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-naïve 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.

Prenatal Stress Exposure Increases the Excitation of Dopamine Neurons in the Ventral Tegmental Area and Alters Their Reponses to Psychostimulants

“…The amphetamine self-administration paradigm used in this study has been employed previously to investigate individual differences in increased responding to psychostimulants (Cain et al, 2008) and its association with increased addiction risk. Therefore, the results from this study are in agreement with previous animal and clinical studies demonstrating that PSE leads to increased addiction risk and associated behavioral phenotypes (Charmandari et al, 2003;Deminiere et al, 1992;Kippin et al, 2008;Moffett et al, 2007;Thomas et al, 2009).…”

“…Therefore, the reversal effect by these psychostimulants in PSE rats, similar to that of apomorphine, further supports that depolarization block is the underlying mechanism for PSE-induced reduction in VTA DA population activity. Importantly, the altered responses to psychostimulants in PSE animals could mediate increased responding to these drugs (eg, in locomotor activity and self-administration; Deminiere et al, 1992;Kippin et al, 2008;Silvagni et al, 2008;Thomas et al, 2009) and increased addiction risk in PSE rats. These behavioral characteristics are similar to those observed after repeated psychostimulant exposure (Suto et al, 2002).…”

“…Perinatal stress also directly leads to increased addiction risk demonstrated by enhanced acquisition (Deminiere et al, 1992;Thomas et al, 2009), greater resistance to extinction training, and enhanced drug-induced reinstatement in the psychostimulant self-administration paradigm (Kippin et al, 2008).…”

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

“…Specifically, the NAcc of adult rats exposed to GC in utero (iuGC) display reduced neuronal numbers and fewer dopamine (DA) inputs from the VTA (12). Further, early life stress is known to influence DA receptor expression in the adult NAcc (16,17), changes associated with increased behavioral responses to stress and cocaine (1,4,18,19). Together, these observations suggest that prenatal exposure to elevated levels of GCs can program the mesolimbic circuit.…”

Exploratory, anti-anxiety, social, and sexual behaviors of rats in behavioral estrus is attenuated with inhibition of 3α,5α-THP formation in the midbrain ventral tegmental area

“…coldwater swim, ether, footshock) increases biosynthesis of pregnane and androstane neurosteroids [14,17,68]. Such levels of stress can enhance dopamine secretion to agonistic levels which may underlie some reward processes such as those seen in acquisition of cocaine [43,44,48,49]. This response can also enhance 3α,5α-THP in response to elevated stress axis factors.…”