The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-tryptophan or tranylcypromine and L-DOPA to rats.

1 The putative 5-hydroxytryptamine (5-HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L-tryptophan (100 mg/kg). Hyperactivity and hyper-reactivity were potentiated with a resultant increase in automated locomotor activity counts. In contrast (-)-propranolol (20 mg/kg) inhibited all features of the syndrome. The same results were obtained with these drugs when the behaviour was elicited by p-chloroamphetamine (10 mg/kg) or by tranylcypromine and tryptamine (10 mg/kg). 2 Methysergide and methergoline had similar effects on the syndrome produced by tranylcypromine and L-DOPA (50 mg/kg) whereas propranolol was without effect. 3 None of the putative 5-HT receptor antagonists affected brain 5-HT turnover as assessed by rate of accumulation of 5-HT following monoamine oxidase inhibition with tranylcypromine. 4 Microinjections of 5,7-dihydroxytryptamine into the spinal cord resulted in a 70% fall in cord 5-HT concentrations without an effect on brain 5-HT concentrations. The behavioural response to the putative 5-HT receptor agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg), was potentiated in these animals suggesting that 5-HT receptors become supersensitive on denervation, and that some components of the behavioural syndrome are mediated by spinal cord 5-HT receptors. 5 Pretreatment with alpha-methyl p-tyrosine (2 X 200 mg/kg) delayed the onset of all components of the behaviour elicited by tranylcypromine/L-tryptophan by 60 min, indicating an involvement of catecholamines in the syndrome. 6 p-Chloroamphetamine-induced 5-HT depletion had no effect on any component of the tranylcypromine-L-DOPA behaviour.     

Evidence for involvement of 5-hydroxytryptamine in the actions of amphetamine

1 Pargyline treatment, 1 h before (+)-amphetamine (1 mg/kg), reduced amphetamine-stimulated motor activity. This inhibition was reversed in animals pretreated with p-chlorophenylalanine (PCPA).2 Following treatment with PCPA or 5,6-dihydroxytryptamine (5,6-DHT), amphetamine-induced locomotor activity was significantly potentiated. The increased response to amphetamine in PCPA-treated rats was reversed in animals pretreated with 5-hydroxytryptophan.3 The inhibition of amphetamine-stimulated locomotor activity by treatment with 6-hydroxydopamine was not reversed by PCPA treatment.4 Stereotypies produced by amphetamine were not found to be altered by depletion of 5-hydroxytryptamine.5 Induction of adrenal tyrosine hydroxylase activity produced by chronic amphetamine administration was significantly potentiated by PCPA, emphasizing the involvement of a 5-hydroxytryptamine inhibitory system in more than one action of amphetamine.     

5-Hydroxytryptamine involvement in the locomotor activity suppressant effects of amphetamine in the mouse

d-Amphetamine, in doses lower than required to increase motor activity, reduced mouse spontaneous locomotor activity when this was assessed using cages equipped with photocell units, using treadwheels, or the measurement of spontaneous climbing behaviour. Actue treatments with the serotonergic agonists quipazine and 5-hydroxy-dl-tryptophan also reduced wheel running activity, spontaneous locomotor activity assessed using photocell cages, and spontaneous climbing behaviour; fenfluramine caused a similar effect. Pretreatment with 5-hydroxy-dl-tryptophan enhanced the inhibitory effects of d-amphetamine. A 3-day treatment with fenfluramine, or lesions of the median raphe nucleus (but not the dorsal raphe nucleus) abolished the ability of d-amphetamine to reduce motor activity in the three test systems. It is concluded that low doses of d-amphetamine can reduce locomotor activity and that the effects may be mediated via an enhancement of the release of 5-hydroxytryptamine from the system arising in the median raphe nucleus.     

Narcotic withdrawal like mouse jumping produced by amphetamine and L-DOPA.

Upward jumping in mice that resembled the narcotic-withdrawal syndrome was produced by a combination of amphetamine (4 mg/kg) and L-DOPA (400 mg/kg) administration. Neither drug alone caused that jumping. Pretreatment with haloperidol (0.16 mg/kg) or pimozide (0.08 mg/kg) but not with phentolamine (10mg/kg) effectively blocked amphetamine-dopa jumping. After DOPA there was an increase in the brain levels of DOPA, dopamine and norepinephrine. Amphetamine, ineffective in itself, enhanced DOPA-induced elevation of brain DOPA and dopamine without affecting brain norepinephrine levels.     

Hypothalamic involvement in the locomotor stimulant or satiety action of thyrotropin-releasing hormone and amphetamine

To determine whether the locomotor stimulant and the anorexic actions of thyrotropin-releasing hormone (TRH) and amphetamine were mediated through the hypothalamic nuclei, rats were infused with either TRH or amphetamine through previously implanted hypothalamic cannulae. Administration of TRH or amphetamine into the ventromedial hypothalamus, but not the lateral hypothalamus and the anterior hypothalamus, caused locomotor stimulation in rats. On the other hand, administration of TRH or amphetamine into the lateral hypothalamus, but not the ventromedial hypothalamus or the anterior hypothalamus, caused a reduction in food consumption without affecting relative water intake (or water-to-food ratio) in the rat. The data indicate that the ventromedial hypothalamus is the most sensitive site of the TRH- or amphetamine-induced locomotor stimulation and the action of TRH or amphetamine on the lateral hypothalamus is also a possible mechanism mediating anorexia.     

Possible involvement of 5-hydroxytryptamine in the antidepressant activity of narcotic analgesics.

The intraperitoneal injection of 5-hydroxytryptophan (5-HTP) elicits in mice a head twitching reaction which is proportional to the amount of free 5-hydroxytryptamine (5-HT) within the brain. This effect is markedly potentiated by the monoamine oxidase inhibitor isocarboxazid and attenuated by (+)-amphetamine and desmethylimipramine. The narcotic agonist morphine, the partial agonist cyclazocine and the antagonist naloxone were examined for their effects upon this head twitching reaction and each of these three agents antagonized it. Recent studies in man and animals have linked some of the pharmacological properties of these narcotics with those of established antidepressant agents. Although the drugs studied do not have identical effects upon the central excitatory effects of 5-HT an interaction with this amine is common to all and, in view of the various hypotheses linking clinical depression with abnormal indole metabolism, it may be of importance in any antidepressant activity possessed by them.     

Effects of lesions in the dorsal or ventral striatum on locomotor activity and on locomotor effects of amphetamine

Bilateral electrolytic lesions in the dorsal portion of the anterior striatum of adult male rats reliably increased spontaneous wheel running, and potentiated the stimulant effects of d,1-amphetamine on activity in both running wheels and stabilimeters. Comparable lesions in the ventral aspects of the striatum produced a decrease in spontaneous wheel running and did not modify the activating effects of amphetamine in either wheels or stabilimeters.     

Noradrenergic and purinergic involvement in spinal antinociception by 5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine.

The adrenergic involvement in spinal antinociception by 5-hydroxytryptamine (5-HT) and 2-methyl-5-hydroxytryptamine (2-Me-5-HT) was examined using the alpha-adrenoceptor antagonists phentolamine, yohimbine and prazosin, and the neurotoxin 6-hydroxydopamine. Intrathecal pretreatment with phentolamine and yohimbine (7.5-30 micrograms), but not prazosin (30 micrograms), reduced the action of 5-HT and 2-Me-5-HT in both the tail flick and hot plate tests. Pretreatment with 6-hydroxydopamine (100 micrograms) reduced (5-HT) or increased (2-Me-5-HT) antinociception in the hot plate test, while tail flick responses were largely unaffected. In other experiments, 8-phenyltheophylline, an adenosine receptor antagonist, reduced the action of 5-HT, but not 2-Me-5-HT, in both tests. These results indicate that (a) antinociception by both 5-HT and 2-Me-5-HT involves some form of interaction with spinal alpha 2-adrenoceptors, but the nature of the interaction for these two agents is different because only 5-HT is dependent on endogenous noradrenaline, (b) release of adenosine from the spinal cord contributes to spinal antinociception by 5-HT but not by 2-Me-5-HT.     

Evidence for catecholamine involvement in the suppression of locomotor activity due to hypoxia

Locomotor activity of mice under 12 or 21% oxygen in nitrogen was measured. Under 12% oxygen there was a decrease in locomotor activity which was not reversed by administration of amphetamine; however, administration of a sub-threshold dose of l-dopa in combination with a peripheral decarboxylase inhibitor before the amphetamine restored the locomotor stimulant action of the drug under hypoxia. In contrast to amphetamine, the increase in locomotor activity after the administration of a combination of noradrenaline and dopamine receptor stimulating agents, Clonidine plus apomorphine respectively, was not inhibited by hypoxic conditions. Data suggest an involvement of central catecholamine neurotransmission in the disruption of locomotor activity due to hypoxia.     

Evidence for the involvement of 5-HT1A receptors in the mediation of exploratory locomotor activity in the rat

The 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 0.1 mg/kg(-1) subcutaneously, produced a suppression of horizontal ('locomotion') and vertical ('rearing') activity, in an open field arena. This effect was partially antagonized by treatment with (-)pindolol, 2 mg/kg(-1) subcutaneously. (-)Pindolol by itself produced a small, but statistically significant suppression of locomotor activity. There were no effects on rearing activity by (-)pindolol. In comparison with saline-treated controls, 8-OH-DPAT increased peripheral, relative to total, horizontal activity in the open field arena. (-)Pindolol adminis tration restored this pattern of activity to normal levels in 8-OH-DPAT-treated animals, without altering the relation peripheral to total activity by itself.     

Effect of ergot drugs on central 5-hydroxytryptamine neurons: Evidence for 5-hydroxytryptamine release or 5-hydroxytryptamine receptor stimulation

In combined biochemical and functional studies it has been possible to show that ergocornine (0.5-5 mg/kg) and the ergolene derivative (5R,8R)-8-(4-p-methoxyphenyl-1-piperazinylmethyl)-6-methylergolene (PTR 17402; MPME) (0.25-5 mg/kg) reduce in a dose-dependent way brain 5-hydroxytryptamine (5-HT) turnover in rat as evaluated with the tryptophan hydroxylase inhibitor, alpha-propyl-dopacetamide (H 22/54), whereas 2-Br-alpha-ergocryptine (CB 154; Br-EC) had no effect on brain 5-HT turnover. Effects on 5-HT receptor activity were evaluated using the extensor hindlimb reflex of acutely spinalized rats. It was found that ergocornine increased the 5-HT receptor activity independent of presynaptic 5-HT stores and that it didnot have any effects on uptake, retention and spontaneous overflow of 3-H-5-HT in vitro but reduced the fiedl stimulation-induced release of 3-H-5-HT in vitro. Therefore, it is suggested that ergocornine is a 5-HT recpetor-stimulating agent, an effect which may lead to reduction of nervous impulse flow in the 5-HT neurons and subsequently of 5-HT release and turnover. MPME, on the other hand, seems to increase 5-HT receptor release of 5-HT stores, mainly from extragranular sites. Thus, the increase in extensor reflex activity found after MPME was reduced by reserpine and H 22/54 and enhanced by nialamide and in vitro MPME markedly increased 3-H-5-HT overflow in cortical slices of nialamide-pretreated rats and inhibited uptake and retention of 3-H-5-HT (EC50 equals 1.6 times 10-minus 6 M) in cortical slices of normal rats. Inhibition of the 5-HT membrane pump does not seem to be of any major importance, since chlorimipramine was only weakly active on the extensor reflex in the pharmacological models used and since MPME did not block but rather enhanced the 5-HT depletion caused by 4-methyl-alpha-ethyl-m-tyramine. It is suggested that MPME is a releaser of extragranular 5-HT stores leading to increased 5-HT receptor activity and reduction of 5-HT turnover in the same way as indicated for ergocornine. This new ergolene derivative may represent a new class of antidepressant drugs acting via release of extragranular 5-HT stores.     

Single and repeated administration of neuroleptic drugs to rats: Effects on striatal dopamine-sensitive adenylate cyclase and locomotor activity produced by tranylcypromine and L-tryptophan or L-dopa

Injection of tranylcypromine and L-tryptophan results in rats displaying behavioural changes including hyperactivity, probably due to stimulation of post-synaptic 5-hydroxytryptamine (5-HT) receptors. Increased locomotor activity of a different type is elicited by injection of tranylcypromine and L-dopa, a procedure which increased dopaminergic function in the brain. It has now been demonstrated that the neuroleptic drugs, chlorpromazine, -flupenthixol, haloperidol and spiroperidol block both syndromes. The inhibition produced by these drugs on 5-HT-induced hyperactivity is probably because a dopaminergic system is involved in the behavioural expression of the 5-HT induced hyperactivity. The structurally related drugs with no neuroleptic activity (ethopropazine, promethazine and -flupenthixol) are without effect on these hyperactivity syndromes. Also ineffective were the neuroleptics pimozide and clozapine.Striatal dopamine sensitive adenylate cyclase activity in vitro was inhibited by the administration of chlorpromazine (100 mg/kg) in vivo.Rats treated for 4 or more days with chlorpromazine, -flupenthixol, spiroperidol and haloperidol subsequently showed enhanced locomotor activity in response to tranylcypromine and L-Dopa. Administration of those drugs which did not block hyperactivity acutely did not result in enhancement. Only chlorpromazine, when given for 4 days, enhanced the hyperactivity response following tranylcypromine and L-tryptophan, probably because the drug also blocks 5-HT receptors.In rats displaying enhanced behavioural responses no evidence was found for enhanced sensitivity of striatal adenylate cyclase to dopamine.     

Evidence for 5-hydroxytryptamine1A receptor involvement in the control of prolactin secretion in man

The effects of pindolol pretreatment (2 days) on prolactin and cortisol responses to a single dose of (+)-fenfluramine (30 mg po) were examined in nine healthy male volunteers. Pindolol pretreatment attenuated the (+)-fenfluramine-induced increase in prolactin concentrations but failed to affect the (+)-fenfluramine-induced cortisol increase. These data provide evidence in support of 5-HT1A receptor involvement in the regulation of prolactin secretion but question its importance in the regulation of cortisol secretion in man     

Effects of monoamine oxidase inhibition by clorgyline, deprenil or tranylcypromine on 5-hydroxytryptamine concentrations in rat brain and hyperactivity following subsequent tryptophan administration.

1 The effect of various doses of tranylcypromine on the degree of inhibition of rat brain monoamine oxidase (MAO) using 5-hydroxytryptamine (5-HT), dopamine and phenylethylamine as substrates has been examined 120 min after injection of the inhibitor. The concentration of brain 5-HT was also examined both after tranylcypromine alone and also when L-tryptophan (100 mg/kg) had been given 30 min after the tranylcypromine. 2 All doses of tranylcypromine greater than 2.5 mg/kg totally inhibited MAO oxidation of 5-HT, phenylethylamine and dopamine as measured in vitro and produced a similar rise of brain 5-HT in vivo. When tryptophan was also given, there was a further rise of brain 5-HT, which was comparable after all doses of tranylcypromine above 2.5 mg/kg and the characteristic syndrome of hyperactivity made is appearance. 3 Clorgyline (a "Type A" MAO inhibitor), in doses up to 10 mg/kg, did not totally inhibit MAO activity towards phenylethylamine although it did inhibit 5-HT oxidation by 100%. Deprenil (a "Type B" MAO inhibitor) at doses up to 10 mg/kg did not fully inhibit 5-HT oxidation although phenylethylamine oxidation was inhibited almost completely. Administration of either compound alone did not produce as great an accumulation of brain 5-HT as that seen after tranylcypromine (2.5 mg/kg) and subsequent administration of tryptophan did not cause hyperactivity or the rise of brain 5-HT seen after tranylcypromine (2.5 mg/kg) plus tryptophan. 4 Administration of clorgyline plus deprenil (2.5 mg/kg of each) almost totally inhibited oxidation of both 5-HT and phenylethylamine; subsequent tryptophan administration resulted in a rise of brain 5-HT nearly as great as that seen following tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive. 5 No evidence was found pointing to the formation of any other 5-substituted indole in the brain following tranylcypromine plus L-tryptophan administration as suggested by others. 6 It is concluded that while 5-HT may normally be metabolized in the brain by "Tye A" MAO in vivo, when this form is inhibited, 5-HT can still be metabolized by "Type B" enzyme. It is only when both forms are almost totally inhibited that the largest rise of brain 5-HT is seen and subsequent tryptophan administration produces the hyperactivity syndrome.     

Tolerance to the increased locomotor activity produced by l-5-hydroxytryptophan following peripheral decarboxylase inhibition in mice

The development of tolerance to hyperactivity produced by l-5-hydroxytryptophan (5-HTP) was studied in mice pretreated with the peripheral decarboxylase inhibitor MK-486. The results of Experiment I indicated that partial tolerance developed to 5-HTP given twice daily (i.p.) at a dose of 400 mg/kg, but not at a dose of 800 mg/kg. Sustained hyperactivity at the greater dose (800 mg/kg) apparently resulted from the induction of seizures and stereotypy rather than increased locomotor activity. When 5-HTP (400 mg/kg) or saline was administered three times daily (Experiments II and III), the locomotor activity of saline control groups did not differ significantly from chronic 5-HTP-treated groups, but both differed significantly from that of acute 5-HTP-treated animals. Cessation of treatments resulted in a recovery of 5-HTP-induced hyperactivity for experimental animals when later retested. These findings suggest that mice develop tolerance to the effects of 5-HTP on locomotor activity and agree with the hypothesis that behavior change is more closely correlated with the rate of change in concentration of neurotransmitters than the absolute concentrations.     

Modulation of neuronal activity in the hippocampus by 5-hydroxytryptamine and 5-hydroxytryptamine1A selective drugs

The interactions between 5-hydroxytryptamine (5-HT), 8-hydroxy-2-(N,N-dipropylamino)-tetralin (8-OH-DPAT), buspirone, 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3- (2H)one-1, 1-dioxide-hydrochloride (TVX Q 7821) and ketanserin, and putative 5-HT receptors were analyzed using both radioligand techniques and an in vitro hippocampal slice preparation. The potencies of the drugs were determined at 5-HT1A binding sites labelled by [3H]8-OH-DPAT in hippocampal membranes from the rat. The binding site had similar affinity for 5-HT, 8-OH-DPAT, buspirone and TVX Q 7821, whereas ketanserin was essentially inactive. Physiological effects of these drugs were also examined using an in vitro hippocampal slice preparation. With the exception of ketanserin, application of each drug to the bath modulated the amplitude of the field potential recorded in the pyramidal layer of CA1 evoked by stimulation of Schaffer collaterals. Application of micromolar concentrations of 5-HT produced an initial increase in the population spike followed by a return to near baseline levels within 5 min. By contrast, the amplitude of the population spike was reduced in a dose-dependent manner by micromolar concentrations of 8-OH-DPAT, buspirone and TVX Q 7821, beginning 5 min after application of drug. Ketanserin did not affect the amplitude of the population spike and it did not antagonize the effects of 5-HT, buspirone or TVX Q 7821. Neither buspirone nor 8-OH-DPAT altered the initial increase in population spike induced by 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)