The main finding of the present study is that escalating doses of OFQ/N administered ICV or directly into the VTA prior to systemic cocaine administration blocked the development of cocaine-induced behavioral sensitization. The action of OFQ/N was not context-dependent and was blocked by J-113397, an ORL-1 receptor antagonist.
The ability of OFQ/N to modulate dopaminergic and glutamatergic neurotransmission in the central nervous system is well established. Since dopamine and particularly glutamate systems have been implicated in cocaine-induced behavioral sensitization (for review, see Vanderschuren and Kalivas 2000
), in the present investigation we determined the action of OFQ/N on this phenomenon. Consistent with our previous findings, we found that OFQ/N administration, either ICV or directly into the VTA, acutely suppressed basal motor activity and the motor stimulatory action of cocaine (Narayanan and Maidment 1999
; Lutfy et al. 2001a
). Similarly, we observed a trend for the motor stimulatory effect of cocaine to be enhanced when OFQ/N was administered repeatedly into the VTA (and to a lesser extent after ICV administration) in the absence of cocaine treatment (, and ). However, our earlier report (Narayanan and Maidment 1999
) showed that intra-VTA OFQ/N administration failed to block cocaine-induced behavioral sensitization. Since, in the previous study, the same dose of OFQ/N was administered each day during the induction of sensitization, we considered the possibility that tolerance may have developed to the action of OFQ/N (Devine et al. 1996b
; Lutfy et al. 1999
). The present study was therefore designed to re-investigate the action of OFQ/N on cocaine-induced behavioral sensitization using an escalating dosing paradigm in an attempt to counteract the development of tolerance. Using this approach, we first tested the effect of ICV OFQ/N administration on cocaine-induced behavioral sensitization. Subsequently, we determined the effect of OFQ/N administered directly into the VTA on this phenomenon because the inhibitory action of OFQ/N on motor activity and extracellular dopamine is mediated, at least in part, in the VTA (Murphy and Maidment 1999
; Narayanan and Maidment 1999
; Lutfy et al. 2000
). In each case, the use of escalating doses produced the predicted attenuation of cocaine-induced motor stimulation on each day of the 3-day treatment period. Furthermore, the data clearly show that concomitant administration of escalating doses of OFQ/N via either route of administration blocked the development of cocaine-induced behavioral sensitization.
OFQ/N shows structural similarities to endogenous opioid peptides, particularly to dynorphin A (1−17) (Meunier et al. 1995
; Reinscheid et al. 1995
), administration of which also blocks sensitization to cocaine (for review, see Shippenberg and Rea 1997
). Since we used relatively high doses of OFQ/N, the possibility that OFQ/N was acting through the kappa site to block cocaine-induced motor stimulation and behavioral sensitization has to be considered. Indeed, Florin and colleagues (1996)
suggested that motor suppression at high doses of OFQ/N might be explained by non-specific binding of OFQ/N to kappa opioid receptors. However, we found that the action of OFQ/N on cocaine-induced motor stimulation and behavioral sensitization was blocked by J-113397, an ORL-1 receptor antagonist (Kawamoto et al. 1999
), indicating that OFQ/N's actions in this regard are mediated via a specific interaction with the ORL-1 receptor.
It is possible that OFQ/N blocked the development of behavioral sensitization to cocaine simply by virtue of its ability to attenuate the acute effect of cocaine on days 1−3. However, one should bear in mind that the motor stimulatory action of cocaine on days 1−3 was not totally blocked by OFQ/N. Indeed, cocaine still produced a significant (P
<0.05) motor stimulation as compared to control rats ( and ; compare OFQ/N-COC versus OFQ/N-SAL). However, the development of sensitization was totally blocked. Furthermore, there is some evidence showing that blockade of motor stimulatory action of cocaine by a dopamine receptor antagonist does not lead to blockade of cocaine-induced behavioral sensitization (Steketee 1998
; White et al. 1998
; for review, see also Vanderschuren and Kalivas 2000
and references therein). Nevertheless, since OFQ/N attenuated the motor stimulatory action of cocaine on days 1−3, it is possible that rats that received OFQ/N prior to cocaine experienced the test environment quite differently from the rats that received aCSF prior to cocaine administration on days 1−3. This is an important consideration because a component of cocaine-induced behavioral sensitization is context-dependent (for review, see Post et al. 1987
). However, OFQ/N retained the ability to block the development of cocaine-induced behavioral sensitization when OFQ/N and cocaine were administered in the home cage during the induction of sensitization and challenged in a novel environment (). Thus, it appears that OFQ/N is acting through a novel mechanism to block acquisition of cocaine sensitization, primarily involving prevention of long-term plastic changes produced by repeated cocaine administration.
Our data provide no further information as to the mechanisms underlying this action of OFQ/N. Repeated intermittent cocaine treatment has been shown to modify endogenous opioid peptide gene expression (Sivam 1989
; Hurd et al. 1992
) and opioid receptor number (Hammer et al. 1989; Unterwald et al. 1992
). Furthermore, mu and delta opioid receptor antagonists have been shown to block the development of cocaine sensitization (Sala et al. 1995
; Heidbreder et al. 1996
). OFQ/N has been shown to oppose the action of mu and delta opioid receptor agonists in a number of physiological systems (for review, see Mogil and Pasternak 2001
). It is therefore possible that OFQ/N acts in a similar manner to block the development of cocaine-induced behavioral sensitization.
In summary, OFQ/N when administered ICV or directly into the VTA, in escalating doses, prior to systemic cocaine administration, blocks the development of cocaine-induced locomotor sensitization. This action of OFQ/N was selectively mediated through the ORL-1 receptor because OFQ/N failed to exert its inhibitory effects in the presence of J-113397, an ORL-1 receptor antagonist. Given the proposed importance of such sensitized response to addictive process, OFQ/N and its receptor could represent new pharmacotherapeutic targets for the treatment of cocaine addiction.