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20 microgram TRH injected bilaterally into the caudate-putamen, tuberculum olfactorium, nucleus accumbens, amygdala, lateral ventricles, midbrain or cerebral cortex failed to induce any increase in locomotor activity (measured using photocells), although other behavioural changes were observed after each injection, and included body shakes, limb tremor, repetitive head and limb movements, biting, scratching and an alert appearance. These behavioural changes could result in positive readings from equipment used to measure locomotor activity, but careful investigations focussing on the nucleus accumbens used photocell boxes, activity wheels and Animex recorders to emphasise the inability of intracerebral TRH (10--40 microgram) to enhance locomotor activity. Intraaccumbens TRH also failed to enhance amphetamine hyperactivity or reduce the motor depression caused by haloperidol and analeptic drugs. The data do not support a central locomotor stimulant action of TRH.

Morphine preference and tendency to relapse to morphine tolerance and dependence were studied in rats which were previously made morphine dependent. Tolerance to, and physical dependence on, morphine were initially produced by administration of increasing concentrations of morphine sulphate in 5% sucrose solution for 3 weeks. A test for drinking preference was performed 4 days after the rats had been successfully detoxified and showed no significant signs of morphine dependence. It was found that, while control animals drank only negligible amounts of morphine solution, previously morphine-dependent rats consumed significantly larger volumes of morphine solution and had recurrence of morphine tolerance and dependence. The present findings show that chronic administration of morphine in drinking fluid produces tolerance and physical dependence as well as addiction in rats; the latter definition is exemplified by these animals having a high tendency to relapse after successful drug withdrawal.

Captopril (1-5 mg/kg, i.v.) did not affect the vasodepressor responses to substance P (1-30 micrograms/kg, i.v.) in anaesthetized rats. Substance P (100 micrograms/kg, s.c.) produced significant algesia in mice; this was not potentiated by the smaller doses of captopril (1-2 mg/kg, i.p.), but was instead antagonized by the high dose (5 mg/kg, i.p.). It is concluded that captopril does not have any influence on substance P degradation in vivo since the pharmacological actions of the undecapeptide are not enhanced after captopril treatment.

1. In chloralose anaesthetized rats intravenous administration of captopril (0.5 mg/kg) was followed by an approximately 100-fold decrease in sensitivity to the pressor actions of angiotensin I. Concomitantly there was a 100-fold increase in sensitivity to the depressor effects of bradykinin. 2. Depressor responses to intravenous prostacyclin (PGI2), prostaglandin E2 (PGE2) or a low dose of arachidonic acid (1 mg/kg) were not changed by captopril administration, but responses to a high dose of arachidonic acid (3 mg/kg), given either intravenously or into the aortic arch, were enhanced for up to two hours afterwards. 3. Depressor responses to arachidonic acid, both before and after captopril, were inhibited after intravenous indomethacin (1 mg/kg). 4. These results support the hypothesis that increased synthesis of prostaglandins in the circulation contributes to the hypotensive action of captopril.

Intravenous administration of captopril (0.1-0.3 mg/kg) to normotensive pithed rats, with or without unilateral nephrectomy, was followed by a sustained fall in arterial blood pressure. Concomitantly pressor responses to electrical stimulation of the spinal sympathetic outflow (T11-L3), ganglion stimulation with McNeil-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride) or intravenous injection of noradrenaline were reduced. Attenuation by captopril (1 mg/kg) of pressor responses to McNeil-A-343 persisted after intravenous propranolol (1 mg/kg). Tachycardia caused by electrical stimulation of the spinal sympathetic nerves (C7-T2) was unchanged after 3.0 mg/kg captopril. After procedures reducing the activity of the renin angiotensin system, bilateral nephrectomy or induction of mineralocorticoid hypertension by unilateral nephrectomy and administration of desoxycorticosterone acetate, pressor responses to McNeil-A-343 or noradrenaline were unchanged after 1 mg/kg captopril. It is concluded that in the pithed rat, basal arterial blood pressure and the height of pressor responses to either postganglionic sympathetic nerve activation or intravenous noradrenaline depend on converting enzyme activity maintaining circulating angiotensin II levels.