Can the ”state-dependency" hypothesis explain prevention of amphetamine sensitization in rats by NMDA receptor antagonists?

Abstract

Many laboratories have reported that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative "state-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK-801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the "state-dependency" hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction.

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

“…Selective ablation of NR1 expression in striatal neurons has been used to study the role of NMDA receptor signaling in the acquisition of behavioral sensitization and conditioned place preference (Heusner and Palmiter, 2005;Agatsuma et al, 2010). These studies clarify previous research showing that blockade of NMDA receptor is disruptive to the development of sensitization and place preference (Haracz et al, 1995;Kim et al, 1996;Li and Wolf, 1999).…”

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

“…Despite these differences, however, the behavioral findings with amphetamine are consistent with those of cocaine. Competitive, non-competitive, and glycine-site NMDAR antagonists interfere with both the acute and sensitized responses to amphetamine [45,46,27,47,48,52].…”

“…For example, her lab [52] found that CGS19755 produced a "clean block" of sensitization by preventing any increase in amphetamine-induced activity across training days and during the sensitization challenge test. However, in both this and a prior study [27], the acute response to amphetamine was dramatically increased when CGS19755 was coadministered (compare [52], their Figs. 1A and 2A, day 1 response for amphetamine only and amphetamine with CGS19755 and [27], their Fig.…”

“…This difference in time course makes a later sensitization challenge test difficult to interpret. It seems that most competitive NMDAR antagonists interfere with the acute behavioral response to psychostimulants; CPP, CGS19755, and AP5 have all been shown to alter the acute responses to cocaine and amphetamine [45,46,27,47,48,[51][52][53][54][55]. These findings highlight the need for more studies using selective NMDAR antagonists and more attention to the effect of NMDAR antagonism on acute psychostimulantinduced behaviors.…”

“…A few studies have used cleaner, competitive NMDAR antagonists in examining psychostimulant-induced sensitization [45,46,17,20,27,29,41,[47][48][49][50][51][52][53][54]. For example, Wolf et al [27] used CGS19755 and found a "clean block" of amphetamine sensitization -i.e., stereotyped and locomotor behavior did not increase with repeated administration in rats co-administered CGS19755 with amphetamine.…”