Search

The effects of sibutramine (0.25–10 mg kg−1, i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane‐anaesthetized rats were compared with those of d‐amphetamine (1–3 mg kg−1, i.p.) using in vivomicrodialysis. The role of presynaptic α2‐adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective α2‐adrenoceptor antagonist, RX821002.Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose‐response relationship was described by a bell‐shaped curve with a maximum effect at 0.5 mg kg−1. In contrast, d‐amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose.Pretreatment with the α2‐adrenoceptor antagonist, RX821002 (dose 3 mg kg−1, i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg−1) and reduced the latency of sibutramine to reach its maximum effect from 144–56 min.RX821002‐pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d‐amphetamine alone (10 mg kg−1) and had no effect on the latency to reach maximum.These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivoand that the effects of this drug are blunted by indirect activation of presynaptic α2‐adreno‐ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d‐amphetamine is consistent with this being mainly due to an increase in Ca2+‐independent release of noradrenaline.

The effects of sibutramine (0.25–10 mg kg−1i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely‐moving rats were investigated using microdialysis. The role of presynaptic α2‐adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined.Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration.In both the cortex and hypothalamus, pretreatment of rats with the α2‐adrenoceptor antagonist RX821002 (3 mg kg−1i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg−1i.p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus.Infusion of RX821002 (1 μM) viathe probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg−1i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex.These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic α2‐adrenoceptors. Furthermore, the data suggest that terminal α2‐adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex.

Summary [3H]SCH 23390 is a selective high affinity ligand for D1 receptors in vitro. Using this ligand persistent blockade of D1 receptors by SCH 23390 and cis-flupenthixol was shown to significantly increase the number of D1 receptor binding sites in rat striatum. In contrast, repeated administration of the D2-selective antagonist, clebopride, resulted in a small, but significant, reduction in number. No differences in binding affinity were observed and a single dose of these compounds was without effect. The D2-selective antagonist, haloperidol, the non-selective D1/D2 receptor antagonist, chlorpromazine, the dopamine reuptake inhibitors, bupropion, GBR 12909 and nomifensine, and the dopamine releasing agent, d-amphetamine, had no effect on D1 receptors. The antidepressant treatments, desipramine, zimeldine, amitriptyline, tranylcypromine, mianserin and ECS and the monoamine reuptake inhibitor, sibutramine, similarly did not alter striatal D1 sites. Thus, of the treatments investigated only chronic receptor blockade by high affinity antagonists altered D1 receptor binding in rat striatum.

1Effects on 5‐HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)‐fenfluramine and (+)‐amphetamine.2In vitrosibutramine weakly inhibited [3H]‐5‐HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [3H]‐5‐HT uptake inhibitors, whereas (+)‐fenfluramine and (+)‐amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [3H]‐5‐HT from brain slices at 10−5M, (+)‐fenfluramine and (+)‐amphetamine concentration‐dependently increased [3H]‐5‐HT release.3Sibutramine and fluoxetine had no effect on 5‐hydroxytryptophan (5‐HTP) accumulation in either frontal cortex or hypothalamus at doses <10 mg kg−1. In contrast, (+)‐amphetamine (3 mg kg−1) reduced 5‐HTP in hypothalamus, whilst (+)‐fenfluramine (1 mg kg−1) decreased 5‐HTP in both regions.4Sibutramine (10 mg kg−1i.p.) and fluoxetine (10 mg kg−1i.p.) produced slow, prolonged increases of extracellular 5‐HT in the anterior hypothalamus. In contrast, (+)‐fenfluramine (3 mg kg−1i.p.) and (+)‐amphetamine (4 mg kg−1i.p.) induced rapid, short‐lasting increases in extracellular 5‐HT.5Only (+)‐fenfluramine (10 mg kg−1) altered 5‐HT2Areceptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity.6These results show that sibutramine powerfully enhances central 5‐HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5‐HT uptake inhibition. By contrast, (+)‐fenfluramine enhances 5‐HT function predominantly by increasing 5‐HT release. (+)‐Amphetamine, though weaker than (+)‐fenfluramine, also enhances 5‐HT function by release.

Administration of the a2-adrenoceptor agonist clonidine (0.1 mg/kg) produces hypoactivity in mice. This sedation response was unaltered by pretreatment with either the 5-HT reuptake inhibitor zimeldine (1 or 10 mg/kg) or the 5-HT agonist quipazine (0.25 or 2.5 mg/kg). The 5-HT1B agonist RU 24969 (0.2 or 1 mg/kg) enhanced hypoactivity responses at the higher dose. The non-selective 5-HT antagonists methysergide (1 or 10 mg/kg) and metergoline (0.2 or 1 mg/kg) potentiated clonidine-induced hypoactivity. However, the marked enhancement produced by metergoline may have been due to its potent action as a a1-adrenoceptor antagonist. Nevertheless, the 5-HT2 antagonists ritanserin (0.1 or 1 mg/kg) and ketanserin (0.1 or 1 mg/kg) both potentiated clonidine hypoactivity in a dose-dependent manner. ß-Adrenoceptor antagonists also inhibit 5-HT1 receptors at high dose. Pindolol (10 mg/kg) had no effect on sedation, but [-]-propranolol (20 mg/kg) caused some attenuation. This latter effect was probably not due to inhibition of 5-HT1 receptors, because this reduction also occurred at low dose (2 mg/kg). Destruction of 5-HT neurones by intracerebroventricular injection of 5,7-dihydroxytryptamine (50 µg) resulted in a marginal increase in hypoactivity. In conclusion, these data shown that central 5-HT function can influence a2-adrenoceptor-mediated hypoactivity responses. However, since these effects were usually only apparent after severe manipulation of 5-HT function, it suggests that while these interactions may be of pharmacological interest, they are probably not of physiological importance.

The hypothermic and motor behavioural responses to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been investigated in the rat. The dose-effect relationship showed that hypothermia appeared at a lower dose than a definite motor syndrome. The hypothermic response to 8-OH-DPAT was attenuated following depletion of 5-hydroxytryptamine (5-HT) by repeated intraperitoneal (IP) administration of parachlorophenylalanine (200 mg/kg) or by injection of 5,7-dihydroxytryptamine (5,7-DHT, 100 µg) into the region of the third ventricle; the motor behavioural response produced simultaneously was not. Indeed, after 5,7-DHT, it was increased. Quipazine (1 mg/kg, IP) antagonised the hypothermic response and facilitated the motor behaviour. Clenbuterol (2.5 mg/kg, IP) increased both hypothermic and motor responses. (±)-propranolol was without effect on the simple hypermotility produced by 8-OH-DPAT, although it is known to antagonise the hypothermic and stereotyped motor responses. It is concluded that 8-OH-DPAT probably produces its hypothermic effects by actions at 5-HT receptors located presynaptically on 5-HT neurones, while the stereotyped components of the serotonin syndrome appear to be mediated by post-synaptic receptors.

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, a-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 ß-flupenthixol) are without effect on these hyperactivity syndromes. Also ineffective were the neuroleptics pimozide and clozapine.

Summary The effects of administration to rats of repeated electroconvulsive shock (ECS), clenbuterol and desipramine (DMI) onΒ-adrenoceptor number in cortex, and noradrenaline (NA) and dopamine (DA) turnover in whole brain has been investigated by examining the rate of decline of NA concentration (kNA) following injection ofα-methyl-p-tyrosine. A single injection of clenbuterol (5 mg/kg) raised brain NA content and decreased the rate constant (kNA), leaving the turnover rate unaltered. Acute DMI injection decreased kNA and turnover rate, while a single ECS did not change NA metabolic rate. Repeated treatment with either ECS (5 seizures over 10 days), clenbuterol (5 mg/kg for 14 days) or DMI (5 mg/kg twice daily for 14 days) decreasedΒ-adrenoceptor density in cortex. No change in NA content, rate constant or turnover rate was observed after repeated ECS or clenbuterol administration. Ninety min after the last dose of DMI brain NA content was significantly decreased but kNA was unchanged compared with control animals, possibly because of the presence of subsensitive presynapticα2-adrenoceptors. At 18 hours after the last dose brain NA content was still lower than control animals but kNA was enhanced. This is presumably a “withdrawal” effect, the uptake inhibitory effect of the drug now being decreased. The treatments had little effect on DA turnover apart from DMI decreasing synthesis rate. Clearly there is no obvious relationship between the ability of antidepressant treatments to alter NA turnover and decreaseΒ-adrenoceptor number.

Summary Clonidine-induced hypoactivity was studied in rats made neonatally hypo- and hyperthyroid (PTU or T4 administered between 1–27 days postnatally) as an indication of central presynaptica2-adrenoceptor function. Paradoxically, at 28 days postnatally both treatments caused an increase in clonidine-hypoactivity compared with untreated control animals, which was not due to sex differences amongst littermates in the various groups. It is proposed that whereas the hyperthyroid neonate data perhaps reflect an enhancement of presynaptica2 function similar to that seen in the adult rat brain, the result obtained for the hypothyroid neonates could perhaps be due to a retardation of the ontogeny of central noradrenergic neurones.

Summary The effect of thyroid status on noradrenergic synaptic function in the mature rat brain was examined by measuring presynaptica2- and post-synapticß-adrenoceptors.

Injection of rats with tranylcypromine and l-dopa increased brain dopamine concentrations and produced a behavioural syndrome that includes hyper-activity. It also elevated caudate nucleus cyclic AMP concentrations by approximately 50% in vivo, probably by stimulating dopamine receptors. Pretreatment with chlorpromazine inhibited both the tranyl-cypromine/l-dopa-induced behaviour and elevated cyclic AMP concentrations in a dose-dependent manner. Haloperidol and a-flupenthixol also inhibited both effects, while ß-flupenthixol and pimozide were without effect. Since none of these drugs altered the tranylcypromine/l-dopa-induced rise of brain dopamine, it is likely that they produced their effect by inhibiting dopamine-sensitive adenylate cyclase.

Following repeated electroconvulsive shocks (ECS) (once daily for 10 days), rats display enhanced hyperactivity responses to tranylcypromine and l-tryptophan, a procedure which increases brain 5-hydroxytryptamine (5-HT) concentrations, or to the suggested 5-HT agonist quipazine. The enhanced responses last for about 6 days following the last shock. Repeated sub-convulsive shocks did not produce this behavioural enhancement.

CERTAIN strains of the insect pathogen Bacillus thuringiensis produce a heat-stable exotoxin which is toxic to species from several orders of insects1,2and also affects mammals3–5. The exotoxin inhibits ecdysone-stimulated insect RNA polymeras of mice both in vivo6and in vitro7.