Marty Cauley

Sazetidine-A, a Selective α4β2 Nicotinic Receptor Desensitizing Agent and Partial Agonist, Reduces Nicotine Self-Administration in Rats

Adequate treatment of tobacco addiction remains problematic. Part of the problem with treatment is a poor understanding of the pharmacologic aspects of nicotine contributing to addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also desensitizes them. It is currently not known how much of each of nicotines actions contribute to its particular behavioral effects. Sazetidine-A (saz-A) is a novel nicotinic receptor-desensitizing agent and partial agonist with high selectivity for α4β2 receptors. The current experiments were conducted to determine whether saz-A would reduce nicotine self-administration in rats and to characterize its ancillary effects. Adult male Sprague-Dawley rats were allowed to self-administer nicotine. After initial food pellet training followed by 10 sessions of nicotine self-administration training, the rats were administered saz-A (0.1–3 mg/kg s.c.) or the saline vehicle in a repeated-measures counterbalanced design. Saz-A at the 3 mg/kg dose significantly decreased nicotine self-administration relative to performance of the same rats after saline injections. In a second study, long-term administration of this dose of sazetidine-A over the course of 10 sessions significantly reduced nicotine self-administration with no apparent diminution of effect. Saz-A in this dose range had only modest effects on locomotor activity, without any overall decrease in activity over a 1-h-long session. Saz-A significantly reduced food self-administration, but this effect was smaller than its effect on nicotine self-administration. Saz-A, which is a selective α4β2-desensitizing agent and partial agonist, effectively reduces nicotine self-administration. This type of treatment holds promise for a new therapy to aid smoking cessation.

Lorcaserin, a 5-HT2C Agonist, Decreases Nicotine Self-Administration in Female Rats

Lorcaserin, a selective 5-hydroxytryptamine2C (5-HT2C) agonist, has been shown to facilitate weight loss in obese populations. It was assessed for its efficacy in reducing nicotine self-administration in young adult female Sprague-Dawley rats. The effect of short-term doses (subcutaneous) on nicotine self-administration (0.03 mg/kg per infusion) with a fixed ratio 1 schedule was assessed in 3-h sessions. Short-term lorcaserin doses (0.3125–20 mg/kg) were administered in a counterbalanced order. Significant reduction of nicotine self-administration was achieved with all of the short-term doses in this range. Tests of lorcaserin on locomotor activity detected prominent sedative effects at doses greater than 1.25 mg/kg with more modest transient effects seen at 0.625 to 1.25 mg/kg. Long-term effects of lorcaserin on locomotor activity were tested with repeated injections with 0.625 mg/kg lorcaserin 10 times over 2 weeks. This low lorcaserin dose did not cause an overall change in locomotor activity relative to that of saline-injected controls. Long-term lorcaserin (0.625 mg/kg) significantly reduced nicotine self-administration over a 2-week period of repeated injections. Long-term lorcaserin at this same dose had no significant effects on food self-administration over the same 2-week period of repeated injections. These studies support development of the 5-HT2C agonist lorcaserin to aid tobacco smoking cessation.

Threshold of adulthood for the onset of nicotine self-administration in male and female rats

The great majority of tobacco addiction begins during adolescence. More heavily addicted smokers begin smoking earlier, but differentiating the neurobehavioral impact of nicotine self-administration during adolescence from self-selection bias (whereby people more prone to heavy addiction also begin earlier) cannot be ethically unconfounded in humans. The goals of this research were to determine the age threshold for the adult-like nicotine self-administration and determine sex differences. Male and female Sprague-Dawley rats were tested for nicotine self-administration starting at 4, 5, 6, 7, and 8 weeks of age in an operant FR1 schedule for IV nicotine (0.03 mg/kg/infusion) in 45-min sessions for 2 weeks, with 1 week of enforced abstinence and 1 week of resumed access. This study replicated our earlier work that nicotine self-administration was increased in adolescent vs. adult rats and that the effect was more pronounced in adolescent males, but the increased nicotine self-administration was more persistent in adolescent-onset females. The age threshold for adult-like behavior was 6-7 weeks of age. Adolescent-onset nicotine self-administration had persisting effects of eggaurated increases of nicotine self-administration when fixed-ratio requirements for self-administration were lowered. Female rats that had begun nicotine self-administration during adolescence showed exaggerated increases in nicotine self-administration after a switch back to FR1 from FR8, indicating a lessened control over their self-administration. Adolescent-onset nicotine self-administration was not found to potentiate cocaine self-administration. Adolescent-onset nicotine self-administration causes persistent increases in nicotine self-administration in female rats even after they reach adulthood and disrupts control over self-administration behavior.

Role of individual and developmental differences in voluntary cocaine intake in rats.

RationaleEarly-onset drug taking is associated with increased likelihood of addiction, but it is unclear whether early onset is causal in development of addiction. Many other factors are associated with increased risk of addiction and also promote early intake. Here, a rodent model is used to explore the causality of early onset in development of self-administration and addiction-like behavior and to examine factors that promote self-administration.MethodsWe used cocaine self-administration to examine drug taking and addiction-like behavior in adolescent and adult rats a priori characterized for their locomotor responses to novelty and cocaine and behavior in the light–dark task.ResultsAdolescent animals initially sought more cocaine than adults. However, as the adolescents matured, their intake fell and they did not differ from adults in terms of unreinforced lever-pressing, extinction or reinstatement behavior. For both age groups, self-administration was positively correlated with the locomotor response to novelty, the locomotor response to cocaine, and with time in light in the light–dark task. The rats that were insensitive to cocaines locomotor effects and that spent the least time in light in the light–dark task sought the least cocaine, appearing to be “protected” from the reinforcing effects of cocaine. There was no difference between the two age groups in appearance of this “protected” phenotype.ConclusionsThese results suggest that early onset of drug taking may promote increased use, but does not promote progression to addiction-like behavior. Furthermore, protective factors, such as innate anxiety and insensitivity to cocaines pharmacological effects, function across developmental stages.

Improvement of attentional function with antagonism of nicotinic receptors in female rats.

Nicotinic agonists have been shown in a variety of studies to improve cognitive function. Since nicotinic receptors are easily desensitized by agonists, it is not completely clear to what degree receptor desensitization or receptor activation are responsible for nicotinic agonist-induced cognitive improvement. In the current study, the effect of the neuronal nicotinic cholinergic α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) and the α7 nicotinic receptor antagonist methyllycaconitine (MLA) on attentional function was determined. Adult female Sprague-Dawley rats were trained on the visual signal detection task. They were required to discriminate whether or not a light signal occurred on a trial and respond with a lever press on one side after a signal and the opposite side after the absence of a signal in order to receive a food pellet reinforcer. Acute administration of the α4β2 antagonist DHβE improved attentional function either alone or in reversing the attentional impairment caused by the NMDA glutamate antagonist dizocilpine (MK-801). Acute administration of MLA also significantly attenuated the dizocilpine-induced attentional impairment. In previous research we have shown that the α4β2 nicotinic desensitizing agent and partial agonist sazetidine-A also was effective in reversing dizocilpine-induced attentional impairments on the signal detection task and that low doses of the general nicotinic antagonist mecamylamine improved learning and memory. The current studies indicate that blockade of nicotinic receptors can effectively attenuate attentional impairments. Development of drugs that provide a net decrease in nicotinic receptor activity either through antagonism or desensitization could be worth exploring for beneficial effects for treating cognitive impairments.

Histamine H1 antagonist treatment with pyrilamine reduces nicotine self-administration in rats

Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin 5HT(2) and histamine H(1) receptors, has been found to decrease smoking. Previously we found that the serotonin 5HT(2) antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H(1) receptor interaction with nicotine self-administration. Young adult female Sprague-Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of pyrilamine, a histamine H(1) antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20mg/kg) or chronic infusion via osmotic minipumps (50mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H(1) antagonist ebastine was ineffective in reducing nicotine self-administration, pointing to central H(1) receptor blockade as key for the effectiveness of pyrilamine. H(1) antagonists may be a promising avenue to explore for new treatments to aid smoking cessation.

Attenuation of pharmacologically-induced attentional impairment by methylphenidate in rats

Methylphenidate is widely used as a treatment option for attention deficit hyperactivity disorder. In animal models of attentional impairment, it is an important validation to determine whether this clinically effective treatment attenuates deficits. The purpose of the current study was to determine whether methylphenidate can diminish attentional impairment induced by three pharmacological agents with different mechanisms of action: scopolamine, mecamylamine, and dizocilpine. Female rats were trained on an operant visual signal detection task. Ten min before the test, the rats were injected subcutaneously with methylphenidate (0, 0.1, 0.3 mg/kg), scopolamine (0, 0.005, 0.01 mg/kg), mecamylamine (0, 2, 4 mg/kg), dizocilpine (0, 0.025, 0.05 mg/kg) or combinations of methylphenidate with these drugs. In each of the experiments, all rats received every treatment in a repeated measures counterbalanced order. Correction rejection accuracy was impaired by all three of the antagonists and these effects were attenuated by methylphenidate. Both scopolamine at 0.01 and dizocilpine at 0.05 mg/kg significantly impaired percent correct rejection choice accuracy, an effect that was ameliorated by methylphenidate. Mecamylamine (4 mg/kg) impaired attentional performance by reducing percent hit and percent correct rejection. Co-administration of methylphenidate failed to significantly affect the mecamylamine-induced attentional impairment. Methylphenidate alone at 0.3 mg/kg significantly improved percent hit choice accuracy only in low-performing rats in one experiment, an effect which was reversed by scopolamine. These data show that methylphenidate effectively reverses the attentional impairment caused by scopolamine and dizocilpine. These findings further validate the operant visual signal detection task for assessing attentional impairments and their reversal.

Lorcaserin, a selective 5-HT2C receptor agonist, decreases alcohol intake in female alcohol preferring rats

Serotonergic systems in the brain have been found to be important in the addiction to alcohol. The purpose of this study was to evaluate the efficacy of a novel 5-HT2c receptor agonist, lorcaserin for reducing alcohol consumption in alcohol-preferring (P) rats. Adult female rats were allowed to drink water or alcohol (12%, v/v) using a standard two-bottle choice procedure. Once stable baselines were established, the acute (0, 0.3125, 0.625 and 1.25 mg/kg, s.c.), and chronic (0, 0.625 mg/kg, sc for 10 days) effects of lorcaserin on alcohol intake and preference were assessed at different time points. In a separate experiment, the effects of lorcaserin on locomotor activity were determined. Our results show that both 0.625 and 1.25 mg/kg lorcaserin significantly reduced alcohol intake at 2, 4 and 6 h. after the drug administration. The chronic administration of 0.625 mg/kg lorcaserin significantly reduced alcohol intake up to 6h every day after the injection and there was no sign of diminished efficacy of the drug during 10-day treatment. To determine the effects of lorcaserin on sucrose intake, rats were put on a two-bottle choice of water vs a solution of 7% sucrose. The high dose of lorcaserin (1.25 mg/kg, s.c.) reduced sucrose intake only for up to 2 h. When tested for locomotor activity, lorcaserin injected 20 min before testing significantly reduced locomotor activity at all doses. However, when it was injected 5.5h before the start of the 1-h session, neither dose had a significant effect on locomotor activity. These results show the efficacy of lorcaserin in reducing alcohol intake without a significant effect on water intake and locomotion suggesting the involvement of 5-HT2c receptors in alcohol seeking behavior. Further research is warranted to determine the possible efficacy of lorcaserin or similar drugs as treatments for the treatment of alcoholism.

Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats.

Background and rationaleNicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801).MethodsAdult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control.ResultsDizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01–1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment.ConclusionsAZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.

Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats.

Nicotine has been well characterized to improve memory and attention. Nicotine is the primary, but not only neuroactive compound in tobacco. Other tobacco constituents such as anabasine and anatabine also have agonist actions on nicotinic receptors. The current study investigated the effects of anabasine and anatabine on memory and attention. Adult female Sprague-Dawley rats were trained on a win-shift spatial working and reference memory task in the 16-arm radial maze or a visual signal detection operant task to test attention. Acute dose-effect functions of anabasine and anatabine over two orders of magnitude were evaluated for both tasks. In the radial-arm maze memory test, anabasine but not anatabine significantly reduced the memory impairment caused by the NMDA antagonist dizocilpine (MK-801). In the signal detection attentional task, anatabine but not anabasine significantly attenuated the attentional impairment caused by dizocilpine. These studies show that non-nicotine nicotinic agonists in tobacco, similar to nicotine, can significantly improve memory and attentional function. Both anabasine and anatabine produced cognitive improvement, but their effectiveness differed with regard to memory and attention. Follow-up studies with anabasine and anatabine are called for to determine their efficacy as therapeutics for memory and attentional dysfunction.