Behavioural effects of selective tachykinin agonists in midbrain dopamine regions.

The effects of selective NK-1, NK-2 and NK-3 tachykinin agonists in midbrain dopamine cell containing regions were investigated in the rat. The NK-3 agonist senktide induced locomotion, rearing and sniffing following infusion into the substantia nigra pars compacta, and to a lesser extent in the ventral tegmental area. These behavioural responses were not seen following infusion of the selective NK-1 agonist [Sar9,Met (O2)11]SP or the NK-2 agonist [N1e10]NKA4-10. In contrast, grooming was induced only by the NK-1 agonist administered into the substantia nigra. Yawning, chewing mouth movements and wet dog shakes were all seen following infusion of senktide into the ventral tegmental area. These findings suggest that (i) dopamine-mediated behavioural responses seen following tachykinin administration into the midbrain are dependent upon stimulation of NK-3 tachykinin receptors, (ii) tachykinin-induced grooming is mediated by stimulation of NK-1 receptors and (iii) some of the previously described 5-HT mediated behaviours seen following administration of NK-3 tachykinin agonists are probably generated by stimulation of 5-HT cell bodies in the ventral tegmental area.     

Autoradiographic visualization of NK-3 tachykinin binding sites in the rat brain, utilizing [3H]senktide.

The autoradiographic distribution of the selective NK-3 tachykinin agonist [3H]senktide was investigated in rat brain. [3H]Senktide bound with high affinity (KD less than 2.5 nM) and high specificity (greater than 75%) to cerebral cortex and numerous subcortical sites, including the substantia nigra pars compacta. In addition, moderately dense binding was seen in the median but not the dorsal raphe nucleus, and this was disrupted by 5,7-dihydroxytryptamine (5,7-DHT)-induced destruction of 5-HT neurons. 5,7-DHT lesions did not affect the binding of [3H]senktide to forebrain regions, suggesting that 5-HT terminals are devoid of NK-3 receptors.     

Interactions between relatively selective monoamine oxidase inhibitors and an inhibitor of 5-hydroxytryptamine re-uptake, clomipramine

Features of interactions with combined antidepressants in man were evoked by clomipramine in rats pretreated with both the relatively selective monoamine oxidase (MAO) inhibitors clorgyline and deprenyl, but not when clomipramine was given to rats pretreated with deprenyl or clorgyline alone, i.e. inhibition of both MAO A and B was a likely prerequisite for clomipramine to elicit the syndrome (with the larger dose of clorgyline and deprenyl, MAO A and B inhibition exceeded 95%). The features evoked were myoclonic—forelimb flexor-extensor movements, wet dog shakes and head and body twitches; hyperthermia and ECG anomalies also developed, and locomotor activity was augmented. Myoclonic phenomena were prevented when the above pretreatment also included p-chlorophenyl-alanine, but were unaffected or even intensified when pretreatment instead included -methyl-p-tyrosine; these phenomena were attenuated or abolished by pirenperone, a 5HT₂ antagonist. Relevance of these findings to safer combinations of antidepressants is discussed.     

Interactions of non-selective monoamine oxidase inhibitors, tranylcypromine and nialamide, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake

Rats pretreated with tranylcypromine and given clomipramine, developed head and body twitches, forelimb flexor-extensor movements and wet dog shakes, phenomena which failed to develop when pretreatment incorporated p-chlorophenylalanine (PCPA) but were unabated when this included alpha-methyl-p-tyrosine (AMPT). Locomotor activity, itself enhanced by tranylcypromine, was further and significantly elevated compared to saline, by clomipramine or imipramine in grouped rats (n = 3) but not in single or paired rats; desipramine lacked such action. This effect of clomipramine was prevented when PCPA was incorporated into the pretreatment and that of imipramine by including PCPA or AMPT. Brain monoamine oxidase (MAO) A inhibition was 92% and that of MAO B, 80%. Cortical hydroxytryptamine (5-HT) and noradrenaline concentrations as well as hypothalamic 5-HT, were significantly elevated by tranylcypromine, as was dopamine in the striatum, nucleus accumbens and tuberculum olfactorium. Hyperthermia developed in tranylcypromine pretreated rats given paroxetine or fluoxetine. Myoclonic phenomena were elicited by paroxetine, fluoxetine, clomipramine or imipramine in nialamide pretreated rats but these were less intense than in rats pretreated with phenelzine or tranylcypromine. Fatalities were fewer than in rats pretreated with tranylcypromine or phenelzine. Brain MAO A inhibition was 92% and that of MAO B, 69%.     

Involvement of 5-HT2 receptors in the LSD- and L-5-HTP-induced suppression of lordotic behavior in the female rat

Summary Copulatory behavior in the ovariectomized rat, the lordotic response (L. R.), was induced by estrogen followed by progesterone. L. R. is inhibited by lysergic acid diethylamide (LSD) (0.05 mg/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (2.5 mg/kg). The effects of the putative 5-HT antagonists lisuride, metergoline, methysergide, mianserin, cinanserin, cyproheptadine, pirenperone and altanserin on the LSD-induced inhibition of L. R. were tested. Lisuride, metergoline, methysergide and mianserin were found to have no LSD-blocking effect. In contrast, cinanserin, cyproheptadine and pirenperone acted antagonistically to LSD, within a critical dose range. The selective 5-hydroxytryptamine₂ (5-HT₂) receptor antagonist altanserin effectively prevented the LSD-induced inhibition of L. R., and the doses required (0.05–0.20 mg/kg) indicated a comparatively high antagonistic potency. In addition altanserin (0.2 mg/kg) effectively prevented the lordosis inhibitory effect induced by L-5-HTP (2.5 mg/kg), after pretreatment with pargyline and RO4-4602. It is suggested that the suppression of copulatory behavior caused by LSD and L-5-HTP is mediated by 5-HT₂ receptors.     

Melatonin protects against the effects of chronic stress on sexual behaviour in male rats.

The effects of chronic mild stress (CMS) on both sexual behaviour and wet dog shakes (WDS), a serotonergic type 2A (5-HT2A) receptor-mediated behaviour, were explored in the male rat. In addition, the possible attenuation of these effects by chronic treatment with melatonin, a putative 5-HT2A antagonist, was examined. The CMS procedure resulted in a significant increase in WDS and an overall decrease in all aspects of sexual behaviour. Concurrent melatonin administration attenuated the CMS-induced effects on sexual behaviour, but not the effects on either spontaneous WDS or WDS in response to the 5-HT2A agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, suggesting a mechanism of action other than exclusive 5-HT2A antagonism. These results are the first to demonstrate that melatonin significantly protects against the detrimental effects of a chronic stressor on sexual behaviour.     

Intra-raphe neurokinin-induced hyperactivity: effects of 5,7-dihydroxytryptamine lesions

Rats were implanted with cannulae in the median raphe nucleus (MR). 5,7-Dihydroxytryptamine (5,7-DHT) or vehicle was infused either directly through the MR cannula, or bilaterally into the medial forebrain bundle (MFB). The MR 5,7-DHT lesions completely blocked the hyperactivity elicited by injections into the MR of the neurokinin (NK) 3 agonists, DiMe-C7 and senktide, and the NK-2 agonist, neurokinin A. In contrast, the MFB 5,7-DHT lesions did not affect the locomotor hyperactivity produced by intra-MR administration of DiMe-C7 and senktide, but appeared to attenuate the effects of NKA. The data indicate that intra-raphe neurokinin-induced hyperactivity is mediated by 5-HT neurons, and that 5-HT projections to the forebrain may be involved in the behavioral activation induced by intra-raphe neurokinin A administration, but not that induced by intra-MR NK-3 agonists.     

Enhancement of some 5-HT-dependent behavioural responses following repeated immobilization in rats

Responses to drugs affecting 5-hydroxytryptamine (5-HT) and dopaminergic (DA) systems have been examined in rats after repeated immobilization. Groups of rats were immobilized for 2 h per day for up to 7 days. Twenty-four hours later their behavioural responses to various drugs were tested. Rats immobilized for 7 days showed decreased sniffing and increased grooming and body shakes. When given amphetamine (3 mg/kg, i.p.) the intensity of classical dopamine-dependent behaviours was similar to that of non-immobilized controls. Some responses to the 5-HT releaser p-chloroamphetamine (PCA) (4 and 10 mg/kg, i.p.) and the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MEODMT) (5 mg/kg, i.p.) (forepaw treading and tremor) were enhanced after 7 days immobilization. Backward walking and body shakes induced by PCA were also enhanced after 7 days immobilization. Concentrations of 5-HT, DA and their metabolites in striatum, cortex, hippocampus, hypothalamus and midbrain of non-drug-treated control and immobilized groups were comparable. Brain PCA concentrations 30 min after injection were also comparable. The above biochemical and behavioural data suggest that repeated immobilization increases some 5-HT postsynaptic functions. These results are discussed in relation to non-drug-provoked behavioural abnormalities occurring 24 h after the first immobilization but no longer evident after 7 periods of immobilization.     

Effect of the repeated administration of (+/-)-3,4-methylenedioxymethamphetamine on the behavioral response of rats to the 5-HT1A receptor agonist (+/-)-8-hydroxy-(di-n-propylamino)tetralin

In this study, we examined the effect of the subcutaneous administration (twice daily for 4 consecutive days) of 3,4-methylenedioxymethamphetamine (MDMA, 20 mg/kg) or saline (1 ml/kg) on the response of rats to the behavioral effects of the 5-HT1A agonist (+/-)-8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) 30 days after the last saline or MDMA treatment. The reciprocal forepaw treading elicited by the 0.25-mg/kg dose of 8-OH-DPAT was significantly lower in animals pretreated with MDMA compared to vehicle-treated animals. However, there were no significant differences between the MDMA- and vehicle-treated animals in flat body posture, locomotor activity and rectal temperature measured after the systemic administration of 8-OH-DPAT. Overall, our results suggest that the depletion of 5-HT levels by the repeated administration of MDMA does not produce a supersensitivity of central 5-HT1A receptors in the rat as determined via our approach.     

Identification of mechanisms for duodenal contraction induced by tachykinins in the rat

Mechanisms for contractile effects of tachykinins on muscle strips of rat duodenum were studied using substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and neuropeptide K (NPK), and the tachykinin analogues SP methyl ester (SPME), Nle¹⁰-NKA(4–10) (NleNKA) and senktide (SENK) selective for neurokinin (NK)-1, NK-2 and NK-3 receptors, respectively. NK receptors responsible for smooth muscle contraction were identified using selective ligands to protect NK receptors combined with inactivation of residual receptors with N-ethylmaleimide. Tachykinins (10^?9 to 10^?5 M) caused dose-related contractions of the muscle strips. The order of potency of native tachykinins was NKA > NKB > SP > NPK in circular, and NKB > NKA > NPK > SP in longitudinal muscle, whereas that of selective tachykinin analogues was SENK > NleNKA > SPME. NKA, NleNKA and SENK were equieffective as acetylcholine, whereas SP, SPME, NKB and NPK were less effective. Spantide decreased the sensitivity to all tachykinin analogues. Atropine reduced the sensitivity to SENK only, whereas hexamethonium reduced the sensitivity to SENK and SPME, but not to NleNKA. Selective receptor protection with SPME, NleNKA or SENK protected contractions induced by SPME, NleNKA and SENK, respectively. Responses to tachykinin analogues were reduced in Ca²⁺-free medium. Thus, NKA is suggested to be the dominating tachykinin to stimulate contraction of the rat duodenum via NK receptors coupled to Ca²⁺-dependent signal transduction pathways. Of the receptors available, the NK-1 subtype involves a nicotinic transmission step, and the NK-3 subtype also a muscarinic step, whereas the NK-2 receptor subtype is not dependent on cholinergic mechanisms.     

Role of central tachykinin peptides in cardiovascular regulation in rats.

The mechanisms of action of tachykinin peptides thought to be involved in central cardiovascular regulation were examined. Intracerebroventricular injections (i.c.v.) of tachykinin peptides caused dose-dependent increases in blood pressure and heart rate. The pressor responses to substance P (SP) (10 micrograms, i.c.v.) and neurokinin A (NKA) (10 micrograms, i.c.v.) were blocked by peripheral administration of pentolinium or phentolamine, and partially attenuated by adrenalectomy. In contrast, the only initial pressor response to the neurokinin B (NKB) analogue senktide (10 micrograms, i.c.v.) was blocked by pentolinium or phentolamine. The pressor response to senktide was inhibited by pretreatment with a vasopressin V1 receptor antagonist (d(CH2)5OMe(Tyr)AVP) (10 micrograms/kg, i.v.), and senktide (10 micrograms, i.c.v.) caused an increase in plasma vasopressin level. However, the vasopressin antagonist did not influence the SP- and NKA-induced pressor responses. These results suggest that central SP and NKA increase the blood pressure and heart rate via sympathetic nerve activity, whereas central NKB increases the blood pressure mainly via release of vasopressin from the hypothalamus.     

Turning behaviour induced by stimulation of the 5-HT receptors in the subthalamic nucleus

The basal ganglia, which receive a rich serotonergic innervation, have been implicated in hyperkinetic and hypokinetic disorders. Moreover, a decrease in subthalamic nucleus (STN) activity has been associated with motor hyperactivity. To address the role of subthalamic serotonergic innervation in its motor function, turning behaviour was studied in rats with stimulation of the subthalamic serotonin (5-HT) receptors by intracerebral microinjections. The intrasubthalamic administration of 5-HT induced dose-dependent contralateral turning behaviour, with a maximal effect at a dose of 2.5 microg in 0.2 microL. Similar results were observed with microinjections of other 5-HT receptor agonists: quipazine (a 5-HT2B/C/3 agonist), MK-212 (a 5-HT2B/C agonist) and m-chlorophenylbiguanidine (a 5-HT3 agonist), while microinjections of 5-HT into the zona incerta or in the previously lesioned STN were ineffective. The effect of 5-HT was blocked by coadministration of the antagonist mianserin. Stimulation of subthalamic 5-HT receptors in animals bearing a lesion of the nigrostriatal pathway did not modify the motor response, which indicates that the dopamine innervation of the nucleus is not involved in this effect. Kainic acid lesion of the substantia nigra pars reticulata (SNr) suppressed the contralateral rotations elicited by stimulation of 5-HT2B/C/3 subthalamic receptors. This suggests a role of the subthalamic-nigral pathway in the turning activity. Furthermore, the partial blockade of glutamatergic receptors in the SNr by the antagonist DNQX increased the contralateral circling elicited by stimulation of 5-HT receptors in the STN. We concluded that the activation of the 5-HT2B/C and 5-HT3 subthalamic receptors elicited contralateral turning behaviour, probably via the subthalamic-nigral pathway.     

Behavioural and biochemical responses following activation of midbrain dopamine pathways by receptor selective neurokinin agonists.

Preferential activation of mesolimbic and nigro-striatal dopamine (DA) pathways by receptor-selective and peptidase-resistant neurokinin (NK) agonists is reported. The DA cell body region of the mesolimbic pathway appears to be activated by NK agonists selective for NK-1 and NK-3 receptors whereas the DA cell bodies in the substantia nigra are under an excitatory NK-2 receptor-mediated influence. Stimulation of the mesolimbic DA pathway by NK-1 (Ava[L-Pro9,N-Me-Leu10]SP (7-11) [GR73632]) or NK-3 (Senktide) agonists increase locomotor activity. Additional studies showed that this elevated motor response observed after intra-VTA infusion of GR73632 was accompanied by a corresponding increase in DA turnover in the terminal fields of this pathway. Similarly, unilateral activation of the nigro-striatal DA pathway by NK-2 selective agonists (Ava (D-Pro9) SP (7-11) [GR51667] or [Lys3,Gly8,R-Lac-Leu9]NKA (3-10) [GR64349]) elicit contralateral rotational activity and an increase in DA turnover in the ipsilateral striatum. The rotational response was attenuated by prior administration of an NK-2 antagonist (cyclo (Gln, Trp, Phe, Gly, Leu, Met)] L-659877]) into the nigra. Peripheral injection of haloperidol, a DA antagonist, also blocked the NK-2 agonist induced rotations.     

Pharmacological characterization of grooming induced by a selective NK-1 tachykinin receptor agonist

Bilateral intranigral administration of the selective NK-1 tachykinin receptor agonist [AcArg⁶, Sar⁹, Met(O₂)¹¹]SP_6–11 (0–11 nmol total bilateral dose) selectively induced grooming in rats. This response was blocked by concurrent intranigral administration of the NK-1 tachykinin receptor antagonist RP 67580 (2 nmol), but not by NK-2 (L-659, 877) or NK-3 ([Trp⁷, β-Ala⁸]NKA_4–10) antagonists. Pretreatment with systemic opioid (naloxone 1.5 mg/kg) and D₁ dopamine (SCH 23390 100 μg/kg) receptor antagonists also attenuated tachykinin-induced grooming, which was unaffected by D₂ dopamine (sulpiride 30 mg/kg) or 5-HT_2A+C (ritanserin 2 mg/kg) antagonists. Grooming induced by intranigral [AcArg⁶, Sar⁹, Met(O₂)¹¹]SP_6–11 was also attenuated by bilateral 6-hydroxydopamine lesions of te substantia nigra. These findings indicate that grooming induced by intranigral tachykinins reflects activation of NK-1 receptors and is dependent upon endogenous dopamine and consequent selective stimulation of D₁ dopamine receptors.     

Intraventricular injections of tachykinin NK3 receptor agonists suppress the intake of "salty" tastes by sodium deficient rats

Intraventricular injections of the tachykinin NK3 receptor (NK3-R) agonist, senktide, suppress the ingestion of hypertonic (0.5 M) NaCl by decreasing the initial lick rate and accelerating the decay in lick rate in sodium deficient rats. The present experiment examined whether the effects of intraventricular injections of senktide on lick rate were selective for NaCl solution, or if the ability of NK3-R agonists to inhibit intake generalizes other sodium-containing solutions. The effects of lateral ventricular injections of isotonic saline or senktide (200 ng) on intake and lick rate of 0.5 M solutions of sodium chloride (NaCl), sodium acetate (Na acetate), sodium bicarbonate (Na bicarbonate), and monosodium glutamate (MSG) were measured in sodium deficient rats. Compared to saline injection, senktide injection had no effect on the lick rate or intake of Na bicarbonate. In contrast, intraventricular injection of senktide suppressed the intake of NaCl, Na acetate, and MSG compared to saline injection. Senktide injection accelerated the decay in lick rate for NaCl, Na acetate and MSG, but only suppressed the initial lick rate for NaCl and Na acetate. The results show that activation of NK3-R in sodium deficient rats suppresses the intake of tastes that are classified as "salty" tasting and that the decrease in intake reflects effects on the initial lick rate, the decay in lick rate, or both.     

Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes

Fenfluramine releases serotonin (5-HT) via the 5-HT transporter (SERT). Previous work has shown that amphetamine increases particulate protein kinase C (PKC) activity in striatal synaptoneurosomes. The increased PKC activity is linked to the outward transport of dopamine, and when release is diminished, the inward transport of amphetamine inhibits PKC instead. Since there is homology among monoamine transporters, this study was undertaken to determine if D-fenfluramine has similar effects on PKC. The role of 5-HT receptors and endogenous 5-HT were also examined. Naive rats and rats pretreated with p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, were sacrificed. Cortical synaptoneurosomes were prepared and incubated with fenfluramine. PKC activity was determined by thiophosphorylation of endogenous substrates. It was found that 5-HT, D/L-fenfluramine, and D-fenfluramine increased PKC activity in a time- and dose-dependent manner. The 5-HT-mediated increase in PKC activity was attenuated by pretreatment with the 5-HT(2) antagonist ketanserin, but not with the SERT inhibitor fluoxetine. The D-fenfluramine-induced increase in PKC activity was completely prevented, however, by pretreatment with SERT inhibitors and partially with ketanserin. It was also attenuated by pretreatment with PCPA, resulting in a dose-dependent inhibition of PKC instead. Thus, when 5-HT release was diminished the uptake of D-fenfluramine inhibited PKC. Similar effects have been observed with amphetamine. Unlike D-fenfluramine, the D/L-fenfluramine-induced increase in PKC activity was partially resistant to PCPA pretreatment but was attenuated with bupropion, a dopamine transporter (DAT) inhibitor. SERT inhibitors (sertraline, paroxetine, citalopram, and fluoxetine) also increased PKC activity. Nefazodone and bupropion increased PKC activity, but mirtazapine was relatively inactive. The SERT inhibitor-induced increase in PKC was unaffected by pretreatment with PCPA but was inhibited by calcium. Similar effects on PKC activity have been observed with DAT inhibitors. These results, showing that D-fenfluramine altered PKC activity similar to D-amphetamine, suggest that the topographic homology between DAT and SERT may extend to their effects on PKC activity.     

Serotonin agonists increase transferrin levels via activation of 5-HT1C receptors in choroid plexus epithelium.

Choroid plexus epithelial cells are enriched in mRNA for proteins such as the iron carrier transferrin, which acts as a trophic factor in the brain. Choroid plexus epithelial cells also have a high density of 5-HT1C receptors linked to activation of the phosphoinositide (PI) hydrolysis second messenger system. The present studies show that the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potently increases PI hydrolysis and the levels of transferrin in primary cultures of rat choroid plexus epithelial cells. These effects are blocked by the 5-HT1C/5-HT2 receptor antagonists mesulergine and mianserin, but not by the 5-HT2 receptor-selective antagonist spiperone. Similarly, mesulergine and mianserin, but not spiperone, block the increases in transferrin levels and PI hydrolysis elicited by 5-carboxamidotryptamine (5-CT), a 5-HT1 receptor-selective agonist, and by serotonin. We conclude, therefore, that 5-HT1C receptor activation in the choroid plexus leads to an increase in the production of transferrin. By promoting transferrin synthesis in the choroid plexus, 5-HT may indirectly influence brain development and differentiation.     

Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI).

1. There has been considerable research in the field of schizophrenia over the past few years with emphasis on the discovery of better drugs, particularly those with 5-HT2 antagonist activity. 2. In an effort to enhance identification of such compounds and to further understand the contribution of 5-HT2 activity to the effects of antipsychotic drugs, a series of conventional, atypical and purported antipsychotic compounds were assessed as antagonists of DOI-induced behaviors in rats. 3. DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) is an hallucinogen having high affinity and selectivity as an agonist at 5-HT2A/2C receptors. Over a 30-min period after injection, DOI (0.3-10.0 mg/kg; i.p.) produced dose-related behavioral effects including head-and-body shakes, forepaw tapping and skin-jerks. Effects of the antipsychotic drugs and other compounds (30 min pretreatment; i.p.) were examined against a fixed dose of DOI (3.0 mg/kg). 4. In a dose-dependent manner, M100907 (MDL 100,907), risperidone, haloperidol, clozapine, iloperidone, olanzapine, amperozide, remoxipride, ritanserin and the neurotensin agonist NT1 (N alpha MeArg-Lys-Pro-Trp-Tle-Leu) antagonized each of the three behavioral effects of DOI. Drugs attenuating the head-and-body shakes were equally effective in blocking both forepaw tapping and skin-jerks indicating that these behaviors are mediated by similar mechanisms. The following compounds had either inconsistent or no effect on the DOI-induced behaviors: SB 200646A, citalopram, imipramine, fluoxetine, morphine, CP 99994, diazepam, ondansetron and SKF 97541. 5. The data show that antipsychotic agents, as a drug class, effectively block the effects of DOI. These actions are selective, as a series of nine non-antipsychotic and centrally-acting drugs were generally inactive in the procedure.     

5-HT depletion with 5,7-DHT, PCA and PCPA in mice: differential effects on the sensitivity to 5-MeODMT, 8-OH-DPAT and 5-HTP as measured by two nociceptive tests

Depletion of 5-hydroxytryptamine (5-HT) in mice was produced by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT, 80 micrograms) or by systemic injections of p-chloroamphetamine (PCA, 3 X 40 or 4 X 40 mg/kg), p-chlorophenylalanine (PCPA, 5 X 400 or 14 X 400 mg/kg) or combined PCA (3 X 40 mg/kg) + PCPA (11 X 400 mg/kg). Neither of the pretreatments altered nociception in the increasing temperature hot-plate test, whereas hyperalgesia was demonstrated in 5,7-DHT lesioned animals in the tail-flick test. 5,7-DHT-pretreatment enhanced the antinociceptive effect of the 5-HT agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-hydroxytryptophan (5-HTP). This effect was observed after 2, 5 and 8 days in the tail-flick test and after 5 and 8 days in the hot-plate test. However, pretreatment with PCPA or PCA failed to alter the antinociception elicited by the 5-HT agonists, although a tendency towards enhancement of antinociception was found after combined treatment with PCA and PCPA. It is suggested that the injection of 5,7-DHT induces denervation supersensitivity of post-synaptic 5-HT receptors. The lack of such supersensitivity after PCPA-pretreatment which induces similar 5-HT depletion to 5,7-DHT, may suggest that other factors than the absence of 5-HT may contribute to the development of denervation supersensitivity. Alternatively, the three 5-HT depleting agents may produce a qualitatively different reduction of 5-HT.     

Interactions of a non-selective monoamine oxidase inhibitor, phenelzine, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake

Interactions of combined antidepressants which occur in man were reproduced in rats pretreated with phenelzine, features elicited including myoclonic phenomena, an augmented lower limb flexor reflex, muscle fasiculation and fatalities, particularly with combinations incorporating 5-hydroxytryptamine (5-HT) re-uptake inhibitors. Combinations of antidepressants included phenelzine with 5-HT re-uptake inhibitors (paroxetine, fluoxetine, clomipramine); with "mixed" re-uptake inhibitors affecting 5-HT and noradrenaline (imipramine, amitriptyline); with noradrenaline re-uptake inhibitors (desipramine, maprotiline, nisoxetine) and with dopamine re-uptake inhibitors (benztropine, nomifensine). Myoclonic phenomena such as forelimb flexor-extensor movements, head and body twitches, occurred in phenelzine pretreated rats after paroxetine, fluoxetine, clomipramine, imipramine, amitriptyline and desipramine. Wet dog shakes, the most intense phenomenon, were obtained only after paroxetine, fluoxetine, clomipramine and imipramine. Myoclonic features were prevented when pretreatment included p-chlorophenylalanine but were unaffected when this incorporated alpha-methyl-p-tyyrosine; there were attenuated by methysergide, cyproheptadine, clozapine or pimozide. The myoclonic phenomena were reproduced by combination of 5-hydroxytryptophan but not L-3,4-dihydroxyphenylalanine with clomipramine. Electrocortical changes observed included 2-4 Hz, 5-8 Hz, large amplitude potentials unrelated to the myoclonic incidents and unaffected by sensory stimulation. Following phenelzine, brain monoamine oxidase (MAO) A inhibition was 99% and that of MAO B, 88%; 5-HT concentration was significantly elevated in the cortex and hypothalamus, as was hypothalamic noradrenaline. Peak and basal tensions of a lower-limb flexor reflex were elevated in phenelzine pretreated spinal rats by fluoxetine, paroxetine, clomipramine and imipramine, effects attenuated by cyproheptadine. Forelimb flexor-extensor movements and body twitches were elicited by fluoxetine and paroxetine in phenelzine pretreated spinal rats in the presence of electrical stimulation of the central stump of a divided posterior tibial nerve. Pressor responses were observed in phenelzine pretreated spinal rats given 5-HT re-uptake inhibitors, "mixed" re-uptake inhibitors and those affecting noradrenaline re-uptake; ECG anomalies occurred in such rats given clomipramine.