Protracted ‘Pro-Addictive’ Phenotype Produced in Mice by Pre-Adolescent Phenylpropanolamine

Abstract

For decades, the sympathomimetic phenylpropanolamine (PPA; 7-norepinephrine) was an active ingredient found in popular children's over-the-counter (OTC) cold, cough, and allergy medications. To examine the possibility that pre-adolescent PPA exposure may induce neuroadaptations that influence behavioral and neurochemical responding to cocaine, C57BL/6J mice were pretreated with PPA (0-40 mg/kg) during postnatal days 21-31. The behavioral and neurochemical responses to acute and repeated cocaine (4 Â 15 mg/kg) were then assessed in adulthood when the mice were 10 weeks of age. Whereas pre-adolescent PPA exposure did not influence the acute locomotor response to 15 mg/kg cocaine, PPA pre-exposure dose-dependently enhanced the expression of cocaine-induced place conditioning, reduced the expression of locomotor sensitization, but did not influence cocaine-induced stereotypy. Pre-adolescent PPA exposure completely prevented the capacity of cocaine to elevate extracellular levels of catecholamines in the nucleus accumbens, but facilitated the development of cocaine-induced glutamate sensitization. Neither acute nor repeated cocaine altered extracellular GABA levels in the accumbens of control mice; however, 15 mg/kg cocaine lowered GABA levels by approximately 40% in PPA pretreated mice and this effect showed tolerance with repeated cocaine administration. These data provide the first evidence that early exposure to an OTC compound produces protracted effects upon cocaine-induced changes in nucleus accumbens neurotransmission that may contribute to a 'pro-addictive' phenotype in adulthood.

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.…”

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation

“…An ESA 5014B analytical cell with two electrodes was used for the electrochemical detection of monoamines—the reduction analytical electrode (E1, −150 mV), and an oxidation analytical electrode (E2, +220 mV). Dopamine and serotonin content in each sample was analyzed by peak height and compared to external standard curves (one for each neurotransmitter) for quantification (e.g., Szumlinski et al, 2007). Unfortunately, our HPLC conditions did not permit reliable detection of norepinephrine in the dialysate.…”

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.…”