Prenatal stress enhances responsiveness to cocaine

Abstract

Early environmental events have profound influences on a wide range of adult behavior. In the current study, we assessed the influence of maternal stress during gestation on psychostimulant and neurochemical responsiveness to cocaine, cocaine self-administration, and reinstatement of cocaine-seeking in adult offspring. Pregnant, female Sprague-Dawley rats were subjected to either no treatment or to restraint stress three times per day for the last 7 days of gestation and cocaine-related behavior was assessed in offspring at 10 weeks of age. Relative to controls, a noncontingent cocaine injection elevated locomotor activity as well as nucleus accumbens levels of extracellular dopamine and glutamate to a greater extent in both cocaine-naive and cocaine-experienced prenatal stress (PNS) rats and elevated prefrontal cortex dopamine in cocaine-experienced PNS rats. To assess the impact of PNS on cocaine addiction-related behavior, rats were trained to lever press for intravenous (i.v.) infusions of cocaine (0.25, 0.5, or 1 mg/kg/infusion), with each infusion paired with a light+tone-conditioned stimulus. Lever-pressing was extinguished and cocaine-seeking reinstated by re-exposure to the conditioned cues or by intraperitoneal cocaine-priming injections (5 or 10 mg/kg). PNS elevated active lever responding both during extinction and cocaine-primed reinstatement, but not during self-administration or conditioned-cued reinstatement. PNS also did not alter intake during self-administration. These findings demonstrate that PNS produces enduring nervous system alterations that increase the psychomotor stimulant, motivational, and neurochemical responsiveness to noncontingent cocaine. Thus, early environmental factors contribute to an individual's initial responsiveness to cocaine and propensity to relapse to cocaine-seeking.

Figure 1

Schematic diagram illustrating sequence of behavioral tests employed in the investigation of responsiveness to cocaine in naïve rats (test condition 1) and those with a history of cocaine self-administration (test condition 2). Behavioral tests were conducted on PNS (produced by maternal restraint three times per day for the last 7 days of gestation) or control rats in adulthood.

Figure 2

Novelty- and cocaine-induced locomotor activity exhibited by PNS and control rats in distance (m) as measured by photobeam breaks. (a) Response to initial placement in a novel test environment in a 60-min test in control (n = 44 comprised three to eight rats from seven litters) and PNS (n = 46 comprised three to eight rats from nine litters) rats. (b) Response to vehicle injection (empty arrow) and cocaine injection (15 mg/kg i.p., filled arrow) in sequential 120 min tests in control (n = 12 comprised one to two rats from seven litters) and PNS rats (n = 12 comprised one to two rats from seven litters) without a history of cocaine-experience. Data shown as mean±SEM; symbol indicates a significant difference between the PNS and control rats (*p<0.05).

Figure 3

Basal and cocaine-stimulated (15 mg/kg, i.p.) neurotransmitter levels in the NAC in PNS (n = 7 comprised one to two rats from five litters) and control (n = 7 comprised one to two rats from five litters) rats without a history of cocaine self-administration. (a) Summary of the NAC placements of the active membrane of the microdialysis probes of PNS (solid lines) and control (gray-filled lines) rats. (b–d) Absolute levels of dopamine, serotonin, and glutamate in the NAC before and after a cocaine challenge. (b′ and d′) Changes from baseline in NAC dopamine, serotonin, and glutamate levels following a cocaine challenge; data shown as mean±SEM transformed to percent change from the basal levels derived from the average of the final three prechallenge samples. Symbol indicates a significant difference between the PNS and control rats (*p<0.05).

Figure 4

Basal and cocaine-stimulated (15 mg/kg, i.p.) neurotransmitter levels in the PFC in PNS (for dopamine and serotonin, n = 6 comprised one to two rats from four litters; for glutamate, n = 7 comprised one to two rats from five litters) and control (for dopamine and serotonin, n = 5 comprised one to two rats from four litters; for glutamate, n = 4 comprised one rat from four litters) rats without a history of cocaine self-administration. (a) Summary of the PFC placements of the active membrane of the microdialysis probes of PNS (solid lines) and control (gray-filled lines) rats. (b–d) Absolute levels of dopamine, serotonin, and glutamate in the PFC before and after a cocaine challenge. (b′ and d′) Changes from baseline in PFC dopamine, serotonin, and glutamate levels following a cocaine challenge; data shown as mean±SEM transformed to percent change from the basal levels derived from the average of the final three prechallenge samples.

Figure 5

Cocaine self-administration and extinction behavior exhibited in PNS and control rats. During self-administration, active lever responses resulted in the delivery of a cocaine infusion and simultaneous presentation of a light±tone stimulus complex. Each reinforced lever press was followed by a 20-s time-out period. During extinction, active lever responses had no programmed consequences. Separate groups of rats were trained to self-administer cocaine doses of 0.25 mg/kg/infusion (control, n = 10 comprised one to two rats from seven litters; PNS, n = 12 comprised one to two rats from eight litters), 0.5 mg/kg/infusion (control, n = 11 comprised one to two rats from seven litters; PNS, n = 12 comprised one to two rats from nine litters), and 1.0 mg/kg/infusion (control, n = 10 comprised one to two rats from seven litters; PNS, n = 10 comprised one to two rats from nine litters). (a) Intake (mg/kg) per daily session averaged across the last three sessions for PNS and control rats trained with 0.25, 0.5, and 1.0 mg/kg infusions. (b) Active and inactive lever responses per daily session averaged across the last three sessions for PNS and control rats trained with 0.25, 0.5, and 1.0 mg/kg infusions. (c) Active and inactive lever responses during daily extinction sessions for PNS and control rats (data collapsed across training infusion doses; one PNS rats trained with 1.0 mg/kg/infusion failed to exhibit extinction of active lever pressing and was omitted from analyses). Data shown as mean±SEM; symbol indicates a significant difference between the PNS and control rats (*p<0.05).

Figure 6

Conditioned-cued reinstatement of cocaine-seeking, cocaine-primed reinstatement of cocaine-seeking and post-self-administration cocaine-induced locomotor activity exhibited by PNS and control rats. Rats were trained to self-administer cocaine doses of 0.25 mg/kg/infusion (control, n = 10 comprised one to two rats from seven litters; PNS, n = 12 comprised one to two rats from eight litters), 0.5 mg/kg/infusion (control, n = 11 comprised one to two rats from seven litters; PNS, n = 12 comprised one to two rats from nine litters), and 1.0 mg/kg/infusion (control, n = 10 comprised one to two rats from seven litters; PNS, n = 10 comprised one to two rats from nine litters) but the lack of training dose effects or interactions warranted collapsing data across this variable for presentation. (a) Responses on the active and inactive lever during the last two extinction session served as a baseline (b) for the subsequent five daily conditioned cued reinstatement tests in which active lever responses resulted in presentation of the light±tone stimulus complex (FR1 with 20-s time-out period). (b) Responses on the active and inactive lever during primed reinstatement tests after i.p. injection with 0 (vehicle), 5, or 10 mg/kg cocaine under extinction conditions. (c) Locomotor activity following vehicle injection (empty arrow) and cocaine injection (15 mg/kg i.p., filled arrow). Data shown as mean±SEM; symbol indicates a significant difference between the PNS and control rats (*p<0.05).

Figure 7

Basal and cocaine-stimulated (15 mg/kg, i.p.) neurotransmitter levels in the NAC in PNS (for dopamine and serotonin, n = 9 comprised one to three rats from six litters; for glutamate, n = 11 comprised one to three rats from six litters) and control (for dopamine, serotonin, and glutamate, n = 11 comprised one to three rats from five litters) rats following a history of cocaine self-administration. (a) Summary of the NAC placements of the active membrane of the microdialysis probes of PNS (solid lines) and control (gray-filled lines) rats. (b–d) Absolute levels of dopamine, serotonin, and glutamate in the NAC before and after a cocaine challenge. (b′ and d′) Changes from baseline in NAC dopamine, serotonin, and glutamate levels following a cocaine challenge; data shown as mean±SEM transformed to percent change from the basal levels derived from the average of the final three prechallenge samples. Symbol indicates a significant difference between the PNS and control rats (*p<0.05).

Figure 8

Basal and cocaine-stimulated (15 mg/kg, i.p.) neurotransmitter levels in the PFC in PNS (for dopamine, n = 11 comprised one to three rats from six litters; for serotonin and glutamate, n = 10 comprised one to two rats from six litters) and control (for dopamine, n = 11 comprised one to three rats from five litters; for serotonin and glutamate, n = 10 comprised one to three rats from five litters) rats following a history of cocaine self-administration. (a) Summary of the PFC placements of the active membrane of the microdialysis probes of PNS (solid lines) and control (gray-filled lines) rats. (b–d) Absolute levels of dopamine, serotonin, and glutamate in the PFC before and after a cocaine challenge. (b′ and d′) Changes from baseline in PFC dopamine, serotonin, and glutamate levels following a cocaine challenge; data shown as mean±SEM transformed to percent change from the basal levels derived from the average of the final three prechallenge samples. Symbol indicates a significant difference between the PNS and control rats (*p<0.05).