Kenneth W. Locke

Effects of opiate antagonists and putative mu- and kappa-agonists on milk intake in rat and squirrel monkey

The effects of a number of relatively pure opiate antagonists (naloxone, naltrexone, diprenorphine), and putative mu- (morphine, etorphine) and kappa- (ketocyclazocine, ethylketocyclazocine) receptor agonists on sweetened condensed milk intake were examined over a broad range of doses in non-deprived rats and squirrel monkeys. The antagonists consistently decreased milk intake in both the rat and squirrel monkey. There were, however, species differences: diprenorphine was 30 times more potent than either naloxone or naltrexone in the squirrel monkey, but was of similar potency in the rat. The effects of the opiate agonists were more variable than those of the antagonists. In both species, all agonists decreased milk intake at high doses that also produced behavioral depression. Significant increases in drinking were produced only by low doses of ketocyclazocine and ethylketocyclazocine in the rat. The suppression of milk intake by the antagonists supports a modulatory role of opiate receptors in the control of drinking behavior, however, the effects of the agonists on drinking are less easily interpreted within this conceptual framework.

D1 Agonist Dihydrexidine Releases Acetylcholine and Improves Cognitive Performance in Rats

Dihydrexidine is a selective, full-efficacy dopamine D1 receptor agonist that has displayed therapeutic potential in Parkinsons disease by reversing motor deficits of MPTP-treated monkeys. The present study monitored the effects of dihydrexidine on acetylcholine release in rat brain by using in vivo microdialysis. Moderate doses of dihydrexidine [3 and 10 mg/kg, intraperitoneally (I.P.)] elevated extracellular concentrations of acetylcholine by 40-60% in rat striatum; higher doses did not significantly alter acetylcholine release. SCH 23390 blocked the dihydrexidine-induced increase, indicating a D1 receptor-mediated action. A more robust stimulatory effect of dihydrexidine on acetylcholine release was observed in prefrontal cortex (to 300% of basal output) than in striatum. Dihydrexidine was also evaluated in a passive avoidance procedure in rats to determine if its neurochemical effects translated into cognition-enhancing activity; in this assay, dihydrexidine (0.3 mg/kg, I.P.) significantly improved the scopolamine-induced deficits. The results of these studies suggest that the acetylcholine-releasing properties of dihydrexidine and other D1 agonists may underlie their cognition-enhancing activity and thus may have clinical value in the treatment of dementia.

Characterization of the discriminative stimulus effects of centrally administered morphine in the rat

The discriminative stimulus effects of centrally administered morphine were characterized in rats trained to discriminate 3.0 mg/kg SC morphine from saline in a two-choice discrete-trial avoidance paradigm. The intracerebroventricular (ICV) administration of 0.3–10 μg morphine engendered morphine-appropriate responding, morphine administered ICV being nearly 1000 times as potent as morphine administered SC. Cannula implantation itself did not affect the sensitivity of the rats to the discriminative effects of morphine. The onset of the discriminative stimulus effects of ICV morphine was not immediate; stimulus generalization comparable to that produced by 3.0 mg/kg morphine occurred 30–60 min after the injection of 1.0 or 10 μg ICV morphine and persisted for 90 and 150 min, respectively. Naltrexone blocked the discriminative stimulus effects of 10 μg ICV morphine in a dose-related manner. Complete antagonism of the stimulus effects of this dose of morphine was obtained with 0.01–0.03 mg/kg SC naltrexone. When administered centrally, the relatively lipid insoluble naltrexone methobromide completely antagonized the discriminative effects of 3.0 mg/kg morphine at a median effective dose of 0.3 μg. In contrast, when injected systemically at a dose of 1.0 mg/kg (approximately 500 μg), naltrexone methobromide failed to block the discriminative stimulus effects of either 10 μg ICV morphine or the SC training dose. Thus, periventricular brain sites appear to be involved in mediating the discriminative stimulus effects of morphine in the rat.

Discriminative stimulus effects of melatonin in the rat

To provide initial information on the potential mechanisms underlying the discriminative stimulus effects of melatonin, rats were trained to discriminate melatonin (150 mg/kg, IP) from saline in a two-choice discrete-trial avoidance paradigm. Stimulus generalization curves for melatonin were steep; complete generalization with melatonin occurred at 100–150 mg/kg. Triazolam generalized completely with melatonin (n=7). Flurazepam generalized completely with melatonin in only two out of six rats; however, partial generalization was produced in the remaining four animals. The melatonin-appropriate responding produced by triazolam was antagonized completely (in six out of seven rats) by 0.3–10 mg/kg flumazenil (Ro 15–1788). In contrast, the dose of flumazenil sufficient to block completely the melatonin-like discriminative effects of triazolam failed to block the stimulus effects of the training dose of melatonin. Pentobarbital produced primarily melatonin-appropriate responding, with complete generalization with melatonin in five out of seven rats. Diphenhydramine generalized completely with melatonin in two out of seven rats; however, little or no partial generalization was observed in the remaining five rats. These results suggest that melatonin may produce its discriminative effects through sites on the GABAA-benzodiazepine receptor complex distinct from the benzodiazepine binding sites.

Mu-opioid component of the ethylketocyclazocine (EKC) discriminative stimulus in the rat

The opioid receptor selectivity of the EKC discriminative stimulus was characterized in Fischer rats trained to discriminate 0.3 mg/kg EKC (SC) from saline in a twochoice discrete-trial avoidance paradigm. The putative kappa-opioid receptor agonists EKC and U50,488H completely generalized with the EKC aue at doses of 0.3 and 10 mg/kg, respectively. The putative mu-opioid receptor agonists morphine (M) and fentanyl also dose-dependently generalized with the EKC stimulus. The generalization of M with EKC was not symmetrical, EKC and U50,488H produced little or no M-appropriate responding in rats trained to discriminate 3.0 mg/kg M (SC) from saline. This generalization pattern may reflect a lack of opioid receptor selectivity of the EKC stimulus. However, distinct muopioid and kappa-opioid components of the EKC cue could be identified using graded doses of naloxone in EKC-trained rats. The discriminative effects of morphine and fentanyl were blocked completely by doses of 0.1–1.0 mg/kg naloxone, whereas doses of naloxone 3–10 times greater were necessary to block the discriminative effects of EKC and U50,488H. These results suggest that EKC produces a complex discriminative stimulus with mu-opiod and kappa-opioid components that can be separated using antagonists such as naloxone.

Enhancement of salt intake by choline chloride

The ingestion of salt (NaCl) in most societies far exceeds levels that are considered necessary and safe. To reduce salt intake, a rat model of salt taste acceptance was created to identify novel, more palatable salt substitutes/enhancers. To induce salt craving, male Sprague-Dawley rats were placed on a low-salt diet and injected weekly (SC) with either 100 mg/kg of deoxycorticosterone acetate (DOCA) or its vehicle, peanut oil. Following 16 h of fluid deprivation, intake was evaluated in a one-bottle acceptance procedure. The DOCA-injected animals consumed large volumes of salt-containing solutions (up to 120 ml in 2 h) and showed sensitivity to and specificity for the salt taste (generally lacking acceptance of dextrose, KCl, ammonium chloride, and water solutions). Using this model, choline chloride was identified as having salt taste-enhancing properties. Choline chloride (0.1-0.7%) significantly enhanced the intake of a dilute salt solution (0.1%). The relevance of the rat model was demonstrated in human taste trials; choline chloride enhanced the palatability of and preference for foods containing this compound. The results of the present experiments support the use of this animal model for evaluating compounds for salt-like taste qualities and suggest that choline chloride will be an effective salt taste enhancer in man.

Dexfenfluramine lacks amphetamine-like abuse potential

1. The amphetamine-like abuse potential of dexfenfluramine (dFEN) was evaluated using drug discrimination and self-administration procedures. 2. Male Fischer rats were trained to discriminate either dFEN (1.0 mg/kg) or d-amphetamine (dAMP; 1.0 mg/kg) from saline in a two-choice discrete-trial avoidance paradigm. 3. In dAMP-trained rats, dFEN (0.5-4.0 mg/kg) engendered almost exclusively saline-appropriate responding. In dFEN-trained rats, dAMP (1.0-4.0 mg/kg) engendered entirely saline-appropriate responding in 3 of 6 rats and intermediate levels of dFEN-appropriate responding in the remaining animals. 4. Potential reinforcing effects of dFEN were also evaluated in 3 male rhesus monkeys trained to self-administer cocaine (i.v.) during daily 60 min sessions under a fixed-ratio (FR)-10 schedule. 5. Various doses of dFEN (30-1000 micrograms/kg/infusion) and dAMP (10 micrograms/kg/infusion) were substituted for cocaine in 4 consecutive daily sessions. In all subjects, dFEN maintained rates of self-administration within the range of rates maintained by saline and considerably below those maintained by cocaine and dAMP. Furthermore, the within-session distribution of responding with dFEN resembled that produced by saline. 6. Taken together, these results strongly suggest that dFEN will not have amphetamine-like abuse potential in humans.