The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner.

Neuropsychiatric and neurodevelopmental disorders such as major depressive disorder (MDD) and autism spectrum disorder (ASD) are complex conditions attributed to both genetic and environmental factors. There is a growing body of evidence showing that serotonergic signaling and mitochondrial dysfunction contribute to the pathophysiology of these disorders and are linked as signaling through specific serotonin (5-HT) receptors drives mitochondrial biogenesis. The serotonin transporter (SERT) is important in these disorders as it regulates synaptic serotonin and therapeutically is the target of selective serotonin reuptake inhibitors which are a major class of anti-depressant drug. Human allelic variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) such as the S/S variant, are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using a rat model that is haploinsufficient for SERT and displays reduced SERT expression similar to the human S/S variant, we demonstrate that reduced SERT expression modulates mitochondrial copy number and expression of respiratory chain electron transfer components in the brain. In the frontal cortex, genotype-related trends were opposing for males and females, such that reduced SERT expression led to increased expression of the Complex I subunit mt-Nd1 in males but reduced expression in females. Our findings suggest that SERT expression and serotonergic signaling have a role in regulating mitochondrial biogenesis and adenosine triphosphate (ATP) production in the brain. We speculate that the sexual dimorphism in mitochondrial abundance and gene expression contributes to the sex bias found in the incidence of neuropsychiatric disorders such as MDD and ASD.

Preweaning environmental enrichment alters neonatal ultrasonic vocalisations in a rat model for prenatal infections.

OBJECTIVE: Maternal infections are a well-known risk factor for neurodevelopmental defects. Such defects are associated with a range of symptoms, and environmental enrichment (EE) could be a promising approach to rehabilitate these. We used the well-established prenatal poly I:C (polyinosinic-polycytidylic acid) model in rats to examine the effects of preweaning EE on rat pups' ultrasonic vocalisations (USVs) when separated from their mothers. USVs are one of the earliest indicators of a pup's functional level and, thus, well-suited as a marker of neurodevelopmental abnormalities. METHODS: We used a two-by-two factorial design in which pregnant Sprague-Dawley rats received either saline or the viral mimic poly I:C, and one group of pups was exposed to preweaning enrichment. We measured maternal separation-induced USVs both before postnatal day (PND) 7 and after preweaning enrichment on PND 14. RESULTS: Poly I:C significantly reduced the number of USVs on PND 7. EE interacted with the poly I:C treatment in that poly I:C pups in the enrichment group called more, whereas saline pups in the enriched environment called less on PND 14 than the respective controls. CONCLUSION: We showed that the effects of maternal poly I:C on the offspring's USVs could be reduced by early EE. If replicated, it could open novel and safe avenues for treating children of mothers who were exposed to infections during pregnancy.

Evaluation of i-Motif Formation in the Serotonin Transporter-Linked Polymorphic Region.

Neuropsychiatric disorders such as major depressive disorder (MDD) arise from a complex set of genetic and environmental factors. The serotonin transporter (SERT) is a key regulator of synaptic serotonin (5-HT), and its inhibition is an important pharmacological target for treating MDD. The SERT-linked polymorphic region (5-HTTLPR) contains two major variants (short and long) that have been implicated in modulating susceptibility to MDD by altering the level of expression of SERT. Both variants contain C-rich repeats that conform to consensus i-motif folding sequences. i-Motifs are quadruplex DNA structures that have been proposed to have a role in transcription regulation. With spectroscopic techniques, we demonstrate that both alleles are able to form i-motifs at acidic pH, and at neutral pH under conditions of molecular crowding. This highlights the potential for i-motif formation to contribute to transcriptional regulation of the serotonin transporter, with a potential role in the pathophysiology of neuropsychiatric disorders.

The role of dopamine D1 receptors in MDMA-induced memory impairments.

(±) 3,4-Methylenedioxymethamphetamine (MDMA) is a recreationally abused psychostimulant that impairs memory performance. This effect is often attributed to a working memory impairment resulting from compromised serotonin systems. However, recent evidence from non-human animal experimental studies suggests that acute MDMA may indirectly impair memory performance through overstimulation of dopamine (DA) D1 receptors, which increases perseverative responding during memory tasks. This hypothesis was explored using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional D1 receptors. Adult male Wistar DAD1-/- rats and wild type controls were trained over 25 sessions on a spatial working memory T-maze delayed non-matching to position (DNMTP) task. Once trained, the rats were administered MDMA (1.5, 2.25 and 3 mg/kg) or saline fifteen minutes prior to testing on DNMTP with all subjects experiencing all drug doses and saline three times. We predicted that controls would demonstrate decreased task accuracy following MDMA, driven by an increase in perseverative errors. In contrast, we predicted that DAD1-/- rats would be protected from MDMA-induced perseverative errors due to their reduced D1 receptor function. As predicted, during the third block of MDMA administration, control rats demonstrated decreased task accuracy following 2.25 and 3 mg/kg doses, driven by an increase in perseverative errors. In addition, DAD1-/- rats were protected from MDMA-induced task deficits. These findings challenge the assumption that MDMA's acute effects on memory performance are predominantly due to serotonergic mechanisms and provide support for the hypothesis that acute MDMA impairs memory performance in rats via overstimulation of D1 receptors by increasing perseverative behaviour.

CGRP in a gene-environment interaction model for depression: effects of antidepressant treatment.

OBJECTIVE: Genetic and environmental factors interact in the development of major depressive disorder (MDD). While neurobiological correlates have only partially been elucidated, altered levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) in animal models and in the cerebrospinal fluid of depressed patients were reported, suggesting that CGRP may be involved in the pathophysiology and/or be a trait marker of MDD. However, changes in CGRP brain levels resulting from interactions between genetic and environmental risk factors and the response to antidepressant treatment have not been explored. METHODS: We therefore superimposed maternal separation (MS) onto a genetic rat model (Flinders-sensitive and -resistant lines, FSL/FRL) of depression, treated these rats with antidepressants (escitalopram and nortriptyline) and measured CGRP-LI in selected brain regions. RESULTS: CGRP was elevated in the frontal cortex, hippocampus and amygdala (but not in the hypothalamus) of FSL rats. However, MS did not significantly alter levels of this peptide. Likewise, there were no significant interactions between the genetic and environmental factors. Most importantly, neither escitalopram nor nortriptyline significantly altered brain CGRP levels. CONCLUSION: Our data demonstrate that increased brain levels of CGRP are present in a well-established rat model of depression. Given that antidepressants have virtually no effect on the brain level of this peptide, our study indicates that further research is needed to evaluate the functional role of CGRP in the FSL model for depression.

Heart and soul: heart rate variability and major depression.

There is a bidirectional relationship between affective disorders and cardiovascular abnormalities, often described as a downward spiral, whereas major depressive disorders (MDD, and anxiety disorders) significantly increase the risk of developing cardiovascular diseases (CVD); CVD are also associated with increased risk of developing MDD (and anxiety disorders). Moreover, the prognosis and progression of CVD is significantly worsened in the presence of MDD. Heart rate variability (HRV) has often been suggested as a potential mediator in this comorbidity. In this review, we discuss HRV alterations in MDD. However, we mainly focus on the direct relationship between HRV alterations and psychiatric symptoms, rather than its relationship with CVD, as this has been reviewed elsewhere. After a general introduction to HRV and how it can be measured, we review how HRV is altered in MDD. We subsequently describe how antidepressant drugs affect HRV, showing that some classes (such as tricyclics) generally worsen HRV, whereas others (most notably selective serotonin reuptake inhibitors) have a more positive influence. We also review the effects of several other treatments, with a special focus on vagal nerve stimulation, finishing with some further considerations and recommendation for further research, both in humans and animals.

Nicotine self-administration reverses cognitive deficits in a rat model for schizophrenia.

High comorbidity between schizophrenia and tobacco addiction has been well established. Explanatory theories include nicotine as a cognitive enhancer ameliorating symptoms of schizophrenia and underlying shared substrates increasing susceptibility to addiction in these individuals. To test these non-mutually exclusive theories, the maternal immune activation (MIA) model was utilized. To this end, pregnant Sprague Dawley rats were subcutaneously injected with a bacterial endotoxin, lipopolysaccharide (0.5 mg/kg), on gestation days 10 and 11. Selective attention and working memory in adult male offspring were subsequently assessed using the latent inhibition and delayed non-matching to sample paradigms both before and after nicotine or saline self-administration. MIA led to deficits in both latent inhibition and delayed non-matching to sample in male offspring. Further, these animals showed a small but significantly increased responding for nicotine during self-administration acquisition, although there was no difference in dose-response effect or in progressive ratio testing. However, nicotine, but not saline self-administration, significantly ameliorated the cognitive deficits induced by MIA. While the male offspring of mothers prenatally exposed to lipopolysaccharide was only slightly more sensitive to the reinforcing effects of nicotine, after self-administration, the MIA-induced cognitive deficits significantly improved. These data lend support for the self-medication hypothesis of schizophrenia.

Of rodents and men: understanding the emergence of motor and cognitive symptoms in Huntington disease.

Arguably, one of the most important milestones in Huntington disease research since the discovery of the gene responsible has been the generation of different genetic animal models. Although clinical reports have shown evidence of progressive cognitive impairments in gene carriers before motor symptoms are diagnosed, such symptoms have been much less obvious in animal models. In this review, we summarize the three main classes of animal models for Huntington disease and describe some relevant translational assays for behavioural deficits evaluation. Finally, we argue that a good knowledge of the emergence of motor and cognitive symptoms in mice and rat models is indispensable for the selection of endpoint measures in early preclinical drug screening studies.

Can 5-HT3 antagonists contribute toward the treatment of schizophrenia?

In one of his earlier papers, Lex Cools stated that the 'concept of an impaired balance between the in series connected […] dopamine system, […] 5-HT system and […] noradrenaline system offers a single coherent and integrated theory of schizophrenia' (Cools, 1975). Since then, considerable attention has focused on the interaction between dopamine and 5-HT and it is now well accepted that most antipsychotics (especially the second-generation drugs) modulate both dopaminergic and serotonergic receptors. However, the vast majority of research has focused on the 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present paper, we review the literature pertaining to the 5-HT3 receptor, the only ionotropic 5-HT receptor. We discuss both the interactions between 5-HT3 receptors and dopamine, and the animal and human literature investigating the role of 5-HT3 receptors in schizophrenia. The results show that the interactions between 5-HT3 receptors and dopamine are complex, but that 5-HT3 receptors do not have a strong influence on the positive symptoms of schizophrenia. However, when added to standard antipsychotic medication, several recent studies have found that 5-HT3 receptor antagonists can induce a statistically significantly improvement in negative and cognitive symptoms. The implications of these findings in relation to animal modelling and drug development are discussed.

Dopamine D1 receptor and effort-based decision making in rats: The moderating effect of sex.

Dopamine is a modulating factor in effort-based decision-making, and emerging evidence from pharmacological research suggests that the dopamine D1 receptor is the primary regulator. Given the limited selectivity of pharmacological tools, we further explored this hypothesis using dopamine D1 mutant (DAD1-/-) rats which have a specific genetic reduction in functional D1 receptors. Moreover, given the strong focus on males in neuroscience research in general and in the role of D1 receptors in effort-based learning, we compared both sexes in the present study. Adult male and female DAD1-/- mutant rats and wild type controls were trained to press a lever for a reinforcer. Once trained, subjects completed multiple fixed ratio, progressive ratio, and operant effort-choice (concurrent progressive ratio/chow feeding task [PROG/chow]) experiments. We predicted that DAD1-/- mutant rats would press the lever significantly less than controls across all experiments, have lower breakpoints, and consume more freely available food. As predicted, DAD1-/- mutant rats (regardless of sex) pressed the lever significantly less than controls and had lower breakpoints. Interestingly, there was a sex * genotype interaction for acquisition rates of lever pressing and change in breakpoints with free food available. Only 31% of DAD1-/- mutant males acquired lever pressing while 73% of DAD1-/- mutant females acquired lever pressing. Additionally, DAD1-/- mutant males had significantly larger decreases in breakpoints when free food was available. These findings extend the pharmacological research suggesting that the dopamine D1 receptor modulates decisions based on effort, which has implications for the development of treatment targeting amotivation in neuropsychiatric disorders. The sex * genotype interaction highlights the importance of including both sexes in future research, especially when there are sex differences in incidences and severity of neuropsychiatric disorders.

Sex bias in the serotonin transporter knockout model: Implications for neuropsychiatric disorder research.

Serotonergic signalling is implicated in the aetiology of many neuropsychiatric disorders. The serotonin reuptake transporter (SERT) is an important regulator of synaptic serotonin, being an important pharmacological target with genetic variants implicated with risk of developing neuropsychiatric disorders. Animal models have played an important role in understanding the genetic risk and role of SERT function in brain development having highlighted sex differences in incidence, presentation, and treatment efficacy, however, sex bias due to unequal representation of sexes in research remains a significant issue. While more studies are addressing sex as a biological variable this is not reflected in studies using SERT knockout models as the proportion including sex comparisons has declined since 2000. This bias needs to be addressed if research findings from animal studies are to have translation relevance to human conditions.

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol.

RATIONALE: Alcohol use disorder (AUD) is shown to have an overall heritability of around 50%. One of the genes associated with AUD is SLC6A4 (solute carrier family 6 member A4) which codes for the serotonin transporter (SERT). The study looked at serotonin dysfunction on ethanol consumption in adolescents and the subsequent intergenerational effects of drinking by using a rat model: SERT+/+ (regular functioning), SERT+/- (50% transporter reduction) and SERT-/- (complete reduction). OBJECTIVES: We investigated sex and genotype differences in ethanol consumption in SERT knock-out Wistar rats (F0) followed by studying behaviour in the offspring (F1) of the male drinkers to assess effects of paternal alcohol consumption. METHODS: An intermittent access two-bottle choice paradigm (IA2BC) was used to yield ethanol drinking behaviour in F0 adolescent Wistar rats. The highest drinking males were mated to alcohol-naive females and their offspring were compared with controls. Drinking behaviour (IA2BC) and ethanol-induced motor coordination effects (via rotarod) were measured in the F1s. RESULTS: F0 drinking saw no SERT genotype differences in males. However, females consumed higher volumes of ethanol compared to males, with SERT-/- females showing the highest intake. A clearer genotype effect was seen in the F1 animals, with reduction in SERT activity leading to enhanced ethanol intake in both sexes. Importantly, paternal exposure to ethanol significantly reduced the ethanol induced motor side effects in offspring, independent of sex and genotype. CONCLUSIONS: These indicate a difference in the way genetic factors may act across sexes and suggest the involvement of epigenetic mechanisms in the intergenerational effects of alcohol.

Genetic Knockout of the Serotonin Reuptake Transporter Results in the Reduction of Dendritic Spines in In vitro Rat Cortical Neuronal Culture.

Dysregulation of the serotonergic system has been reported to have a significant role in several neurological disorders including depression, autism and substance abuse disorders. Changes in the expression of the serotonin transporter (SERT) through polymorphisms in the regulatory regions of the SERT gene have been associated, but not yet been conclusively linked to, neuropsychiatric disorders. In turn, dendritic spine structure and function are critical for neuronal function and the disruption of dendritic spine formation at glutamatergic synapses is a hallmark of several neuropsychiatric disorders. To understand the effect of SERT depletion on dendritic spine formation, neuronal cultures were established from the cortex of postnatal day 0-1 SERT knockout (KO) rats. Cortical neurons were subsequently allowed to mature to 21 days in vitro, and dendritic spine density was assessed using immunocytochemical co-labelling of drebrin and microtubule associated protein 2. Genetic knockout of the SERT had a gene-dose effect on dendritic spine densities of cortical neurons. The results of this paper implicate SERT function with the formation of dendritic spines at glutamatergic synapses, thereby offering insight into the aetiology of several neuropathologies.

Long-Term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms.

Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.

Pmch expression during early development is critical for normal energy homeostasis.

Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch(-/-) rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch(-/-) rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries.

Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans.

In order to identify the molecular mechanisms that may contribute to the enhanced susceptibility to depression under serotonin transporter (SERT) dysfunction, we analyzed the expression of brain-derived neurotrophic factor (BDNF), a key player in neuronal plasticity, which is implicated in the etiology and treatment of depression. We found that BDNF levels were significantly reduced in the hippocampus and prefrontal cortex of SERT knockout rats, through transcriptional changes that affect different neurotrophin isoforms. The reduction of BDNF gene expression observed in prefrontal cortex is due, at least in part, to epigenetic changes that affect the promoter regions of exons IV and VI. Moreover, BDNF gene expression is also significantly reduced in leukocytes from healthy subjects carrying the S allele of the 5-HTTLPR, suggesting that the changes observed in SERT mutant rats may also be present in humans and may confer enhanced vulnerability to mood disorders.

Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders.

A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a reduced expression of Aph-1b, a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. The reduced expression is due to a duplicon-based genomic rearrangement event resulting in an Aph-1b dosage imbalance. The expression levels of the other gamma-secretase components were not affected. However, gamma-secretase cleavage activity was significantly changed, and the APO-SUS/-UNSUS Aph-1b genotypes segregated with a number of behavioral phenotypes. Thus, a subtle imbalance in the expression of a single, developmentally important protein may be sufficient to cause a complex phenotype.

A genetic deletion of the serotonin transporter differentially influences the behavioural effects of MDMA.

BACKGROUND: While (±)-3,4-methylenedioxymethamphetamine (MDMA) primarily induces serotonin release, it also affects dopamine and noradrenaline transmission. It is, however, unclear what role each of these neurotransmitters play in the behavioural profile of MDMA. METHODS: In this study we used the drug discrimination (DD) and the acoustic startle (ASR) paradigms to examine the behaviour of rats with and without a genetic deletion of the serotonin transporter SERT (SERT-/- and SERT+/+ rats). In DD, rats were trained to respond on different levers following an injection of 1.5 mg/kg MDMA, or saline. After acquisition, they were given a challenge dose of 0.5 mg/kg amphetamine (AMPH). In the ASR paradigm, SERT+/+ and SERT-/- rats were given 0, 5 or 10 mg/kg MDMA. RESULTS: In DD, significantly fewer SERT-/- rats acquired MDMA discrimination. When the acquirers were challenged with AMPH, SERT+/+ showed partial, while SERT-/- rats showed full generalisation to MDMA. In the ASR paradigm, MDMA significantly reduced prepulse inhibition and startle habituation in SERT+/+ rats, while having no effect in SERT-/- rats. CONCLUSION: Together these data suggest that in wildtype rats the interoceptive cues of MDMA are primarily mediated by serotonin and to a lesser extent by dopamine and noradrenaline, while the effects in the startle paradigm are almost exclusively mediated via serotonin. Together, these data contribute to our understanding of the complex pharmacodynamics of MDMA.

Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats.

RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT-/-) rat and the involvement of compensatory changes in 5-HT1A receptor function are the objectives of the study. MATERIALS AND METHODS: The SERT-/- rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine self-administration. In addition, the function and expression of 5-HT1A receptors was assessed using telemetry and autoradiography, respectively, and the effect of 5-HT1A receptor ligands on cocaine's psychomotor effects were studied. RESULTS: Cocaine-induced hyperactivity and conditioned place preference, as well as intravenous cocaine self-administration were enhanced in SERT-/- rats. Furthermore, SERT-/- rats displayed a reduced hypothermic response to the 5-HT1A receptor agonist 8-OHDPAT. S-15535, a selective somatodendritic 5-HT1A receptor agonist, reduced stress-induced hyperthermia (SIH) in wild-type controls (SERT+/+), while it increased SIH in SERT-/- rats. As 5-HT1A receptor binding was reduced in selective brain regions, these thermal responses may be indicative for desensitized 5-HT1A receptors. We further found that both 8-OHDPAT and S-15535 pretreatment increased low-dose cocaine-induced locomotor activity in SERT-/- rats, but not SERT+/+ rats. At a high cocaine dose, only SERT+/+ animals responded to 8-OHDPAT and S-15535. CONCLUSION: These data indicate that SERT-/- -associated 5-HT1A receptor adaptations facilitate low-dose cocaine effects and attenuate high-dose cocaine effects in cocaine supersensitive animals. The role of postsynaptic and somatodendritic 5-HT1A receptors is discussed.

Stress-induced hyperthermia and basal body temperature are mediated by different 5-HT(1A) receptor populations: a study in SERT knockout rats.

Disturbances in the serotonergic system are implicated in many central nervous system disorders. The serotonin transporter (SERT) regulates the serotonin homeostasis in the synapse. We recently developed a rat which lacks the serotonin transporter (SERT(-/-)). It is likely that adaptive changes take place at the level of pre- and postsynaptic 5-HT receptors. Because autonomic responses are often used to measure 5-HT(1A) receptor function, we analysed these responses by examining the effects of a 5-HT(1A) receptor agonist and antagonist under in vivo conditions in the SERT(-/-) rat. Moreover, we studied the effect of a mild stressor on the body temperature (stress-induced hyperthermia) because of the known involvement of 5-HT(1A) receptors in this phenomenon. Results show that core body temperature did not differ between genotypes under basal, non-stressed conditions. Compared to SERT(+/+) rats, stress-induced hyperthermia was reduced in SERT(-/-) rats. The 5-HT(1A) receptor agonist [R(+)-N-(2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4-benzodioxin-5-yl)-1-piperazininyl]ethyl)-4-fluorobenzoamide HCl (flesinoxan) reduced stress-induced hyperthermia in both genotypes. The flesinoxan-induced hypothermia in SERT(+/+) rats was blocked by the 5-HT(1A) receptor antagonist [N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY100635). Moreover, WAY100635-induced hyperthermia in SERT(-/-), but not in SERT(+/+) rats. In SERT(-/-) rats, WAY100635 completely blocked the flesinoxan-induced reduction of stress-induced hyperthermia. Interestingly, flesinoxan-induced hypothermia was absent in SERT(-/-) rats. It is concluded that the SERT knockout rat reveals that 5-HT(1A) receptors modulating stress-induced hyperthermia belong to a population of receptors that differs from that involved in hypothermia.