PRIOR EXPOSURE TO COCAINE DIMINISHES BEHAVIORAL AND BIOCHEMICAL RESPONSES TO AVERSIVE-CONDITIONING - REVERSAL BY GLYCINE N-METHYL-D-ASPARTATE ANTAGONIST CO-TREATMENT

Animals will respond with stress-like behavioral and biochemical chang es when exposed to a neutral stimulus that had previously been paired with a stressful stimulus. This phenomenon is generally known as avers ive conditioning or conditioned fear. We tested the effect of prior ex posure to cocaine on rats subjected to an aversive conditioning paradi gm. Rats were given repeated doses of cocaine to develop a reverse tol erance or sensitization to the locomotor stimulant properties of cocai ne. We blocked this sensitization to cocaine in one cocaine-exposed gr oup by co-administering an antagonist of the strychinine-insensitive g lycine site of the N-methyl-D-aspartate receptor complex, R-(+)-HA-966 , which prevented the development of locomotor sensitization to cocain e. After about three weeks, we examined the effect of cocaine sensitiz ation and the prevention of sensitization by R-(+)-HA-966 on aversive conditioning. Rats were exposed to 10 tones (neutral stimuli) paired w ith footshock (stressful stimuli) over 30 min for the conditioning ses sion. The following day, rats were returned to the cages, received 10 tones only over 30 min and were killed. No drugs were given to any rat before either session and control rats received the tones without foo tshock in both sessions. Prior exposure to cocaine caused an attenuati on of the behavioral effects of aversive conditioning, namely the amou nt of time spent immobilized and the number of fecal boli expelled. Ad ditionally, the elevated metabolic activity of dopamine in the medial prefrontal cortex, nucleus accumbens and ventral tegmental area associ ated with aversive conditioning was diminished in rats pre-exposed to cocaine. The behavioral and biochemical effects of pre-exposure to coc aine were reversed in rats that received R-(+)-HA-966 co-treatment wit h the five day cocaine sensitization regimen. These data suggest that prior behavioral sensitization to cocaine diminishes the stressful eff ect of conditioned fear and that these effects are reversed when sensi tization is prevented with R-(+)-HA-966.