Limited Access To Drugs Research Articles

Escalating cocaine intake during extended self‐administration enhances cocaine‐primed reinstatement of operant behavior in rhesus monkeys

The present study assessed the effects of extended cocaine exposure on the magnitude and persistence of cocaine‐primed reinstatement as a model of relapse. Rhesus monkeys (n=6) with an extensive cocaine self‐administration history under a second‐order schedule were allowed extended self‐administration sessions under a fixed‐ratio 20 schedule. Subsequently, saline was substituted for cocaine under the second‐order schedule and subjects underwent extinction. Once extinction criteria were met (<20% of cocaine‐maintained responding), noncontingent cocaine (0.1 mg/kg, iv) was administered prior to an extinction session and peak response rates were measured as an index of reinstatement magnitude. Reinstatement experiments were repeatedly conducted until response rates returned to extinction levels. The number of sessions to this criterion was taken as an index of resistance to extinction. Peak response rates following extended cocaine access were greater for each reinstatement trial compared to the initial limited drug access. In contrast, sessions to reach extinction criteria decreased between cocaine access conditions. These results suggest that extended cocaine experience enhanced cocaine‐induced reinstatement, but not resistance to extinction. USPHS Grant DA016589, DA00517, and RR00165

Rapid Modulation of P-Glycoprotein-Mediated Transport at the Blood-Brain Barrier by Tumor Necrosis Factor-α and Lipopolysaccharide

At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain parenchyma, impeding pharmacotherapy of a number of central nervous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ET(B) receptor, NO synthase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain's innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), activated a TNF-R1 receptor, released ET-1, activated ET(B) receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain's innate immune response, reduced P-glycoprotein activity through TNF-alpha release, ET-1 release, and ET(B) receptor signaling. TNF-alpha and LPS effects had a rapid onset (minutes), were reversible, and did not involve changes in tight junctional permeability. These findings define a signaling pathway through which P-glycoprotein activity is acutely modulated. They show that this key component of the selective/active blood-brain barrier is an early target of cytokine signaling during the innate immune response and suggest ways to manipulate the barrier for improved CNS pharmacotherapy.

Expression of the multidrug resistance P glycoprotein (Pgp) and multidrug resistance associated protein (MRP1) in Down syndrome brains.

Transport by ATP-dependent efflux pumps such as P glycoprotein (Pgp) and multidrug resistance associated protein (MRP), encoded by multidrug resistant (MDR) associated genes, is an increasingly recognized mechanism by which cells maintain substrate homeostasis and evade drug therapy. Pgp and MRP are members of the so-called ATP binding cassette (ABC) transporters superfamily, which are associated with many biological processes in both prokaryotes and eukaryotes, as well as clinical problems. The observation of upregulated sequences that are homologous to the Mycobacterium smegmatis phage resistance (mpr) gene and putative ABC transporters subunits in fetal Down syndrome (DS) using the gene hunting technique, subtractive hybridization formed the Rationale for this study. The expression of Pgp and MRP1 is therefore investigated in different brain regions of controls and adult DS patients with western blot technique. No apparent changes were observed between controls and DS in levels of Pgp in all brain regions examined. By contrast, MRP1 detection using the rat monoclonal antibody (MRPr1) produced a significant elevation in DS temporal cortex (P < 0.01) and parietal cortex (P < 0.05). Although MRP1 detected with the mouse monoclonal antibody (MRPm6) tended to increase in most of the regions of DS brain, it failed to reach significance level. Age or postmortem interval did not correlate with protein levels in both controls as well as DS. Taken together, the current data provide evidence for the presence of MDR related pumps in different regions of the human brain. In addition, overexpression of MRP1 in DS brain may have some relevance to the disorder either by deranging substrate homeostasis or limiting drug access.