Studies on memory: inhibitors of protein synthesis also inhibit catecholamine synthesis.

Abstract

The rates of accumulation of newly synthesized catecholamines and endogenous catecholamine levels in mice were determined after treatment with cycloheximide, acetoxycycloheximide, puromycin, and anisomycin. The rates of accumulation were found to be decreased by all antibiotics tested, weakening the assumption that their amnestic effects are due solely to inhibition of protein synthesis. The hypothesis that protein synthesis is essential for longterm memory has developed from the observation in several species that treatment with an inhibitor of protein synthesis before or shortly after training leads to amnesia of the training experience (1-6). There is evidence, however, that important side-effects on the central adrenergic system may be common to all inhibitors of protein synthesis and that these side-effects may contribute to the amnesia. For example, in mice and rats the amnesia caused by puromycin, acetoxycycloheximide (AXM), and cycloheximide (CXM) is attenuated by adrenergic stimulants or monoamine oxidase inhibitors (7-9). Also consistent with this possibility are the reports that AXM, CXM, and anisomycin (Ani) cause a reduction of tyrosine hydroxylase activity (10,11). This further suggests that the amnestic effects of the antibiotics may depend in part on a reduction of the functional pools of newly synthesized catecholamines (CAs) (12, 13). We found support for involvement of these functional pools by observing that a large amnestic dose of AXM strikingly reduced the rate of accumulation of CAs from circulating tyrosine for at least 12 hr, greatly exceeding in degree and duration what might be anticipated from the loss of tyrosine hydroxylase activity in Vitro. We also found that the antibiotic, in spite of its inhibitory effect on the rate of accumulation of newly synthesized CAs, increased the endogenous levels of CAs for 4 hr after treatment, indicating that it interferes with aspects of CA metabolism in addition to biosynthesis (14).The present experiments extend this approach to CXM, Ani, puromycin, and to the smallest dose of intracerebrally injected AXM found to be amnestic in mice (15). We find all of these antibiotics to have substantial effects on central CAs. In some ways, these effects resemble those produced by inhibitors of tyrosine hydroxylase and dopamine f3-hydroxylase, agents reported to have the same amnestic properties as those of CXM in active or passive avoidance (16, 17) and food-motivated discrimination tasks (18).Male Swiss-Webster and ICR mice (28-32 g) were housed as previously described (14). CXM (120 mg/kg) and Ani (25-30 mg/kg; gift of Pfizer Inc.) were injected subcutaneously in 0.2 ml of water. AXM (10,ug/injection site; gift of the National Cancer Institute) or puromycin (90 gg/injection site; neutralized with NaOH) were injected bitemporally in 12 ,ul of water under light Evipal (150 mg/kg) anesthesia. Controls were injected in the same way with 12 gl of water per injection site. The inhibitor of tyrosine hydroxylase, a-methyl-para-tyrosine (methyl ester-HCl...

On the Dynamic Nature of the Engram: Evidence for Circuit-Level Reorganization of Object Memory Traces following Reactivation

“…While such effects are commonly attributed to protein synthesis inhibition, anisomycin and other protein synthesis inhibitors (PSIs) can influence numerous biochemical processes. For instance, PSIs can inhibit monoamine function (Flexner and Goodman, 1975;Canal et al, 2007), influence post-translational modification of proteins, including MAPK and CREB (Routtenberg and Rekart, 2005), which are important components of memory-related biochemical cascades, and cause apoptosis at doses below those responsible for protein synthesis inhibition (Iordanov et al, 1997;Rudy et al, 2006). Apoptotic effects cannot fully explain the impairments observed in the present withinsubjects study, as there was no reduction in vehicle condition performance by rats treated with anisomycin on previous trials.…”

Intrahippocampal infusions of anisomycin produce amnesia: Contribution of increased release of norepinephrine, dopamine, and acetylcholine

“…This possibility was suggested in early studies (e.g., Flexner and Goodman 1975;Quartermain et al 1977) and has recently been supported by studies of neurotransmitter release at the site of intra-amygdala injections of anisomycin ). In addition to impairing later memory after inhibitory avoidance training, pretraining injections of anisomycin into the amygdala produced rapid and dramatic increases in release of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) at the sites of injection.…”

“…Despite the centrality of experience-induced protein synthesis in contemporary models of memory formation, the necessity of protein synthesis for memory consolidation and long-term potentiation (LTP) stabilization has been questioned since the beginning of experiments of this type (e.g., Flexner and Goodman 1975;Barraco and Stettner 1976;Flood et al 1978;Martinez et al 1981), and continues to be questioned in several recent reviews (Routtenberg and Rekart 2005;Gold 2006Gold , 2008Radulovic and Tronson 2008;Routtenberg 2008;Rudy 2008). There are many instances of intact memories formed in the presence of extensive inhibition of protein synthesis, and a wide range of behavioral and pharmacological manipulations can rescue memory impaired by protein synthesis inhibitors.…”

Previous Experience with Behavioral Control over Stress Blocks the Behavioral and Dorsal Raphe Nucleus Activating Effects of Later Uncontrollable Stress: Role of the Ventral Medial Prefrontal Cortex

“…Because many of these other effects of ANI involve neural depressant or inhibitory processes (Flexner and Goodman, 1975), it is interesting to compare the effects of ANI with those of muscimol. Indeed, the pattern of results was quite different.…”