PRECLINICAL STUDY: Protracted ‘anti‐addictive’ effects of adolescent phenylpropanolamine exposure in C57BL/6J mice

Abstract

Exposure to the once highly prevalent over-the-counter (OTC) sympathomimetic phenylpropanolamine (PPA; +/--norephedrine) during pre-adolescence alters the developmental trajectory of catecholamine and amino acid neurotransmitter systems in the nucleus accumbens (NAC) that culminate in a 'pro-addictive' phenotype in adulthood. Thus, the present study sought to extend these earlier data by examining the long-term consequences of repeated PPA treatment during adolescence upon the behavioral and neurochemical responses to cocaine. For this, C57BL/6J mice were pre-treated with PPA (0-40 mg/kg) during postnatal days 35-44, and the capacity of cocaine (4 x 15 mg/kg) to elicit a conditioned place-preference, as well as behavioral and neurochemical sensitization within the NAC, were then assessed in adulthood. While adolescent PPA exposure did not influence spontaneous locomotor activity or the motor responses to either acute or repeated cocaine (4 x 15 mg/kg), PPA pre-exposure dose-dependently reduced the expression of a conditioned place-preference. As observed previously for juvenile PPA treatment, adolescent PPA administration blunted the dopamine and norepinephrine response to acute cocaine, prevented the development of catecholamine sensitization but did not influence cocaine-induced elevations in serotonin. However, unlike juvenile PPA treatment, adolescent PPA also prevented the development of glutamate sensitization within the NAC. These data provide evidence that adolescent exposure to a formerly prevalent OTC sympathomimetic produces protracted effects upon cocaine-induced changes in NAC glutamate transmission that may reduce vulnerability to cocaine addiction in later life and further the hypothesis that early exposure to sympathomimetic drugs may be an environmental factor contributing to the etiology of addiction.

Imbalances in Prefrontal Cortex CC-Homer1 versus CC-Homer2 Expression Promote Cocaine Preference

“…Glutamate levels were sampled from the NAC shell in the present study, as we have observed previously a positive relation between the magnitude of cocaine CPP in mice and cocaine-elicited increases in extracellular glutamate within this subregion (see Szumlinski et al, 2007; Penzner et al, 2008). The NAC shell receives glutamatergic projections from both the ventral prelimbic (vPL) and the infralimbic (IL) subdivisions of the mPFC (Heidbreder and Groenewegen, 2003), which is in line with our observation that Homer2b cDNA over-expression primarily within the vPL and the vPL-IL interface (Figure 2A) impacted extracellular glutamate within the NAC shell (Figure 5).…”

“…To determine the relevance of our reported cocaine-induced increase in mPFC Homer2 vs. Homer1 expression (Ary and Szumlinski, 2007) for cocaine-induced changes in behavior, the effects of manipulating mPFC Homer2b levels upon cocaine reward and locomotor sensitization were assessed using a unbiased conditioned place-preference (CPP) procedure (e.g., Szumlinski et al, 2007; Penzner et al, 2008). The CPP paradigm was selected for the study of AAV interactions with cocaine for its procedural simplicity, the ability to index both the positive and negative motivational valence of cocaine-associated cues and the ability to index both cocaine reward and locomotor activity.…”

“…Conventional microdialysis was conducted for 1 hour prior to, and 3 hours immediately following, an IP cocaine injection (15 mg/kg), as conducted previously by our group (Szumlinski et al, 2004, 2005b, 2007; Penzner et al, 2008). For all experiments, microdialysis probes (24 gauge; for mPFC: 10 mm in length with ~ 1.0 mm of active membrane; for NAC: 12 mm in length with ~1.0 mm of active membrane) were lowered into the guide cannulae implanted above the intended region and perfused with artificial cerebrospinal fluid (146 nM NaCl, 1.2 mM CaCl2, 2.7 mM KCl, 1.0 mM MgCl2, pH = 7.4) at a rate of 2 μl/min.…”

Rapamycin attenuates the expression of cocaine‐induced place preference and behavioral sensitization

“…Procedures for cocaine place-conditioning and assessment of locomotor activity were similar to those described previously (Penzner et al, 2008; Szumlinski et al, 2007). Briefly, all experiments were conducted in a Plexiglas apparatus (46 cm long × 24 cm high × 22 cm wide) with a sound-attenuating lid and a removable center divider separating 2 compartments of equal size.…”

Homers at the Interface between Reward and Pain

“…The apparatus and procedures for heroin place-conditioning were similar to those employed in our previous studies of drug-conditioned reward in mice (e.g., Penzner et al, 2008) and proceeded in the following four sequential phases: habituation, preconditioning test (Pre-Test), conditioning, postconditioning test (Post-test). All sessions were 15 min in duration and animals received no injections during the habituation, Pre-Test, or Post-Test sessions when they had free-access to both compartments of the apparatus.…”