QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

Published Online
on April 3, 2000

This Article Abstract Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heisler, L. K. Articles by Tecott, L. H. Search for Related Content PubMed PubMed Citation Articles by Heisler, L. K. Articles by Tecott, L. H.

 Previous Article  |  Next Article 

The Journal of Neuroscience, 2000, 20:RC71:1-5

RAPID COMMUNICATION
A Paradoxical Locomotor Response in Serotonin 5-HT_2C Receptor Mutant Mice

Lora K. Heisler and Laurence H. Tecott

Department of Psychiatry and Center for Neurobiology and Psychiatry, University of California, San Francisco, San Francisco, California 94143-0984

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Paradoxical behavioral responses to nonselective neuropsychiatric drugs are frequently encountered and poorly understood. We report that a single receptor gene mutation produces a paradoxical response to the nonspecific serotonin receptor agonist m-chlorophenylpiperazine (mCPP). Although this compound normally suppresses locomotion, it produces hyperactivity in mice bearing a targeted mutation of the 5-HT_2C receptor gene. This effect was blocked by pretreatment with a 5-HT_1B receptor antagonist, indicating that the behavioral consequences of mCPP-induced 5-HT_1B receptor stimulation are unmasked in animals devoid of 5-HT_2C receptor function. Furthermore, this paradoxical response to mCPP was reproduced in wild-type C57BL/6 mice by previous pharmacological blockade of 5-HT_2C receptors, indicating that the mutant phenotype does not result from perturbations of brain development. These effects of 5-HT_1B and 5-HT_2C receptor antagonists likely reflected blockade of pharmacological actions of mCPP, because these compounds did not alter locomotor activity levels when administered alone. Thus, mCPP interacts with distinct 5-HT receptor targets that produce opposing effects on locomotor activity levels. A paradoxical behavioral response is produced by the genetic inactivation of the target that produces the prevailing effect of the drug in the wild-type animal. This genetically based paradoxical drug effect provides a model for considering the effects of genetic load on neurobehavioral responses to drugs.

Key words: serotonin; 5-HT_2C receptor; mCPP; paradoxical; transgenic; locomotion

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

The brain serotonin [5-hydroxytryptamine (5-HT)] system modulates a diverse array of behavioral and physiological processes. Accordingly, defects of serotonergic function have been proposed to contribute to the manifestations of neuropsychiatric conditions such as depression, anxiety disorders, eating disorders, and migraine. The effects of serotonin are mediated by a heterogeneous family of at least 14 distinct 5-HT receptor subtypes. The contributions of particular subtypes to the actions of serotonin and nonselective agonists remain to be clarified, because the availability of subtype-selective agonist and antagonist compounds is limited. The application of molecular genetic approaches to this problem has led to the generation of mutant mouse strains with targeted disruptions of genes encoding particular 5-HT receptor subtypes. Such strains provide tools that complement pharmacological probes for the analysis of receptor function.

We have applied this approach to the 5-HT_2C receptor subtype, which has been implicated in the serotonergic regulation of activity, feeding, and anxiety (Brennan et al., 1997). Animals bearing a targeted mutation of the 5-HT_2C receptor gene display pleiotropic effects of the mutation, such as hyperphagia, altered spatial learning, and enhanced neuronal network excitability (Tecott et al., 1995; Nonogaki et al., 1998; Tecott et al., 1998). 5-HT_2C receptor mutants were also used to determine the contribution of 5-HT_2C receptors to the actions of dexfenfluramine, a compound producing nonselective 5-HT receptor activation by stimulating synaptic serotonin release. Mutants displayed reduced sensitivity to the anorectic effects of dexfenfluramine, implicating 5-HT_2C receptors in this action of the drug (Vickers et al., 1999).

In an analogous manner, we sought to determine the extent to which 5-HT_2C receptors contribute to the actions of the nonselective agonist m-chlorophenylpiperazine (mCPP). In clinical studies, responses to mCPP administration have been frequently used as indicators of central serotonin system function (Schwartz et al., 1997; Southwick et al., 1997; Hollander et al., 1998; Kaye et al., 1998; Broocks et al., 1999). In rodents, mCPP reduces locomotor activity (Kennett and Curzon, 1988; Lucki et al., 1989), suppresses feeding (Samanin et al., 1979; Kennett et al., 1987), and enhances anxiety-like behaviors (Kennett et al., 1989; Whitton and Curzon, 1990). Many of these effects are blocked by antagonists of the 5-HT_2C receptor subtype, for which mCPP displays the highest affinity (pK_i, 7.7) (Hoyer, 1988). mCPP has therefore been considered a pharmacological tool for evaluating 5-HT_2C receptor function (Curzon and Kennett, 1990).

In light of these studies, we anticipated that 5-HT_2C receptor mutant mice would exhibit reduced sensitivity to the behavioral effects of mCPP. However, attempts to determine the effects of this drug on anxiety-related behaviors were complicated by an unexpected hyperlocomotor response to mCPP in mutant mice; a finding antithetical to the suppression of activity produced in wild-type animals by this drug. In the present study, we describe this response and determine its underlying mechanism. Based on these findings, a model is proposed whereby paradoxical behavioral responses to nonselective psychoactive compounds are determined by genetic load.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Subjects. 5-HT_2C receptor mutant mice were originally generated from a 129-derived embryonic stem cell line (Tecott et al., 1995) and have been back-crossed for 12 generations to a C57BL/6 genetic background. Wild-type C57BL/6 males were crossed with females heterozygous for the 5-HT_2C receptor mutation. A PCR-based genotyping strategy was used, as previously described (Brennan et al., 1997). Because the 5-HT_2C receptor gene is X-linked (Milatovich et al., 1992), 50% of the resulting males were hemizygous mutants, and 50% were wild types. This approach was chosen rather than the separate maintenance of mutant and wild-type strains to minimize interlitter variability attributable to potential differences in the maternal behavior of mutant and wild-type mothers. To further control for interlitter variability, wild-type littermate controls were used in studies of 5-HT_2C receptor mutant mice. Twenty 19- to 21-week-old drug-naïve 5-HT_2C receptor mutant and wild-type (n = 10 per genotype) mice were used. For studies using the 5-HT_2C receptor antagonist SB 206553, 16 drug-naïve C57BL/6 mice (Charles Rivers Laboratories, Wilmington, MA) of the same age were used. Animals were group-housed, two to six mice per cage, in standard polycarbonate mouse cages (29 × 18.5 × 13 cm). Animals were given ad libitum access to food and water and were maintained on a 12 hr light/dark cycle (lights on at 6 A.M.). Animals were tested a minimum of 2 weeks after transfer to the laboratory.

Apparatus. Horizontal activity and rearing were assessed with an automated Photobeam Activity System (version 70110; San Diego Instruments). This system consists of two metal rectangular frames surrounding a standard low-profile polycarbonate rat cage (48 × 27 × 13 cm). Horizontal locomotor activity was determined by the lower frame, consisting of a 4 × 8 array of infrared photobeams, spaced 4.4 cm apart on the x-axis and 5.5 cm apart on the y-axis, and elevated 2 cm. Frequency of rearing was identified with the upper frame through a set of eight infrared photobeams, spaced 2.5 cm apart and elevated 7 cm.

Procedure. Approximately 3 min before each assay, animals were removed from their home cage and placed in a clean holding cage. Animals were quickly transferred to the center of the testing chamber, and horizontal activity and rearing were monitored in 5 min intervals for 3 hr. Animals were exposed to the apparatus in two trials before drug treatment to determine basal activity levels and to acclimate animals to the testing environment. During each 3 hr session, drug treatments were administered after 2 hr of habituation to the chamber, and drug pretreatments were injected 30 min before this. Experiments were conducted using a within-subjects design with a 3 d interval between drug trials. Testing was counterbalanced by genotype and treatment condition and conducted during the light cycle. All holding and testing cages were autoclaved between subjects. For dose-response studies with GR 127935 and mCPP, 10 5-HT_2C mutant and 10 wild-type mice were treated with three doses of GR 127935 (0.3, 1.5, and 7.5 mg/kg) and mCPP (2.5, 5.0, and 10.0 mg/kg) and vehicle. To determine the effect of GR 127935 pretreatment on mCPP responses in mutant and wild-type animals, four treatment conditions were used: (1) vehicle pretreatment followed by vehicle, (2) GR 127935 pretreatment (7.5 mg/kg) followed by vehicle, (3) vehicle pretreatment followed by mCPP (2.5 mg/kg), and (4) GR 127935 (7.5 mg/kg) pretreatment followed by mCPP (2.5 mg/kg). To determine the effect of SB 206553 pretreatment on mCPP responses in C57BL/6 mice, 16 animals were pretreated with vehicle or three doses of SB 206553 (1.0, 2.5, and 5.0 mg/kg) before treatment with vehicle or 2.5 mg/kg mCPP. Experimenters were blind to the genotypes of the mice and to the drugs administered in pharmacological experiments

Drugs. mCPP (Sigma, St. Louis, MO) was dissolved in 0.9% sterile saline; the 5-HT_1B/1D receptor antagonist GR 127935 (courtesy of Glaxo Group Research Ltd.) was dissolved in distilled water; and the 5-HT_2B/2C receptor antagonist SB 206553 (Research Biochemicals International, Natick, MA) was dissolved in 0.32% Tween 80 (ICN Biomedicals, Costa Mesa, CA). Appropriate solvents were used for vehicle comparisons, and all injections were made intraperitoneally in a volume of 10 µl/gm of body weight.

Data analysis. The effects of drug treatment and genotype on horizontal activity and rearing were analyzed using repeated measures ANOVA, followed by Tukey's honestly significant difference post hoc tests. For all analyses, significance was assigned at the p 0.05 level.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

A marked difference in response to mCPP was observed by genotype for both horizontal activity [treatment, F_(3,54) = 6.30; p < 0.001; genotype, F_(1,18) = 20.31; p < 0.001; treatment × genotype, F_(3,54) = 7.38; p < 0.001 (Fig. 1a)] and rearing [treatment, F_(3,54) = 12.83; p < 0.001; genotype, F_(1,18) = 30.93; p < 0.001; treatment × genotype, F_(3,54) = 11.67; p < 0.001 (Fig. 1b)]. Post hoc comparisons of the interactions showed that all doses of mCPP were associated with hyperactivity and enhanced rearing in the mutant but not wild-type mice. Analysis of variance revealed no significant order of injection × drug response interactions in these studies.

View larger version (24K): [in this window] [in a new window]   Figure 1.   Effect of mCPP on activity. White bars indicate 5-HT2C receptor mutant mice (n = 10), and black bars represent wild-type mice (n = 10). a, Horizontal activity; b, rears after mCPP treatment (vehicle or 2.5, 5.0, or 10.0 mg/kg, i.p.). Values are expressed as mean + 1 SEM. Significant differences by genotype, ***p  0.001; **p  0.01; *p  0.05.

To determine whether mCPP-induced hyperactivity in mutant mice was dependent on 5-HT_1B receptor stimulation, the 5-HT_1B/1D receptor antagonist GR 127935 was used (Skingle et al., 1993; Starkey and Skingle, 1994). When administered alone (at 0.3, 1.5, or 7.5 mg/kg), this compound did not significantly alter levels of activity or rearing (Fig. 2a). However, pretreatment with 7.5 mg/kg GR 127935 markedly altered the responses of mutant mice to mCPP. Repeated measures ANOVA of both horizontal activity and rearing revealed a significant interaction between treatment condition and genotype [main effects of treatment and genotype, NS; horizontal activity treatment × genotype interaction, F_(3,54) = 5.92; p < 0.01 (Fig. 2b); rearing treatment × genotype interaction, F_(3,54) = 5.76; p < 0.01 (Fig. 2c)]. Post hoc comparisons showed dramatic hyperactivity and enhanced rearing in response to 2.5 mg/kg mCPP in mutant but not wild-type mice. However, after GR 127935 pretreatment, a complete abolition of mCPP-induced hyperactivity was observed in mutant mice.

View larger version (22K): [in this window] [in a new window]   Figure 2.   Effect of GR 127935 and mCPP on activity. White bars indicate 5-HT2C receptor mutant mice, and black bars represent wild-type mice. a, Horizontal activity after GR 127935 treatment (vehicle or 0.3, 1.5, or 7.5 mg/kg, i.p.; n = 10 per genotype). b, Horizontal activity; c, rears after either vehicle or GR 127935 (7.5 mg/kg, i.p.) pretreatment and vehicle or mCPP (2.5 mg/kg, i.p.) treatment (n = 10 per genotype). Values are expressed as mean + 1 SEM. Significant differences by genotype, **p  0.01.

To determine whether mCPP-induced hyperactivity resulted from developmental compensations in 5-HT_2C receptor mutants, we tested whether 5-HT_2C receptor antagonist pretreatment would alter mCPP responses of C57BL/6 mice in a manner that mimicked the mutant phenotype. Although the 5-HT_2C/2B receptor antagonist SB 206553 (Kennett et al., 1996) (1.0, 2.5, and 5.0 mg/kg) did not alter horizontal activity or rearing when administered alone (Fig. 3a), it produced a substantial increase in activity when combined with mCPP. When administered alone, the dose of mCPP used (2.5 mg/kg) produced a significant reduction in locomotor activity relative to a vehicle control [dependent t test, t₍₁₃₎ = 2.57; p < 0.05 (Fig. 3b)]. However, SB 206553 pretreatment combined with mCPP administration produced a significant effect on horizontal activity [F_(4,60) = 9.18; p < 0.001 (Fig. 3b)], such that the highest dose of SB 206553 administered before mCPP produced marked hyperactivity compared with mCPP and vehicle alone. A significant treatment effect was also found for rearing [F_(4,60) = 4.71; p < 0.01 (Fig. 3c)]. Post hoc analysis revealed that pretreatment with the highest dose of SB 206553 before mCPP administration was associated with significantly greater rearing than mCPP alone.

View larger version (22K): [in this window] [in a new window]   Figure 3.   Effect of SB 206553 and mCPP on activity in C57BL/6 mice. White bars indicate vehicle treatment, and black bars represent drug treatment. a, Horizontal activity after SB 206553 treatment (vehicle or 1.0, 2.5, or 5.0 mg/kg, i.p.; n = 16). b, Horizontal activity; c, rears after either vehicle or SB 206553 (1.0, 2.5, or 5.0 mg/kg, i.p.) pretreatment and vehicle or mCPP (2.5 mg/kg, i.p.) treatment (n = 16). Values are expressed as mean + 1 SEM. Significant differences, ***p  0.001; **p  0.01.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

These results reveal a mechanism through which a single receptor gene lesion can predispose animals to a completely paradoxical behavioral response to a nonselective drug. The locomotor-suppressing effects of mCPP have been well established and attributed to its 5-HT_2C receptor agonist activity (Kennett and Curzon, 1988; Lucki et al., 1989). Based on such studies, it was expected that 5-HT_2C receptor mutant mice would exhibit decreased mCPP-induced suppression of locomotor activity. We were therefore surprised to observe a robust enhancement of locomotor activity in the mutants.

Previous studies of the influence of 5-HT_2C receptor antagonists on the locomotor effect of mCPP have yielded inconsistent results. After pretreatment with such antagonists, mCPP has been observed to produce decreases (Bonhaus et al., 1997), increases (Gleason and Shannon, 1998), or no change (Kennett and Curzon, 1988; Lucki et al., 1989; Kennett et al., 1994) in locomotor activity, depending on the particular antagonist used. This may reflect the limited specificity of both the antagonists and mCPP, which displays nearly equivalent high affinities for the 5-HT_2B, 5-HT_2C, and 5-HT₃ receptor subtypes and significant affinity for the 5-HT_1B receptor subtype (Hoyer, 1988; Hamik and Peroutka, 1989; Baxter et al., 1995). We hypothesized that mCPP-induced hyperactivity in animals lacking 5-HT_2C receptors reflected an unmasking of the actions of this compound at other 5-HT receptors. The 5-HT_1B receptor was the leading candidate for this effect because of its high-affinity interactions with mCPP and because of the known hyperlocomotor effects of 5-HT_1B receptor stimulation (Oberlander et al., 1987; Hoyer, 1988; Saudou et al., 1994; O'Neill et al., 1996). The blockade of mCPP-induced hyperactivity in mutants by pretreatment with the 5-HT_1B/1D receptor antagonist GR 127935 supported this hypothesis.

The interpretation of these results was complicated, however, by the constitutive nature of the 5-HT_2C receptor mutation. It remained possible that this anomalous drug response resulted from developmental compensation in animals that lacked 5-HT_2C receptors throughout development. To determine whether mCPP-induced hyperactivity required developmental perturbations in 5-HT_1B signaling and/or in other neural systems, we used a pharmacological approach in normal adult mice. Pretreatment of C57BL/6 mice with the relatively selective 5-HT_2C/2B receptor antagonist SB 206553 converted the mCPP response from activity reduction to an enhancement of activity, resembling the mutant phenotype. Thus, the mutant phenotype predicted this behavioral consequence of 5-HT_2C receptor blockade in the wild-type animal.

These findings provide a simple model for explaining the complex effects of mCPP on locomotor activity. Previous studies and our results indicate that the stimulation of brain 5-HT_2C and 5-HT_1B serotonin receptors produces opposite effects on locomotor activity levels. When both receptor subtypes are activated by mCPP, the locomotor suppression produced by 5-HT_2C receptor stimulation predominates. However, when this component of the mCPP response is eliminated by either genetic means or by antagonist pretreatment, then the 5-HT_1B receptor-stimulating properties of the drug are unopposed, leading to paradoxical hyperactivity.

Thus, the paradoxical response of 5-HT_2C receptor mutants to mCPP provides an example of the complexity of the mechanisms through which nonselective serotonergic agonists modulate behavior. This model may be generalized for considering the genetic basis of paradoxical behavioral responses to nonselective drugs. When a compound alters the function of multiple gene products with opposing influences on behavior, then mutations or allelic variants of such genes may lead to individual differences in responses and to paradoxical effects.

In humans, paradoxical behavioral responses to nonselective drugs are frequently encountered. For example, mCPP administration produced paradoxical effects in a study of alcoholics, leading to enhanced anger and anxiety in some and to euphoria in others (George et al., 1997). In addition, serotonin reuptake-blocking antidepressants (e.g., fluoxetine and fluvoxamine) that nonspecifically enhance serotonin receptor activation frequently produce agitation in some individuals and sedation in others (Beasley et al., 1991; Freeman, 1991). Both environmental and genetic factors interact to influence individual variability in responses to drugs. Heritable differences in genes encoding drug-metabolizing enzymes have long been known to influence drug responses; the impact of variability in neural genes is a more recent focus of attention (Lin and Poland, 1995). mCPP-induced hyperactivity in 5-HT_2C receptor mutant mice provides a useful model for considering the effects of neural genes on neurobehavioral responses to drugs.

	FOOTNOTES

Received Dec. 22, 1999; revised Feb. 23, 2000; accepted Feb. 23, 2000.

This work was supported by grants from the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the Bank of America Giannini Foundation to L.K.H. and the National Institute on Drug Abuse, the NARSAD, and the EJLB Foundation to L.H.T. We thank Preetpaul Bajwa for technical assistance with these studies, Noura Sall for mouse colony maintenance, and Nelson Freimer and Irwin Lucki for critical reading of this manuscript.

Correspondence should be addressed to Laurence H. Tecott, Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143-0984. E-mail: tecott{at}itsa.ucsf.edu.

This article is published in The Journal of Neuroscience, Rapid Communications Section, which publishes brief, peer-reviewed papers online, not in print. Rapid Communications are posted online approximately one month earlier than they would appear if printed. They are listed in the Table of Contents of the next open issue of JNeurosci. Cite this article as: JNeurosci, 2000, 20:RC71 (1-5). The publication date is the date of posting online at www.jneurosci.org.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

• Baxter G, Kennett G, Blaney F, Blackburn T (1995) 5-HT2 receptor subtypes: a family re-united? Trends Pharmacol Sci 16:105-110[Medline].
• Beasley Jr CM, Sayler ME, Bosomworth JC, Wernicke JF (1991) High-dose fluoxetine: efficacy and activating-sedating effects in agitated and retarded depression (see comments). J Clin Psychopharmacol 11:166-174[Medline].
• Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM (1997) RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 36:621-629[Medline].
• Brennan TJ, Seeley WW, Kilgard M, Schreiner CE, Tecott LH (1997) Sound-induced seizures in serotonin 5-HT2C receptor mutant mice. Nat Genet 16:387-390[Medline].
• Broocks A, Meyer T, George A, Hillmer-Vogel U, Meyer D, Bandelow B, Hajak G, Bartmann U, Gleiter CH, Rüther E (1999) Decreased neuroendocrine responses to meta-chlorophenylpiperazine (m-CPP) but normal responses to ipsapirone in marathon runners. Neuropsychopharmacology 20:150-161[Medline].
• Curzon G, Kennett GA (1990) m-CPP: a tool for studying behavioural responses associated with 5-HT1c receptors. Trends Pharmacol Sci 11:181-182[Medline].
• Freeman CP (1991) Fluvoxamine: clinical trials and clinical use. J Psychatr Neurosci 16:19-25[Medline].
• George DT, Benkelfat C, Rawlings RR, Eckardt MJ, Phillips MJ, Nutt DJ, Wynne D, Murphy DL, Linnoila M (1997) Behavioral and neuroendocrine responses to m-chlorophenylpiperazine in subtypes of alcoholics and in healthy comparison subjects. Am J Psychiatry 154:81-87[Abstract].
• Gleason SD, Shannon HE (1998) meta-Chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 as well as 5-HT2C receptors in mice. Eur J Pharmacol 341:135-138[Medline].
• Hamik A, Peroutka SJ (1989) 1-(m-Chlorophenyl)piperazine (mCPP) interactions with neurotransmitter receptors in the human brain. Biol Psychiatry 25:569-575[Medline].
• Hollander E, Kwon J, Weiller F, Cohen L, Stein DJ, DeCaria C, Liebowitz M, Simeon D (1998) Serotonergic function in social phobia: comparison to normal control and obsessive-compulsive disorder subjects. Psychiatry Res 79:213-217[Medline].
• Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Receptor Res 8:59-63[Medline].
• Kaye WH, Greeno CG, Moss H, Fernstrom J, Fernstrom M, Lilenfeld LR, Weltzin TE, Mann JJ (1998) Alterations in serotonin activity and psychiatric symptoms after recovery from bulimia nervosa. Arch Gen Psychiatry 55:927-935[Medline].
• Kennett GA, Curzon G (1988) Evidence that mCPP may have behavioural effects mediated by central 5-HT1c receptors. Br J Pharmacol 94:137-147[Medline].
• Kennett GA, Dourish CT, Curzon G (1987) 5-HT1B agonists induce anorexia at a postsynaptic site. Eur J Pharmacol 141:429-435[Medline].
• Kennett GA, Whitton P, Shah K, Curzon G (1989) Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Eur J Pharmacol 164:445-454[Medline].
• Kennett GA, Wood MD, Glen A, Grewal S, Forbes I, Gadre A, Blackburn TP (1994) In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. Br J Pharmacol 111:797-802[Medline].
• Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P, Blackburn TP (1996) In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties. Br J Pharmacol 117:427-434[Medline].
• Lin K-M, Poland RE (1995) Ethnicity, culture and psychopharmacology. In: Psychopharmacology: the fourth generation of progress (Bloom FE, Kupfer DJ, eds), pp 1907-1917. New York: Raven.
• Lucki I, Ward HR, Frazer A (1989) Effect of 1-(m-chlorophenyl)- piperazine and 1-(m-trifluoromethylphenyl)piperazine on locomotor activity. J Pharmacol Exp Ther 249:155-164[Abstract].
• Milatovich A, Hsieh CL, Bonaminio G, Tecott LH, Julius DJ, Francke U (1992) Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-FG4). Hum Mol Genet 1:681-684[Medline].
• Nonogaki K, Strack A, Dallman M, Tecott LH (1998) Leptin-insensitive hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 4:1152-1156[Medline].
• Oberlander C, Demassey Y, Verdu A, Van de Velde D, Bardelay C (1987) Tolerance to the serotonin 5-HT1 agonist RU 24969 and effects on dopaminergic behaviour. Eur J Pharmacol 139:205-214[Medline].
• O'Neill MF, Fernández AG, Palacios JM (1996) GR 127935 blocks the locomotor and antidepressant-like effects of RU 24969 and the action of antidepressants in the mouse tail suspension test. Pharmacol Biochem Behav 53:535-539[Medline].
• Samanin R, Mennini T, Ferraris A, Bendotti C, Borsini F, Garattini S (1979) m-Chlorophenylpiperazine: a central serotonin agonist causing powerful anorexia in rats. Naunyn Schmiedebergs Arch Pharmacol 308:159-163[Medline].
• Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L, Buhot MC, Hen R (1994) Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 265:1875-1878[Medline].
• Schwartz PJ, Murphy DL, Wehr TA, Garcia-Borreguero D, Oren DA, Moul DE, Ozaki N, Snelbaker AJ, Rosenthal NE (1997) Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects. Diurnal responses and nocturnal regulatory mechanisms. Arch Gen Psychiatry 54:375-385[Medline].
• Skingle M, Scopes DIC, Feniuk W, Tyers MB, Connor HE, Carter MC, Clitherow HW (1993) GR127935, a potent and orally active 5-HT1D receptor antagonist. Br J Pharmacol 110:9P.
• Southwick SM, Krystal JH, Bremner JD, Morgan III CA, Nicolaou AL, Nagy LM, Johnson DR, Heninger GR, Charney DS (1997) Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch Gen Psychiatry 54:749-758[Medline].
• Starkey SJ, Skingle M (1994) 5-HT1D as well as 5-HT1A autoreceptors modulate 5-HT release in the guinea-pig dorsal raphé nucleus. Neuropharmacology 33:393-402[Medline].
• Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D (1995) Eating disorder and epilepsy in mice lacking 5HT2C serotonin receptors. Nature 374:542-546[Medline].
• Tecott LH, Logue SF, Wehner JM, Kauer JA (1998) Perturbed dentate gyrus function in 5-HT2C receptor mutant mice. Proc Natl Acad Sci USA 95:15026-15031[Abstract/Full Text].
• Vickers SP, Clifton PG, Dourish CT, Tecott LH (1999) Reduced satiating effect of D-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology 143:309-314[Medline].
• Whitton P, Curzon G (1990) Anxiogenic-like effect of infusion 1-(3-chlorophenyl) piperazine (mCPP) into the hippocampus. Psychopharmacology 100:138-140[Medline].

---

Copyright © 2000 Society for Neuroscience  0270-6474/00/$05.00/0

This article has been cited by other articles:

				M. Hajos, W. E. Hoffmann, and R. J. Weaver Regulation of Septo-Hippocampal Activity by 5-Hydroxytryptamine2C Receptors J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 605 - 615. [Abstract] [Full Text] [PDF]

				B. A. Rocha, E. H. Goulding, L. E. O'Dell, A. N. Mead, N. G. Coufal, L. H. Parsons, and L. H. Tecott Enhanced Locomotor, Reinforcing, and Neurochemical Effects of Cocaine in Serotonin 5-Hydroxytryptamine 2C Receptor Mutant Mice J. Neurosci., November 15, 2002; 22(22): 10039 - 10045. [Abstract] [Full Text] [PDF]

				M. G. Bankson and K. A. Cunningham 3,4-Methylenedioxymethamphetamine (MDMA) as a Unique Model of Serotonin Receptor Function and Serotonin-Dopamine Interactions J. Pharmacol. Exp. Ther., June 1, 2001; 297(3): 846 - 852. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heisler, L. K. Articles by Tecott, L. H. Search for Related Content PubMed PubMed Citation Articles by Heisler, L. K. Articles by Tecott, L. H.

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help