Jack R. Nation

Augmentation of cocaine hyperactivity in rats by systemic ghrelin

The feeding-relevant pathway by which food deprivation (FD) augments cocaine action is unknown. Systemic administration of the 28 amino acid acylated peptide ghrelin (1-10 nmol) increases food intake in rats and circulating levels of rat ghrelin are up-regulated by FD. The present experiment examined the impact of ghrelin or vehicle pretreatment on the locomotion and stereotypy induced by systemic cocaine hydrochloride. Male Sprague-Dawley rats were pretreated at -60 min with 0 or 5 nmol rat ghrelin (IP) and then injected (IP) at time 0 with 0, 2.5, 5.0, or 10.0 mg/kg cocaine. Locomotor activity was monitored over a 45-min post-cocaine period. Rats received the same ghrelin dose, but a different cocaine dose (in random order) on each of the four drug trials, with each drug trial separated by at least 2 days. Administration of 5 nmol ghrelin-0 mg/kg cocaine slightly increased locomotion relative to that of 0 nmol ghrelin-0 mg/kg cocaine. Cocaine increased locomotion as a function of dose in the 0 nmol ghrelin group, but the effect of cocaine was even greater when preceded by 5 nmol ghrelin. These results indicate that acute injection of ghrelin, at a feeding-relevant dose, augments the acute effects of cocaine on locomotion in rats.

Impairment of acquisition of cocaine self-administration in rats maintained on a high-fat diet

Variations in dietary constituents such as carbohydrate are known to alter psychostimulant function in brain. Relatively few studies have examined the reinforcing effects of psychostimulants in subjects maintained on high-fat diets. The present experiment compared the rate of acquisition of an operant response for intravenous (i.v.) cocaine infusions (0.2 mg/kg) in rats fed either a chow-pellet diet or a 35.9% (by weight) high-fat diet for 45 days prior to cocaine self-administration testing. Rats maintained on a high-fat diet for 45 days exhibited diminished acquisition of cocaine self-administration, and this effect was not a function of dietary-induced obesity. The results suggest that prolonged exposure to a high-fat diet diminishes the efficacy of cocaine reinforcement.

Cocaine-induced hypophagia and hyperlocomotion in rats are attenuated by prazosin

The present studies examined the effects of antagonizing alpha(1)-adrenoceptors via systemic administration of prazosin on the behavioral actions of cocaine in rats, including induction of locomotion and suppression of eating. In Experiment 1, locomotor activity was monitored in automated chambers for 80 min in adult male rats pretreated with the alpha(1)-adrenoceptor antagonist prazosin (0, 0.5, or 2 mg/kg, i.p.) and then treated (i.p.) with either 0, 10, 20, or 40 mg/kg cocaine hydrochloride. Cocaine dose-dependently increased total distance traveled and the number of stereotypy counts, and significantly decreased rest time. Each dose of prazosin produced a significant attenuation of the locomotor effects of a limited range of cocaine doses (i.e. 10 and/or 20 mg/kg cocaine, but not 40 mg/kg cocaine). Prazosin alone did not alter any measure of locomotion. In Experiment 2, eating and drinking were monitored for 60 min in male rats pretreated with prazosin (0, 1, and 2 mg/kg, i.p.) and then treated with 0, 10, 20, or 40 mg/kg (i.p.) cocaine. Rats pretreated with vehicle exhibited a dose-dependent suppression of eating, but not drinking, to cocaine. The impact of prazosin on cocaine-induced hypophagia paralleled that noted for locomotion in that administration of prazosin significantly attenuated the hypophagic action of 20 mg/kg cocaine, but not that of 40 mg/kg cocaine. These findings confirm earlier studies noting a partial role for alpha(1)-adrenoceptors in the locomotor stimulant actions of cocaine and extend those findings to the feeding-inhibitory actions of cocaine.

(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.

Effects of combined lead and cadmium exposure: changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites

Adult male rats were maintained on 1 of 4 ad-lib diets: Group Control-Diet received a normal laboratory diet that contained no added chemicals: Group Lead-Diet received a diet containing 500 ppm (parts per million) lead: Group Cadmium-Diet received a diet containing 100 ppm cadmium: and Group Lead-Cadmium-Diet received a diet containing both 500 ppm lead and 100 ppm cadmium. After 60 days of exposure to their respective diets, animals were placed on restricted diets (15 g/day) of the identical food received during the exposure period. Each animal was trained to lever press on a fixed-interval 1-min schedule for 21 sessions (1 session day). The results of schedule training showed that lead alone or cadmium alone was associated with increased lever pressing relative to control diet. However, when lead and cadmium were exposed jointly, performance was not significantly different from control performance. Similar attenuation of effects were observed for central neurotransmitter functions. Specifically disturbances in dopamine and serotonin turnover that were produced by lead alone were attenuated by the cotreatment of cadmium and lead. Possible accounts of the apparent antagonism between cadmium and lead are discussed.

Behavioral antagonism between lead and cadmium.

Adult male rats were exposed to one of four dietary conditions for a period of 60 days. Group Control-Diet received a diet containing no added lead or cadmium, group Lead-Diet received a diet that contained 500 ppm added lead, group Cadmium-Diet received a diet that contained 100 ppm added cadmium, and group Lead-Cadmium-Diet received a diet that contained both 500 ppm added lead and 100 ppm added cadmium. Subsequent to exposure, animals were tested in a Digiscan activity monitor. Animals were then sacrificed and metal concentrations were determined in blood and brain. The results from this experiment showed that lead alone increased movement and vertical activity. Cadmium alone decreased movement and increased rest time. Cotreatment with lead and cadmium failed to produce behavioral differences relative to controls; thus, it seems that the changes in activity caused by one metal are antagonized by the other. Results from the analyses of residues in tissues revealed that blood lead concentrations were lower in the cotreatment condition than the lead along condition. However, brain residue accumulations were not different for these two exposure conditions. There was no evidence that the presence of lead attenuated increases in cadmium residues in blood or brain. Overall, the residue data agree with a central, as contrasted with a peripheral, account of lead/cadmium interaction effects, at least as relates to behavior. Because lead and cadmium were additive with regard to producing decreased body weights, it seems that the toxic effect of these metals is antagonized by cotreatment in some instances, and augmented in others.

Persistence: the role of partial reinforcement in psychotherapy.

Persistence, which refers to the ability of a learned behavior to survive protracted nonreinforcement (extinction), has been an overlooked dimension of clinical intervention. While persistence of newly acquired coping behavior is desired (and possibly assumed) by all psychotherapeutic procedures, few treatment programs possess features that operate to sustain responding in the face of a nonsupportive, nonreinforcing environment. The present article presents a treatment strategy designed to foster persistence based on the laboratory findings that partial reinforcement schedules produce greater resistance to extinction than continuous reinforcement schedules--a phenomenon referred to as the partial reinforcement extinction effect. The two major theories of persistence (Amsels general theory of persistence and Capaldis sequential theory) are discussed, and the basic principles of these models are extended to a number of therapeutic modalities including depression therapies, systemic desensitization, assertiveness training, and aversion therapy. In addition, procedural considerations including generalized and discriminated persistence are discussed.

Dietary lead increases ethanol consumption in the rat

Rats fed either a diet containing 500 ppm (parts per million) Pb (as lead acetate) or an unadulterated control diet for 50 days were offered a 15% ethanol (ETOH) solution in a nonchoice (one-bottle) test situation. The results from this test indicated that Pb-diet animals consumed greater amounts of the ETOH solution than did controls. In a subsequent choice (three-bottle, two-fluid) test situation offering a nonpreferred ETOH solution or tap water as alternatives, Pb-diet animals once again ingested greater amounts of the ETOH solution. These findings are discussed in terms of possible Pb-induced increases in emotionality and the potential stress-reduction properties of ETOH.

Early developmental lead exposure increases sensitivity to cocaine in a self-administration paradigm

The purpose of this investigation was to determine if lead exposure during pregnancy and nursing alters cocaine sensitivity later in the adult cycle, although lead exposure had been discontinued following early development. Female rats were exposed via gavage to 0 or 16 mg/kg lead daily for 30 days prior to breeding with nonexposed males. The respective daily exposure regimens continued throughout gestation and lactation (perinatal lead exposure). Lead exposure was discontinued on the day of weaning (postnatal day [PND] 21). Beginning on PND 70, male offspring were trained to self-administer cocaine HCl intravenously. Examination of a range of cocaine doses (0.030, 0.060, 0.125, 0.250, and 0.500 mg/kg/infusion) revealed that, as adults, animals exposed to lead during early development self-administered cocaine at significantly greater rates at a low dose of the drug. In addition, self-administration rates were lower among lead-exposed animals at higher doses of cocaine. These findings were observed in metal-exposed animals where blood and brain tissue levels had returned to the levels of controls. Collectively, these data suggest that early developmental lead exposure may increase sensitivity to cocaine later in the life cycle.

The effects of force training and reinforcement schedules on human performance

Instrumental behaviors were conditioned in college students under partial (PRF) or continuous (CRF) reinforcement with either a high or low response force requirement. Half the subjects in the resulting four conditions were transferred to a similar task (shuttle) where they received 20 CRF trials. Remaining subjects were transferred to a dissimilar task where they solved (CRF) five anagrams. A subsequent persistence test (extinction) for similar-task subjects consisted of 70 nonreinforced shuttle trials; a persistence test for dissimilar-task subjects was 10 insoluble anagrams. Phase 1 yielded results that showed that training with either partial reinforcement or a high force requirement occasioned greater instrumental responding than training with continuous reinforcement or a low force requirement did. Differential effort effects were found in both shuttle and anagram acquisition, as subjects previously trained under high force requirements responded significantly faster than those trained under low force requirements. The findings from extinction indicated that partial reinforcement training increased resistance to shuttle extinction, as did training with a high force requirement. Further, the effects of schedules and force were found to be additive. Nondifferential effects were found for anagram extinction. Results were discussed in the context of Amsels frustration theory of persistence and Eisenbergers learned effort hypothesis.