Michael E. Newman

Chronic electroconvulsive shock and desimipramine reduce the degree of inhibition by 5-HT and carbachol of forskolin-stimulated adenylate cyclase in rat hippocampal membranes

The degree of inhibition of forskolin-stimulated adenylate cyclase activity by 5-HT and by carbachol in hippocampal membranes was significantly reduced after administration of either chronic ECS (10 days) or desimipramine (10 mg/kg i.p. for 3 weeks). A single ECS had no effect on the 5-HT response and slightly augmented the carbachol response. These results parallel previous observations on the effects of ECS and antidepressants on behavioral responses to 5-HT1a agonists and on muscarinic receptor number, and indicate the possible involvement of these receptors in the mechanism of action of antidepressant drugs.

Lithium at therapeutic concentrations inhibits human brain noradrenaline-sensitive cyclic AMP accumulation

Lithium at a therapeutically effective concentration of 1 mM caused significant inhibition of the rise in cyclic AMP induced by noradrenaline in fresh surgically-obtained slices of human brain.

Hippocampal cholinergic alterations and related behavioral deficits after early exposure to phenobarbital

Mice were exposed to phenobarbital (PhB) prenatally and neonatally. Prenatal exposure was accomplished by feeding the mother PhB (3 g/kg milled food) on gestation days 9-18. Neonatal exposure was accomplished by daily injections of 50 mg/kg sodium PhB directly to the pups on days 2-21. Long-term biochemical alterations in the pre- and postsynaptic septohippocampal system, as well as related behavioral deficits, were assessed in the treated animals. Significant increase in B(max) values for binding of [3H]QNB to muscarinic cholinergic receptors was obtained on both ages 22 and 50 in prenatally (40-90%, respectively, p less than 0.001) and neonatally exposed (58-89%, p less than 0.001) mice whereas Kd remained normal. Similarly, a significant increase of inositol phosphate (IP) formation in response to carbachol was found after both prenatal and neonatal exposure to PhB (p less than 0.05). No alterations in choline acetyltransferase (ChAT) activity were observed in the prenatally or neonatally treated animals. The early exposed mice showed deficits in the performance in Morris water maze, a behavior related to the septohippocampal pathway. The results suggest that early exposure to PhB induces alterations in postsynaptic components of the hippocampal cholinergic system and concomitantly to impairment in hippocampus-related behavior.

Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts

Despite the basic differences in their underlying biological targets, prenatal exposure to heroin or phenobarbital produces similar syndromes of neurobehavioral deficits, involving defects in septohippocampal cholinergic innervation-related behaviors. At the cellular level, these deficits are associated with cholinergic hyperactivity, characterized by increased concentrations of muscarinic receptors and enhanced second messenger activity linked to the receptors. In the present study, we determined whether the cellular changes are mechanistically linked to altered behavior, using two different approaches: neural grafting and correlations between behavior and biochemistry within the same individual animals. Mice were exposed transplacentally to phenobarbital or heroin on gestation days 9-18 and, as adults, received fetal cholinergic grafts or were sham-operated. Prenatal drug exposure resulted in deficits in behavioral performance tested in the eight-arm radial maze, accompanied by increases in hippocampal M(1)-muscarinic receptor expression and muscarinic receptor-mediated IP formation. Neural grafting reversed both the behavioral deficits and the muscarinic hyperactivity. In the drug-exposed offspring, there was a significant correlation between maze performance and carbachol-induced inositol phosphate (IP) formation. These studies indicate that deficits of cholinergic function underlie the neurobehavioral deficits seen in the hippocampus of animals exposed prenatally to heroin or phenobarbital, and consequently that the observed cholinergic hyperactivity is an unsuccessful attempt to compensate for the loss of cholinergic function. The fact that the damage can be reversed by neural grafting opens up novel approaches to the restoration of brain function after prenatal insults.

The effects of chronic lithium and ECT on A1 and A2 adenosine receptor systems in rat brain.

The influence of chronic dietary lithium administration and electroconvulsive therapy on adenosine A1 and A2 receptors in rat brain were determined. A2 receptor activity was measured by accumulation of cyclic AMP in a cerebral cortical slice preparation after in vitro addition of 2-chloro-adenosine, and was unchanged in animals which received chronic Li but reduced following chronic ECT. A similar reduction was found in the response to noradrenaline and a combination of the two agents. A1 receptors were measured by binding of [3H]cyclohexyladenosine. Both Kd and Bmax values were unchanged after chronic Li or a single ECS, but chronic ECT led to a 70% increase in Bmax. It is proposed that this effect may mediate the reduced locomotor activity seen after chronic ECT in rats, and that it may also be related to the increase in seizure thresholds seen during a course of ECS treatment in humans.

Electroconvulsive shock and cyclic AMP signal transduction: effects distal to the receptor.

Chronic electroconvulsive shock (ECS) induced a significant decrease in noradrenaline‐ and forskolin‐stimulated cyclic AMP production in rat cortical slices, whereas a single ECS had a much smaller effect. In a cortical membrane preparation, adenylate cyclase activity in response to stimulation by forskolin, guanosine‐5′‐(β,γ‐imido)triphosphate, and Mn2+ ions was significantly increased in membranes derived from rats that had received chronic ECS, but was either unchanged or reduced in membranes from rats that received a single treatment only. The results are interpreted in terms of changes occurring at components of the adenylate cyclase enzyme distal to the receptor.

Interstrain correlation between behavioural effects of lithium and effects on cortical cyclic AMP.

Six inbred mouse strains were studied to explore possible correlations between lithium effects on behaviour and on cortical cyclic AMP. The strains were fed lithium in ground food for 3 weeks before behavioural tests and ex vivo evaluation of cyclic AMP accumulation. Replicating previous reports, there was a significant inverse correlation (r = 0.73, n = 6) between spontaneous activity and noradrenaline-induced cyclic AMP, and an almost significant correlation (r = 0.67, n = 6) between spontaneous activity and adenosine-induced cyclic AMP accumulation. The effect of lithium to depress spontaneous activity correlated with its effect to inhibit adenosine-induced rises in cyclic AMP (r = 0.716, n = 6). There were significant strain differences in the behavioural responses to amphetamine. In two strains where amphetamine raised activity and lithium inhibited the amphetamine-induced rise, lithium also significantly inhibited the adenosine-induced rise in cyclic AMP. Two other strains showed amphetamine-induced rises in activity that were not inhibitable by lithium, and these strains showed no significant inhibition by lithium of adenosine-induced cyclic AMP accumulation. The remaining two strains showed no behavioural activity increase with amphetamine.

Septohippocampal cholinergic changes after destruction of the A10-septal dopaminergic pathways

Mice were injected bilaterally into the septum with 6-hydroxydopamine and 6 weeks later the hippocampi were assayed for activity of choline acetyltransferase, muscarinic receptor binding capabilities and for formation of inositol phosphate in response to direct (carbachol) or presynaptically elicited (K+) stimulation of the postsynaptic receptors. Levels of dopamine in the septum were reduced by 70% in the lesioned animals and hippocampal choline acetyltransferase was elevated by the same amount. The Bmax of muscarinic binding was significantly reduced without changes in Kd; nevertheless, carbachol-induced stimulation of formation of inositol phosphate was unaffected. The response to K+ was markedly elevated in the 6-hydroxydopamine-treated animals. Thus, the regulatory effect of A10-septal dopaminergic pathways on the septohippocampal cholinergic innervations is both on the presynaptic and postsynaptic levels.

Vasopressin inhibits cyclic AMP accumulation and adenylate cyclase activity in cerebral preparations

Arginine‐vasopressin (AVP) and lysine vasopressin (LVP) elicited a dose‐dependent inhibition of noradrenaline‐sensitive cyclic AMP accumulation in rat cerebral cortical slices, and of forskolin‐stimulated adenylate cyclase activity in a rat cerebral cortical membrane preparation. In both cases LVP was more potent than AVP, and exerted half‐maximal effects at concentrations similar to those found effective in binding studies on rat hippocampal membranes. In hippocampal slices, AVP did not affect, cyclic AMP accumulation at low concentrations but potentiated the effect of noradrenaline at higher concentrations. In caudate membranes, AVP inhibited dopamine‐stimulated adenylate cyclase with a similar dose‐dependency to that seen for forskolin activation in cortex membranes.

Modulation of second messenger function in rat brain by in vivo alteration of receptor sensitivity: Relevance to the mechanism of action of electroconvulisve therapy and antidepressants

1. The second messengers cyclic AMP and inositol triphosphate are the intracellular mediators for a number of neurotransmitters for which receptors exist on brain neurons. 2. Up- or down-regulation of these receptors in general produce corresponding changes in the associated second messenger systems. 3. Chronic administration of antidepressants including electroconvulsive shock to rats produces a number of changes in cerebral receptors, notably down-regulation of beta-adrenergic and serotonin 5-HT2 receptors and up-regulation of alpha-1 adrenergic receptors. 4. The changes in receptor number induced by such antidepressant treatments are in general accompanied by corresponding changes in the associated second messenger reactions. 5. Antidepressant administration has also been shown to induce increased post-receptor mediated adenylate cyclase activity in cortical membranes, and similar effects have also been reported in striatum after chronic administration of neuroleptics. The relevance of these effects to the mechanism of action of the drugs is discussed.