Effects of (-)-ephedrine on locomotion, feeding, and nucleus accumbens dopamine in rats.

The intent of the present study was to determine the effects of systemic injections of the sympathomimetic agent ephedrine (EPH) on extracellular dopamine (DA) levels within the rat nucleus accumbens (NAC) and to compare these effects with those of EPH on locomotion and on feeding. In experiment 1, adult male rats were prepared with an indwelling 3 mm microdialysis probe positioned within the NAC. The rats were injected (i.p.) with vehicle, 5, 10, or 20 mg/kg (-)-EPH with dialysates collected every 20 min for 100 min after drug injection. Systemic injections of 5, 10 or 20 mg/kg (-)-EPH significantly enhanced extracellular levels of NAC DA over baseline by 79%, 130%, and 400%. Systemic injection of 20 mg/kg EPH significantly reduced NAC levels of DOPAC and HVA by 37% and 31%. The effects of EPH on brain dopamine activity were stereospecific given that an additional group of rats injected with 20 mg/kg (+)-EPH exhibited smaller changes in NAC DA (< 25%), DOPAC (< 10%), and HVA levels (< 20%) than did rats injected with 20 mg/kg (-)-EPH. In experiment 2, adult male rats were injected (i.p.) with 0, 5, 10, or 20 mg/kg (-)-EPH prior to placement in automated activity chambers. Total distance traveled was significantly increased by 10 and 20 mg/kg (-)-EPH, but not by 5 mg/kg (-)-EPH. In experiment 3, adult male rats were injected (i.p.) with 0, 2.5, 5, or 10 mg/kg (-)-EPH or with 0, 2.5, 5, or 10 mg/kg (+)-EPH prior to a 30-min feeding test. Although each EPH enantiomer decreased feeding, (-)-EPH was more potent in feeding suppression than was (+)-EPH. The present results suggest that EPH may alter locomotion and feeding via an indirect action on brain dopamine activity.

Brain and plasma levels of cocaine and benzoylecgonine in lead-expose and cadmium-exposed rats following acute or chronic intraperitoneal administration of cocaine.

Previous investigations of metal/cocaine interactions have shown that chronic oral exposure to inorganic lead or cadmium attenuates the psychoactive effects of acute or repeated administration of cocaine. The purpose of this investigation was to assess the possibility that such interactive effects may derive from metal-induced disturbances in cocaine pharmacokinetics, i.e., delivery of cocaine to critical biologic sites may be disrupted by metal contamination. In this study, adult male rats were exposed to purified diets containing 250 ppm lead acetate (Group Lead), 100 ppm cadmium chloride (Group Cadmium), or unadulterated laboratory chow (Group Control); n = 48/exposure condition. Following ad libitum access to their respective diets in the home cage for 45 days, half the animals from each exposure regimen received single daily IP injections of 5, 10, or 20 mg/kg cocaine HCl for a period of 7 days (n = 8/group). The remaining half the animals received repeated daily injections of saline during this pretreatment phase. On the day following pretreatment, animals previously receiving cocaine injections were administered a single cocaine test challenge at a dose equal to that received in pretreatment. Similarly, saline pretreatment animals received either 5, 10, or 20 mg/kg cocaine. The results of this investigation did not reveal reliable evidence of metal-related differences in brain levels of cocaine. Plasma cocaine and benzoylecgonine (BE) levels also were essentially the same for control and metal-exposed animals. The failure to show that lead or cadmium alters the disposition of cocaine in brain or plasma underscores the need to pursue alternative accounts of metal/cocaine interactions.

Chronic exposure to cadmium attenuates behavioral sensitization to morphine.

The purpose of this investigation was to assess the impact of dietary cadmium on morphine-induced changes in locomotor activity. Adult male rats were exposed ad libitum to an adulterated food supply containing 100 ppm added cadmium chloride, or an identical diet containing no added cadmium, for 45 days prior to testing for the locomotor activating effects of successive daily morphine administration (0, 5, 10, or 20 mg/kg per session) on locomotor activity. On day 1 of testing, increasing doses of morphine produced a dose-related suppression of activity, and this sedative effect was greater in control than in cadmium-exposed animals. Repeated morphine administration resulted in tolerance to the sedative effects of the drug, and a systematic elevation of locomotor activity over the 14-day testing period was observed, with the augmentation (sensitization) effect more pronounced in control than cadmium-exposed animals. There was no indication that conditioning (context) events played a role in the effects observed here.

Chronic lead exposure attenuates sensitization to the locomotor-stimulating effects of cocaine.

Adult male rats were exposed to a water supply containing 500 ppm lead acetate (Lead Group), or a comparable concentration of sodium acetate (Control Group), for 30 days prior to commencing testing for behavioral sensitization to cocaine. Locomotor activity (total distance (cm) travelled) was monitored for animals in both exposure conditions across 14 daily 1 h test sessions. Across successive sessions, baseline activity was recorded for a 20-min baseline period, at which time half the animals from each exposure condition received an i.p. injection of saline or 10 mg/kg cocaine HCl. Post-injection locomotor responding was then monitored for 40 min prior to returning the animal to the home cage where the respective watering regimens remained intact. On the day following the completion of sensitization testing (day 15 of testing), animals in all groups received a saline injection, and on day 16 of testing all animals received a 10 mg/kg cocaine challenge. The results showed that repeated experience with cocaine augmented the stimulatory effects of the drug in both control and lead-exposed animals. However, this behavioral sensitization effect was slower to develop and less pronounced in lead-exposed animals. These data are discussed within the context of lead-related changes in sensitivity to cocaine.

Cadmium exposure attenuates the initiation of behavioral sensitization to cocaine.

Employing a paired-watering procedure to control for differential fluid intake confounds, adult male rats were exposed in the home cage to water containing 100 ppm cadmium chloride, or a control solution containing no added cadmium chloride. On Day 61 of exposure to their respective watering regimens, half the animals from each condition received 12 repeated daily i.p. injections of 10 mg/kg cocaine-HCl, or saline. Locomotor activity (total distance traveled) was recorded in Digiscan Activity Monitors for a 20-min baseline period prior to each injection, and for a 40-min period post-injection. On Day 13 of testing, all animals received saline injections only in the test chambers, in an effort to evaluate the role of conditioned cues in the expression of cocaine sensitization. On Day 14-16 of testing, all animals received successive daily challenges of 10, 20, and 40 mg/kg cocaine in the test chamber. The results indicated that the initiation (development) of behavioral sensitization to 10 mg/kg cocaine was attenuated in cadmium-exposed rats. Moreover, the supersensitivity to higher doses of cocaine during dose-effect testing that was registered by control animals pretreated with cocaine, was not evident in cadmium-exposed pretreatment animals. These data suggests that environmental contaminants may alter drug responsiveness, and thereby may influence patterns of drug selection and use.