Changes in Accumbal and Pallidal pCREB and ΔFosB in Morphine-Sensitized Rats: Correlations with Receptor-Evoked Electrophysiological Measures in the Ventral Pallidum

Abstract

Activation of μ-opioid receptors in the ventral pallidum (VP) is important for the induction of behavioral sensitization to morphine in rats. The present study was designed to ascertain if neurons within the VP demonstrate sensitization at a time when morphine-induced behavioral sensitization occurred (ie 3 or 14 days after five once-daily injections of 10 mg/kg i.p. morphine) in rats. Western blotting was used to evaluate transcription factors altered by opiates, CREB and ΔFosB. CREB levels did not change in the VP, but there was a significant decrease in levels of its active, phosphorylated form (pCREB) at both 3-and 14-days withdrawal. ΔFosB levels were elevated following a 3-day withdrawal, but returned to normal by 14 days. This profile also was obtained from nucleus accumbens tissue. In a separate group of similarly treated rats, in vivo electrophysiological recordings of VP neuronal responses to microiontophoretically applied ligands were carried out after 14-days withdrawal. The firing rate effects of local applications of morphine were diminished in rats withdrawn from i.p. morphine. Repeated i.p. morphine did not alter GABA-mediated suppression of firing, or the rate enhancing effects of the D1 dopamine receptor agonist SKF82958 or glutamate. However, VP neurons from rats withdrawn from repeated i.p. morphine showed a higher propensity to enter a state of depolarization inactivation to locally applied glutamate. Overall, these findings reveal that decreased pCREB in brain regions such as the VP accompanies persistent behavioral sensitization to morphine and that this biochemical alteration may influence the excitability of neurons in this brain region.

Distinct patterns of ΔFosB induction in brain by drugs of abuse

“…Induction of ΔFosB in striatal regions has also been observed after chronic consumption of natural rewards, such as wheel-running behavior (Werme et al, 2002). In addition, there have been several reports of lower levels of ΔFosB induction in certain other brain regions, including prefrontal cortex, amygdala, ventral pallidum, ventral tegmental area, and hippocampus (Liu et al, 2007;McDaid et al, 2006aMcDaid et al, ,2006bNye et al, 1996;Perrotti et al, 2005), in response to some of these drugs of abuse, however, there has never been a systematic mapping of drug induction of ΔFosB in brain. Moreover, despite the investigation of most drugs of abuse, two of the most widely abused substances, ethanol and Δ 9 -THC, have not to date been examined for their ability to induce ΔFosB.…”

“…Study of ethanol and (Δ 9 -THC are particularly important, because these are two of the most widely used drugs of abuse in the US today (SAMHSA, 2005). Moreover, although stimulant or opiate drugs of abuse have been shown to induce ΔFosB in certain other isolated brain regions, which, in addition to nucleus accumbens and dorsal striatum, include prefrontal cortex, amygdala, ventral pallidum, ventral tegmental area, and hippocampus (Liu et al, 2007;McDaid et al, 2006aMcDaid et al, ,2006bNye et al, 1995;Perrotti et al, 2005), there has not been a systematic mapping of ΔFosB induction in brain in response to chronic drug exposure.…”

The Ventral Pallidum is Critically Involved in the Development and Expression of Morphine-Induced Sensitization

“…In the VP, ionotropic glutamate receptors are functionally upregulated 14 days after a sensitizing regimen of morphine (McDaid et al, 2006), and intra-VP injections of glutamatergic antagonists in morphine-sensitized rats block the expression of motor sensitization to a subsequent challenge of i.p. morphine .…”

“…VP opioids regulate local dopamine transmission (for review, see Napier and Mitrovic, 1999), and dopamine receptors in the VP are obligatory for acute motor function mediated by intra-VP m-opioid receptors (Napier, 1992). Locally applied morphine typically enhances VP neuronal activity (Johnson and Napier, 1997;McDaid et al, 2006), reflecting an inhibition of GABAergic inputs from the NAc (Chrobak and Napier, 1993;Johnson and Napier, 1997) and/or dopaminergic inputs from the VTA (Mitrovic and Napier, 2002). In turn, the VP sends GABAergic outputs to the NAc (Hakan et al, 1992) and VTA (Fonnum et al, 1978;Kalivas et al, 1993) that regulate the number of VTA neurons that are able to exist in an active, spiking mode (Floresco et al, 2003).…”

Transcriptional mechanisms of addiction: role of ΔFosB

“…In addition, morphine has been shown to induce DFosB in ventral pallidum (McDaid et al 2006a). In each of these regions, it is the 35-37 kD isoforms of DFosB that accumulate with chronic drug exposure and persist for relatively long periods during withdrawal.…”