Differential effects ofp-chlorophenylalanine on indoleamines in brainstem nuclei and spinal cord of rats. I. Biochemical and behavioral analysis

The involvement of endogenous serotonergic pathways in the mediation of antinociception has been indicated by electrophysiological, pharmacological and behavioral experiments. However, manipulation of the indole pathway, either by lesioning of raphe nuclei or drug intervention, often produces disparate results. In particular, serotonin (5-HT) synthesis inhibition withp-chlorophenylalanine (PCPA) has been reported to produce either hyperalgesia or analgesia, depending upon the type of pain measurement examined. In the present study, we sought to evaluate the effects of PCPA on (1) behavioral responses to noxious stimulation, and (2) levels of serotonin, tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in raphe nuclei (pallidus, obscurus, magnus and dorsalis) and spinal cord regions by HPLC with electrochemical detection. Treatment of rats with 400 or 600 mg/kg of PCPA for 3 consecutive days resulted in significant elevations in pain thresholds assessed by tail withdrawal from radiant heat as well as vocalization to electric shock of the tail. The effect of PCPA on vocalization threshold was particularly striking, for the majority of animals showed a nociceptive-specific attenuation of this response. Although the PCPA induced changes in indole content of the various raphe nuclei were not unequivocally dose-dependent, differential reductions of serotonin and 5-HIAA were clearly detected in the various raphe regions. Nuclei raphe pallidus and obscurus were depleted of 5-HT and 5-HIAA to the greatest extent, whereas levels detected in nuclei raphe magnus and dorsalis were reduced by 30–40% from control values. Metabolism of 5-HT and 5-HIAA appeared unaffected by PCPA in all regions examined except the dorsal portion of the spinal cord. These findings collectively suggest that the effects of PCPA are not uniform throughout the central nervous system and raise the possibility that discrepancies in the behavior literature may be attributed to drug-induced changes in some, but not all serotonergic pathways.     

Phenytoin inhibits isolation-induced aggression specifically in rats with low serotonin

Phenytoin is a widely used anticonvulsant drug that also reduces aggressive behavior. Aggression in humans and animals is often associated with low serotonin levels. This study examined the anti-aggressive properties of phenytoin in rodent isolation-induced aggression using a resident-intruder test to quantify aggression. Chronic treatment with p-chlorophenyl-alanine (PCPA), a competitive inhibitor of serotonin synthesis, significantly enhanced resident attack behavior compared to saline-treated control rats. Phenytoin dose-dependently reduced aggressive behavior specifically in PCPA-treated rats, but had no anti-aggressive properties in saline-treated rats. These data suggest that aggressive behavior in this model may be related to neuronal hyperexcitability that is sensitive to the anticonvulsant effects of phenytoin. Further, these data suggest isolation-induced aggression in PCPA-treated rats may be a useful model to investigate aggression associated with low serotonin in the brain.     

The effects of alaproclate and p-chlorophenylalanine on cued navigation performance in rats

Summary The present study investigates the effects of a serotonin (5-HT) reuptake inhibitor, alaproclate, on water maze cued navigation performance in serotonin depleted and control rats. Treatment with p-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, (400 mg/kg/day×3 i.p.) significantly depleted cerebral levels of both 5-HT (about 80% depletion) and its major metabolite 5-HIAA (about 90% depletion) for at least 7 days. PCPA treatment also slightly decreased cerebral noradrenaline and dopamine levels (16% and 22% reductions, respectively). PCPA treatment alone had no effect on the acquisition of the cued navigation version (visible platform) of the water maze task measured as the distance to find the escape platform, but it significantly increased swimming speeds of the rats. Alaproclate (20 mg/kg i.p.) increased escape distance and slightly decreased swimming speeds of the rats. The effects of alaproclate did not differ between PCPA and sham treated (arabic gum 400 mg/kg/day × 3 i.p.) rats. The results demonstrate that alaproclate induced cued navigation behavioral deficit is maintained after a marked depletion of cerebral serotonin.     

Manipulations of dietary tryptophan: Effects on mouse killing and brain serotonin in the rat

Maintaining rats on a tryptophan-free diet for 4--6 days induced mouse killing in non-killer rats, and significantly facilitated killing in killer rats, as indicated by shorter latencies to kill the mice. The killing responses were similar in topography to the natural killing responses. These changes in killing behavior did not appear to be due to generalized changes in irritability. The increased killing after maintenance on a tryptophan-free diet was accompanied by a 26% reduction in brain serotonin (5-HT) and a 29% reduction in brain 5-hydroxyindoleacetic acid (5-HIAA). When the tryptophan-free diet was supplemented with L-tryptophan (0.5 or 2%), brain 5-HT and 5-HIAA were increased above control levels, and the rat's killing response appeared normal both in terms of latency and topography, similar to that seen in control chow fed animals. While rats consumed less of the tryptophan-free and tryptophan supplemented diets, control subjects deprived of chow such that they lost as much weight as rats fed the tryptophan-free diet, did not show changes in killing behavior. These results are consistent with the hypothesis that central serotonergic systems exert inhibitory control over mouse killing behavior in rats.     

A pharmacological evidence of positive association between mouse intermale aggression and brain serotonin metabolism

The neurotransmitter serotonin (5-HT) is involved in the regulation of mouse intermale aggression. Previously, it was shown that intensity of mouse intermale aggression was positively associated with activity of the key enzyme of 5-HT synthesis - tryptophan hydroxylase 2 (TPH2) in mouse brain. The aim of the present study was to investigate the effect of pharmacological activation or inhibition of 5-HT synthesis in the brain on intermale aggression in two mouse strains differing in the TPH2 activity: C57BL/6J (B6, high TPH2 activity, high aggressiveness) and CC57BR/Mv (BR, low TPH2 activity, low aggressiveness). Administration of 5-HT precursor L-tryptophan (300 mg/kg, i.p.) to BR mice significantly increased the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in the midbrain as well as the number of attacks and their duration in the resident-intruder test. And vice versa, administration of TPH2 inhibitor p-chlorophenylalanine (pCPA) (300 mg/kg, i.p., for 3 consecutive days) to B6 mice dramatically reduced the 5-HT and 5-HIAA contents in brain structures and attenuated the frequency and the duration of aggressive attacks. At the same time, L-tryptophan or pCPA did not influence the percentage of aggressive mice and the attack latency reflecting the threshold of aggressive reaction. This result indicated that the intensity of intermale aggression, but not the threshold of aggressive reaction is positively dependent on 5-HT metabolism in mouse brain.     

The Role of Aromatization in the Restoration of Male Rat Reproductive Behavior

This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 μg/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole’s inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.     

Rodent data and general hypothesis: antipsychotic action exerted through 5-HT2A receptor antagonism is dependent on increased serotonergic tone

Summary. The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390). Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments. PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however in a meta-analysis of six experiments, the locomotion displayed by MK-801-treated animals was diminished 17% by PCPA pretreatment. The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP). On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment. The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA. These results suggest that (1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems. (2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors. (3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism. Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone. Accepted February 9, 1998; received December 16, 1997     

Rat brain serotonin: Biochemical and functional evidence for a sex difference

Summary Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the 5-HT behavioural syndrome was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.     

Prepubertal social subjugation and anabolic androgenic steroid-induced aggression in male rats

Abused children are more prone to abuse drugs, such as anabolic androgenic steroids (AAS), as teenagers and display violence as adults. AAS use has been linked with elevated aggression. Thus, exposure to child abuse and AAS may potentiate aggression. A social subjugation paradigm was used as an animal model of childhood abuse to determine whether prior subjugation increases AAS-induced aggression in male rats. Prepubertal gonadally intact male rats were exposed to social subjugation, a novel cage experience, or remained undisturbed in their home cages. Experimental males were socially subjugated by being placed in the home cage of an adult male. At puberty, both subjugated and nonsubjugated rats were injected with either the AAS testosterone or vehicle. AAS treatment continued for 5 weeks. Aggression was measured during the last week of AAS exposure. AAS was then discontinued. Aggression was again tested 12 weeks after AAS withdrawal. Aggression was tested under three conditions: (i) physical provocation of the experimental male; (ii) provocation of the intruder male; and (iii) without provocation. Both AAS-treated males and socially subjugated males displayed significantly more aggression than did controls. Elevated aggression by subjugated males was still present 17 weeks after social subjugation. AAS males also showed increased aggression 12 weeks after AAS withdrawal. However, exposure to both social subjugation and AAS had no long-term effects on aggression. The results of the present study indicate that social subjugation may have lasting consequences on the expression of adaptive social behaviours.     

Proestrous effects of chlordecone on the serotonin system

This study concentrates on the role of the serotonin system in mediating the proestrous effects of chlordecone on female rodent sexual behavior. The pesticide was examined within the context of serotonin changes taking place on proestrous. Between morning and evening on the day of proestrus there was an increase in 3H-5-HT binding, an increase in serotonin (5-HT) and an increase in 5-hydroxyindoleacetic acid (5-HIAA). Proestrous treatment with chlordecone attenuated the increase in 5-HT and in 3H-5-HT binding but had no effect on 5-HIAA. These findings suggest that the pesticide blocked proestrous changes essential for the female's development of sexual receptivity. The 5-HT1A agonist, 8-OH-DPAT, was an inefficient competitor for 3H-5-HT binding in frontal cortex of females treated with chlordecone. It is speculated that the pesticide disrupts a balance between serotonin sites which facilitate and those which inhibit sexual behavior. Consistent with this speculation, the 5-HT agonist, quipazine, partially attenuated chlordecone's reduction of sexual behavior. Finally, the rapid effects of estradiol and chlordecone on 3H-5-HT binding sites were compared in ovariectomized female rats. These results showed no resemblance between the effects of chlordecone and those of estradiol.     

5-hydroxytryptamine in the central nervous system and sexual receptivity of female rhesus monkeys.

The role of 5-hydroxytryptamine (5-HT) in the control of sexual receptivity in female rhesus monkeys has been studied in 24 adult females paired with 6 adult males. p-Chlorophenylalanine (PCPA, 75 mg/kg or 100 mg/kg, every fourth day), a selective inhibitor of 5-HT, was found to reverse unreceptivity induced by adrenalectomy in ovariectomised, oestrogen-treated females. PCPA-treated females presented more frequently and initiated more sexual behaviour, or else they refused fewer of the male's attempts to mount. These effects were in turn reversed by 5-hydroxytryptophan (5-HTP, 20 mg/kg every second day), when this was given to PCPA-treated animals. In addition, 5-HTP given alone to ovariectomised oestrogen-treated females reduced their receptivity. Parallel biochemical experiments showed that PCPA in the doses used lowered the levels of 5-HT in the brain as measured by the levels of 5-hydroxyindole-3-acetic acid (5-HIAA) in the CSF, and that these were restored by 5-HTP. Both oestradiol benzoate (15 mug/day for 10 days) and testosterone propionate (250 mug/day or 400 mug/day for 10 days) lowered the turn-over rates of 5-HT in the brain (as measured by the probenecid test) in ovariectomised female monkeys. These effects of oestradiol on turnover were antagonised by progesterone (15 mg/day for 10 days, given with oestradiol). A substance other than an adrenal androgen has thus been found to reverse the effects of adrenalectomy on sexual receptivity in female monkeys. It is therefore possible that androgens regulate receptivity in female monkeys by modifying the activity of 5-HT-containing neural systems.     

Effects of insulin on brain serotonin in the young rat: influence of thyroid status

Thyroid status has been shown to modify the adrenal catecholaminergic response to insulin. The influence of thyroid status on the brain serotonergic response to insulin is the subject of the present report. Newborn rats were divided into three groups: euthyroid, hypothyroid (propylthiouracil given to the suckling mother), and hypothyroid-treated with triiodothyronine (T3) as replacement therapy. At 14 days of age, the animals in each group received either insulin (10 IU/kg SC) or saline. Levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in several brain regions. Hypothyroidism induced increases in hypothalamic 5-HT and 5-HIAA and in cortical 5-HIAA levels. The elevations in 5-HIAA levels were reversed by T3. Insulin treatment-induced increases in 5-HIAA levels in all brain regions of both the hypothyroid and the T3-replaced rats. Thyroid status thus influences the serotonergic response to insulin in the young rat, but contrary to what occurred in adrenals for catecholamines, hypothyroidism enhances the central serotonergic response to insulin.     

Comparison of regional serotonin levels and turnover in the brain of naturally high and low aggressive rats

Rats, matched by weight and goal approach, were tested for aggressiveness using a food-competition paradigm. Those winning and those losing all of their matches were designated as high and low aggressive, respectively. A third group of randomly selected rats never fought and were used as a control for the fighting experience. Half of the rats were used to determine serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in discrete brain regions. The other half were used to estimate 5-HT turnover in the same brain regions.High and low aggressive rats did not differ with regard to 5-HT or 5-HIAA levels, but high aggressive rats showed faster 5-HT turnover than low aggressive rats. The turnover differences reached statistical significance in only two of the 3 brain regions examined: (a) all structures (minus olfactory bulbs) rostral to the level of the anterior commissure, and (b) the brain stem (hypothalamus-midbrain-medulla). The observed differences cannot be attributed to differing behavioral experiences since the high and low aggressive groups pooled did not differ from the no-fighting control.These findings are discussed with respect to the involvement of serotonin in rat intraspecies aggression.     

Time course of changes in serotonin and noradrenaline in rat brain after predictable or unpredictable shock

The effects of predictable and unpredictable shock on concentrations of serotonin (5-hydroxytryptamine, 5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan (TP) and noradrenaline (NA) have been studied in 7 regions of rat brain. Two separate experiments have been carried out determining these substances both at 30 min and 2 h after the stress session. Unpredictable shock depleted NA levels in all brain regions except the striatum. However, at 2 h poststress NA in these regions increased significantly in comparison with both controls and predictably shocked rats. Predictable shock also decreased NA in locus coeruleus, brainstem and hypothalamus, which was not observed 2 h later. Both predictable and unpredictable shock decreased 5-HT in brainstem and hypothalamus. At 2 h poststress, 5-HT levels in these regions were still decreased in predictably shocked rats, but had attained control values in unpredictably shocked rats. 5-HT metabolism expressed as the 5-HIAA/5-HT ratio, was significantly increased 30 min after predictable shock in all regions except the locus coeruleus and hippocampus. Unpredictable shock produced a much more marked increase in 5-HIAA/5-HT ratio. At 2 h poststress 5-HT metabolism returned to control values in most of the brain regions of predictably shocked animals, but it remained high after unpredictable shock. The activation of serotonergic metabolism following each type of shock is different according to the nucleus in which the 5-HT nerve endings originate. Only slight increases in tryptophan were observed after both types of shock. Our results suggest that unpredictable shock is perceived as a more anxiogenic situation and that under this condition both 5-HT and NA levels are more effectively normalized with time.     

Serotonergic influences on the social behavior of vervet monkeys (Cercopithecus aethiops sabaeus)

The behavioral effects of altering serotonin neurotransmission by chronic drug treatments in socially living vervet monkeys (Cercopithecus aethiops sabaeus) were examined. Animals received tryptophan (TRP, 20 mg/kg/day), parachlorophenylalanine (PCPA, 80 mg/kg/day), 5-hydroxytryptophan (5-HTP, 40 mg/kg/day), chlorgyline (10 mg/kg/day), or PCPA followed by concurrent PCPA and 5-HTP. Grooming, approaching, resting, and eating were increased by TRP and decreased by PCPA; TRP decreased and PCPA increased locomoting, avoiding, being solitary, and being vigilant. Grooming, being vigilant, and receiving aggression were increased by 5-HTP, and PCPA increased initiating aggression and decreased huddling. Concurrent administration of 5-HTP and PCPA reversed the effects of PCPA on approaching, grooming, and resting; augmented the PCPA effects on avoiding, being solitary, and aggression; and did not alter the PCPA effects on eating, locomoting, and huddling. Chlorgyline increased grooming, approaching, and being vigilant and decreased being solitary. No treatment significantly affected sexual behavior. These data suggest that serotonergic systems contribute relatively substantially to the mediation of grooming and approaching, participate less strongly in resting and locomoting, are implicated still more weakly in being solitary, avoiding, and being vigilant, and have little if any involvement in huddling, aggression, and sexual behavior.     

Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: reciprocal relationships with impulsive aggression in human subjects

While the relationship between cerebrospinal fluid 5-HIAA (CSF 5-HIAA) and aggression is typically reported as inverse, studies of some groups of aggressive individuals demonstrate a positive (or no) relationship, between these two variables. It is possible that simultaneous examination of both CSF 5-HIAA and CSF homovanillic acid (HVA), which co-vary in human subjects may clarify differences in reported findings in different groups of aggressive individuals. CSF 5-HIAA and CSF HVA concentrations were simultaneously examined in 60 healthy human subjects (40 with personality disorder and 20 healthy controls) and were correlated with measures of aggression and impulsivity. CSF 5-HIAA concentrations correlated positively, and CSF HVA concentrations correlated inversely, with a composite measure of impulsive aggression in all subjects as well as in the personality disordered subjects. The CSF 5-HIAA findings are consistent with those demonstrating reduced post-synaptic 5-HT receptor responsiveness to 5-HT agent challenge and suggest differences in the pathophysiology between different groups of subjects with aggressive behavior, particularly with regard to severity of aggressive behavior.     

Chemical lesions of the nucleus accumbens septi in rats: effects on muricide and apomorphine-induced aggression

To assess the influence of monoaminergic neurones in the nucleus accumbens septi (NAS) on muricidal and apomorphine-induced aggression, bilateral intraaccumbens injections of relevant neurotoxins were performed. Neurochemical effects in the mesolimbic area (NAS and tuberculi olfactorii) and striatal tissue were investigated using high performance liquid chromatography. 6-Hydroxydopamine (6-OHDA) with desipramine pretreatment significantly decreased mesolimbic dopamine (DA) metabolism, 5,7-dihydroxytryptamine (5,7-DHT) plus desipramine diminished serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), while DSP-4 depleted noradrenaline (NA), 5-HT, 5-HIAA and tryptophan in the mesolimbic area. No significant biochemical changes were observed in the striatum. Behaviourally, 6-OHDA-treated rats were markedly more aggressive in the apomorphine-induced fighting test. Similarly, DSP-4 injections into the NAS (10 micrograms/1 microliter) enhanced this type of aggression. The 5,7-DHT lesion did not alter apomorphine-induced fighting. None of the neurotoxins induced muricidal behaviour. It is concluded that dopaminergic postsynaptic receptors in the NAS may be involved in the pro-aggressive effect of apomorphine. The results support the hypothesis that NA-containing neurones play an inhibitory role in apomorphine-induced aggression and suggest that such a DA-NA interaction might occur in the NAS.     

Neural control of predatory aggression in wild and domesticated animals

The neural mechanisms of predatory aggression in laboratory animals were investigated in a variety of rodents and members of the order Carnivora. Experimental enhancement of brain serotonin (5-HT) blocked killing behavior in rats, mice, mink and silver foxes, indicating that there is a 5-HT inhibiting mechanism of predatory aggression in animals of different species. Suppressed killing behavior, at least in some strains of mice, does not depend for expression on the inhibitory effect of the brain 5-HT system, but is caused by the low tonus of the system activating predatory behavior. Long-term satiation of mink increased the level of 5-hydroxyindole acetic acid in the lateral hypothalamus and amygdala and enhanced the latency of predatory aggression. It is suggested that 5-HT represents a dietary responsive endogenous factor regulating predatory behavior in carnivores. Selection of Norway rats over many generations for tamed behavior towards man (domestication) leads to an increase in level and turnover of 5-HT in the midbrain and hypothalamus, but does not change predatory aggression. Substantially reduced defensive behavior of domesticated rats is thus unconnected with the neural mechanism of predatory aggression.     

Phenytoin normalizes exaggerated fear behavior in p-chlorophenylalanine (PCPA)-treated rats

Temporal lobe epilepsy may be associated with emotional difficulties such as depression and anxiety. Because the amygdala is involved in both epilepsy and emotion, common neural mechanisms in this temporal lobe structure may underlie the emotional disturbances observed in people with epilepsy. The neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) is implicated in many psychopathologies, and 5-HT also modulates amygdala excitability. Therefore, the present study uses the fear-potentiated startle (FPS) paradigm to investigate the effect of neuronal excitability on fear behavior in rats treated with p-chlorophenylalanine (PCPA) to chronically inhibit 5-HT synthesis. PCPA treatment selectively enhanced FPS in individually housed rats. The exaggerated FPS response was reduced to control level by the anticonvulsant phenytoin at 10mg/kg, and phenytoin at 30mg/kg further decreased FPS behavior. These data suggest that a subseizure state of neuronal excitability mediated by low 5-HT in brain fear circuits may be associated with pathological fear behavior.     

Influence of PCPA and MDMA (ecstasy) on physiology, development and behavior in Drosophila melanogaster

The effects of para-chlorophenylalanine (PCPA) and 3,4 methylenedioxy-methamphetamine (MDMA, 'ecstasy') were investigated in relation to development, behavior and physiology in larval Drosophila. PCPA blocks the synthesis of serotonin (5-HT) and MDMA is known to deplete 5-HT in mammalian neurons; thus these studies were conducted primarily to target the serotonergic system. Treatment with PCPA and MDMA delayed time to pupation and eclosion. The developmental rate was investigated with a survival analysis statistical approach that is unique for Drosophila studies. Locomotion and eating were reduced in animals exposed to MDMA or PCPA. Sensitivity to exogenously applied 5-HT on an evoked sensory-central nervous system (CNS)-motor circuit showed that the CNS is sensitive to 5-HT but that when depleted of 5-HT by PCPA a decreased sensitivity occurred. A diet with MDMA produced an enhanced response to exogenous 5-HT on the central circuit. Larvae eating MDMA from the first to third instar did not show a reduction in 5-HT within the CNS; however, eating PCPA reduced 5-HT as well as dopamine content as measured by high performance liquid chromatography from larval brains. As the heart serves as a good bioindex of 5-HT exposure, it was used in larvae fed PCPA and MDMA but no significant effects occurred with exogenous 5-HT. In summary, the action of these pharmacological compounds altered larval behaviors and development. PCPA treatment changed the sensitivity in the CNS to 5-HT, suggesting that 5-HT receptor regulation is modulated by neural activity of the serotonergic neurons. The actions of acute MDMA exposure suggest a 5-HT agonist action or possible dumping of 5-HT from neurons.