Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-evoked behavioral disinhibition in rats

Abstract

Alterations in the balance of functional activity within the serotonin [5-hydroxytryptamine (5-HT)] system are hypothesized to underlie impulse control. Cocaine-dependent subjects consistently show greater impulsivity relative to nondrug using control subjects. Preclinical studies suggest that the 5-HT(2A) receptor (5-HT(2A)R) contributes to the regulation of impulsive behavior and also mediates some of the behavioral effects of cocaine. We hypothesized that the selective 5-HT(2A)R antagonist M100907 would reduce inherent levels of impulsivity and attenuate impulsive responding induced by cocaine in two animal models of impulsivity, the differential reinforcement of low rate (DRL) task and the one-choice serial reaction time (1-CSRT) task. M100907 reduced rates of responding in the DRL task and premature responding in the 1-CSRT task. Conversely, cocaine disrupted rates of responding in the DRL task and increased premature responding in the 1-CSRT task. M100907 attenuated cocaine-induced increases in specific markers of behavioral disinhibition in the DRL and 1-CSRT tasks. These results suggest that the 5-HT(2A)R regulates inherent impulsivity, and that blockade of the 5-HT(2A)R alleviates specific aspects of elevated levels of impulsivity induced by cocaine exposure. These data point to the 5-HT(2A)R as an important regulatory substrate in impulse control.

Figure 1. The effects of M100907 administration on behavioral disinhibition measured with the DRL-20 sec task

Response rate (A) and number of reinforcers (0.25 sec water deliveries) obtained (B) on the DRL-20 s task test day are presented as % of control (vehicle+saline) (mean ± SEM). (C) The relative frequency (frequency of inter-response time/total number of responses ± SEM) of a given inter-response interval for control and M100907 (0.1 mg.kg) is represented as a single point for each 2-s time bin. M100907 (0.01, 0.03, 0.1, 0.3, 0.5 mg/kg) was administered 15 min prior to saline injections; vehicle (1 mL/kg saline or 1% Tween 80) was administered immediately before DRL-20 sec task test sessions in a counterbalanced within-subjects design. “→” Represents the peak shift for 0.1 mg/kg M100907 versus the control peak relative frequency. Statistical comparisons of descriptive statistics for the inter-response time distributions can be found in Table 1. *p<0.05 vs. control ^p<0.05 vs. vehicle+cocaine (one way repeated measures ANOVA with Dunnett’s procedure)

Figure 2. The effects of M100907 in combination with cocaine administration on behavioral disinhibition measured with the DRL-20 sec task

Response rate (A) and number of reinforcers (0.25 sec water deliveries) obtained (B) on the DRL-20 s task test day are presented as % of control (vehicle+saline) treatment (mean ± SEM). (C) The relative frequency (frequency of inter-response time/total number of responses ± SEM) of a given inter-response interval for control and cocaine alone or M100907 (0.3 mg/kg) + cocaine is represented as a single point for each 2-s time bin. M100907 (0.01, 0.03, 0.1, 0.3, 0.5 mg/kg) was administered 15 min prior to vehicle or cocaine injections; vehicle (1 mL/kg saline or 1% Tween 80) or cocaine (10 mg/kg) was administered immediately before DRL-20 sec task test sessions in a counterbalanced within-subjects design. “←” Represents the peak shift for cocaine versus the control peak relative frequency; “→” represents the peak shift for 0.3 mg/kg M100907 + cocaine versus cocaine peak relative frequency. Statistical comparisons of descriptive statistics for the inter-response time distributions can be found in Table 2. *p<0.05 vs. control ^p<0.05 vs. vehicle+cocaine (one way repeated measures ANOVA with Dunnett’s procedure)

Figure 3. The effects of M100907 administration on behavioral disinhibition measured with the 1-CSRT task

Premature responses (A) and reinforcers obtained (B) on the 1-CSRT task test day are presented as % of control (vehicle+saline) treatment (mean + SEM). M100907 (0.01, 0.03, 0.1, 0.3, 0.5 mg/kg) was administered 15 min prior to saline injections; vehicle (1 mL/kg saline or 1% Tween 80) was administered immediately before 1-CSRT task test sessions in a counterbalanced within-subjects design. *p<0.05 vs. control ^p<0.05 vs. vehicle+cocaine (one way repeated measures ANOVA with Dunnett’s procedure)

Figure 4. The effects of M100907 in combination with cocaine administration on behavioral disinhibition measured with the 1-CSRT task

Premature responses (A) and reinforcers obtained (B) on the 1-CSRT task test day are presented as % of control (vehicle+saline) treatment (mean + SEM). M100907 (0.01, 0.03, 0.1, 0.3, 0.5 mg/kg) was administered 15 min prior to vehicle or cocaine injections; vehicle (1 mL/kg saline or 1% Tween 80) or cocaine (10 mg/kg) was administered immediately before 1-CSRT task test sessions in a counterbalanced within-subjects design. *p<0.05 vs. control ^p<0.05 vs. vehicle+cocaine (one way repeated measures ANOVA with Dunnett’s procedure)