Alterations in anterior hypothalamic vasopressin, but not serotonin, correlate with the temporal onset of aggressive behavior during adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus).

In hamsters (Mesocricetus auratus), anabolic-androgenic steroid (AAS) exposure during adolescence facilitates offensive aggression that is correlated with the enhanced development of the arginine vasopressin (AVP) neural system and reduced development of the serotonin (5-HT) neural system in the anterior hypothalamus (AH). This study examined the temporal onset of these effects by measuring aggression and AH AVP and 5-HT during progressively shorter periods of AAS exposure during adolescent development. The authors tested adolescent hamsters that received AAS for 3, 7, 14, or 28 days for offensive aggression and then examined the hamsters for AVP/5-HT afferent innervation to the AH using immunohistochemistry. While reductions in AH 5-HT afferent innervation were detectable by 7 days of AAS exposure, no concomitant increases in offensive aggression were observed compared to oil-treated littermates. In contrast, by Day 14 of AAS treatment, AH AVP and offensive aggression were significantly higher than oil-treated controls. These data indicate that relatively short-term adolescent AAS exposure alters aggression and AH 5-HT and AVP development, yet only alterations in AH AVP development correlate with temporal onset of the aggressive behavioral phenotype during adolescent AAS exposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin regulation of aggressive behavior in male golden hamsters (Mesocricetus auratus).

These studies examined the neurochemistry and neuroanatomy of the serotonin (5-HT) system innervating the anterior hypothalamus (AH) and the interaction of 5-HT receptor agonists with arginine vasopressin (AVP) in the regulation of offensive aggression in golden hamsters. Because specific 5-HT1A, 5-HT1B, and AVP V1A binding sites were observed within the AH by in vitro autoradiography, the hamsters were tested for offensive aggression after microinjections of AVP in combination with either the 5-HT1A agonist 8-hydroxy-2-(di-n-propylarnino) tetraline (DPAT) or the 5-HT1B agonist CGS-12066A (CGS) directly within the AH. Though treatment with DPAT resulted in a dose-dependent inhibition of AVP-facilitated offensive aggression, CGS was ineffective. In addition, a retrograde tracer was injected within the AH to localize the distribution of 5-HT neurons projecting to the area. Retrogradely labeled 5-HT neurons were found within the dorsal, median, and caudal linear raphe nuclei and are suspected to inhibit AVP-facilitated offensive aggression by an activation of 5-HT1A receptors in the AH. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin Type 3 Receptors Modulate the Aggression-Stimulating Effects of Adolescent Cocaine Exposure in Syrian Hamsters (Mesocricetus auratus).

Repeated cocaine (0.5 mg/kg) exposure throughout adolescence stimulates offensive aggression in hamsters. These studies examined whether the cocaine-induced aggressive response was regulated by serotonin Type 3 (5-HT?) receptor activity and correlated with altered 5-HT? receptor expression. Cocaine-treated Syrian hamsters (Mesocricetus auratus) were tested for aggression after the administration of either the 5-HT? antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron; 0.01-1.20 mg/kg) or the 5-HT? agonist l-(m-chlorophenyl)-biguanide hydrochloride (mCPBG; 5.0-15.0 mg/kg), alone or in combination. Tropisetron alone dose dependently reduced cocaine-induced aggression, with a significant reduction at 0.3 mg/kg, whereas mCPBG was ineffective. mCPBG administered prior to tropisetron required a higher dose (1.2 mg/kg) of antagonist to block aggression, indicating a selective 5-HT? effect. Cocaine-treated hamsters showed altered 5-HT? immunoreactivity in several brain areas implicated in aggression control. These data support a role for 5-HT? receptors in adolescent cocaine-induced aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prolonged alterations in the serotonin neural system following the cessation of adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus).

In hamsters (Mesocricetus auratus), anabolic-androgenic steroid (AAS) exposure during adolescence facilitates offensive aggression that is modulated, in part, by serotonin (5-HT) signaling and development and by signaling and expression of 5-HT1B receptors. To examine whether these effects are persistent or reversible, the authors administered AAS to hamsters, then examined them for aggression at 1, 4, 11, 18, or 25 days following cessation of AAS treatment. Then, 1 day later, hamsters were killed by transcardial perfusion and examined for 5-HT afferents to and 5-HT1B receptor-containing neuronal puncta and somata in areas of the brain altered by AAS, namely, the anterior hypothalamus, ventrolateral hypothalamus, and medial amygdala. Although aggression resulting from AAS exposure returned to control, nonaggressive levels by 18 days following cessation of AAS treatment, alterations in 5-HT afferent innervation and 5-HT1B receptor localization were observed throughout the extended time period examined. These data suggest that adolescent AAS exposure may have long-term, irreversible effects on 5-HT neural systems and that return to nonaggressive behavioral phenotypes following adolescent AAS exposure may not be a function of plasticity in central 5-HT systems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin 5-HT1A and 5-HT? receptors in an impulsive–aggressive phenotype.

In adult male hamsters, individual differences in offensive aggression are correlated with differences in impulsive choice and decreased serotonin (5-HT) innervation. As serotonin 1A (5-HT1A) receptors participate in the inhibition of aggression, whereas 5-HT?receptor activation facilitates aggression, the authors hypothesized that differences in their expression are associated with differences in behavior. The authors confirmed previous behavioral associations, using a delay-discounting paradigm with various delays, as high-aggression (H-Agg) hamsters preferred the immediate-reward lever over the delayed-reward lever under most delays, compared with low-aggression (L-Agg) hamsters. Although the authors observed a greater density of 5-HT1A receptor immunoreactivity in H-Agg hamsters within several areas, it appears to be related to a lack of serotonin release, as supported by further observations of decreased immunoreactive perikarya and 5-HT1A receptors in fluoxetine-treated hamsters. Also, 5-HT? receptor density was greater in H-Agg hamsters within select areas. The data indicate a convergence of impulsive and aggressive characteristics to one phenotype that is associated with various aspects of serotonin function, such as serotonin release and differential expression of 5-HT1A and 5-HT? receptors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine activity in the lateral anterior hypothalamus modulates AAS-induced aggression through D2 but not D5 receptors.

Treatment with anabolic-androgenic steroids (AAS) throughout adolescence facilitates offensive aggression in Syrian hamsters. In the anterior hypothalamus (AH), the dopaminergic neural system undergoes alterations after repeated exposure to AAS, producing elevated aggression. Previously, systemic administration of selective dopamine receptor antagonists has been shown to reduce aggression in various species and animal models. However, these reductions in aggression occur with concomitant alterations in general arousal and mobility. Therefore, to control for these systemic effects, the current studies utilized microinjection techniques to determine the effects of local antagonism of D2 and D5 receptors in the AH on adolescent AAS-induced aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the D2 antagonist eticlopride, or the D5 antagonist SCH-23390, into the AH. Treatment with eticlopride showed dose-dependent suppression of aggressive behavior in the absence of changes in mobility. Conversely, while injection of SCH-23390 suppressed aggressive behavior, these reductions were met with alterations in social interest and locomotor behavior. To elucidate a plausible mechanism for the observed D5 receptor mediation of AAS-induced aggression, brains of AAS and sesame oil-treated animals were processed for double-label immunofluorescence of GAD?? (a marker for GABA production) and D5 receptors in the lateral subdivision of the AH (LAH). Results indicate a sparse distribution of GAD?? neurons colocalized with D5 receptors in the LAH. Together, these results indicate that D5 receptors in the LAH modulate non-GABAergic pathways that indirectly influence aggression control, while D2 receptors have a direct influence on AAS-induced aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential responsiveness to fluoxetine during puberty.

In male golden hamsters (Mesocricetus auratus), attack frequency decreases during puberty. As serotonin inhibits offensive responses in adult hamsters, it is hypothesized that the serotonin system becomes upregulated in the hypothalamus during puberty. This hypothesis was tested through acute treatment with fluoxetine, a serotonin reuptake inhibitor, as well as through analysis of serotonin innervation in specific brain areas. In adults, fluoxetine treatment inhibited aggressive behavior. In juveniles, high doses of fluoxetine only reduced offensive responses (i.e., frequency and repetition of attacks), whereas low doses enhanced them. Juveniles also showed a dose-specific maturation of attack targets. In addition, the density of serotonin innervation of the hypothalamus was 20% higher in adult hamsters compared with juveniles. On the basis of these data, it is proposed that the developing serotonergic system shapes the development of offensive behaviors in male golden hamsters. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Meditation as an adjunct to a happiness enhancement program

Arginine vasopressin (AVP) plays an important role in the control of a gonadal hormone-dependent communicative behavior in the Syrian hamster (Mesocricetus auratus) called flank marking. Previous studies have shown that gonadal hormones alter the amount of flank marking stimulated by the microinjection of AVP into the medial preoptic area-anterior hypothalamus (MPOA-AH). The purpose of the present study was to determine if testicular hormones alter the amount of flank marking stimulated by the microinjection of AVP into two other sites involved in the control of flank marking, the lateral septum-bed nucleus of the stria terminalis (LS-BNST) and the central gray. The data of the present study indicate that testicular hormones may influence the amount of AVP-stimulated marking in the central gray and LS-BNST; however, these effects are subtle and appear to occur primarily at high concentrations of AVP. When taken together with previous studies, these data indicate that gonadal hormones have greater effects on AVP-stimulated marking in the MPOA-AH than in the LS-BNST or central gray.     

Behavioral and neurobiological consequences of social subjugation during puberty in golden hamsters

In golden hamsters, offensive aggression is facilitated by vasopressin and inhibited by serotonin. We tested whether these neurotransmitter systems respond to modifications resulting from the stress of threat and attack (i.e., social subjugation) during puberty. Male golden hamsters were weaned at postnatal day 25 (P25), exposed daily to aggressive adults from P28 to P42, and tested for offensive aggression as young adults (P45). The results showed a context-dependent alteration in aggressive behavior. Subjugated animals were more likely to attack younger and weaker intruders than nonsubjugated controls. Conversely, subjugated animals were less likely to attack animals of similar size and age. After testing, the animals were killed, and their brains were collected to determine whether these behavioral changes are underlined by changes in the vasopressin and serotonin systems. Social subjugation resulted in a 50% decrease in vasopressin levels within the anterior hypothalamus, a site involved in the regulation of aggression. Furthermore, whereas the density of vasopressin-immunoreactive fibers within the area was not significantly altered in subjugated animals, the number of serotonin-immunoreactive varicosities within the anterior hypothalamus and lateral septum was 20% higher in subjugated animals than in their controls. These results establish puberty as a developmental period sensitive to environmental stressors. Furthermore, the results show that changes in the vasopressin and serotonin systems can correlate with behavioral alterations, supporting the role of these two neurotransmitters in the regulation of aggression.     

Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists

One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1-0.3 mg/kg, i.p.) or flesinoxan (0.1-1.0 mg/kg, i.p.). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, i.p.) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, p.o.) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03-0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission.     

Serotonin-1B receptor activity and expression modulate the aggression-stimulating effects of adolescent anabolic steroid exposure in hamsters.

Repeated high dose (5.0 mg/kg) anabolic-androgenic steroid (AAS) exposure during adolescence stimulates offensive aggression in male Syrian hamsters. These studies examined whether AAS-induced aggression was regulated by the activity of serotonin (5HT) type-1B receptors and correlated with altered 5HT1B expression. AAS-treated hamsters were tested for offensive aggression following the administration of the 5HT1B agonist anpirtoline (0.125-0.5 mg/kg). Anpirtoline dose-dependently reduced select components of the AAS-induced aggressive response, with significant reductions observed at 0.25 mg/kg. Aggressive, AAS-treated hamsters showed significant decreases in the area covered by 5HT1B-containing neuronal puncta and increases in the number of 5HT1B-containing neuronal somata in select brain regions implicated in aggression control. Together, these data support a role for site-specific alterations in 5HT1B signaling and expression in adolescent AAS-induced aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Flank-marking behavior and the neural distribution of vasopressin innervation in golden hamsters with suprachiasmatic lesions

In golden hamsters, microinjections of arginine-vasopressin (AVP) within the anterior hypothalamus trigger a stereotyped scent-marking behavior, flank marking. Our experiment was carried out to test the contribution of AVP neurons within the suprachiasmatic nucleus (SCN) in the control of this behavior. Our results suggest that the SCN does not contribute to flank-marking behavior. Whereas SCN lesions disrupted circadian rhythms of wheel running, the same lesions did not disrupt flank-marking. The results also suggest that neurons located outside the SCN contribute significantly to the vasopressinergic innervation of the brain and the expression of AVP-dependent behaviors, such as flank-marking behavior. Although AVP-immunoreactive fibers were severely (ca. 95%) depleted from several forebrain areas in SCN-lesioned hamsters, the effect of the lesions was much more limited within the forebrain areas involved in flank-marking behavior as well as within the midbrain and hindbrain.     

Plasticity in anterior hypothalamic vasopressin correlates with aggression during anabolic-androgenic steroid withdrawal in hamsters.

In hamsters, adolescent anabolic-androgenic steroid (AAS) exposure facilitates offensive aggression, in part by altering the development and activity of anterior hypothalamic arginine vasopressin (AH-AVP). This study assessed whether these effects were lasting by examining aggression and AH-AVP during AAS withdrawal. Adolescent hamsters administered AAS were tested as adults for aggression at 1, 4, 11, 18, or 25 days of withdrawal, sacrificed the following day, and examined for AH-AVP afferent innervation using immunohistochemistry. Through Day 12 of withdrawal, aggression and AVP were significantly higher in AAS-treated hamsters than in controls. These differences were no longer observable by Day 19 of withdrawal, at which point the behavior and neurobiology of AAS-treated hamsters reverted to that observed in controls. These data indicate that adolescent AAS exposure has short-term, reversible effects on both aggression and AH-AVP, correlating AH-AVP with the aggressive/nonaggressive behavioral phenotype during AAS withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activation of serotonergic neurotransmission during the performance of aggressive behavior in rats.

High aggression is often linked to lowered serotonin (5-HT) neurotransmission. Although this may hold for high aggression as a trait characteristic of an individual, serotonergic activity is probably increased during performance of aggressive behavior. To test this hypothesis, first, the 5-HT1A agonist alnespirone and gamma aminobutyric acid-A agonist muscimol were administered into the dorsal raphe nucleus. These treatments which inhibit 5-HT neuronal activity, were shown to decrease performance of aggressive behavior. Second, after a resident-intruder test, the activation of 5-HT neurons (measured by c-fos expression) was increased in high-aggressive rats, compared with low-aggressive rats or control rats that were not subjected to a social confrontation. Results show that performance of aggressive behavior increases 5-HT neuronal activity and that preventing this activation inhibits expression of aggressive behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Forebrain sites of estradiol-17!b action on sexual behavior and aggression in female Syrian hamsters.

The effects of intracranial implants of estradiol in the ventromedial hypothalamus (VMH), the anterior hypothalamus (AH), or the medial amygdala (AMG) on aggression, sexual behavior, and serum estradiol were examined in female Syrian hamsters. Estradiol implants in the VMH, followed by systemic progesterone, stimulated sexual behavior and inhibited aggression. Estradiol implants in other intracranial sites activated sexual behavior but did not reliably inhibit aggression. Intracranially implanted and systemically treated animals had equivalent peripheral estradiol concentrations at sacrifice. Results suggest that (1) the VMH is an important neural site for estradiol actions on sexual and aggressive behavior, (2) the caudal AH and AMG may also be sites of estradiol action on sexual behavior, and (3) intracranial implants may only be effective given systemic estradiol exposure or the concurrent stimulation of multiple brain areas. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Are there preexisting behavioral characteristics that predict the dominant status of male NIH Swiss mice (Mus musculus)?

The behavior of isolated Cr:NIH(S) mice was studied in a holeboard test of exploration, in a plus-maze test of anxiety, in the resident–intruder paradigm of aggression, and in the swim test. Thereafter, mice that were matched for body weight were housed together in groups of 4–5. Within a wk, 1 mouse per cage (the alpha) had attacked all its subordinate cagemates but lacked any signs of attack itself. Subordinate mice had bite marks on their tails and backs. When mice were isolated, no differences were found between the behavior of those that later became alphas and those that became subordinates. In contrast, after the establishment of the social hierarchy, alpha mice spent less time immobile in the swim test and had higher locomotor activities than did the subordinate mice. The results suggest that the differences in behavior between the alpha and subordinate mice result from aggressive social interactions in the home cage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential responses to serotonin receptor ligands in an impulsive-aggressive phenotype.

Offensive aggression in golden hamsters is inhibited by 5-hydroxytryptamine (5-HT)1A receptors and facilitated by 5-HT3 receptor activation. As such, we sought to determine whether these receptors function similarly between animals expressing an impulsive-aggressive phenotype, as compared to normal animals. Animals were screened for aggressive and impulsive choice behaviors and categorized into Low-Aggression (L-Agg) and High-Aggression (H-Agg) groups, and then tested for behavior under effective doses of 5-HT1A receptor agonist 8-hydroxy-N, N-dipropyl-2-aminotetralin (DPAT; 0.1 mg/kg and 0.3 mg/kg) or 5-HT3 receptor antagonist tropisetron (0.3 mg/kg) treatment. Low-dose DPAT treatment inhibited both behaviors in H-Agg animals, however yielding more modest effects in L-Agg animals; while high-dose DPAT effects were confounded by side effects on locomotion. Tropisetron, on the other hand, had differential effects between groups, as aggression and impulsive choice were both inhibited in H-Agg animals, while enhanced in L-Agg individuals. In addition, while the effects of the 5-HT1A receptor were limited, the broad effects of 5-HT3 receptor included repetitive and impulsive elements of behavior, pointing to the importance of the receptor's role in the modulation of these particular aspects within the phenotype. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor

A variety of observations from several rodent species suggest that a serotonin (5-HT) input to the suprachiasmatic nucleus (SCN) circadian pacemaker may play a role in resetting or entrainment of circadian rhythms by non-photic stimuli such as scheduled wheel running. If 5-HT activity within the SCN is necessary for activity-induced phase shifting, then it should be possible to block or attenuate these phase shifts by reducing 5-HT release or by blocking post-synaptic 5-HT receptors. Animals received one of four serotonergic drugs and were then locked in a novel wheel for 3 h during the mid-rest phase, when novelty-induced activity produces maximal phase advance shifts. Drugs tested at several doses were metergoline (5-HT1/2 antagonist; i.p.), (+)-WAY100135 (5-HT1A postsynaptic antagonist, which may also reduce 5-HT release by an agonist effect at 5-HT1A raphe autoreceptors; i.p.), NAN-190 (5-HT1A postsynaptic antagonist, which also reduces 5-HT release via an agonist effect at 5-HT1A raphe autoreceptors; i.p.) and ritanserin (5-HT2/7 antagonist; i.p. and i.c.v.). Mean and maximal phase shifts to running in novel wheels were not significantly affected by any drug at any dose. These results do not support a hypothesis that 5-HT release or activity at 5HT1, 2 and 7 receptors in the SCN is necessary for the production of activity-induced phase shifts in hamsters.     

Behavioural response to pharmacologic manipulation of serotonin receptors in the genetically dystonic hamster

The genetically dystonic (dtsz) hamster is an autosomal recessive mutant that shares several features with paroxysmal dystonia, i.e., a subcategory of inherited idiopathic dystonia in humans. Because the serotonin (5-HT) system has been suggested to be involved in dystonia, we examined the functional responsiveness of the 5-HT system in dystonic hamsters by administering various 5-HT agonists and antagonists selective for different receptor subtypes and observing the effects on dystonic attacks as well as the behavioural responses associated with drug administration. Paradoxically, marked prodystonic effects (i.e., increased severity and/or decreased latency of dystonic attacks) were seen with both the selective 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and the selective and "silent" 5-HT1A receptor antagonist, N-tert-butyl-3[4-(2-methoxyphenyl)piperazin-1-yl]-2- phenylpropionamide [(+)-WAY-100135], whereas other 5-HT1A receptor antagonists, i.e., methyl 4[4-(4-[1,1,3-trioxo-2H-1,2-benzoiosothiazol-2-yl]butyl)-1- piperazinyl]1-H-indole-2-carboxylate (SDZ 216-525) and N1-bromoacetyl-N8-3'-(4-indolyloxy)-2'-hydroxypropyl-(Z)-1,8- diamino-p-methane (pindobind-5-HT1A) did not alter dystonia to any comparable extent. Because among these 5-HT1A receptor antagonists, (+)-WAY-100135 is the only drug known to be not only silent at postsynaptic but also presynaptic (somatodendritic) 5-HT1A receptors, the marked prodystonic effect of this drug could relate to increased 5-HT release as a result of the blockade of somatodendritic 5-HT1A receptors. The only 5-HT1A receptor antagonist that exerted antidystonic effects in hamsters was pindolol, which, however, could be related to its beta-adrenoceptor blocking action. The 5-HT1A receptor partial agonist ipsapirone exerted moderate prodystonic activity. Prodystonic activity was also determined for the mixed 5-HT1A/5-HT2 receptor agonist 5-methoxy-N,N-dimethyltryptamine, although this drug was less potent in this regard than 8-OH-DPAT. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerted prodystonic effects in mutant hamsters, which, however, were also seen after the administration of the 5-HT2 receptor antagonist ritanserin. Collectively, the results of this study demonstrate that dystonia in genetically dystonic hamsters can be affected by pharmacologic manipulation of 5-HT receptors. The data may also indicate that dystonia is not a potential clinical application for selective 5-HT1A or 5-HT2 receptor antagonists.     

5-HT autoreceptors in the regulation of 5-HT release from guinea pig raphe nucleus and hypothalamus

5-HT autoreceptors involved in the regulation of 5-HT release in the guinea pig dorsal raphe nucleus have been studied in comparison with those in the hypothalamus. In vitro release was measured in slices of raphe and hypothalamus prelabelled with [3H]5-HT, superfused with Krebs solution and depolarized electrically. The non-selective 5-HT receptor agonist, 5-carboxamidotryptamine (5-CT) (0.1-10 nM for raphe: 1-100 nM for hypothalamus) and antagonist, methiothepin (10-1000nM), decreased and increased, respectively, the release of [3H]5-HT evoked by electrical stimulation in either of these regions when given alone. The selective 5-HT1B/D receptor antagonist, GR127935 (100-1000 nM), and the 5-HT1D receptor antagonist, ketanserin (300-1000 nM), had no significant effect on this release in either of these regions. Methiothepin and GR127935 (100-1000 nM) shifted to the right the concentration-effect curve of 5-CT in both the raphe and the hypothalamus. At 300 nM, ketanserin shifted to the right the concentration-effect curve of 5-CT in the raphe but did not modify the 5-CT curve in the hypothalamus. In microdialysis experiments ketanserin, applied locally at 10 microM, increased the extracellular levels of 5-HT in the dorsal raphe nucleus of the freely moving guinea pig, whereas 5-HT levels were unchanged in the hypothalamus. Ketanserin at 1 microM did not affect the decrease in 5-HT output induced by the selective 5-HT1B/D receptor agonist, naratriptan (used at 10 microM in raphe and 0.1 microM in hypothalamus), in the raphe or the hypothalamus. In the raphe, WAY100635, a 5-HT1A receptor antagonist, at 1 microM, did not prevent naratriptan (10 microM) from reducing the extracellular levels of 5-HT. These results suggest that, in the conditions used in this study, the release of 5-HT in the dorsal raphe nucleus is possibly modulated in part by 5-HT1B receptors but essentially the control is through 5-HT receptors whose subtype is still to be determined. In the hypothalamus, however, it is clear that only 5-HT1B receptors are involved in the modulation of 5-HT neurotransmission.