Amphetamine and pseudoephedrine cross-tolerance measured by c-Fos protein expression in brains of chronically treated rats

Neuro-Behavioral Biology Center, Institute of Science and Technology, Research and Development, Mahidol University, Salaya, Nakornpathom, 73170, Thailand.
BMC Neuroscience (Impact Factor: 2.67). 11/2008; 9(1):99. DOI: 10.1186/1471-2202-9-99
Source: PubMed


Pseudoephedrine is a drug commonly prescribed as a nasal decongestant and bronchodilator and is also freely available in cold remedies and medications. The structural and pharmacological similarity of pseudoephedrine to amphetamine has led to evaluation of its psychomotor stimulant properties within the central nervous system. Previous investigations have shown that the acute responses to pseudoephedrine were similar to those of amphetamine and other psychostimulants.
This study examined the effect of chronic administration of pseudoephedrine in rat nucleus accumbens and striatum and identified three further similarities to amphetamine. (i) Chronic exposure to pseudoephedrine reduced the c-Fos response to acute pseudoephedrine treatment suggesting that pseudoephedrine induced tolerance in the animals. (ii) In animals chronically treated with amphetamine or pseudoephedrine the acute c-Fos response to pseudoephedrine and amphetamine was reduced respectively as compared to naïve animals indicating cross-tolerance for the two drugs. (iii)The known involvement of the dopamine system in the response to amphetamine and pseudoephedrine was further confirmed in this study by demonstrating that pseudoephedrine similarly to amphetamine, but with lower potency, inhibited [3H]dopamine uptake in synaptosomal preparations.
This work has demonstrated further similarities of the effect of pseudoephedrine to those of amphetamine in brain areas known to be associated with drug addiction. The most significant result presented here is the cross tolerance effect of amphetamine and pseudoephedrine. This suggests that both drugs induce similar mechanisms of action in the brain. Further studies are required to establish whether despite its considerable lower potency, pseudoephedrine could pose health and addiction risks in humans similar to that of known psychostimulants.

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    • "The current results, when taken together with previous studies comparing PE to other psychostimulants (Anderson et al., 2001; Ruskee et al., 2008; Tongjaroenbuangam et al., 1998; Wee et al., 2004), indicate that PE and MA may function as positive reinforcers through a common mechanism of action. The relative positioning of the dose-response functions for PE and MA, taken together with their similarity of shape (see Figure 1, bottom graph), are consistent with drugs that have common mechanisms of action but different relative potencies (Tallarida, 1979). "
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    ABSTRACT: (+)-Methamphetamine (MA) is an illicit psychostimulant that can be synthesized from the nonprescription nasal decongestant, (+)-pseudoephedrine (PE). While MA is widely abused, PE appears to have little or no abuse liability in currently available formulations. However, PE produces centrally-mediated dopaminergic effects that are linked to the reinforcing effects of MA and other illicit psychostimulants and has been reported to function as a positive reinforcer in non-human primates. There has yet to be an assessment of the relative reinforcing effects of MA and PE. Therefore, the current study compared the reinforcing potency and strength of MA and PE, alone and combined, in four rhesus monkeys that were allowed to self-administer MA (0.003-0.3 mg/kg/inj), PE (0.1-3.0 mg/kg/inj), or combinations of the two under a progressive-ratio schedule of reinforcement. (+)-Methamphetamine functioned as a positive reinforcer in a dose-dependent manner. (+)-Pseudoephedrine also functioned as a positive reinforcer, but was less potent than MA. There were no differences in maximum injections between MA, PE, or any of the combinations of the two. Dose-addition analysis and the interaction index indicated that combinations of PE and MA were either additive or sub-additive in their reinforcing effects. These results suggest that, while MA is a more potent reinforcer than PE, the two drugs are comparable in terms of reinforcing strength. However, MA and PE do not appear to interact in a manner that enhances their relative reinforcing effects.
    Full-text · Article · Apr 2010 · Pharmacology Biochemistry and Behavior