Jack R. Nation - US grants

The primary purpose of the proposed research is to demonstrate that the range of toxicant/ethanol interactions extends beyond ingestive behavior, and includes operant phenomena controlled by positive and aversive outcomes. Inorganic lead and cadmium administered via the diet are know to cause an increase in the volitional intake of ethanol in rats, and the present study is designed to assess whether the reinforcing effectiveness of ethanol in an operant context involving schedule-controlled responding may be similarly affected. Also, this project is concerned with determining the impact of lead and cadmium contamination of the anti- conflict properties of ethanol. Experiments 1 and 2 will involve exposing rats to dietary lead or cadmium for 60 days prior to commencing a sucrose- fading procedure which is designed to condition animals to lever press for ethanol reinforcement (in concentrations as high as 40% v/v). Using a concurrent FR4 FR4 schedule that presents water and ethanol as alternative reinforcers, choice responding relative to control conditions will be recorded in an effort to determine the effect of the metals on ethanol's reinforcing potential. Experiments 3 and 4 will expose animals to lead or cadmium, and subsequently test them on a conditioned punishment task that employs a "conflict" preparation. Specifically, metal-exposed and control animals will be water deprived and then permitted to drink in a test chamber where electric shock will be delivered contingent on drinking responses. Ethanol will be injected i.p. and the differential attenuation effects of the drug noted for lead-exposed, cadmium-exposed, and control animals. The data from the proposed project should help determine the relation between environmental pollution and drug effects, and in this regard move us toward the ultimate goal of this study: the elucidation of the role of exogenous chemical contamination in drug use.

Previous investigations have shown that recurrent exposure to dietary lead or cadmium results in increased volitional intake of ethanol. The present proposal will help define a suitable rationale for interpreting metal/ethanol interactions. Specifically, it is proposed that metal-treated animals may consume more ethanol because the pharmacologic and behavioral effects associated with the drug are attenuated by toxic exposure. In this context, increased consumption by treated animals would be viewed as compensatory. To test this idea, the impact of lead or cadmium toxicity on ethanol-induced changes in motor performance, operant responding, and thermoregulation will be studied. Experiment 1 will expose adult rats to a diet containing 500 ppm lead (as lead acetate) for 60 days prior to testing for ethanol-induced impairment of locomotor activity, roto-rod performance, and the aerial righting reflex. Experiment 2 will 'involve the same behavioral tests, but animals will be exposed to food containing 100 ppm cadmium (as cadmium chloride). Experiments 3 and 4 will examine the effects of metal exposure on the rate-depressant action of ethanol in an operant context (FR 32 water-reinforced responding). Experiments 5 and 6 will test for possible attenuation of ethanol-produced poikilothermia in lead-exposed and cadmium-exposed rats. Experiment 7 will examine the effect of lead and cadmium exposure on ethanol metabolism. In all experiments, a full range of ethanol doses will be used for testing.

Previous investigations have shown that recurrent exposure to dietary lead or cadmium results in an attenuated response to ip injections of cocaine HCL. Specifically, these metals reduced the psychostimulant effects of a 10mg/kg dose of cocaine HCL, but not a 20 or 40 mg/kg dose, in adult male rats. Because lead and cadmium are competitive with calcium, and inasmuch as calcium-mediation is central to the neurochemical and behavioral effects of cocaine, it is possible that these toxicants may attenuate the pharmacologic effects of cocaine. Relevant to this issue, four separate lines of investigation are proposed. Experiments 1 and 2 will examine the effects of chronic low- level exposure to lead or cadmium on the rate-dependent effects of acute cocaine exposure, in an operant context. The second series of experiments will assess the impact of lead (Exp. 3) or cadmium (Exp. 4) on the discriminative stimulus effects associated with cocaine. Experiments 5 and 6 will test for the rewarding effects of cocaine in lead-treated and cadmium-treated animals, using an intravenous self- administration paradigm. Also, the effects of lead (Exp. 7) or cadmium (Exp. 8) on cocaine-induced increases in extracellular levels of dopamine within the nucleus accumbens and prefrontal cortex will be determined, using a microdialysis technique. Finally, the effect of lead or cadmium on cocaine pharmacokinetics will be assessed (Exp. 9-10). In all experiments a full range of drug doses will be used. The results from this project will provide valuable information about the possible link between xenobiotic contamination and the response to a prominently abused psychoactive drug.

DESCRIPTION: (ADAPTED FROM APPLICANT'S ABSTRACT) Regarding metal/drug interaction experiments, previous self-administration reports have been limited to the effects of adult lead or cadmium exposure on ethanol or cocaine intake. To date, there have been no studies on the effects of developmental metal exposure on the patterns of drug selection and intake later in the adult cycle. Relevant to this issue, this laboratory has observed that responsiveness to cocaine and other dopamine agonists is altered by perinatal exposure to lead or cadmium, and these disturbances persist well into the adult cycle long after toxicants have gained clearance from soft tissue. Such seemingly permanent and potentially nonreversible effects are of potential importance with respect to predicting use patterns of drugs that impact dopamine and related systems. Accordingly, this project aims to investigate the effects of prenatal, postnatal, and perinatal exposure to lead or cadmium on the self-administration of cocaine, heroin, and combinations of heroin and cocaine. Dams will be exposed to 0, 8, or 16 mg lead (Exp. 1-3) or 0, 2.5, or 5 mg cadmium (Exp. 4-6), and cross-fostered pups will be tested as adults for the intravascular (iv) self-administration of cocaine, heroin, or cocaine/heroin combinations (speedball). Exp. 7-9 will determine the effects of prenatal, postnatal, and perinatal cadmium exposure on regional accumulation of cadmium in brain, as well as in blood, liver, kidney, and bone (tibia). Because lead exists in such high concentrations in the inner cities where drug abuse is more common, and because over 20 percent of pregnant women in the United States smoke tobacco that contains cadmium which is readily distributed to the fetus/neonate, results of the proposed project should enhance our understanding of possible linkages between environmental contamination during early development and drug selection and use later in life.