Robert T. Burkey

(R)-methanandamide, but not anandamide, substitutes for delta 9-THC in a drug-discrimination procedure.

Fourteen male rats were trained to discriminate between injections of 2 mg/kg delta-9-tetrahydrocannabinol (delta 9-THC) and vehicle in a 2-lever operant drug-discrimination paradigm. Following training, substitution tests using a cumulative dosing procedure revealed that anandamide (0.5-16 mg/kg ip), the putative endogenous camabinoid receptor ligand, failed to generalize to the discriminative stimulus properties of the training dose of delta 9-THC. However, dose-dependent generalization to the delta 9-THC cue was observed following administration of both CP-55,940 (0.05-0.8 mg/kg ip), a synthetic cannabinoid, and (R)-methanandamide (0.5-8 mg/kg ip), a metabolically stable analog of anandamide. Collectively, these results demonstrate a cannabinoid-specific in vivo effect of an anandamide compound and suggest that the naturally occurring form of anandamide may be metabolized too rapidly to produce a cannabimimetic intercceptive state when administered peripherally.

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.

Effects of Chronic Lead Exposure on Cocaine-induced Disturbance of Fixed-interval Behavior

Chronic lead exposure has been shown to attenuate cocaine-induced increases in extracellular dopamine levels in the region of the nucleus accumbens, and antagonize the locomotor stimulating effects of the drug. The purpose of this study was to determine if similar lead-induced disturbances in the effects of cocaine include the impact of the drug on schedule-controlled responding. Adult male rats exposed ad libitum to water containing 500 ppm lead acetate (Group Lead), or a comparable concentration of sodium acetate (Group Control), were placed on a restricted diet (12-15 g food/day) prior to commencing fixed-interval (F1-5 min) schedule training on Day 33 of exposure. After 27 days of operant training, animals received a sequence of no injection, saline injection, and cocaine injection tests, repeating the sequence for 3, 10, 20 and 40 mg/kg cocaine HCl (i.p.). Local rates were determined for successive 30 s segments of the interval and the pattern of responding was compared under conditions of saline and cocaine injection. For both groups, cocaine increased responding, especially early in the interval. However, the rate enhancing effects of cocaine were less pronounced in lead-exposed animals than controls, at least at the 20 mg/kg dose. These data extend earlier findings and accent the need to examine further the interactive relations between the external chemical environment and drug sensitivity.

Lead/ethanol interactions II: Pharmacokinetics

Adult male rats were exposed ad libitum to water containing either 500 ppm lead acetate (group-lead) or an equivalent amount of sodium acetate (group-control) for 60 days prior to receiving ip injections of either 1.0, 2.0, or 3.0 g/kg ethanol (20% v/v). Blood alcohol concentrations (BACs) were recorded over a 6-h time period postinjection, and the groups were compared at each dose for differences in the pattern of ethanol pharmacokinetics. While there was a dose-related effect obtained with increasing ethanol doses producing increasing BAC values, at no dose was there any evidence of group separation at any point during the 6-h postinjection period. These data are instructive with respect to understanding the nature of previously demonstrated lead/ethanol interactions, and rule out the possibility that lead-induced disturbances in the catalysis of ethanol, or some other pharmacokinetic operation, is the basis for the effects of lead on ethanol intake and ethanol administration. Alternative possible accounts of this curious interaction between a xenobiotic contaminant and alcohol are discussed.

Lead/ethanol interactions. I: Rate-depressant effects

Adult male rats were exposed to a diet containing 500 ppm added lead as lead acetate (group lead-diet) or a control diet containing no added chemicals (group control-diet) for 61 days prior to commencing fixed-ratio 32 (FR 32) lever press training for water reinforcement. After steady state responding was achieved, all animals received serial administrations of acute doses of ethanol prior to the daily training session. Specifically, lead-diet and control-diet rats received i.p. injections of .25, .5, .75, 1.0, and 1.25 g/kg ethanol, in ascending order, alternating daily with injections of saline. The results revealed a dose-dependent rate-depressant effect, with higher doses of ethanol producing more behavioral suppression than lower doses for both groups. In addition, at the dose of 1.0 g/kg it was observed that the suppressive effects of ethanol on schedule-controlled responding were reduced among lead-treated animals relative to controls. These data are discussed in terms of lead-induced attenuation of the pharmacologic effects of ethanol.

Attenuation of cocaine-induced elevation of nucleus accumbens dopamine in lead-exposed rats

Fourteen adult male rats were placed on an ad lib watering regimen where they received water containing 500 ppm lead acetate (group lead) or an equivalent concentration of sodium acetate (group control) for 61 days. Subsequently, a microdialysis cannula was surgically implanted in the nucleus accumbens. Following recovery, the seven animals in group lead and the seven animals in group control were presented with a challenge of 10 mg/kg cocaine HCL (IP). Dopamine efflux was measured prior to and at 20, 40, and 60 min postinjection, using HPLC technology. The results of this experiment showed that cocaine caused a significantly greater increase in extracellular nucleus accumbens dopamine in control animals relative to lead-treated animals.

Chronic lead exposure attenuates ethanol-induced hypoalgesia

Adult male rats were exposed to drinking fluid containing either 500 ppm lead acetate (group lead), or an equivalent concentration of sodium acetate (group control) for 61 days prior to pain reactivity testing using a tail-flick procedure. Rats were placed in restraining tubes for a 20 min acclimation period, and then baseline tail-flick latencies in response to a radiant heat source were measured. Subsequently, half the animals from each group were serially injected IP with either 1.0, 2.0, or 3.0 g/kg body weight of a 20% v/v ethanol solution, and the other half were injected with an equivalent volume of saline. Tail-flick latencies were reassessed at 20-min intervals over the next 2 h. Results indicated dose-dependent ethanol-induced hypoalgesia at all doses, but at the two higher doses the magnitude of the hypoalgesic response was significantly greater in the group control animals than in the group lead animals across the 2-h postinjection period. Results are discussed in terms of an attenuation of the pharmacological properties of ethanol by lead.

The effects of cadmium exposure on ethanol pharmacokinetics

Twenty-four adult male rats were exposed in the home cage to water containing 100 ppm added cadmium chloride. An additional 24 animals were pair-watered with water containing no added cadmium. Following 60 days of exposure to their respective watering regimens, one third of the animals in each exposure group (N = 8/condition) received IP injections of 1.0, 2.0, or 3.0 g/kg ethanol (20% v/v). Serum alcohol concentrations were measured at 15, 30, 60, 120, 180, 240, and 360 min postinjection. Although serum alcohol concentrations increased with dose for both cadmium-exposed and control animals, there was no indication at any dose of group differences. The lack of differences in ethanol pharmacokinetics reported here is instructive with respect to improving our understanding of the mechanisms underlying cadmium/ethanol interactions.

Brain stimulation reward following chronic lead exposure in rats.

Adult male rats were exposed to drinking water containing either 500 parts per million (ppm) lead acetate or an equal concentration of sodium acetate for 80 days. Bipolar electrodes were then implanted into the medial forebrain bundle (MFB), and rats were allowed to recover for 7 days. On Day 8 postsurgery, control and lead-treated rats were placed in an operant chamber and shaped to press a lever to receive 200-ms trains of current. Data from a range of current intensities and frequencies were recorded to obtain threshold values for each rat, defined as the stimulation needed to support half-maximal lever responding. Results indicated that chronic lead exposure attenuated the reinforcing effect of brain stimulation. Because of the large number of reward systems mediated by the MFB-nucleus accumbens pathway, these data suggest that a variety of motivational phenomena may be affected by contaminant exposure.

A FortRan 77 Program for Testing Trends among Independent Correlations

A FORTRAN 77 program is presented which computes a procedure developed by Levy (1976) for testing a priori trends among independent correlations.