D. G. Grahame-Smith

Further observations on the effect of repeated electroconvulsive shock on the behavioural resposes of rats produced by increases in the functional activity of brain 5-hydroxytryptamine and dopamine

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.Administration of indomethacin (2 mg/kg) 25 min before the ECS did not prevent the enhanced 5-HT response suggesting that the enhanced response is not the result of the reported rise in prostaglandins F following ECS.Repeated ECS shortened the time to loss of righting following pentobarbital (50 mg/kg) but did not alter the total sleeping time.Repeated ECS enhances locomotor activity produced by methamphetamine. It also enhances circling produced by methamphetamine and apomorphine in unilateral nigrostriatal lesioned rats, suggesting an enhanced postsynaptic response.No evidence was found for ECS altering the response of striatal adenylate cyclase to dopamine nor for any alteration of striatal cyclic AMP concentration.These data taken with our previous study reinforce the suggestion that electroconvulsive therapy (ECT) produces increased responses to 5-hydroxytryptamine and dopamine receptor stimulation.

Enhanced 5-hydroxytryptamine-mediated behavioural responses in rats following repeated electroconvulsive shock: relevance to the mechanism of the antidepressive effect of electroconvulsive therapy.

Treatment of rats with one electroconvulsive shock (ECS) per day for 10 days enhanced the hyperactivity syndrome produced by administration of tranylcypromine (10 mg kg-1) and l-tryptophan (50 mg kg-1) given 24 h after the final shock. Similar enhancement was seen whether the shock was alternating sinusoidal or direct current (fractionated), whether it was given through unilaterally or bilaterally placed electrodes and whether or not a neuromuscular blocking agent (fazadinium) was used. Five shocks spread over 10 days or 8 shocks spread over 17 days were similarly effective, whilst 8 shocks in 1 day were ineffective. Therefore when ECS are given to rats in ways similar to those in which electroconvulsive therapy is given to patients with depression, enhancement of behavioural responses to increased 5-HT function is produced.

β‐ADRENOCEPTOR AGONISTS ENHANCE 5‐HYDROXYTRYPTAMINE‐MEDIATED BEHAVIOURAL RESPONSES

1 The β‐adrenoceptor agonists, salbutamol, terbutaline and clenbuterol, were investigated for their effect on 5‐hydroxytryptamine‐mediated (5‐HT) hyperactivity. 2 The lipophilic β‐adrenoceptor agonist, clenbuterol (5 mg/kg) enhanced the behaviours induced by quipazine (25 mg/kg), including headweaving, forepaw treading and hind‐limb abduction and thus increased automated activity recording. Clenbuterol (5 mg/kg) also enhanced the hyperactivity syndrome produced by the 5‐HT agonist, 5‐methoxy N,N‐dimethyltryptamine (2 mg/kg) and the combination of tranylcypromine (10 mg/kg) and L‐tryptophan (50 mg/kg). Salbutamol and terbutaline potentiated quipazine‐induced hyperactivity only when given at the higher dose of 20 mg/kg. 3 The effect of clenbuterol in enhancing quipazine hyperactivity was blocked by the centrally acting β1‐adrenoceptor antagonist, metoprolol (5 mg/kg), but not by the β2‐adrenoceptor antagonist, butoxamine (5 mg/kg) or the peripherally acting β1‐adrenoceptor antagonist, atenolol (5 mg/kg). 4 Clenbuterol (5 mg/kg) did not enhance the circling responses produced by methamphetamine (0.5 mg/kg) in unilateral nigrostriatal‐lesioned rats. 5 The results suggest that β‐adrenoceptor agonists in common with some established antidepressant treatments produce enhancement of 5‐HT‐mediated behavioural responses.

CHANGES IN PLATELET α2-ADRENOCEPTOR BINDING POST PARTUM: POSSIBLE RELATION TO MATERNITY BLUES

Abstract Platelet α 2 -adrenoceptor binding characteristics were investigated in 28 healthy women during the peripartum period. The number of platelet α 2 -adrenoceptors fell after childbirth, corresponding to a fall in the circulating levels of oestrogen and progesterone. Two- thirds of the women had an episode of maternity blues. At 7-10 days post partum the platelet α 2 -adrenoceptor capacity in these subjects was significantly higher than in those women who did not show signs of maternity blues and significantly higher than a control group of normally menstruating women. We conclude that platelet α 2 -adrenoceptors may be affected by the circulating levels of endogenous oestrogen and progesterone and that a delayed or diminished fall in platelet α 2 -adrenoceptor capacity after childbirth may be associated with the development of maternity blues.

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, α-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 β-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, α-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.

ELECTROCONVULSIVE THERAPY AND THE BRAIN: EVIDENCE FOR INCREASED DOPAMINE-MEDIATED RESPONSES

The growth-hormone (GH) response to subcutaneous administration of the dopamine agonist, apomorphine (0.005 mg/kg), was assessed in 15 depressed patients at the beginning and at the end of a course of electroconvulsive therapy (ECT). After ECT there was a significant increase in the GH response to apomorphine, supporting the hypothesis that ECT produces an enhancement of dopamine-mediated responses in the brain. Additional studies in depressed patients receiving other antidepressant treatment suggested that the increase in apomorphine response following ECT was not attributable either to concurrent antidepressant medication or to clinical recovery from depressive illness.

The effect of metergoline on endocrine responses to L-tryptophan.

The effects of the 5-HT receptor antagonist, metergoline, on the prolactin and growth hormone responses to intravenous L-tryptophan were assessed in seven normal subjects. Pretreatment with metergoline lowered baseline prolactin concentration and abol ished the increase in prolactin following L-tryptophan. In contrast, neither baseline nor the response to L-tryptophan was altered by metergoline. These results are consistent with the proposal that the prolactin response to L-tryptophan is mediated by 5-HT1 receptors; however, metergoline might also reduce prolactin responses by a dopaminergic action. The nature of the 5-HT receptor involved in the growth hormone response to L-tryptophan remains to be identified.

Neuroleptic drugs block both the hyperactivity and the increase in caudate nucleus cyclic AMP concentration produced by the administration of tranylcypromine and l-dopa to rats

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 α-flupenthixol also inhibited both effects, while β-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.A good correlation was found to exist between the neuroleptic inhibition of both the increased behavioural activity and the increased caudate nucleus cyclic AMP concentrations produced by tranylcypromine and l-dopa.