Biomedical subjects

W A Corrigall

Publications and source records attributed to W A Corrigall.

At least 37 records · Page 2Linked to original sources

PubMed1997

Effect of CYP2D1 inhibition on the behavioural effects of d-amphetamine.

In rats, amphetamine (AMP) conversion to 4-OH-AMP is metabolized by CYP2D1, the rat equivalent of the human enzyme CYP2D6. To determine the impact of impaired AMP metabolism on its behavioural effects, AMP-induced hyperactivity, AMP discrimination and AMP self-administration were examined in male Wistar rats with or without pretreatment with the CYP2D1 inhibitors quinine and budipine. In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) increased the plasma area under the curve of AMP 4-fold and 3.6-fold respectively, and decreased the plasma levels of 4-OH-AMP, 3-fold and 8.6-fold, confirming that the doses used suppressed CYP2D1 activity. Both inhibitors prolonged AMP-induced hyperactivity (0.3 mg/kg) and prolonged the duration of AMP-appropriate responding for periods of up to 90 min post-AMP administration in a drug discrimination procedure. In rats given a preload dose of AMP (0.8 mg/kg) 3 h prior to the self-administration test session, CYP2D1 inhibition resulted in fewer AMP infusions being taken compared with rats receiving the AMP preload dose alone. These studies indicate that AMP is responsible for the behavioural effects seen in rats and that a rat phenocopy model of the human CYP2D6 deficiency state can be produced by CYP2D1 inhibitors.

Alcohol Oxidoreductases↗

PubMed1994

Amygdala dopamine levels are markedly elevated after self- but not passive-administration of cocaine.

The influence of cocaine on rat brain monoaminergic neurotransmitters (dopamine, serotonin, noradrenaline) and their metabolites, and on binding of [3H]WIN 35,428 and [3H]GBR 12,935 to the dopamine transporter was measured after 4 weeks of cocaine exposure. Cocaine (mean daily dose 9.25 +/- 0.48 mg/kg) was self-administered (responders) or passively received (yoked) during sessions which lasted for 1 h per day. As compared with the controls, mean dopamine and serotonin levels were significantly elevated (+ 107% and + 47%, respectively) in amygdala of responders, but not of yoked rats, sacrificed 1 h after the last cocaine session. Dopamine and metabolite levels were normal in all other brain areas examined, including striatum, nucleus accumbens and medial prefrontal cortex, at both 1 h and 4 weeks withdrawal from cocaine. [3H]WIN 35,428 and [3H]GBR 12,935 binding were unaltered after cocaine exposure. These data provide additional support for the involvement of the amygdala in the acquisition of drug seeking behavior associated with cocaine self-administration.

Amygdala↗

PubMed1994

Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area.

Microinfusions of the nicotinic antagonist dihydro-beta-erythroidine (DH beta E) were used to examine the role of the mesolimbic dopamine system in nicotine reinforcement in rats. Infusions of DH beta E into the ventral tegmental area (VTA) prior to the start of i.v. nicotine self-administration sessions resulted in a significant decrease in the number of nicotine infusions voluntarily obtained. In contrast, the same doses of DH beta E infused into the nucleus accumbens were without effect on nicotine self-administration. The reductions caused by DH beta E were specific to nicotine reinforcement; neither operant responding maintained by food, cocaine self-administration, or spontaneous locomotor activity were altered by local applications of DH beta E within the VTA. The reduction in nicotine self-administration following treatment in the VTA was also specific to the nicotinic antagonist, and was not duplicated by infusions of the muscarinic antagonist atropine. Partial lesions of the pedunculopontine tegmental nucleus, the likely origin of cholinergic fibers to the VTA, were without effect on nicotine self-administration, suggesting that the effects of DH beta E were not due to disruption of a tonically active cholinergic input to the VTA from this source. These data show that nicotine acts within the VTA region to initiate processes which are critical to the reinforcing properties of the drug.

Animals↗

PubMed1994

The CCKA receptor antagonist devazepide does not modify opioid self-administration or drug discrimination: comparison with the dopamine antagonist haloperidol.

We previously reported that the selective cholecystokininA (CCKA) receptor antagonist, devazepide, blocked the acquisition of a morphine conditioned place preference (ref 28). An interpretation of this finding is that devazepide may either affect an opioid discriminative stimulus and/or modify the rewarding properties of opioids. The present study was designed to investigate these issues by determining the effect of equivalent doses of devazepide in a morphine drug discrimination paradigm and a model of heroin self-administration. In each case, devazepide (0.001-1 mg/kg) was ineffective, i.e there was no antagonism of a morphine discriminative cue, and in a separate group of rats trained to self-administer heroin (0.03 mg/kg/infusion, FR5 schedule, 1h per day), devazepide did not alter the pattern of heroin responding. Because of evidence implicating an interaction between accumbens CCK and dopamine (DA) systems and evidence suggesting an apparent differential involvement of DA in opioid place conditioning, self-administration and drug discrimination behaviour, the effect of the DA antagonist haloperidol was examined in the latter two paradigms. In each test, haloperidol produced an effect inconsistent with a direct DAergic involvement. In a final study the CCKB antagonist L365-260 was also found not to affect an opioid discriminative cue. The present results therefore cast doubt on the potential utility of selective CCKA antagonists as treatments for opioid abuse, and further suggest that CCKB antagonists may not potentiate the subjective effects of opioids, an important finding considering that such drugs have been proposed as adjuncts to opioid therapy for the treatment of pain relief.

Animals↗

PubMed1994

Dopamine receptor density, sensitivity and mRNA levels are altered following self-administration of cocaine in the rat.

The effects of cocaine administration and withdrawal on D1 and D2 dopamine receptor number, affinity, and mRNA levels were examined in rats trained to self-administer cocaine for four weeks on a continuous reinforcement schedule. Two hours after the last infusion of cocaine there was a decrease in the number and agonist sensitivity of dopamine D1 receptors in the anterior forebrain as well as in the limbic region. In contrast, there were no discernible changes in dopamine D2 receptors in any of the brain regions examined. Examination of dopamine receptor gene expression using Northern blot analysis revealed that there was an increase in D1 receptor mRNA levels in the forebrain, whereas D1 and D2 receptor mRNA levels both were increased in the limbic region. One week following the last infusion of cocaine, D1 and D2 receptor mRNA levels had returned to baseline. In the limbic region, D1 receptor numbers also had normalized by this time, whereas in the forebrain, changes in D1 receptors persisted. These data indicate that repeated exposure to cocaine induces regional changes in D1 receptor sensitivity and gene expression, suggesting that the D1 dopamine system plays an important role in mediating the reinforcing effects of cocaine.

Animals↗

PubMed1994

Influence of 5-HT3 receptor antagonists and the indirect 5-HT agonist, dexfenfluramine, on heroin self-administration in rats.

The purpose of the present study was to examine the effects of the 5-HT3 antagonists ondansetron and MDL72222, and the 5-HT releaser and reuptake inhibitor dexfenfluramine, on intravenous heroin self-administration by Wistar rats. Using separate squads of animals, two separate schedules of heroin reinforcement were used; a relatively low dose (0.03 mg/kg per infusion) made available under a FR5 schedule for 1 h each day, and a moderate heroin dose (0.1 mg/kg per infusion) available under a FR1 schedule for 2 h each day. Following the acquisition of stable levels of responding across days, both naloxone pretreatment (0.25 mg/kg SC) and halving the heroin infusion dose produced increases in operant responding for heroin at each concentration. Neither ondansetron (0.01-1 mg/kg SC) nor MDL72222 (0.1-3 mg/kg SC) pretreatment influenced heroin self-administration. Chronic treatment (5 day) of ondansetron (0.01-0.1 mg/kg) was similarly ineffective. However, dexfenfluramine (0.5-2.5 mg/kg IP) consistently reduced heroin self-administration at doses producing only modest decreases in food responding. These findings are in contrast to place conditioning studies, which show that 5-HT3 antagonists but not indirect 5-HT agonists block a morphine-induced place preference. Reasons for such discrepancies remain to be determined.

Animals↗

PubMed1994

Dopamine mechanisms play at best a small role in the nicotine discriminative stimulus.

The ability of D1 and D2 dopamine antagonists to reduce the subjective effects of nicotine was examined in rats trained to discriminate nicotine (0.3 mg/kg, base) from saline. Each of SCH 23390 (a D1 antagonist) and spiperone (a D2 antagonist) reduced responding on the drug-appropriate lever, and produced a reduction in overall response rates. The nicotine cue was also tested for generalization to the dopamine reuptake blocker GBR 12909. Doses of GBR 12909 that produced complete responding on the drug-appropriate lever in cocaine-trained animals led to only minimal selection of the nicotine-appropriate lever in nicotine-trained animals; as with the dopamine antagonists, response rates after GBR 12909 were markedly reduced in nicotine-trained, but not in cocaine-trained, rats. These data suggest that dopaminergic mechanisms play, at best, a small role in the discriminative stimulus properties of nicotine.

Animals↗

PubMed1994

Nicotine self-administration and locomotor activity are not modified by the 5-HT3 antagonists ICS 205-930 and MDL 72222.

The subtype-selective serotonin 5-HT3 antagonists MDL 72222 and ICS 205-930 were tested for their ability to modify nicotine self-administration and locomotor activity in rats. In self-administration experiments, MDL 72222 produced no statistically significant changes over a dose range of 1 to 30 micrograms/kg, nor at the considerably higher dose of 1 mg/kg. MDL 72222 was similarly without effect in nicotine-produced locomotor activity, except at the 1 mg/kg dose, which reduced scores. In an initial test on nicotine self-administration, ICS 205-930 produced a small decrease in drug-taking behavior at 1 and 3 micrograms/kg which just reached statistical significance, but had no effects at higher doses. However, these low-dose effects could not be replicated. In addition, ICS 205-930 was without effect on nicotine locomotor activity, even at the two low doses that had reduced self-administration. We conclude that these 5-HT3 antagonists do not modulate nicotine reinforcement or behavioral arousal.

Animals↗

PubMed1992

The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine.

Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.

Animals↗

PubMed1992

The reinforcing and discriminative stimulus properties of para-ethoxy- and para-methoxyamphetamine.

The purpose of this study was two-fold: 1) to assess the degree to which para-methoxyamphetamine and para-ethoxyamphetamine maintain self-administration behavior, and 2) to determine the similarity or difference between these drugs and amphetamine in drug discrimination tests. Animals were trained to self-administer 0.3 mg/kg/infusion cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Substitution of para-ethoxyamphetamine (PEA), para-methoxyamphetamine (PMA), or saline produced similar results; in all cases responding decreased substantially. A separate group of animals was trained to discriminate amphetamine (1 mg/kg) from saline in a fixed-ratio (FR10), food-reinforced paradigm. PEA and PMA produced only limited responding on the amphetamine-appropriate lever (maximum of approximately 30%). Both PMA and PEA had effects on response rate which were similar to those of amphetamine, although PMA had slightly greater rate-decreasing effects than the other two compounds. These data suggest that neither PMA nor PEA are reinforcing in rats, and do not possess amphetamine-like discriminative properties.

Amphetamines↗

PubMed1992

Discriminative stimulus properties of substituted amphetamine derivatives.

Animals were trained to discriminate amphetamine (1 mg/kg) from saline in a fixed-ratio (FR 10), food-reinforced paradigm. Amphetamine-appropriate responding was engendered by the training dose, and by 3 mg/kg, while at lower doses there was a progressive decrease in the extent of responding on the drug-appropriate lever. The following three novel amphetamine derivatives were tested for their ability to produce amphetamine-appropriate responding: 2,5-dimethoxy-4-ethoxy-amphetamine (DMEA); 2,5-dimethoxy-4-methylthio-amphetamine (DMMTA), and 2,4,5-trimethoxy-amphetamine (TMA). DMEA produced only minimal (< 20%) amphetamine-appropriate responding over a dose range of 0.1-10 mg/kg. Substantial decreases in response rate limited testing of the other amphetamines to a dose maximum of 3 mg/kg, but over the range of 0.1-3.0 mg/kg there was little evidence for generalization. At 3 mg/kg of either DMMTA or TMA, only 2 of 10 animals completed at least one uninterrupted FR 10 on either lever, and with either compound only 1 of these 2 animals responded more than 50% on the drug-appropriate lever. Of the three compounds tested, DMMTA had the greatest response rate-decreasing effect.

Amphetamines↗

PubMed1991

Opiate antagonists reduce cocaine but not nicotine self-administration.

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.

Animals↗

PubMed1991

Selective dopamine antagonists reduce nicotine self-administration.

The effects of selective D1 (SCH23390) and D2 (spiperone) dopamine antagonists, as well as of haloperidol, were examined on nicotine self-administration, food-maintained responding, and locomotor activity in rats. Antagonists reduced both operant responding and locomotor activity. Response patterns indicated that motor impairment was not the cause of the decreases, since responding was attenuated only in the latter half of operant sessions. Locomotor activity scores were significantly reduced by SCH23390, but not by spiperone. The effects of dopamine antagonists on nicotine self-administration are different from the effects of these antagonists on cocaine self-administration. Results are discussed in terms of the role of dopamine in drug reinforcement versus its role in sensorimotor integration.

Animals↗

PubMed1991

Cocaine self-administration is increased by both D1 and D2 dopamine antagonists.

Rats were trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement with a 1-min time-out period following each infusion. Cocaine was available at doses of either 0.1, 0.3 or 1.0 mg/kg/infusion. A low dose (3 microgram/kg) of the D1 antagonist SCH23390 caused an increase in cocaine self-administration which was more prominent at higher, as compared to lower, doses of cocaine. Higher doses of SCH23390 generally caused decreases in self-administration which may in part be due to the response-decreasing properties of this agent. The D2 antagonist spiperone generally caused an increase in self-administration of cocaine. These data suggest that cocaine reinforcement depends upon both D1 and D2 receptor subtypes.

Animals↗

PubMed1991

Understanding brain mechanisms in nicotine reinforcement.

Current understanding of the mechanisms through which nicotine acts to reinforce behavior is limited. Demonstrated interactions between nicotine and the mesolimbic dopamine system have provided the impetus for investigations of the role of this particular brain pathway in nicotine reinforcement, and preliminary studies do indeed suggest that the dopamine system might be involved in self-administration of nicotine. However, there are clearly other possible brain sites and neurotransmitter mechanisms that could be critical to reinforcement processes for nicotine. This article proposes that a broadly-based attack on the question of nicotine reinforcement would be the most fruitful; basic biological research should aim to verify the involvement of the mesolimbic dopamine system, but also to elucidate other candidate brain systems that may contribute to the reinforcing properties of nicotine.

Animals↗

PubMed1990

Selective D1 and D2 dopamine antagonists decrease response rates of food-maintained behavior and reduce the discriminative stimulus produced by heroin.

Animals were trained to discriminate heroin from saline in a two-lever food-reinforced paradigm. Tests with the heroin metabolites O6-monoacetylmorphine and morphine suggest that the heroin discriminative stimulus was mediated by monoacetylmorphine. The heroin discriminative stimulus was not blocked by pretreatment with low doses of the D1 dopamine antagonist SCH23390 or the D2 antagonist spiperone; higher doses of the antagonists produced decreases both in selection of the drug-appropriate lever after heroin, and in food-maintained responding. The data suggest that dopamine may mediate the heroin discriminative stimulus. When administered in the absence of opioids, the D2 antagonist spiperone did not have rate-decreasing effects, whereas SCH23390 did. Heroin partially reversed the rate-decreasing effects of SCH23390, possibly as a result of the ability of opioids to release dopamine.

Animals↗

PubMed1989

Nicotine maintains robust self-administration in rats on a limited-access schedule.

Intravenous nicotine maintained substantial responding on the drug-reinforced lever with a limited-access, fixed-ratio 5 schedule of self-administration. Responding demonstrated the expected pharmacological sensitivity; it was dose-dependently reduced by pre-session treatment with either nicotine or mecamylamine but not with hexamethonium. In addition, responding was dependent on the size of the unit dose, with maximum values occurring at 0.01 and 0.03 mg/kg/infusion. Self-administration behavior decreased at doses both above and below these, and extinction followed the substitution of saline for nicotine. Total session drug intake increased with unit dose up to a maximal value of approximately 0.5 mg/kg at 0.03 mg/kg/infusion, but did not increase further at the 0.06 mg/kg/infusion dose. A decrease in the time-out duration at the dose of 0.03 mg/kg/infusion also did not change the total session intake of nicotine. It is suggested that nicotine intake is controlled both by the total amount of drug obtained and by the magnitude of the unit dose. These results demonstrate that intravenous nicotine can maintain substantial self-administration behavior in rodents.

Animals↗

PubMed1989

Fixed-interval schedules for drug self-administration in the rat.

The practicality of using second-order fixed-interval schedules in studies of heroin reinforcement with rats was examined. Optimum rates of responding were obtained with a dose of 0.03 mg/kg/infusion and an interval duration of 3 min. In addition, schedules consisting of a only a single interval were shown to be practical, leading to response rates comparable to those obtained with cocaine or food as reinforcer.

Animals↗