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Impaired object recognition memory following methamphetamine, but not p-chloroamphetamine- or d-amphetamine-induced
Annabelle M Belcher1, Steven J O'Dell, John F Marshall
11Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
Abstract:
Repeated moderate doses of methamphetamine (mAMPH) damage forebrain monoaminergic terminals and nonmonoaminergic cells in somatosensory cortex, and impair performance in a novelty preference task of object recognition (OR). This study aimed to determine whether the memory deficit seen after a neurotoxic mAMPH regimen results from damage to dopamine (DA) and/or serotonin (5-HT) terminals. Animals were given a neurotoxic regimen of mAMPH, p-chloroamphetamine (PCA, preferentially damages 5-HT terminals), d-amphetamine (d-AMPH, preferentially damages DA terminals), or saline. After 1 week, animals were trained and tested for OR memory. Rats treated with mAMPH showed no recognition memory during the short-term memory (STM) test, whereas both PCA- and d-AMPH-treated rats showed OR STM scores comparable to controls. After behavioral testing, the specificity of monoaminergic lesions was determined by postmortem [125I]RTI-55 binding to dopamine (DAT) and serotonin (SERT) transporter proteins. Tissue from a separate group of animals killed 3 days after drug treatment was processed for Fluoro-Jade (F-J) fluorescence histochemistry to detect damaged cortical neurons. mAMPH-treated rats showed reductions in striatal DAT and hippocampal (HC) and perirhinal (pRh) SERT, as well as degeneration of neurons in primary somatosensory cortex. In PCA-treated rats, HC and pRh SERT were substantially depleted, but striatal DAT and cortical neuron survival were unaffected. By contrast, d-AMPH-treated animals showed marked depletions in striatal DAT and cortical neurodegeneration, but HC and pRh SERT were unaffected. This pattern of results indicates that no single feature of mAMPH-induced neurotoxicity is sufficient to produce the OR impairments seen after mAMPH treatment.
Insights
Methamphetamine (mAMPH) impairs object recognition memory by damaging dopamine and serotonin systems. This study found that neither dopamine nor serotonin terminal damage alone explains the memory deficit caused by mAMPH.
Area of Science:
- Neuroscience
- Pharmacology
- Neurotoxicity
Background:
- Repeated methamphetamine (mAMPH) exposure causes neurotoxicity in forebrain monoaminergic terminals and cortical neurons.
- This neurotoxicity is associated with impaired object recognition (OR) memory performance.
Purpose of the Study:
- To investigate whether damage to dopamine (DA) and/or serotonin (5-HT) terminals underlies the memory deficits induced by a neurotoxic mAMPH regimen.
- To differentiate the specific roles of DA and 5-HT neurotoxicity in methamphetamine-induced object recognition memory impairment.
Main Methods:
- Animals received neurotoxic regimens of mAMPH, p-chloroamphetamine (PCA; 5-HT selective), d-amphetamine (d-AMPH; DA selective), or saline.
- Object recognition (OR) memory was assessed using a novelty preference task.
- Monoaminergic transporter binding ([125I]RTI-55) and Fluoro-Jade (F-J) histochemistry were used to quantify neurotoxicity.
Main Results:
- Methamphetamine (mAMPH) treatment resulted in significant object recognition memory deficits.
- p-chloroamphetamine (PCA) and d-amphetamine (d-AMPH) treatments did not impair short-term memory (STM) for object recognition.
- mAMPH caused reductions in striatal dopamine transporters (DAT) and hippocampal/perirhinal serotonin transporters (SERT), along with cortical neuron degeneration. PCA primarily depleted SERT, while d-AMPH primarily depleted DAT and caused cortical neurodegeneration.
Conclusions:
- The memory impairment observed after mAMPH treatment is not solely attributable to damage in either dopamine or serotonin terminals.
- Methamphetamine's neurotoxic effects on object recognition memory likely involve complex interactions or damage to non-monoaminergic systems.
- Neither selective serotonin nor selective dopamine terminal damage replicates the full spectrum of mAMPH-induced neurobehavioral deficits.
