Cocaine (0.032 mg/kg) maintained self-administration in all baboons during the daily 2-h baseline sessions. All baboons obtained near maximal numbers of injections (25 to 30) when cocaine was available. The mean run rate (responses/s) during the cocaine baseline sessions was calculated separately for each pretreatment group. Cocaine maintained high run rates in each pretreatment group [responses/s (±1 SEM): baclofen, 2.45 (0.51); CGP44532, 3.37 (0.53); tiagabine, 3.4 (0.93)]. When saline was substituted for cocaine, the number of self-injections decreased over consecutive days. The number of saline injections on the day before reinstatement tests ranged from 1-8.
The three pretreatment groups (baclofen vs. CGP44532 vs. tiagabine) were not significantly different from each other for baseline levels of cocaine self-injection or for saline self-injection under extinction conditions. Across pretreatment groups, there was a significant main effect for cocaine priming dose (F (4,40)=52.43, P < 0.0001). Although only saline was available for injection, administration of priming doses of cocaine (0.1-1.8 mg/kg, i.v.) following extinction periods increased lever responding (i.e., cocaine-seeking) in a dose-dependent manner; the number of ratios completed (which resulted in saline injections) increased as a function of the priming dose administered ().
Figure 1 Effects a. baclofen (N=5), b. CGP44532 (N=5), and c. tiagabine (N=3) on the reinstatement of extinguished lever responding by cocaine priming dose injections. Data shown are the group mean number of ratios completed on the cocaine-associated lever after (more ...)
As shown in , pretreatment with baclofen attenuated the reinstatement of cocaine-seeking produced by priming injections of cocaine. ANOVA of the baclofen group data confirmed a significant main effect for 0.32 mg/kg baclofen pretreatment (F(1,20)=21.32, P < 0.001) and cocaine priming dose (F(4,20)=22.63, P < 0.0001). There was also a significant interaction for baclofen pretreatment and cocaine dose (F(4,20)=3.48, P < 0.03). Bonferroni t-tests indicated a significant difference between means for treatment conditions (baclofen vs. vehicle) following 1.0 (P < 0.001) and 1.8 (P < 0.05) mg/kg priming injections of cocaine.
Like baclofen, pretreatment with 0.32 mg/kg CGP44532 attenuated the reinstatement of cocaine-seeking produced by priming injections of cocaine (). ANOVA of the CGP44532 group data confirmed that there were significant main effects for CGP44532 pretreatment (F(1,20)=46.74, P < 0.0001) and cocaine priming dose (F(4,20)=3.72, P < 0.02). There was also a significant interaction for CGP44532 pretreatment and cocaine dose (F(4,20)=8.22, P < 0.0004). Bonferroni t-tests indicated a significant difference between means for treatment conditions (CGP44532 vs. vehicle) following 1.0 (p< 0.01) and 1.8 (p< 0.001) mg/kg priming injections of cocaine.
In contrast, pretreatment with 0.32 mg/kg tiagabine did not systematically affect the number of saline self-injections following cocaine priming doses (). Results of ANOVA of the tiagabine group data confirmed a main effect of cocaine priming dose (F(4,16)=8.76, P<.001). Tiagabine pretreatment (vehicle vs. 0.32 mg/kg tiagabine) and the interaction for tiagabine pretreatment and cocaine dose treatment were not significant.
Interestingly, the latency to the first injection of saline following administration of the IV cocaine priming doses progressively increased in a dose dependent manner (F(3,30)=10.77, p<.0001). shows the mean (SEM) latency (s) to the first saline injection following IV administration of cocaine priming doses alone and with 0.32 mg/kg baclofen, 0.32 mg/kg CGP44532, or 0.32 mg/kg tiagabine pretreatments. Pretreatment with baclofen, CGP44532, or tiagabine did not systematically affect the latency to the first injection. In addition, once the first response in the ratio occurred, the remaining response requirement was completed at a high rate, regardless of the cocaine priming dose or the pretreatment condition. shows the mean run rate (and SEM) for injections of saline following administration of the IV cocaine priming doses alone (no pretreat) and following pretreatment prior to administration of the IV cocaine priming (pretreat) for each treatment group. Pretreatment with baclofen, CGP44532 or tiagabine prior to the cocaine priming injection did not significantly or systematically change the local response rate (run rate). Administration of 0.32 mg/kg baclofen, 0.32 mg/kg CGP44532 or 0.32 mg/kg tiagabine alone also did not significantly alter run rates.
Mean (SEM) latency (in sec) to the first saline injection following IV administration of cocaine priming doses alone and with 0.32 mg/kg baclofen, 0.32 mg/kg CGP44532, or 0.32 mg/kg tiagabine pretreatments
Mean (SEM) run rate (r/sec) to the first saline injection following IV administration of cocaine priming doses alone and with 0.32 mg/kg baclofen, 0.32 mg/kg CGP44532, or 0.32 mg/kg tiagabine pretreatments
Although pretreatments did not alter the latency or rate of responding, the GABAB agonists baclofen and CGP445432 did alter the pattern of responding over time during the 2-hr sessions. shows within session patterning of injections over time in a representative baboon for each pretreatment (baclofen, CGP44532 and tiagabine) across the different testing conditions. As shown in , when cocaine was available for self-injection, the latency to complete the first response requirement and receive the first injection of cocaine was very short (i.e., within the first few minutes after the session began) and a regular pattern of evenly spaced injections were received throughout the 2 h session. In comparison, during saline extinction (), low numbers of saline injections were taken and the within session pattern of injections was irregular; injections occurred in groups near the beginning of the session. The rate and pattern of responding after vehicle substitution were characterized by greater pausing between bursts of responding; but when responding did occur, the local run rate was generally >1 response/s. Administration of IV priming injections of cocaine during saline extinction reinstated lever responding and the within session pattern of injections was related to the dose of cocaine administered. The increased latency to complete the first response requirement and receive the first self-injection of saline following priming injections of 0.32 and 1.0 mg/kg cocaine (as shown for the group in ) is evident in the patterning of injections shown in . After the first injection, the pattern of saline injections produced by a priming dose of 0.32 mg/kg cocaine were similar to those maintained by cocaine for the first 60-min but were more erratic over time when compared to the cocaine baseline sessions (). Injections continued to be received throughout the session following the 1.0 mg/kg cocaine priming injection (). When either baclofen (, left panels) or CGP44532 (, center panels) were administered before the cocaine priming injection, a similar pattern of saline injections was obtained at the beginning of the session, but responding (and therefore injections received) terminated sooner and few injections were received later in the session. In contrast, when the tiagabine pretreatment was administered prior to the 0.32 mg/kg ( right panel), or the 1.0 mg/kg cocaine priming injection (, right panel), the pattern of saline injections was comparable to that following the cocaine priming injections alone (no pretreat).
Figure 2 Within session pattern of injections over time and across experimental conditions. Data for a representative baboon are shown for each pretreatment group (Baboon JA for baclofen, Baboon BA for CGP44532, and Baboon KR for tiagabine). Each tick mark along (more ...)