William A. Corrigall

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.

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.

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.

Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress.

Abstract Acamprosate (calcium-acetyl homotaurinate) is a new compound used in the treatment of alcohol abuse. Because of the putative link between alcoholism and the endogenous opioid systems in both humans and laboratory animals, we tested in rats the effects of acamprosate on behavioral and neurochemical effects of opioid drugs related to their abuse potential. These included sensitization to the behavioral effects of morphine, morphine-induced dopamine (DA) release in the nucleus accumbens (NAS), intravenous (IV) heroin self-administration and relapse to heroin seeking in drug-free rats. In experiment 1, rats were injected daily with either morphine (10 mg/kg, SC) or saline for 14 days. Three days later in a test for the expression of sensitization, an injection of morphine (10 mg/kg) resulted in increased locomotor activity and enhanced DA release in the NAS in rats previously exposed to morphine. Acamprosate (two injections of 200 mg/kg; 12 h apart; IP) suppressed the expression of the sensitized responses, but did not alter the effects of morphine in drug-naive control rats. In experiment 2, it was found that acamprosate (two injections of 50–200 mg/ kg; IP) had no consistent effects on IV heroin self-administration (50–100 μg/kg per infusion) and, in experiment 3, that acamprosate (100–200 mg/ kg, IP) did not alter reinstatement of drug seeking induced by priming injections of heroin (0.25 mg/kg, SC) or a footshock stressor (15 min; 0.5 mA) after a 5- to 8-day period of extinction. Thus, although acamprosate attenuated the expression of sensitized locomotor activity and DA release in the NAS, it did not have any consistent effect on either the intake of heroin during the maintenance phase or the relapse to heroin seeking in a drug-free state. Thus, to the extent that the self-administration and the reinstatement procedures provide valid preclinical models for drug use and relapse in humans, our data suggest that acamprosate may not be effective in altering drug-taking behavior in heroin users.

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.

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.

Nicotine-induced fos expression in the pedunculopontine mesencephalic tegmentum in the rat.

The aim of this study was to assess the effects of a single dose of nicotine (NIC, 0.3 or 1.0 mg/kg, s.c.), after survival times of 30, 60 or 120 min, on immediate early gene expression in the pedunculopontine mesencephalic tegmentum (PMT), using Fos-immunocytochemistry. Either doses of NIC strongly increased Fos-immunoreactivity in both the pedunculopontine tegmental nucleus (PPTg) and the laterodorsal tegmental nucleus (LDTg), as compared to the saline controls, at 30 min and 60 min. In comparison, the effects of NIC-induced Fos expression in the caudate-putamen (CP) were not as strong as the ones observed in the PPTg and LDTg. In fact, at 30 min the 0.3 mg/kg dose of NIC did not induce Fos-expression, unlike the PPTg and LDTg. The CP response was more noticeable in the mediodorsal than in the laterodorsal region. Double-labelling studies using Fos-immunoreactivity and NADPH-diaphorase histochemistry for cholinergic cells in the PPTg and LDTg revealed that, in general, cholinergic neurons had Fos negative nuclei, although double-labelled neurons were occasionally seen in the PPTg. In conclusion, systemically administered NIC activates the neuronal population of the PPTg and the LDTg possibly by directly targeting nicotinic receptors that may be located in non-cholinergic neurons. We postulate that activation of these non-cholinergic neurons modulates the activity of cholinergic cells in the PMT, which in turn may alter dopamine release in the mesolimbic system.

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.

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.

Regulation of Intravenous Nicotine Self-Administration — Dopamine Mechanisms

Intravenous self-administration of nicotine has been obtained in rats with a limited-access model. Nicotine is a powerful reinforcer in this situation. Dependency upon dose is greatest at high and low ends of the dose range, but responding is relatively insensitive to dose at mid-range values; this is similar to the dependency of cigarette smoking behavior on nicotine delivery. The role of dopamine in nicotine reinforcement has been examined using this self-administration paradigm. Selective D1 (SCH23390) and D2 (spiperone) dopamine antagonists reduce nicotine self-administration in a dose-dependent fashion. The same dose range of D1 and D2 antagonists produce compensatory increases in cocaine self-administration. These differences in the effects of dopamine antagonists may stem from the different regulation of nicotine as compared to cocaine. Lesions of the mesolimbic dopamine system made by microinfusions of the neurotoxin 6-hydroxydopamine into the nucleus accumbens attenuate both nicotine self-administration and food-maintained behavior. These data suggest that dopamine mechanisms, perhaps in the mesolimbic system, play a role in nicotine reinforcement.