(2C) receptor antagonist and also D2 agonist, mesulergine, on its own produced a significant dose-dependent increase in both protein and carbohydrate diets (1.0 and 3.0 mg/kg i.p., respectively). Combined treatment with m-CPP, at its maximum effective dose, and mesulergine dose-dependently reversed m-CPP-induced hypophagia, during the 4-h test period. In order to clarify the effects of mesulergine on dietary choices since it is simultaneously a dopamine agonist besides its antiserotonergic properties, the D2 agonist apomorphine was also used. Apomorphine caused a dose-dependent increase in protein intake while carbohydrate and total food intake remained nearly unchanged (0.5 and 1.0 mg/kg i.p., respectively). It is concluded that the mesulergine-induced hyperphagic response on both diets is the expression of a dual mode of action, due to its 5-HT(2C) antagonist activity together with D2 agonist properties. The results further indicate that the activation of hypothalamic 5-HT(2C) receptors may be involved in both protein sparing and carbohydrate suppressing effects of 5-HT (m-CPP-like effect), whereas an important role in increase of protein consumption seems to have the dopaminergic system probably through D2 receptors (apomorphine-like and mesulergine-like effects, respectively).     

Differential effects of 5-HT1 and 5-HT2 receptor agonists on hindlimb movements in paraplegic mice

The effects induced by serotonergic (5-HT) agonists of the 5-HT1 and 5-HT2 subclasses were examined on hindlimb movement generation in adult mice completely spinal cord transected at the low thoracic level. One week postspinalization, intraperitoneal injection (0.5-10 mg/kg) of meta-chlorophenylpiperazine (m-CPP; 5-HT(2B/2C) agonist) or trifluoromethylpiperazine (TFMPP; 5-HT(1B) agonist) failed to induce locomotor-like movements. However, dose-dependent nonlocomotor movements were induced in air-stepping condition or on a motor-driven treadmill. In contrast, hindlimb locomotor-like movements were found after the injection of quipazine (5-HT(2A/2C) agonist; 1-2 mg/kg). Combined with L-DOPA (50 mg/kg, i.p.), low doses of quipazine but not of m-CPP and TFMPP produced locomotor-like and nonlocomotor movements in air-stepping condition or on the treadmill. Subsequent administration of m-CPP or TFMPP significantly reduced and often completely abolished the hindlimb movements induced by quipazine and L-DOPA. Altogether, these results demonstrate that 5-HT(2A/2C) receptor agonists promote locomotion while 5-HT(1B) and 5-HT(2B/2C) receptor agonists interfere with locomotor genesis in the hindlimbs of complete paraplegic mice. These results suggest that only subsets of spinal 5-HT receptors are specific to locomotor rhythmogenesis and should be activated to successfully induce stepping movements after spinal cord injury.     

5-HT2C receptor involvement in female rat lordosis behavior

Adult, hormone-primed, ovariectomized rats (CDF-344) with bilateral implants within the ventromedial nucleus of the hypothalamus (VMN), were injected with 0.5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone. This priming produced rats with 2 different levels of sexual receptivity. Rats with a lordosis to mount ratio (L/M)>/=0.5 were used to examine the potential lordosis-inhibiting effects of the 5-HT2A receptor antagonist, R(+)-a-(2, 3-dimethoxyphenyl)-1-[2(4-fluoro-phenylethyl)]-4-piperidine-methanol (MDL 100,907), and the 5-HT2C receptor antagonist, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2, 3-f]indole (SB 206553). Rats with low sexual receptivity (L/M<0.5) were bilaterally infused with the 5-HT2A/2C receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), or DOI plus either MDL 100,907 or SB 206553 to determine if either drug would attenuate the lordosis-facilitating effects of DOI. The 5-HT2C receptor antagonist, but not the 5-HT2A receptor antagonist, effectively inhibited lordosis behavior. Similarly, SB 206553 was more effective than MDL 100,907 in reducing the DOI-induced increase in lordosis responding. However, both drugs limited the duration of lordosis responding initiated by DOI. These results are consistent with prior suggestions that 5-HT2A/2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that 5-HT2C, rather than 5-HT2A, receptors are primarily responsible for the effects of 5-HT2 receptor-active drugs on lordosis behavior.     

Area postrema and the anorectic actions of dexfenfluramine and amylin

The present study examined whether the area postrema and adjacent nucleus of the solitary tract (AP/NTS) is necessary for the expression of anorexia to two classes of anorectic agent. The first agent is the serotonergic agonist, dexfenfluramine (DFEN) and the second is the pancreatic peptide, amylin. Rats were prepared with either aspiration lesions of the AP/NTS or a sham operation. Rats with such lesions (APX) displayed normal anorexia following administration of DFEN, but the anorectic effect of amylin was completely eliminated. The magnitude of a conditioned flavor aversion to DEN was similar in APX and sham operated controls but, unlike controls, APX rats did not reduce total intake in the two-bottle preference test. Finally, the induction of Fos-like immunoreactivity (Fos-ir) following either DFEN or amylin was examined in both APX and sham operated groups. Both agents induced Fos-ir in the AP and/or NTS of sham operated rats, and this region was entirely absent in the APX rats. DFEN-induced Fos-ir was reduced greatly in the PVN of APX rats, but appeared normal in several other regions surveyed, including the central nucleus of the amygdala and the dorsal striatum. In contrast, amylin-induced Fos-ir was reduced in many rostral brain regions of APX rats. These data indicate that neither the anorexia nor the flavor aversion that are produced by DFEN are dependent upon the AP, and in particular that Fos-ir induced by DFEN in the LPBE is not due to afferents from the AP/NTS. In contrast, the anorectic effect of amylin seems to be due principally to its direct action at the AP/NTS.     

5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy

The present study was conducted to investigate the role of 5-HT(2C) and 5-HT(1A) receptors in the generation of spike-wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG/Rij rats). We have determined the effects of the 5-HT(2C) receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT(2C) receptor antagonist SB-242084, the selective 5-HT(1A) receptor antagonist WAY-100635, two selective serotonin re-uptake inhibitors (SSRI, fluoxetine and citalopram) and their combinations in this model. The 5-HT(2C) agonist m-CPP caused marked, dose-dependent decreases in the cumulative duration and number of SWD administered either intraperitoneally (0.9 and 2.5 mg/kg) or intracerebroventricularly (0.05 and 0.1 mg/kg). Treatment with SB-242084 (0.2 mg/kg, ip) alone failed to cause any significant change in SWD compared to vehicle. Pretreatment with SB-242084 (0.2 mg/kg, ip) eliminated the effects of m-CPP on SWD. Fluoxetine (5.0 mg/kg, ip) alone caused moderate increase in SWD. After pretreatment with SB-242084, the effect of fluoxetine was significantly enhanced. The combination of SB-242084 and citalopram (2.5 mg/kg, ip) caused a similar effect, namely an increase in SWD. In contrast, pretreatment with WAY-100635 significantly attenuated the effect of fluoxetine. In conclusion, these results indicate that the increase in endogenous 5-HT produces a dual effect on SWD; the inhibition of epileptiform activity is mediated by 5-HT(2C), the activation by 5-HT(1A) receptors.     

m-CPP-induced self-grooming is mediated by 5-HT2C receptors

m-Chlorophenylpiperazine (m-CPP), a potent 5-HT receptor agonist, is known to induce self-grooming in rats and exacerbate symptoms in patients with obsessive-compulsive disorder (OCD). To characterise the possible role, 5-HT(2B) and 5-HT(2C) receptors play in m-CPP-induced self-grooming, subtype-selective receptor antagonists were used. m-CPP significantly increased the amount of self-grooming in male Sprague-Dawley rats. This effect followed a bell-shaped dose-response curve with a peak at 0.6 mg/kg, i.p. Pretreatment with SB-242084, a subtype-selective 5-HT(2C) receptor antagonist (0.1-0.5 mg/kg, i.p.), reversed m-CPP-induced self-grooming. In contrast, pretreatment with the subtype-selective 5-HT(2B) receptor antagonist SB-215505 (1 mg/kg, i.p) did not block the effect of m-CPP. Two days after depletion of brain 5-HT by p-chlorophenylalanine (p-CPA, 2 x 50, 2 x 100 mg/kg, i.p.) m-CPP-induced responses were significantly enhanced compared to controls. Our studies provide evidence that direct activation of 5-HT(2C) receptors mediate m-CPP-induced self-grooming and the depletion of brain 5-HT sensitizes these receptors.     

Effect of estrogen on the lordosis-inhibiting action of ketanserin and SB 206553

The effects of the 5-HT(2A/2C) receptor antagonist, ketanserin, and the 5-HT(2C) receptor antagonist, SB 206553, on lordosis behavior were investigated in ovariectomized rats hormonally primed with estradiol benzoate (EB) (0.5 or 25 microg) and progesterone (500 microg). Both ketanserin and SB 206553 inhibited lordosis behavior after infusion into the ventromedial nucleus of the hypothalamus (VMN), but ketanserin was slightly more effective than the 5-HT(2C) receptor antagonist. Either drug was more effective in rats primed with 0.5 microg EB than in rats hormonally primed with 25 microg EB. These findings support the suggestion that estrogen may enhance functioning of the 5-HT(2) receptor family and thereby protect against the 5-HT(2) receptor antagonists. These data are consistent with prior suggestions that estrogen modulates functioning of 5-HT(2) receptors within the VMN and that 5-HT(2) receptors play a facilitatory role in the modulation of female rat lordosis behavior.     

Loss of serotonin uptake sites and immunoreactivity in rat cortex after dexfenfluramine occur without parallel glial cell reactions

The frontal cortices of rats which received eitherd,l- ord-fenfluramine (DFEN) for 4 days were examined 18 h to 2 weeks following treatment for changes in synaptosomal uptake of serotonin (5HT), paroxetine binding, 5HT-immunoreactivity (5HT-IR), and both astrocytic (GFAP) and microglial markers. Additional rats received intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT). Consistent with previous reports,d,l- and DFEN produced dose-dependent losses of both 5HT uptake and paroxetine binding, and loss of 5HT-IR which coincided with an abnormal or ‘swollen’ appearance of immunoreactive axon processes. Recovery of these serotonergic indices was greatest following the lowest doses of DFEN, but was absent after 5,7-DHT treatment. No evidence for an increase in GFAP synthesis or microglial activation was observed in frontal cortices of rats treated with either DFEN or 5,7-DHT. We conclude that the presence of swollen 5HT-IR axons in the cortices of both the 5,7-DHT and DFEN groups is insufficient to trigger the glial responses often associated with neuronal degeneration. Thus, it remains to be determined if swollen 5HT-IR axons are a prelude to neurodegeneration, or whether they represent reversible changes in axonal immunochemistry associated with decreases in 5HT levels. The implications of the data for the clinical safety of DFEN are briefly discussed.     

Role of 5-HT(2) receptor subtypes in depletion of 5-HT induced by p-chloroamphetamine in the mouse frontal cortex

A serotonin (5-hydroxytryptamine, 5-HT)-releasing drug, p-chloroamphetamine elicited decreases in 5-HT levels in the mouse frontal cortex. 5-HT reduction elicited by p-chloroamphetamine was inhibited by the 5-HT(2A/2B/2C) receptor antagonist, LY 53857 and the 5-HT(2A) receptor antagonist, ketanserin. However, the 5-HT(2B/2C) receptor antagonist, SB 206553, enhanced it. LY 53857 and ketanserin can inhibit hyperthermia elicited by p-chloroamphetamine, although SB 206553 enhances it. The effects of the 5-HT(2) receptor antagonists on neurotoxicity are very similar to those on hyperthermia. Since hyperthermia facilitates neurotoxicity induced by amphetamine analogue, these 5-HT(2) receptor antagonists may modify 5-HT depletion induced by p-chloroamphetamine through responses to body temperature.