Figure 1.
(A) Timeline for behavioral testing. (B) Timeline for injections and activity recording on each of the 5 cocaine sensitization days. P, pretreatment (saline, disulfiram, or nepicastat); A, mice placed in activity chambers; S, saline injection; C, cocaine injection; R, mice returned to their home cage. (C) Pretreatment and treatment groups for each genotype.
Figure 2.
Dbh −/− mice are hypersensitive to cocaine-induced locomotion.
(A) Drug-naïve Dbh +/− (n = 9) and Dbh −/− mice (n = 8) were placed in automated locomotor activity chambers, injected with cocaine (15 mg/kg, i.p.) 30 minutes later, and locomotor activity was recorded for 2 hours. Shown are mean ± SEM ambulations (consecutive beam breaks). *** p<0.0001, ** p<0.01, * p<0.05 compared with Dbh −/− mice at that time point. (B) On each of the next 5 days, mice were administered saline (3 injections of 10 ml/kg, each injection spaced 2 hours apart). Ninety minutes after the last saline injection, mice were placed in automated locomotor activity chambers, injected with cocaine (15 mg/kg, i.p.) 30 minutes later, and locomotor activity was recorded for 2 hours. Shown are mean ± SEM ambulations (consecutive beam breaks) for the 2 hours following cocaine administration. * p<0.05 between genotypes for that day.
Figure 3.
Effects of chronic disulfiram or nepicastat administration on cocaine-induced locomotor activity in Dbh +/− mice during the development of sensitization.
Each day for 5 consecutive days, Dbh +/− mice were administered saline (n = 9), disulfiram (3 injections of 100 mg/kg, i.p., each injection spaced 2 hours apart; n = 13), or nepicastat (3 injections of 50 mg/kg, i.p., each injection spaced 2 hours apart; n = 7). Ninety minutes after the last pretreatment, mice were placed in automated locomotor activity chambers, injected with cocaine (15 mg/kg, i.p.) 30 minutes later, and locomotor activity was recorded for 2 hours. (A) shows data with all disulfiram-treated mice in a single group. (B) shows data with disulfiram-treated mice divided into “no stereotypy” and “with stereotypy” groups. * p<0.01 compared to saline-treated group.
Figure 4.
Effects of chronic disulfiram or nepicastat administration on cocaine-induced locomotor activity and stereotypy in Dbh +/− mice during the expression of sensitization.
Ten days following the 5 day sensitization paradigm (see Fig. 3 legend), all mice were placed in the activity chambers for 30 min, given an injection of cocaine (15 mg/kg, i.p.), and locomotor activity was recorded for 2 hr and stereotypy was scored. (A) Mean ± SEM ambulations for mice in the groups that received cocaine injections during the 5 day sensitization period (saline+cocaine (“Sal”), n = 9; disulfiram+cocaine that did not display stereotypy (“Dis - NS”), n = 5; disulfiram+cocaine that displayed stereotypy (“Dis - S”), n = 8; nepicastat+cocaine (“Nep”), n = 7). (B) Mean ± SEM ambulations for mice in the groups that received saline injections during the 5 day sensitization period (saline+saline, n = 7; disulfiram+saline, n = 8; nepicastat+saline, n = 7). (C) Percentage of mice in the groups that received cocaine injections during the 5 day sensitization period (saline+cocaine, disulfiram+cocaine, nepicastat+cocaine) that primarily engaged in stereotypy. (D) Percentage of mice in the groups that received saline injections during the 5 day sensitization period (saline+saline, disulfiram+saline, nepicastat+saline) that primarily engaged in stereotypy following cocaine challenge. * p<0.05 compared with the saline control for that group (saline+cocaine for panel C, saline+saline for panel D).
Figure 5.
Effects of chronic disulfiram or nepicastat administration on cocaine-induced locomotor activity in Dbh −/− mice during the development and expression of sensitization.
Dbh −/− mice were put through the 5 day sensitization paradigm followed by cocaine challenge after 10 days of withdrawal paradigm (see Fig. 3 and Fig. 4 legends). (A) Mean ± SEM ambulations for the 2 hours following cocaine administration during the 5 day sensitization period sensitization in the groups that received cocaine injections (saline+cocaine, n = 8; disulfiram+cocaine, n = 7; nepicastat+cocaine, n = 4). (B) Mean ± SEM ambulations for the 2 hours following cocaine challenge after 10 days of withdrawal in the groups that received cocaine injections during the 5 day sensitization period (saline+cocaine; disulfiram+cocaine; nepicastat+cocaine). (C) Mean ± SEM ambulations for the 2 hours following cocaine challenge after 10 days of withdrawal in the groups that received saline injections during the 5 day sensitization period (saline+saline, n = 7; disulfiram+saline, n = 7; nepicastat+saline, n = 6).