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Neurochemical and behavioral effects of catecholamine and protein synthesis inhibitors in mice
Abstract:
A series of biochemical and behavioral experiments tested the hypothesis that anisomycin (ANI), a protein synthesis inhibitor, produced decrements in long-term memory by raising free tyrosine levels and by the accumulation of catecholamines (CAs) rather than by its primary effect on protein synthesis. We compared the effects of ANI and three catecholamine synthesis inhibitors (CAIs)--diethyldithiocarbamic acid, alpha-methyl-p-tyrosine, and tetrabenazine--on cerebral concentrations of tyrosine and CAs and on the rate of accumulation of CAs. ANI had a relatively small effect, whereas the CAIs resulted in large reductions. When ANI and a CAI were used in combination, effects on CA levels were determined mainly by the CAI. The amnestic effects of ANI and the CAIs were also compared across seven experimental paradigms. Pretraining administration of any of the four drugs could result in amnesia for passive avoidance training, but only when training was weak. With an increase in training strength, a series of three injections of ANI (one pre- and two post-training) caused amnesia, but a similar series of CAI injections did not. Substituting one CAI injection for the second of three successive ANI injections did not cause amnesia, but substituting cycloheximide, another protein synthesis inhibitor, resulted in amnesia. With an active avoidance test, ANI caused amnesia while AMPT did not; d-amphetamine blocked the amnestic effect of ANI but caused amnesia in AMPT injected mice. Whereas ANI lengthened the temporal gradient over which electroconvulsive shock produced amnesia, AMPT or DDC did not. DDC caused only transient amnesia for passive avoidance training, while the amnestic effect of ANI remained constant at 24-hr and 1-week retention tests. We conclude that ANI and CAIs have distinctly different abilities to produce amnesia. These experiments provide additional support for the hypothesis that protein synthesis is required for formation of long-term memory.
Insights
Anisomycin (ANI) causes memory loss by inhibiting protein synthesis, not by increasing catecholamines. This study confirms protein synthesis is crucial for long-term memory formation.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Anisomycin (ANI) is a protein synthesis inhibitor known to impair memory.
- A hypothesis suggested ANI's amnestic effects stem from increased tyrosine and catecholamines (CAs), not protein synthesis inhibition.
Purpose of the Study:
- To investigate whether anisomycin impairs long-term memory by altering catecholamine levels or through direct protein synthesis inhibition.
- To compare the amnestic effects of anisomycin with catecholamine synthesis inhibitors (CAIs).
Main Methods:
- Biochemical analysis of cerebral tyrosine and CA concentrations after drug administration.
- Behavioral experiments using seven different paradigms to assess memory impairment.
- Comparative studies involving anisomycin, CAIs (diethyldithiocarbamic acid, alpha-methyl-p-tyrosine, tetrabenazine), and cycloheximide.
Main Results:
- CAIs significantly reduced CA levels, while anisomycin had a minor effect.
- Anisomycin induced amnesia under conditions where CAIs did not, particularly with stronger training.
- Substituting a CAI for anisomycin abolished amnesia, whereas substituting cycloheximide retained it.
- Anisomycin's amnestic effects were more persistent than those of CAIs.
Conclusions:
- Anisomycin and CAIs exhibit distinct abilities to produce amnesia.
- The findings support the hypothesis that protein synthesis is essential for the formation of long-term memory.