Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

Abstract

Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.

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

“…Consistent with previous studies in rodents (eg, Pierce et al, 1996;Szumlinski et al, 2004aSzumlinski et al, , b, 2005bSzumlinski et al, , 2006, an acute injection of 15 mg/kg cocaine to either group of mice did not affect NAC extracellular levels of glutamate ( Figure 6a); however, following repeated cocaine administration, cocaine elicited a significant increase in glutamate above baseline in control mice (time effect p ¼ 0.06; time  cocaine injection number: F(11,253) ¼ 3.20, po0.0001). As depicted in Figure 6a, the cocaine-sensitized increase in extracellular glutamate was significantly greater in mice pretreated with PPA (PPA pretreatment effect: p ¼ 0.70; PPA  time: p ¼ 0.60; PPA pretreatment  cocaine injection number  time: F(11,253) ¼ 1.84, p ¼ 0.04).…”

Prenatal Stress Enhances Responsiveness to Cocaine

“…Nevertheless, the pattern of neurochemical differences between naïve PNS and control rats may contribute to their differences in novelty-and cocaine-induced locomotor behavior. In particular, enhanced dopamine (basal and stimulated) and low basal with greater stimulated glutamate have been implicated in the sensitized locomotor response observed following repeated psychostimulant drug treatments (Heidbreder et al, 1996;Hooks et al, 1994;Kalivas and Duffy, 1993;Pierce et al, 1996;Reid and Berger, 1996;Szumlinski et al, 2006) and probably contribute to the presensitized behavioral responding of PNS rats. Further, serotonin inhibits dopamine (eg Rothman and Baumann, 2006) and glutamate (Szumlinski et al, 2004) transmission in the NAC.…”

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

“…The set of transcripts examined, while not comprehensive, represent well-characterized gene alterations from several cocaine administration procedures. Specifically, the immediate early genes Fos (Graybiel et al, 1990), EGR1 (Daunais and McGinty, 1995), Arc (Fosnaugh et al, 1995), and Nr4a1 (Freeman et al, 2002b); neuropeptides CART (Douglass et al, 1995) and Neuropeptide Y (NPY; Westwood and Hanson, 1999); glutamate receptors (Carlezon and Nestler, 2002;Boudreau and Wolf, 2005), and homer genes (Szumlinski et al, 2006) were examined. Furthermore, for those genes that demonstrated persistent changes in mPFC mRNA abundance, histone H3 hyperacetylation was examined as a potential regulatory mechanism.…”