Injection Of P-chloroamphetamine Research Articles

In vivo [¹⁸F] FDG PET imaging reveals that p-chloroamphetamine neurotoxicity is associated with long-term cortical and hippocampal hypometabolism.

p-Chloroamphetamine (PCA) is a neurotoxin that selectively degenerates the serotonin (5-HT) axon terminals. In order to study the brain metabolic consequences induced by serotonergic denervation, a single dose of PCA (2.5 or 10 mg/kg i.p.) was administered to male adult rats. In vivo regional brain metabolism was evaluated 3 and 21 days after PCA (2.5 or 10 mg/kg; i.p.) injection by 2-deoxy-2-[(18)F] fluoro-D-glucose ([(18)F] FDG) positron emission tomography (PET). At day 22, the following markers of neurotoxicity were determined: (a) 5-HT axon terminal lesion by 5-HT transporter (SERT) autoradiography, (b) reactive gliosis by glial fibrillary acidic protein immunohistochemistry, and (c) eventual neurodegeneration by DAPI/Fluoro-Jade C labeling. An average of 20 % reduction of [(18)F] FDG uptake in most brain areas was observed at day 21 under 10 mg/kg PCA treatment. Instead, 2.5 mg/kg PCA only reduced metabolic activity in neocortex. Likewise, the high dose of PCA exerted a strong decrease (>30 %) in SERT density in several 5-HT innervated regions, but no effect was found in midbrain raphe nuclei, the main source of serotonergic neurons. Although PCA induced astroglial activation both in hippocampus and cortex in response to axotomy, no signs of neuronal death in these areas were detected. Overall, [(18)F] FDG PET revealed that the reduction of the brain metabolic activity induced by PCA is related to 5-HT axon terminal lesion, with no apparent affectation of neuronal viability.

P-Chloroamphetamine-induced rat ejaculation is not associated with the preoptic nucleus or medial nucleus amygdala.

Aim: In the rat, intraperitoneal injection of p-chloroamphetamine (PCA), which releases central 5-hydroxytryptamine (5-HT) from serotonergic nerve terminals, induces ejaculation, even in the absence of an estrus female or female-related smell information. It is well known that the medial preoptic nucleus (MPN) and the medial nucleus amygdala (MEA) play a major role in the control of male sexual behavior in mammals. We examined whether or not neuronal activity of the MPN and/or the MEA was associated with PCA-induced ejaculation. Methods: Using c-Fos immunohistochemistry, we demonstrated a difference in the neural activities of the MPN and the MEA for ejaculation during copulation with an estrus female and ejaculation by PCA injection. Results: Increased numbers of c-Fos-immunoreactive (c-Fos-IR) cells were found in the MPN and the MEA in the brains of the mating animals, whereas in the brains of the animals undergoing PCA-induced ejaculation there was no increase in the number of c-Fos-IR cells in the MPN and a small increase in the MEA. Conclusion: Based on these results, ejaculation induced by PCA is not associated with the MPN. Moreover, the MEA is not the main act for this ejaculation. (Reprod Med Biol 2008; 7: 37-43).

Activation of D2‐like receptors induces sympathetic climactic‐like responses in male and female anaesthetised rats

In anaesthetised male rats an intravenous (i.v.) injection of p-chloroamphetamine (PCA) produced a specific patterned bursting response in the sympathetic vas deferens nerve (VDN) that corresponds to ejaculation. In the present, study selective dopamine agonists and antagonists were used to investigate whether dopaminergic mechanisms influence the generation of this ejaculatory-related response. Administration of a mixed D(1/2) receptor agonist (0.1-1.0 mg kg(-1) apomorphine i.v.) also evoked the characteristic bursting pattern responses in the VDN. Similar, but fewer, burst pattern responses could also be evoked by a selective D(2/3) receptor agonist (0.1-2.0 mg kg(-1) piribedil). Responses to 1.0 mg kg(-1) apomorphine were blocked by pretreatments with either 0.5 mg kg(-1) remoxipride (D(2) receptor antagonist) or 0.5 mg kg(-1) nafadotride (D(3) receptor antagonist), suggesting that D(2)-like receptors were involved. Responses could not be evoked by i.v. injections of apomorphine (1.0 mg kg(-1)) in anaesthetised male rats with a midthoracic spinal section, indicating that activation of D(2)-like receptors at supraspinal sites leads to an increase in the excitability of the lumbosacral pattern generator for ejaculation. In anaesthetised female rats a similar patterned bursting response occurred in the uterine nerve (UN) in response to apomorphine (0.5-2.0 mg kg(-1) i.v.). Thus a common neural mechanism may regulate sexual climactic reflexes in both sexes.

Behavioral sensitization to amphetamine results from an uncoupling between noradrenergic and serotonergic neurons

In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhances this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. We show here that, in naïve animals, noradrenergic and serotonergic systems, besides their behavioral activating effects, inhibit each other by means of the stimulation of alpha1b-adrenergic and 5-HT(2A) receptors and that this mutual inhibition vanishes with repeated injections of d-amphetamine; this uncoupling may be responsible for behavioral sensitization and for an increased reactivity of dopaminergic neurons. First, after repeated d-amphetamine injections, a d-amphetamine challenge induces a dramatic increase in cortical extracellular norepinephrine (NE) levels. This increased cortical NE release still occurs after 1 month of withdrawal but is diminished or blocked if sensitization is performed in the presence of prazosin, SR46349B, or both alpha1-adrenergic and 5-HT(2A) receptor antagonists, respectively. A strong correlation between increases in cortical extracellular NE levels and the expression of behavioral sensitization was found. Second, repeated d-amphetamine injections induce an increased reactivity of serotonergic neurons measured by cortical extracellular serotonin (5-HT) levels after the administration of a 5-HT releaser, p-chloroamphetamine. Third, knockout mice for alpha1b-adrenergic (alpha1b-AR KO) or 5-HT(2A) (5-HT(2A)-R KO) receptor, respectively, exhibit a behavioral and biochemical hyperreactivity to the acute injection of p-chloroamphetamine (alpha1b-AR KO; 5-HT levels) and d-amphetamine (5-HT(2A)-R KO; NE levels). Uncoupling between noradrenergic and serotonergic neurons may occur not only in addiction but also during chronic stressful situations, thus facilitating the onset of mental illness.

Evidence for an involvement of peripheral serotonin in p-chloroamphetamine-induced ejaculation of rats

The purpose of the present study was to determine the mechanism of the ejaculatory response induced by the 5-HT-releasing compound p-chloroamphetamine (PCA) in rats. The ejaculatory response was assessed by weighing the coagulated seminal materials accumulated over 1 h. Intraperitoneal injection of PCA (0.5–5.0 mg/kg) produced a dose-related increase in both the incidence of ejaculation and the weight of the accumulated seminal materials. The ejaculatory response induced by PCA (5.0 mg/kg) was abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine, the 5-HT receptor antagonists methysergide and MDL72222, or by the selective 5-HT reuptake inhibitor citalopram, suggesting that the 5-HT-releasing property of PCA mainly involved the expression of ejaculation. Neither the section of the spinal cord at thoracic (T8–9) level nor the lumbosacral spinal 5-HT denervation by intrathecal (i.t.) injection of 5,7-dihydroxytryptamine affected the ejaculatory response induced by PCA. The i.t. injection of PCA (20–160 μg/rat) at lumbosacral spinal level did not exert the systemic PCA-like prominent effect on ejaculation, whereas i.t. injection of lidocain at the same site completely abolished the response to systemic PCA. Additionally, the peripherally administered 5-HT (0.1 and 0.25 mg/kg, i.p.) enhanced the proejaculatory effect at a threshold dose (1.0 mg/kg, i.p.) of PCA. From these observations, it is concluded that the ejaculatory response induced by PCA is mainly a spinally mediated reflex response that is triggered by the release of 5-HT in the peripheral sites.

Long-lasting behavioral sensitization to psychostimulants following p-chloroamphetamine-induced neurotoxicity in mice

Amphetamine analogs such as p-chloroamphetamine (PCA) cause serotonergic and dopaminergic neurotoxicity. The behavioral consequences and the responsiveness to psychostimulants following the neurotoxic insult are unclear. The present study was undertaken to investigate the outcome of neurotoxic and non-neurotoxic PCA pre-treatments on the sensitivity of Swiss Webster mice to the psychomotor stimulating effects of PCA, 3,4-methylenedioxymethamphetamine (MDMA) and cocaine. PCA (15 mg/kg×2; i.p.) caused 37–70% depletion of dopaminergic and serotonergic markers in mouse brain. Saline and PCA (15 mg/kg×2) mice were challenged on days 5, 12, 40 and 74 with one of the following drugs: PCA (5 mg/kg), MDMA (10 mg/kg) and cocaine (20 mg/kg). The PCA pre-exposed mice showed marked locomotor sensitization from days 5–74 to all three drugs tested. The time course of the sensitized response coincided with the time course of the neurotoxic insult as determined by reduced densities of striatal dopamine transporter and frontal cortex serotonin transporter binding sites. A single injection of PCA (5 mg/kg) caused neither neurotoxicity nor sensitization to the locomotor stimulating effects of PCA, MDMA and cocaine. Repeated administration of a low non-neurotoxic dose of PCA (5 mg/kg/day; 6 days) caused a transient locomotor sensitization to PCA that dissipated after one month. Results of the present study suggest that PCA-induced serotonergic and dopaminergic neurotoxicity coincides with long-lasting locomotor sensitization to psychostimulants. These findings may be relevant to the psychopathology of amphetamines-induced neurotoxicity.

Characterization of p-chloroamphetamine-induced penile erection and ejaculation in anesthetized rats

Methodological shortcomings present in elicitation of male sexual reflexes in anesthetized animals. The present study has demonstrated, however, that intraperitoneal (i.p.) injection of p-chloroamphetamine (PCA), an indirect serotonin (5-HT) agonist, elicited simultaneously both penile erection and ejaculation in anesthetized rats. PCA (2.5–10.0 mg/kg, i.p.) caused an intermittent cluster of genital responses consisting of penile erection, glans erections, and penile cups, which closely resembles the response observed during the ex copula tests in unanesthetized rats. Measurements of intracavernous penile pressure showed that rhythmic changes in penile pressure were produced by PCA, together with glans erections and penile cups. PCA also caused a frequent ejaculations and the weighing of ejaculate accumulated over 0.5 hr was increased in a bell-shaped pattern, and the maximum effect was observed at 5.0 mg/kg. Pretreatment with p-chlorophenylalanine, a serotonin (5-HT) - synthesis inhibitor, significantly inhibited the expression of PCA-induced penile erection and ejaculation, while acute spinal transection at thoracic level did not affect the sexual responses. These results indicate that PCA-induced penile erection and ejaculation in anesthetized rats are mainly produced by the release of 5-HT, which is limited to the lower spinal cord and/or the peripheral sites. Furthermore, the sexual responses can be easily and reliably elicited by administration of PCA, which may be useful for the study of the mechanisms underlying male sexual functions.

Serotonin depletion and barrel cortex development: impact of growth impairment vs. serotonin effects on thalamocortical endings.

Converging evidence supports a role of serotonin (5-hydroxytryptamine; 5-HT) in barrel cortex development. Systemic administration of 5-HT-depleting drugs reduces cross-sectional whisker barrel areas in the somatosensory cortex (SSC) of neonatal rats. Here we assess the relative impact on barrel pattern formation of (i) 5-HT depletion and (ii) decreased brain growth, which is often associated with pharmacological 5-HT depletion, by comparing the effects of 5-HT-depleting drugs with those of reduced protein intake. Left hemisphere 5-HT levels in the SSC and right hemisphere whisker barrel areas were assessed at postnatal day 6 (P6) in the same animal following injection of p-chloroamphetamine (PCA) or p-chlorophenylalanine (PCPA) at P0. Both drugs significantly reduced cortical 5-HT content and mean barrel areas at P6, but also body and brain growth. Differences in brain weight accounted for 84.4% of the variance in barrel size, with negligible contributions by cortical 5-HT content. PCPA-treated animals sacrificed at P14 yielded similar trends, albeit less pronounced. Finally, reduced protein intake resulted in lower body weight and cortical 5-HT levels at P6, but yielded no change in brain weight or mean barrel area. Barrel formation therefore appears markedly less sensitive to 5-HT depletion per se than to drug-induced growth impairment.

Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain

The aim of the present study was to investigate whether changes in brain 5-HT concentrations affect the expression of BDNF mRNA in rat brain. Brain 5-HT concentration in the rat was elevated by combined treatment with tranylcypromine and l-tryptophan, tranylcypromine alone, by a single dose of the 5-HT releasing agent p-chloroamphetamine (PCA) or by the selective 5-HT reuptake inhibitor paroxetine. 5-HT was depleted by either multiple p-chlorophenylalanine ( pCPA) or PCA injections.The extent of 5-HT depletion following pCPA or PCA was monitored using 5-HT immunocytochemistry. BDNF mRNA abundance in treated rats and the corresponding vehicle injected control rats was studied by in situ hybridization histochemistry (ISHH). Two hours after the combined administration of tranylcypromine and l-tryptophan BDNF mRNA abundance in the dentate gyrus was significantly decreased but increased in the frontal cortex. Tranylcypromine alone or a single injection of PCA had similar effects on BDNF mRNA expression to the combination of tranylcypromine and l-tryptophan, i.e. they caused significant reductions of BDNF mRNA expression in dentate gyrus and increased it in frontal cortex. Paroxetine also reduced BDNF mRNA in DG but was without effect in frontal cortex. Multiple injections of both pCPA or PCA resulted in marked reductions of 5-HT immunoreactive axons in the hippocampus, pCPA being more effective. Both drugs significantly increased BDNF mRNA abundances in the dentate gyrus. Multiple PCA injections also increased BDNF mRNA expression in parietal cortex, while pCPA induced 5-HT depletion was ineffective. These results suggests that 5-HT modulates BDNF mRNA levels in rat brain.

Brain serotonin depletion attenuates diabetogenic effects of streptozotocin

The diabetogenic effects of streptozotocin (STZ) were studied on blood glucose, plasma insulin, feeding and drinking, body weight, islet morphology, and hypothalamic serotonin (5-HT) release in vehicle-pretreated rats and in rats pretreated with either intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT; a 5-HT nerve fiber depletor), intraperitoneal injection of p-chlorophenylalanine (PCPA; a tryptophan hydroxylase inhibitor), or intraperitoneal injection of p-chloroamphetamine (PCA; a neurotoxin for 5-HT nerve fiber). At four days after STZ administration, vehicle-treated rats displayed hyperglycemia, polydipsia, polyphagia, decreased plasma insulin level, derangement of islet morphology (few insulin cells, accumulation of glucagon cells), and elevated 5-HT release in the hypothalamus. The above diabetogenic effects of STZ were attenuated by brain serotonin depletion induced by 5,7-DHT, PCPA, or PCA. Furthermore, the STZ-induced hyperglycemia or derangement of islet morphology was attenuated by peripheral sympathectomy or adrenalectomy. It is concluded that brain serotonin depletion attenuates diabetogenic effects of STZ by reducing sympathetic efferent activity in rats.

5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine

1. The present study has investigated whether the neurotoxic effects of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxins, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'), p-chloroamphetamine (PCA) and fenfluramine on hippocampal and cortical 5-HT terminals in rat brain could be prevented by administration of either chlormethiazole or dizocilpine. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in an approximate 30% loss of cortical and hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content 4 days later. Injection of chlormethiazole (50 mg kg-1) 5 min before and 55 min after the MDMA provided complete protection in both regions, while dizocilpine (1 mg kg-1, i.p.) protected only the hippocampus. 3. Administration of a single dose of chlormethiazole (100 mg kg-1) 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex. This regime also attenuated the sustained hyperthermia (approx +2.5 degrees C) induced by the MDMA injection. 4. Injection of PCA (5 mg kg-1, i.p.) resulted in a 70% loss of 5-HT and 5-HIAA content in hippocampus and cortex 4 days later. Injection of chlormethiazole (100 mg kg-1, i.p.) or dizocilpine (1 mg kg-1, i.p.) 5 min before and 55 min after the PCA failed to protect against the neurotoxicity, nor was protection afforded by chlormethiazole when a lower dose of PCA (2.5 mg kg-1, i.p.) was given which produced only a 30% loss of 5-HT content. Chlormethiazole did prevent the hyperthermia induced by PCA (5 mg kg-1), while the lower dose of PCA (2.5 mg kg-1) did not produce a change in body temperature.5. Neither chlormethiazole nor dizocilpine prevented the neurotoxic loss of hippocampal or cortical 5-HT neurones measured 4 days following administration of fenfluramine (25 mg kg-1, i.p.).6. In general, chlormethiazole and dizocilpine were effective antagonists of the 5-HT-mediated behaviours of head weaving and forepaw treading which appeared following injection of all three neurotoxins.7. Both chlormethiazole and dizocilpine have previously been shown to prevent the neurotoxic effects ofa high dose of methamphetamine on cerebral 5-HT and dopamine pathways. These drugs also prevent MDMA-induced neurotoxicity of 5-HT pathways, but not that induced by injection of PCA or fenfluramine. This suggests that the mechanisms of neurotoxic damage to 5-HT pathways produced by substituted amphetamines cannot be identical. The monoamine loss does not appear to result from the hyperthermia produced by the neurotoxic compounds.

高齢雄ラットに対する<I>p</I>-Chloroamphetamine (PCA) 投与による誘起射精

In general, sexual activity in normal animals declines with increasing age. In aged male rats, for example, no ejaculation occurs when paired with receptive females. The ejaculatory response induced by p-chloroamphetamine (PCA) in aged adult rats, 14 to 18 months of age, was observed. The animals were treated intraperitoneally with PCA. The ejaculation rates were 0.28.6, 57.1 and 100% at doses of 0.3125, 0.625, 1.25 and 2.5 mg/kg, respectively. These animals, with a few exceptions, showed an ejaculation within 2 hrs of PCA injection. These data for aged adults are similar to those for young adults.

Phencyclidine-induced wet-dog shakes observed in rats after withdrawal from reserpine treatment

This study was designed to assess the involvement of serotonergic neurons in phenycyclidine (PCP)-induced wet-dog shakes in rats after termination of reserpine treatment. Administration of L-5-hydroxytryptophan (7.5–12.5 mg/kg) to rats 30 min following pretreatment with pargyline induced wet-dog shakes which included head shake and whole body shake. p-Chloroamphetamine (PCA) (5 mg/kg) alone also produced wet-dog shakes in the vehicle-pretreated rats, but PCP (2.5–7.5 mg/kg) and tryptophan (100 mg/kg) alone did not. The number of wet-dog shakes significantly increased after the injection of PCA (2.5 and 5 mg/kg) in the reserpine-pretreated rats, in which the 5-hydroxyindoleacetic acid/serotonin (5-HT) ratio was significantly higher and postsynaptic 5-HT receptors were also in a state of supersensitivity, compared to that of the vehicle-pretreated rats. PCP (2.5–7.5 mg/kg) also produced wet-dog shakes in a dose-dependent fashion in rats after pretreatment with reserpine. Furthermore, PCP-induced wet-dog shakes were potentiated by imipramine, a 5-HT-uptake blocker, and prevented by mianserin, a 5-HT receptor-blocker. Tryptophan (100 mg/kg) alone produced wet-dog shakes in the reserpine-pretreated rats and it was enhanced in combination with imipramine. These results may indicate that the PCP-induced wet-dog shakes after reserpine withdrawal are due to an increased release of 5-HT from the functional pool and supersensitivity of postsynaptic 5-HT receptors.

Serotonergic regulation of the release of renin is not mediated by the autonomic nervous system but involves beta adrenoceptors

p-Chloroamphetamine (PCA) which releases serotonin is known to increase the activity of plasma renin in conscious rats by stimulating serotonergic neurotransmission in the brain. The present studies were designed to investigate whether this effect is mediated from the serotonin receptors in the brain to the kidneys via the sympathetic nervous system. The effect of PCA on the activity of plasma renin was completely blocked by the beta receptor blockers sotalol and atenolol, but was not prevented by the sympathetic inhibitor, bretylium tosylate. In additional studies, chemical sympathectomy with 6-hydroxydopamine, combined with adrenal medullectomy did not prevent the effect of PCA on the activity of plasma renin even though the renal content of norepinephrine was reduced to undetectable levels. Furthermore, complete transection of the spinal cord between the first and second thoracic vertebrae did not prevent the effect of PCA on the activity of plasma renin, suggesting that the sympathetic nervous system and adrenal catecholamines do not mediate the effect of PCA. Studies by others have suggested that extrarenal beta receptors play an important role in the regulation of secretion of renin. The results of the present study support this possibility. The role of the parasympathetic nervous system in the rise in the activity of plasma renin induced by PCA was investigated by pretreatment of the rats with the peripheral muscarinic receptor blocker, methyl atropine. Methyl atropine caused a small increase in the activity of plasma renin but did not prevent the effect of PCA, suggesting that the parasympathetic nervous system does not mediate the effect of PCA on the secretion or renin. Finally, bilateral nephrectomy blocked the effect of PCA on the activity of plasma renin and reduced it to very low levels, indicating that the kidney is the source that releases renin into the circulation after an injection of PCA.

Lesions of the ascending serotonergic pathways and antinociceptive effects after systemic administration of p-chloroamphetamine in mice.

The present study reports a method for lesioning of the ascending serotonergic system. The neurotoxic substance p-chloroamphetamine (PCA) was given IP on 2 consecutive days (40 mg/kg/day). After each injection, the animals were kept at 4 degrees C for 4 hr since a lower dose of PCA (25 mg/kg) induced severe hyperthermia. The mortality rate was 12%, considerably lower than previously reported in similar studies. Evaluated 9 days after the last injection of PCA, the uptake of 14C-5-HT into cortical and hippocampal crude synaptosomal preparations was reduced by 50 and 60%, respectively, while the uptake into spinal synaptosomes was unaffected. The uptake of 3H-NA was not significantly altered in any of the structures. Measurements of PCA performed 30 min to 4 hr after IP injections of 5 to 40 mg/kg demonstrated higher concentrations in the cortex than in the lumbar spinal cord. Administration of PCA (5 mg/kg) had an acute antinociceptive effect in the hot-plate and formalin tests, but not in the tail-flick test. Prior treatment with neurotoxic doses of PCA prevented the antinociception but had in itself no effect on the responsiveness in any of the tests. Thus systemic administration of PCA produces highly selective and functional lesions of the ascending serotonergic pathways in mice.

Fluoxetine enantiomers as antagonists of p-chloroamphetamine effects in rats

The dextrorotatory enantiomer of fluoxetine was slightly more potent than the levorotatory enantiomer in antagonizing the depletion of brain serotonin by p--chloroamphetamine in rats. The time course of the depletion of brain serotonin at times out to 24 hr after the injection of p-chloroamphetamine was determined with or without simultaneous administration of one of the fluoxetine enantiomers. The dextrorotatory enantiomer prevented the depletion of brain serotonin at any time after p-chloroamphetamine. The levorotatory enantiomer prevented the initial depletion of brain serotonin at 2 and 4 hr, but by 8 hr brain serotonin concentration was decreased and by 24 hr the depletion of serotonin was almost as great as in rats treated with p-chloroamphetamine alone. The elevation of serum corticosterone that occurres acutely after injection of a low dose of p-chloroamphetamine was significantly antagonized by both enantiomers of fluoxetine, the dextrorotatory enantiomer being slightly more potent. In contrast, the lowering of DOPAC (3,4-dihydroxyphenylacetic acid) concentration in rat brain by p-chloroamphetamine was not antagonized by either enantiomer of fluoxetine, indicating this effect is not secondary to serotonin release by p-chloroamphetamine. The results are consistent with other evidence that both enantiomers of fluoxetine are potent inhibitors of serotonin uptake, the dextrorotatory enantiomer being longer-acting than the levorotatory enantiomer in rats.

P-Chloroamphetamine: Effect on sleep and respiration in the rat

Rats, fitted with chronic EEG and EMG electrodes and a thoracic pneumograph, were monitored electrophysiologically for three successive days before and after an IP injection of p-chloroamphetamine (PCA) (2 mg/kg). During the 12 hours post PCA treatment, sleep onset was delayed, the percentage of Rapid Eye Movement (REM) sleep was decreased and the breathing rate during both the Non-REM (NREM) and REM sleep states was reduced. By 24 and 48 hours after the PCA injection, the sleep pattern and NREM respiratory rate had returned to control values; however, respiratory rate during REM sleep still tended to be decreased. The results suggest that PCA, at this dose, is capable of inducing insomnia and reducing REM sleep acutely without chronically altering the sleep pattern. The data also suggest that respiratory rate during sleep may decrease following PCA treatment.

PCA: Effects on ejaculation, thermoregulation, salivation, and irritability in rats

The short term monoamine releaser p-chloroamphetamine (PCA) was injected intraperitoneally in male rats housed at 20°C. Within 2 hr of PCA injections (2.5, 5.0, 8.0 or 10.0 mg/kg), rats showed ejaculation, decreased colonic temperature, increased salivation, and increased irritability. Ejaculation and salivation scores were considerably lower in the 2.5 mg/kg than in the higher dose groups, but otherwise were not dose dependent at the doses used. Hypothermia was of similar magnitude in all groups, but lasted longer in the higher dose groups. Irritability increased with dose size. In order to study the role of ambient temperature in PCA-induced behavioral changes, observations were made on an additional group or rats housed at the higher ambient temperature of 25°C. In these rats an increase, rather than a decrease, in mean colonic temperature was observed following PCA injection (5 mg/kg). Ejaculation and irritability scores were similar to those observed at the lower ambient temperature, but salivation was enhanced. It is suggested that PCA induces ejaculation, salivation, irritability and, depending on the ambient temperature, either hypothermia or hyperthermia.

A frequency analysis of behavior components of the serotonin syndrome produced by p-chloroamphetamine

A time-sampling frequency analysis was made of criterion behaviors following injection of 2.5–10 mg/kg dosages of p-chloroamphetamine (PCA). Stereotypic behaviors (forepaw treading, circling, head weaving and inching) increased with increasing dosages and normal behaviors (grooming, rearing, and instances of inactivity) decreased. Composite scores of stereotypic behavior were a positive, linear function of PCA dosage. Composite scores of normal behavior showed near maximal inhibition at 5 mg/kg. Splayed hindlimbs is a reliable and sensitive indicator of PCA action, but vocalization, tremors, diarrhea and autonomic signs are not. Preinjection of PCA strongly attenuated the PCA-induced syndrome, as expected, since the preinjection should deplete brain serotonin and reduce the amount released by the second PCA injection.

Importance of duration of drug action in the antagonism of p-chloroamphetamine depletion of brain serotonin—comparison of fluoxetine and chlorimipramine

Fluoxetine inhibited both the rapid depletion of brain serotonin by p-chloroamphetamine (PCA) and the ultimate irreversible effects of PCA on brain serotonin neurons in rats; the differences between fluoxetine and chlorimipramine as PCA antagonists appeared to be related to the duration of uptake inhibition by these agents. Fluoxetine given along with PCA in a single dose prevented serotonin depletion at all times after PCA. Chlorimipramine antagonized serotonin depletion initially, but at later times there was little or no protection against PCA effects. The dose-dependence of the antagonism of PCA by fluoxetine did not vary greatly with the time of serotonin measurement after PCA. but with chlorimipramine the effectiveness of a given dose depended markedly on that time interval. Lengthening the pretreatment interval prior to PCA injection from 0 to 16 hr diminished the effectiveness of chlorimipramine but not fluoxetine as antagonists of serotonin depletion. The differences between fluoxetine and chlorimipramine may arise primarily because these compounds are metabolized by N-demethylation. The demethylated metabolite of fluoxetine was as potent and specific as fluoxetine itself as a serotonin uptake inhibitor both in vitro and in vivo, whereas the demethylated metabolite of chlorimipramine was less active than chlorimipramine as a serotonin uptake inhibitor and more active as a norepinephrine uptake inhibitor. Chlorimipramine was a more effective PCA antagonist when injected into mice in repeated doses or when injected into rats along with an inhibitor of liver microsomal enzymes. Thus, comparison of uptake inhibitors as antagonists of PCA is strongly influenced by the pharmacokinetics of the drugs involved.