Simultaneous expression of cocaine-induced behavioral sensitization and conditioned place preference in individual rats

Abstract

Conditioned place preference and locomotor sensitization are rodent behavioral models commonly used to investigate the actions of drugs of abuse. However, few studies have examined both paradigms in the same group of animals. We were interested in developing a combined protocol which successfully induced both conditioned place preference and sensitization simultaneously in cocaine-treated Sprague-Dawley rats in order to test the hypothesis that the magnitude of these two phenomena would be positively correlated. We used an open-field with a removable place preference insert to assess these measures independently. Cocaine-conditioned animals demonstrated a significant shift in preference for the drug-paired compartment and a sensitized locomotor response which was not observed in saline-conditioned animals challenged with cocaine. There was no significant relationship between locomotor sensitization and conditioned place preference in individual animals. We further examined these results with respect to each rat's initial response to cocaine, response to a novel environment and central zone entries in an open-field. Locomotor sensitization demonstrated an inverse correlation with the initial cocaine response. In contrast, conditioned place preference demonstrated an inverse correlation with the centre response. These results demonstrate that the combination of the acute cocaine response and the centre response in a novel open-field environment can be used to indicate the propensity of a given rat to exhibit either behavioral sensitization or conditioned place preference; however, it seems that sensitization and place preference are not necessarily co-expressed to a similar extent in the same individual animal.

Figure 1. Conditioned place preference following repeated administration of cocaine

Cocaine treated animals spent significantly more time in the drug-paired compartment after conditioning than their control counterparts. (a) Cocaine conditioned animals spent significantly more time in the drug-paired compartment on the CPP test day compared to the saline-conditioned animals (denoted by an asterisk) and also to the pretest day (denoted by a hash). (b) A significant shift in the preference of the cocaine treated animals was observed following conditioning compared to saline-treated animals (denoted by an asterisk). The shift in preference represents change in time spent in drug-paired compartment at the CPP test and Pre-test (sec). Data are expressed as mean ± SEM with n=29 (Veh), n= 8 (Coc 10 mg/kg), n=24 (Coc 15 mg/kg) and n=10 (Coc 20 mg/kg). Statistical significance was determined with p<0.05.

Figure 2. Total photocell counts after injection of saline or cocaine on conditioning days

Animals were conditioned with either 10 (triangles), 15 (squares) or 20 (diamonds) mg/kg i.p. cocaine or with vehicle (open circles). (a) Cocaine-conditioned animals are significantly more active on drug-paired sessions compared to saline controls. (b) There is no significant difference between any of the groups during the vehicle-paired sessions. Data represent mean ± SEM and statistical significance with p<0.05 is represented by an asterisk for drug/vehicle-paired vs. saline paired, a hash for cocaine vs. saline treatment and a cross for specific day differences compared to Day 3. n=29 (Veh), n= 8 (Coc 10 mg/kg), n=24 (Coc 15 mg/kg) and n=10 (Coc 20 mg/kg)

Figure 3. Locomotor sensitization to cocaine following repeated administration

Graphs illustrate the total horizontal counts 30 min prior to and 60 min after an i.p. injection of 10 mg/kg cocaine or saline in 10 min bins. Panel (a) depicts total horizontal counts before and following i.p. injection on the activity day. n= 29 (Veh), n= 42 (Coc). Panels (b–d) depict total horizontal counts before and following i.p. injection on the challenge day. Eleven of the saline-conditioned group received cocaine instead of saline (grey circles). The total horizontal counts for the (b) 10 mg/kg, (c) 15 mg/kg and (d) 20 mg/kg cocaine-conditioned groups are shown with respect to the saline-conditioned group. Significant differences by Holm-Sidak post-hoc test (p<0.05) are indicated by an asterisk (SS vs. CC), by a hash (SC vs. CC), by a cross (SS vs. SC) and by a dollar sign (activity day vs. challenge day). n=18 (SS), n=11 (SC), n=8 (CC10), n=24 (CC15) and n=10 (CC20).

Figure 4. Relationship between behavioral sensitization and cocaine, novelty or centre response in cocaine-treated animals

A significant inverse correlation was observed between the sensitization score and the initial cocaine response (a) and the average sensitization score for the low cocaine responders significantly greater than the high cocaine responders (b). No relationship was determined between sensitization score and novelty response (c) and there was no difference between low and high novelty responders in their average sensitization scores (d). Similarly, no significant correlation was detected between the sensitization score and the centre response (e), and there was no significant difference between low and high centre responders in their average sensitization scores (f). Statistical significance is indicated by an asterisk with p<0.05.

Figure 5. Relationship between conditioned place preference and either cocaine or novelty response in cocaine-treated animals

No significant correlations were observed between the CPP score and the initial cocaine response (a) or novelty response (c). The average CPP score for the cocaine responders (b) or the novelty responders (d) did not show any difference between their responder groups. However, there was a significant inverse relationship detected between the CPP score and the centre response (e), with the average CPP score for the low centre responders significantly higher than the high centre responders (f). Statistical significance is indicated by an asterisk with p<0.05.

Figure 6. Lack of relationship between behavioral sensitization and conditioned place preference

The sensitization score of each 15 mg/kg cocaine-conditioned animal was plotted against its’ CPP score (a). Furthermore, there was no significant correlation between sensitization and conditioned place preference in animals conditioned with 10 (b) and 20 (c) mg/kg cocaine.