Mechanisms of Locomotor Sensitization to Drugs of Abuse in a Two-Injection Protocol

Abstract

A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, its mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization revealed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS). The first cocaine injection induced a locomotor sensitization that was completely context-dependent, increased during the first week, and persisted 3 months later. The induction of sensitized responses to cocaine required dopamine D1 and glutamate NMDA receptors. A single injection of the selective dopamine transporter blocker GBR12783 was sufficient to activate extracellular signal-regulated kinase (ERK) in the striatum to the same level as cocaine and to induce sensitization to cocaine, but not to itself. The induction of sensitization was sensitive to protein synthesis inhibition by anisomycin after cocaine administration. Morphine induced a pronounced context-dependent sensitization that crossed with cocaine. Sensitization to morphine injection was prevented in knock-in mutant mice bearing a Thr-34-Ala mutation of DARPP-32, which suppresses its ability to inhibit protein phosphatase-1, but not mutation of Thr-75 or Ser-130. These results combined with previous ones show that TIPS in mouse is a context-dependent response, which involves an increase in extracellular dopamine, stimulation of D1 and NMDA receptors, regulation of the cAMP-dependent and ERK pathways, inhibition of protein phosphatase-1, and protein synthesis. It provides a simple and sensitive paradigm to study the mechanisms of long-term effects of drugs of abuse.

Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization

“…These studies are generally consistent with the model that activity of direct-pathway MSNs (D1R-expressing) stimulates locomotion, whereas activity of indirect pathway MSNs (D2R-expressing) inhibits locomotion (17). In addition to evidence that D1R and D2R neurons have antagonistic effects in psychostimulant sensitization, a growing body of work suggests that convergence of NMDAR and D1R signaling are required to mediate changes associated with repeated psychostimulant treatment (4,(18)(19)(20). These data led us to hypothesize that inactivating NMDARs specifically on D1R neurons, while leaving those on D2R neurons intact, might reveal a role for NMDAR signaling in the NAc in AMPH sensitization.…”

The competitive NMDA receptor antagonist CPP disrupts cocaine-induced conditioned place preference, but spares behavioral sensitization

“…It has been accepted that NMDARs are critical for the development of cocaine-induced sensitization. This notion is primarily based on evidence that co-administration of MK801 with cocaine completely blocks [15][16][17][18][19][20][21][22][23] or reduces [16,33,49,76,77] cocaine-induced sensitization. However, this conclusion is still highly controversial and the role of NMDARs in addiction remains unclear [78].…”

“…Co-administration of MK801 prevents the development of sensitization to cocaine [15][16][17][18][19][20][21][22][23], amphetamine [24][25][26][27][28] and methamphetamine [29,30]. Moreover, MK801 similarly prevents the development of cocaine, amphetamine, and methamphetamineinduced conditioned place preference, a prominent associative memory model of drug seeking behavior [31][32][33].…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Sensitization is most commonly assayed by measuring increases in locomotor activity after repeated experimenter-administered (noncontingent) drug delivery. Although a single drug injection may be sufficient to elicit behavioral sensitization lasting a few days (Post and Weiss, 1988;Valjent et al, 2010), repeated drug administration more generally appears necessary to produce enduring (weeks to months) sensitization. In rodent models of sensitization, augmented behavior to an acute drug challenge is reliably paralleled by enhanced dopaminergic activity in the NAc (Kalivas and Duffy, 1990;Johnson and Glick, 1993;Paulson and Robinson, 1995;Cadoni and Di Chiara, 2000) (with the possible exception of alcohol; see Zapata et al, 2006).…”