Effects of minocycline on cocaine sensitization and phosphorylation of GluR1 receptors in 5-lipoxygenase deficient mice

Abstract

In wild-type (WT) mice, the antibiotic minocycline inhibits development of cocaine-induced locomotor sensitization. Some of the actions of minocycline may involve the 5-lipoxygenase (5-LOX) pathway. We used the model of 5-LOX-deficient mice to investigate whether 5-LOX participates in minocycline’s influence on the effects of cocaine. Locomotor sensitization was induced by 4 daily cocaine injections and the phosphorylation status of GluR1 glutamate receptors was assayed in brain samples. Minocycline failed to affect cocaine sensitization in 5-LOX-deficient mice. In these mice, neither cocaine nor minocycline 4-day treatment altered GluR1 phosphorylation. In WT mice in which minocycline inhibited development of cocaine sensitization, a 4-day cocaine treatment increased GluR1 phosphorylation at both Ser831 and Ser845 sites in the frontal cortex but not the striatum; further, this effect was prevented by minocycline. Under basal conditions and in response to a single cocaine injection the levels of GluR1, GluR2, and GluR3 AMPA receptor subunits did not differ between WT and 5-LOX-deficient mice, but the response of GluR1 phosphorylation to a single cocaine injection was greater under the 5-LOX deficiency. Hence, in WT mice GluR1 phosphorylation increased only in the frontal cortex and only at the Ser831 site. In 5-LOX-deficient mice, acute cocaine injection increased both Ser831 and Ser845 phosphorylation both in the frontal cortex and in the striatum. We suggest that in studying minocycline’s action on cocaine’s effects and/or addiction in humans, it would be important to consider the characterization of the subjects’ 5-LOX system.

RETRACTED ARTICLE: Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease

“…Interestingly, the above described 5LO-dependent beneficial effects on the LTP parameters are in line with previously reported enhancements of the GluR1/AMPA receptor phosphorylation by 5LO genetic absence or pharmacologic inhibition 23,24 . Importantly, despite the fact that some of the 5LO biologic effects are mediated by an involvement of the γ-secretase pathway, no alteration of the Notch signaling has been reported 10 .…”

Differential contribution of lipoxygenase isozymes to nigrostriatal vulnerability

“…Mice deficient in 5- or 12-LOX exposed to repeated cocaine exposures do not develop locomotor sensitization as is noted in wildtype control mice (Kurtuncu et al, 2008). This effect is likely attributable to enhanced site-specific GluR1 phosphorylation which occurs in striatum of 5-LOX-deficient mice (Chen and Manev, 2011), that impacts membrane insertion of the receptor and its activity; similar alterations have been observed using a pharmacological model of 5-LOX inhibition, minocycline (Imbesi et al, 2008). Thus, it is possible that products of the isozyme's activity, through interactions with AMPA receptors, contribute to a 5-LOX-mediated response to dopaminergic agents.…”

“…The isozymes, for example, affect the behavioral and biochemical responses to the dopamine re-uptake inhibitor cocaine (Kurtuncu et al, 2008, Chen and Manev, 2011). Mice deficient in 5- or 12-LOX exposed to repeated cocaine exposures do not develop locomotor sensitization as is noted in wildtype control mice (Kurtuncu et al, 2008).…”

Interactions of HIV and Drugs of Abuse

“…Propentofylline, which is thought to affect multiple molecular targets in both astroglia and microglia (Sweitzer, Schubert, & De Leo, 2001; Sweitzer & De Leo, 2011), impairs reinstatement to cocaine through an EAAT-2-related mechanism (Reissner et al, 2014). Furthermore, anti-inflammatory drugs with preferential actions in glia such as minocycline and/or ibudilast can limit key aspects of methamphetamine’s locomotor behaviors and/or reinforcing properties (Snider et al, 2012; Snider, Vunck, Hendrick, & Beardsley, 2012) or aspects of cocaine sensitization (Chen, Uz, & Manev, 2009; Chen & Manev, 2011). …”