Richard Laverty

Is Adenosine an Endogenous Anticonvulsant

Summary: The anticonvulsant properties of adenosine were tested pharmacologically on amygdala‐kindled seizure activity in rats. The adenosine analogue 2‐chloroadenosine and the adenosine uptake blocker papaverine both increased the latency to behavioral clonus as well as reduced the duration and severity of the clonic motor convulsion. Both drugs, however, failed to alter the postkindling afterdischarge (AD) threshold. Theophylline, an adenosine antagonist, had the opposite effects, prolonging the AD and motor seizure durations and facilitating partially kindled seizures, but again not altering the prekindling or postkindling AD thresholds of amygdala‐elicited seizures. In contrast, carbamazepine raised AD thresholds, suggesting that it does not produce its anticonvulsant effects through adenosine systems. Since endogenous adenosine can impede seizure spread and seizure continuation, but does not affect seizure initiation from the amygdala, perhaps endogenous adenosine has the special property of being brought into play as an anticonvulsant only by the seizure itself.

The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of the rat brain

Abstract The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine and metabolite levels in regions of the rat brain has been studied using fluorimetric and radioisotopic techniques. The results indicate that these minor tranquillizers decrease noradrenaline turnover in the thalamus-midbrain, cortex and cerebellum regions, and dopamine turnover in the striate region. These drugs also antagonized the increased catecholamines turnover, in the above regions due to electro-footshock stress. It is suggested that the mode of action of chlordiazepoxide, diazepam and nitrazepam involves catecholamines in the central nervous system.

Differences between rats and mice in MDMA (methylenedioxymethylamphetamine) neurotoxicity

In both rats and mice a single large dose of methylenedioxymethylamphetamine (MDMA; 25 mg/kg i.p.) caused a fall 3 h after injection in the content of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in cortex, a fall in noradrenaline in hippocampus and cerebellum, and a rise in dopamine (DA) but fall in dihydroxyphenylacetic acid (DOPAC) in striatum. These effects were transient, levels being essentially back to normal by 24 h after injection. Repeated large doses (3 x 25 mg/kg in 24 h) of MDMA caused a large long-lasting fall in the content of 5-HT and 5-HIAA in cortex in rats but had only a slight effect in mice. Increasing the dose to 3 x 50 mg/kg in mice produced a large long-lasting fall in striatal DA. The analogue MDEA(3,4-methylenedioxyethylamphetamine) caused a similar slight fall in 5-HT but in contrast to MDMA caused a slight rise in DA content in mice. The nature and degree of neurotoxicity with methylenedioxyamphetamines appears to be drug and species-specific.

Changes in brain amine levels associated with the morphological and behavioural development of the worker honeybee

SummaryChanges in biogenic amine levels associated with the morphological and behavioural development of the worker honeybee are examined.A significant increase in amine levels in the head of the honeybee is associated with transition from the larval to pupal stage. Adult emergence is also accompanied by a significant increase in 5-HT levels in the brain, but no significant change in brain dopamine (DA) levels. NADA (N-acetyldopamine) levels increase during larval and pupal development, but in contrast to both DA and 5-HT, drop significantly during the transition from pupa to adult.Levels of DA in the brain of nectar and pollen forager bees, presumed to be among the oldest adults sampled, were found to be significantly higher than in nurses, undertakers or food storers. These results suggest that an age-dependent change in amine levels occurs in the brain of the worker bee. In the optic lobes, levels of DA and 5-HT were found to be significantly higher in pollen forager bees than in all other behavioural groups. Significant differences in amine levels in the optic lobes of nectar foragers and pollen foragers indicate that some differences in amine levels occur independent of worker age. The functional significance of differences in brain amine levels and whether or not biogenic amines play a direct role in the control of honeybee behaviour has yet to be established.

Propranolol uptake into the central nervous system and the effect on rat behaviour and amine metabolism.

Propranolol readily penetrated all areas of the central nervous system after acute intraperitoneal administration and was cleared within 8–16 hr. Propranolol levels in the heart followed a similar pattern. After chronic oral administration brain levels of propranolol were equal to those 3 hr after intraperitoneal injection. Propranolol caused no significant difference in the brain levels of noradrenaline, normetanephrine, dopamine, 3‐methoxytyramine, homovanillic acid, 5‐hydroxy‐tryptamine or total indoles, nor did it cause measurable changes in rat behaviour. An increase by propranolol in sleeping time after chloral hydrate in rats and mice was observed; this effect could not be correlated with changes in brain amine concentrations.

TheN-methyl-D-aspartate antagonists aminophosphonovalerate and car☐ypiperazinephosphonate retard the development and expression of kindled seizures

To investigate the possible role of N-methyl-D-aspartate (NMDA) receptors in the development and expression of amygdaloid-kindled seizures, rats were either chronically infused with 2-amino-5-phosphonovalerate (APV, 20-40 mM) or pre-injected with carboxypiperazine-phosphonate (CPP, 1-10 mg/kg), both selective NMDA-receptor antagonists, and then kindled from the amygdala. At the higher dose (40 mM), APV blocked the induction of long-term potentiation in the dentate gyrus. APV also retarded clinical seizure development dose-dependently and increased seizure thresholds without affecting afterdischarge (AD) duration. These same doses of APV had only small anticonvulsant effects on established kindled seizures. Although CPP (1-10 mg/kg) had no effect when rats were kindled 45 min after injection it dose-dependently retarded focal and generalization stages at the 150 min injection-kindling interval. Once relieved of drug, animals proceeded to develop stage 5 seizures with shorter duration ADs than saline-control animals. When the previously-kindled, saline groups were crossed to CPP a small depressant effect on seizure expression was observed. These results suggest that NMDA receptors are primarily involved in kindling development rather than in maintaining the kindled state.

3,4-Methylenedioxymethamphetamine induces Fos-like proteins in rat basal ganglia: reversal with MK 801

Injections of 3,4-methylenedioxymethamphetamine (MDMA, 25 mg/kg, i.p.) to rats lead to an accumulation of c-fos protein (Fos) and Fos-related antigens in caudate-putamen, nucleus accumbens and olfactory tubercle. This induction occurred at least 2 h (but not at 10 min) after injection and Fos levels had returned to baseline after 24 h, although Fos-related antigens remained elevated 24 h after injection. The NMDA antagonist MK 801 inhibited Fos and Fos-related antigen induction after MDMA injections, whereas fluoxetine, a serotonin uptake inhibitor, had no effect. Thus, MDMA induces Fos and Fos-related antigens in striatal neurons in an NMDA-reversible fashion.

A NERVOUSLY‐MEDIATED ACTION OF ANGIOTENSIN IN ANAESTHETISED RATS

In rats under chloralose anaesthesia, angiotensin in large doses caused a nervously‐mediated vasoconstriction in the vascularly‐isolated innervated hind limb, whereas in small doses it caused a nervously mediated peripheral vasodilatation. Noradrenaline over an equipressor dose range caused only a nervously‐mediated peripheral vasodilatation. These peripheral responses were abolished by section of the nerves leading to the hind limb.

The infusion of an NMDA antagonist into perirhinal cortex suppresses amygdala-kindled seizures

The seizure-modulating role of N-methyl-D-aspartate (NMDA) receptors located in several limbic areas was investigated. Amygdala-kindled rats were microinfused with the selective NMDA-receptor antagonist 2-amino-5-phosphonovalerate (APV, 1 microliter, 70 nmol) or artificial cerebrospinal fluid (ACSF) applied through a cannula located in either the amygdala or perirhinal, pyriform or deep prepyriform cortices. APV infused into the stimulation site raised the threshold for seizure generation. Surprisingly, APV infused into perirhinal cortex, but not into other regions, also dramatically suppressed behavioural seizures and afterdischarges (AD) elicited 5 min after the infusion. If stimulus intensities were markedly elevated however, the seizure suppression was overcome. This latter effect was reversible and repeatable, as seizures and AD were reliably reinstated when these animals were stimulated after infusion with ACSF. A similar effect, whereby perirhinal infusions blocked seizure activity, was also demonstrated in an animal kindled from the olfactory bulb and in one kindled from the perforant path. These results suggest that NMDA receptors located in the perirhinal cortex may play a major role in the modulation of AD activity elicited from more distal brain regions. Furthermore, activation of perirhinal cortex may be a critical requirement for the generation of amygdala-stimulated AD in the kindled animal.

Role of brain nitric oxide in (±)3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats

The role of nitric oxide (NO) in the long-term serotoninergic neurotoxicity induced by (+/-)3,4-methylenedioxymethamphetamine (MDMA) in rats was investigiated. Pretreatment with Nomega-nitro-L-arginine (L-NOARG) (10 mg kg-1), a nitric oxide synthase (NOS) inhibitor, partially protected against long-term serotonin (5-HT) depletion induced by MDMA (40 mg kg-1) in frontal cortex and parietal cortex, but not in other brain regions examined. Brain NOS activities in these two regions were significantly elevated at 6 h after MDMA administration. Moreover, L-NOARG pretreatment caused significant inhibition of brain NOS activity but did not affect the acute 5-HT and dopamine (DA) changes or the hyperthermia induced by MDMA. These results suggest that it is the NOS inhibitory properties of L-NOARG, rather than its effects on the acute monoamine changes or the hyperthermia induced by MDMA, that are responsible for the prevention of neurotoxicity. The regional differences on the protection of L-NOARG and on the activation of NOS by MDMA indicate the unequal role that NO may play in MDMA-induced neurotoxicity in different brain regions.