Another important consideration with respect to

Another important consideration with respect to drug conditioning suggested by the present findings is the observation of an attenuated α-mangostin sale on the second extinction trial. Seemingly, if ERK measurements were made following a partial reduction in the conditioned response the ERK response would present but reduced. This partial reduction in the conditioned response also suggests that if the immediate apomorphine post-trial treatments were delayed until after the second extinction trial that a sufficient dopamine trace were still present that could be strengthened by the apomorphine treatment such that a conditioned response would be restored and manifested on the subsequent third extinction trial. This possibility raises the question as to the potential efficacy of post-trial treatments given on an intermittent schedule. In the present study, the presumed post-trial activation of dopamine projection areas expressed as ERK activation can be seen as a response that was enhanced by the immediate post-trial apomorphine treatments. When the dopamine trace is viewed as a response that can be modified by post-trial apomorphine treatments then it is possible to consider the use of the post-trial drug treatments on an intermittent schedule. This consideration appears relevant to drug conditioning and drug addiction in that psychostimulant dopaminergic drugs are addictive and conditioned drug effects are an important contributor to the addiction and are difficult to eliminate [54,55]. In typical addictive drug usage, it seems unlikely that exposure to conditioned cues are always followed by drug, it is more likely that cue exposure is linked to drug use on an intermittent basis. In conditioning, it has been long established that intermittent reinforcement substantially increases resistance to extinction [56]. When drug conditioning is considered from this perspective the persistence of the conditioned drug responses of addictive drugs appears explicable. Until this possibility is experimentally assessed, however, it is speculative but remains of heuristic value. In linking the posttest apomorphine effects on the conditioned drug response to its effect on re-consolidation of the memory trace the post-test apomorphine treatments seemingly would increase the level of dopamine activation that is associated with the re-consolidation of the memory trace. Viewed in this way the immediate apomorphine post-trial enhancement of the dopamine trace does not generate the association per-se but rather alters expression of conditioning by modulation of the incentive/salience level of the association [57,58]. In the present study and in our earlier report [27] we observed increases in ERK activity in dopamine projection areas after either 5 or 30 min. exposures to test cues that elicited the conditioned response. In the post-test treatment protocols, we have used apomorphine treatments are administered right after removal from the test environment. Similarly, the increases in ERK are also observed right after removal from the test environment. It remains to be determined as to how long the increase in ERK persists after removal from the test environment when a conditioned response has been elicited. While the posttest apomorphine treatments are administered immediately after removal from the test environment the onset of the drug effect is less certain. Possibly, the post-test measurement of ERK activity in dopamine projection sites at different temporal intervals posttest (eg. 1, 2, 5 min.) may provide a way to identify a posttest dopamine trace. In view of the extinction of the conditioned apomorphine response when the posttest administration is delayed 15 min. it would also be important to determine if the increased ERK response is absent when measured after a 15 min. post-test delay.
Acknowledgements This research was supported by FAPERJ - Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (nº E-26/203.551/2015). R.I.S. is a CNPq research fellow. This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).