Methamphetamine-induced neural and cognitive changes in rodents

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-4550, USA.
Addiction (Impact Factor: 4.74). 05/2007; 102 Suppl 1(s1):61-9. DOI: 10.1111/j.1360-0443.2006.01780.x
Source: PubMed


Although psychostimulant drug abuse carries with it several potential health risks, the chronic abuse of amphetamines carries the danger of permanent brain injury. The purpose of these experiments is to develop animal models to understand the long-lasting influences of methamphetamine exposure on cerebral cortex and cognitive function.
The approach taken is to administer a regimen of methamphetamine known to be neurotoxic to dopamine and serotonin nerve terminals in the rat, and to investigate the influences of that dosing regimen on (i) cortical neuron integrity and function using anatomical stains and (ii) novel object recognition memory.
In rodents, repeated administration of methamphetamine during a single day produces long-lasting damage to striatal dopamine and forebrain serotonin terminals as well as degeneration of somatosensory cortical neurons. The degeneration of somatosensory cortical neurons may represent only the most visible form of long-term deleterious effects on cerebral cortex, as exposure of rats to methamphetamine can reduce the immediate early gene responses of neurons in widespread cortical areas, even long after exposure to the drug. Together with the death and long-lasting functional impairments of cortical neurons, rats exposed to methamphetamine have impaired cognitive function. When tested for object recognition memory, methamphetamine-treated rats show deficiencies lasting for at least 3 weeks after drug exposure.
Using a rodent model, these findings provide an avenue to study the cortical influences of methamphetamine and their cognitive sequelae.

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    • "Recent studies support the possibility that METH-induced neurotoxicity may not lead to METH-mediated cognitive deficits. For example , a 2-week neurotoxic regiment of METH significantly decreases striatal dopamine levels without evidence of any cognitive impairment (Marshall et al., 2007). Consistently, Marshall et al. (Belcher et al., 2005) have shown that even a 65% decrease in striatal DA nerve terminals following an acute METH exposure paradigm fails to disrupt visual recognition memory (Belcher et al., 2005). "
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    ABSTRACT: Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long-term deficits in short-term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex-vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short-term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short-term memory when measured after 14 days ofMETH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH-exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short-term as well as long-term consequences of methamphetamine exposure. Synapse, 2012. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · May 2013 · Synapse
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    • "Few studies in humans have reported a loss of the SERT in methamphetamine (METH) users, likely since primates are far less vulnerable to methamphetamine-induced 5-HT injury than to dopamine injury (Easton and Marsden, 2006; Nordahl et al., 2003). However, METH and (þ/À)3,4-methylenedioxymethamphetamine (MDMA, " ecstasy " ), reduced brain SERT density, which was associated to cognitive deficits (Herring et al., 2008; McCann et al., 2008; Marshall et al., 2007; Scott et al., 2007). For instance, abstinent MDMA users with a history of using substantial MDMA (two or more doses over a 3-to 12-h period) and age-, gender-, and education-matched controls participated (McCann et al., 2008). "
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    ABSTRACT: The serotonin transporter (SERT) has been associated to diverse functions and diseases, though seldom to memory. Therefore, we made an attempt to summarize and discuss the available publications implicating the involvement of the SERT in memory, amnesia and anti-amnesic effects. Evidence indicates that Alzheimer's disease and drugs of abuse like d-methamphetamine (METH) and (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") have been associated to decrements in the SERT expression and memory deficits. Several reports have indicated that memory formation and amnesia affected the SERT expression. The SERT expression seems to be a reliable neural marker related to memory mechanisms, its alterations and potential treatment. The pharmacological, neural and molecular mechanisms associated to these changes are of great importance for investigation.
    Full-text · Article · Sep 2011 · Neuropharmacology
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    • "A single-day of binge mAMPH has been reported to result in cortical changes, affecting metabolism and gene expression in several cortical areas (Pontieri et al 1990; Belcher et al 2009). Such functional 5-HT changes can occur secondarily to changes in DA transmission (Marshall et al. 2007; Belcher et al. 2009) and might predispose the organism to work and/or delay aversion. Serotonin in the frontal cortex is also altered after mAMPH (Hotchkiss and Gibb 1980). "
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    ABSTRACT: Methamphetamine (mAMPH) administration in animals can lead to a variety of cognitive and behavioral deficits. We previously reported non-acute reversal learning impairments after a single-day administration of mAMPH, providing evidence of this drug's selective effects on inhibitory control. Effortful decision-making (i.e., how much effort to invest in rewards) is an aspect of cognition that has not yet been explored after mAMPH. Given that frontostriatal circuitry mediating this type of choice is vulnerable to the effects of mAMPH, we tested the hypothesis that mAMPH may also affect decision-making involving effort, another form of cognitive flexibility. We examined the non-acute effects of an experimenter-administered single day of mAMPH on effort discounting. In this task, rats previously treated with mAMPH or saline (SAL) could select a high reward at the cost of climbing over a tall barrier or a low reward with no barrier impeding its procurement. Following treatment, mAMPH rats were more work-averse than SAL rats. A control task showed there were no treatment group differences when the high and low rewards involved equal work: all rats chose the high reward preferentially. There were no significant treatment group differences in [(125)I]RTI-55 binding to dopamine and serotonin transporters (DAT, SERT) in any of the regions assayed; however, there were significant correlations of accumbens DAT and cingulate SERT with post-treatment performance. These findings suggest that even modest dose mAMPH exposure has long-lasting effects on effortful decision-making and may do so through influences on forebrain monoaminergic systems.
    Full-text · Article · Jun 2011 · Psychopharmacology
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