Effect of chronic nicotine on brain stimulation reward. I. Effect of daily injections.

Previous work has shown that nicotine facilitates brain stimulation reward (BSR) but that the maximum effect obtainable with nicotine is similar to that seen with nonaddictive compounds. This study examined whether repeated nicotine injections would enhance the facilitatory action of nicotine on BSR. Rats with lateral hypothalamic stimulating electrodes were tested using a threshold-tracking procedure. This procedure determined the minimum stimulation frequency (i.e. stimulation threshold) necessary to maintain 30 presses/min during 30-min test sessions. Rats were injected daily with nicotine bitartrate (0.5 mg/kg, s.c., dose expressed as free base weight) or physiological saline (1 ml/kg, s.c.) immediately before testing for 21 consecutive days. Nicotine lowered thresholds across the 21-day injection regimen. Neither tolerance nor sensitization to this effect was apparent. The magnitude of threshold lowering produced by nicotine was similar to that previously reported for acute nicotine and for mild stimulants with low addiction liabilities (i.e. caffeine and pseudoephedrine). This finding suggests that even under chronic administration, nicotine's profile in this animal model is that of a substance with a low addiction liability.

Effect of chronic nicotine on brain stimulation reward. II. An escalating dose regimen.

This study examined whether repeated nicotine injections, using an escalating dose regimen, would produce brain stimulation reward facilitation indicative of a strong rewarding action. Male, Long-Evans rats with lateral hypothalamic stimulating electrodes were injected daily with escalating doses of nicotine bitartrate across 5-day cycles: 0.5, 1, and 2 mg/kg/day (dose expressed as freebase weight) were administered subcutaneously (s.c.) in consecutive 5-day cycles. Nicotine lowered thresholds across the first two 5-day cycles (i.e. 0.5 and 1 mg/kg/day doses), but thresholds returned to baseline levels during the last 5-day cycle (i.e. 2 mg/kg/day). The maximum threshold lowering produced by nicotine was similar to that previously reported for acute and chronic nicotine and for mild stimulants with a low addiction liability (i.e. caffeine and pseudoephedrine). Forty-eight h after terminating the nicotine injection regimen, thresholds were elevated revealing a nicotine withdrawal reaction. However, the high nicotine dose used during the last 5-day cycle is probably not pharmacologically relevant, thus making the significance of the withdrawal effect unclear. Overall, this study suggests that even under chronic administration using escalating doses, nicotine's profile in this animal model is that of a substance with a low addiction liability.

Nitric oxide synthesis inhibition attenuates haloperidol-induced supersensitivity.

Increased responsiveness to psychomotor stimulants can be produced by either chronic stimulant administration or by chronic dopamine receptor blockade. This study examined the role of nitric oxide in the development of neuroleptic-induced supersensitivity. N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) administered during chronic intraperitoneal (i.p.) haloperidol treatment (0.2 mg/kg/d for 14 d) was used to inhibit nitric oxide synthesis. Locomotor activity following a cocaine(i.p.) challenge injection (10 mg/kg) administered at 3 and 10 d after cessation of haloperidol treatment demonstrated the development of supersensitivity. Haloperidol animals pretreated with L-NAME i.p. (30 mg/kg) showed significantly less cocaine-stimulated locomotor activity on both tests than saline-pretreated animals. This finding suggests that nitric oxide is involved in haloperidol-induced supersensitivity and that a common neural mechanism may underlie the development of supersensitivity and stimulant-induced sensitization. This study also suggests that treatment with a nitric oxide synthesis inhibitor may decrease the side effects accompanying long-term treatment with antipsychotic medications.

Opiate reinforcement processes: re-assembling multiple mechanisms.

Opiate reinforcement processes can be described within the context of operant conditioning theory. Both positive and negative reinforcing effects may motivate drug-taking behavior, although the strongest evidence attributes drug-taking to a simple positive reinforcement process. Empirical research has focused largely on a positive reinforcement mechanism involving the ventral tegmental dopamine system, but three additional reinforcement mechanisms can be argued on logical grounds. These other mechanisms involve neuroadaptive changes produced by chronic opiate administration and may contribute to the strong motivational impact of opiates following long-term drug use.

Nitric oxide synthesis inhibition does not affect brain stimulation reward.

The effect of nitric oxide synthesis inhibition on brain stimulation reward was examined. A wide range of doses of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 30-300 mg/kg IP) failed to affect frequency thresholds for brain stimulation reward. The effect of L-NAME on cocaine's facilitation of brain stimulation reward was also examined. Nitric oxide synthesis inhibition had no effect on cocaine's ability to lower reward thresholds for electrical brain stimulation. Despite reports that nitric oxide may modulate dopamine release, these data suggest that nitric oxide is not involved in the dopamine-dependent rewarding effect of electrical brain stimulation or the reward facilitation produced by cocaine's enhancement of dopaminergic activity. Because L-NAME potently decreases cerebral blood flow, its lack of effect on cocaine-enhanced brain stimulation reward has additional significance. The failure of a moderate dose of L-NAME (30 mg/kg IP) to attenuate cocaine's lowering of reward thresholds argues against pharmacokinetic explanations of L-NAME's effect on other cocaine-induced behaviors.

Cocaine fatalities increased by restraint stress.

Laboratory rats injected daily with a moderate dose of cocaine hydrochloride (30 mg/kg, i.p.) showed increased fatalities when cocaine injections were followed by 30 min of restraint stress. The 5-day mortality rate was 58% for the cocaine-plus-stress group, while 17% of the animals receiving cocaine without restraint stress died. This finding suggests that stress can augment the toxic effect of cocaine and that minimizing stress may be an important consideration in the clinical management of cocaine overdose.

Physical dependence produced by central morphine infusions: an anatomical mapping study.

Morphine sulfate (1.5 nmoles/h) was chronically infused into various brain regions in rats. After 72 h of continuous infusions, an intraperitoneal injection of naloxone hydrochloride (5 mg/kg) was given to determine if physical dependence had developed. Various withdrawal signs were present following the naloxone challenge in rats chronically infused with morphine into the periventricular gray region. These withdrawal signs included escape behavior, wet-dog shakes, and teeth chattering. Several other brain regions (e.g., amygdala, caudate nucleus, lateral hypothalamus, nucleus accumbens, thalamus) were also tested, but morphine infusions into these areas produced only slight physical dependence. The magnitude of physical dependence produced by morphine infusions into the rostral aspect of the periventricular gray was comparable to that seen following repeated systemic morphine injections, while the physical dependence produced by caudal infusions into the vicinity of the locus coeruleus was considerably less. These data confirm the importance of the periventricular gray region in the development of physical dependence on morphine and reveal that a drug action in the more rostral aspect of this brain region produces the strongest signs of physical dependence.

L-NAME and MK-801 attenuate sensitization to the locomotor-stimulating effect of cocaine.

Locomotor activity was tested daily following cocaine injections across 21 consecutive days. Subjects were pretreated 30-min before testing with physiological saline, the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NAME), or the NMDA-receptor antagonist MK-801. Other rats received daily injections of physiological saline instead of cocaine just prior to testing. Rats pretreated with saline and injected daily with cocaine showed increased locomotor activity across the 21-day test period. L-NAME pretreatment depressed cocaine-stimulated locomotor activity, while MK-801 pretreatment increased locomotor activity. To test for behavioral sensitization to cocaine, rats were injected with cocaine 72 hours after their last daily injections. Sensitization was seen in saline pretreated subjects injected daily with cocaine compared to subjects injected daily with saline only, but both L-NAME and MK-801 pretreatment strongly attenuated cocaine sensitization. This finding is consistent with the proposed roles of nitric oxide and NMDA-receptors in cellular adaptation and learning.

Evidence for the rewarding effects of ethanol using the conditioned place preference method.

Rats were tested for the rewarding effects of ethanol using a place preference conditioning procedure. After receiving a total of 15 daily conditioning trials under 1.0 g/kg ethanol (IP), a significant place preference was produced. Subjects conditioned using saline or 0.5 g/kg ethanol showed no changes in place preference. This study suggests that failures to demonstrate rewarding effects from ethanol with the conditioned place preference method may be due to an insufficient number of conditioning trials or to an inadequate exposure to the drug. The fact that place preference conditioning was effective in demonstrating ethanol reward while other methods have been equivocal suggests that this method may be a valuable technique for studying the mechanisms of ethanol reward.

Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats.

Rats were trained to lever press for intravenous cocaine (1.0 mg/kg/injection) and then switched to bromocriptine (0.3, 1.0, or 3.0 mg/kg/injection) on a FR-1 reinforcement schedule. Bromocriptine sustained responding at all three doses; hourly drug intake increased linearly with log-dose. In a second experiment, animals were trained to respond for cocaine (1.0 mg/kg/injection) or heroin (0.1 mg/kg/injection) reinforcement; drug was available for the first 2 h of each daily session; saline was substituted for cocaine or heroin for 5 subsequent hours. One hour into each saline substitution session, an intravenous injection of saline or bromocriptine (0.0, 0.5, 1.0, or 2.0 mg/kg) was given. Bromocriptine reinstated both cocaine-trained and heroin-trained lever pressing; under these conditions, the drug was most effective in the heroin-trained animals. Reinforcing doses of clonidine (0.0625 and 0.125 mg/kg), methohexital, and nicotine (0.05 and 0.1 mg/kg), and a sub-intoxicating dose of ethanol (2 g/kg) failed to reinstate cocaine-trained responding. These data indicate that bromocriptine has cocaine-like and heroin-like stimulus and reinforcing effects.

New perspectives on cocaine addiction: recent findings from animal research.

Research with laboratory animals has provided several insights into the nature of cocaine abuse and addiction. First, the nature of drug addiction has been reevaluated and the emphasis has shifted from physical dependence to compulsive drug-taking behavior. Second, animal studies suggest that cocaine is at least as addictive as heroin and possibly even more addictive. Third, cocaine is potentially more dangerous than heroin as evidenced by the higher fatality rate seen in laboratory animals given unlimited access to these drugs. Fourth, the neural basis of cocaine reinforcement has been identified and involves an enhancement of dopaminergic neurotransmission in the ventral tegmental dopamine system. Other addictive drugs (e.g., opiates) may also derive at least part of their reinforcing impact by pharmacologically activating this reward system. Fifth, although the biological consequences of repeated cocaine self-administration on central nervous system functioning are poorly understood, preliminary findings suggest that intravenous cocaine self-administration may decrease neural functioning in this brain reward system. This has important clinical implications because diminished functioning of an important brain reward system may significantly contribute to relapse into cocaine addiction. These and other findings from experimentation with laboratory animals suggest new considerations for the etiology and treatment of drug addiction.

Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats.

Group-housed and individually housed rats were tested for the acquisition of a lever-pressing response reinforced by intravenous heroin or cocaine; animals in each housing condition quickly learned to self-administer drug. In the first experiment the isolated rats learned to self-administer heroin earlier than the group-housed animals, but the two groups self-administered similar levels of heroin by the fifth week of testing. In the second experiment cocaine self-administration was learned with equal speed in the two groups, and similar levels of cocaine were self-administered by both groups throughout the experiment. These data indicate that while social isolation can influence levels of heroin self-administration, isolation is not a necessary condition for heroin or heroin or cocaine injections to be reinforcing.

Feeding elicited by dynorphin (1-13) microinjections into the ventral tegmental area in rats.

Both the endogenous opioid peptide, dynorphin (1-13) (DYN), and morphine elicited dose-dependent feeding when microinjected into the ventral tegmental area of food-satiated rats. DYN was 50,000 times more potent than morphine in producing feeding. Whereas the ED50 for morphine was in the nanomole range, the ED50 for DYN was in the femtomole range. Administration of a narcotic antagonist attenuated DYN-elicited feeding. These data suggest a possible role for DYN in the VTA in opioid modulation of feeding behavior.

Effect of dopamine-receptor blockade on stimulation-induced feeding.

The effect of pimozide on stimulation-induced feeding was tested in food satiated rats. Pimozide produced a dose-dependent decrease in the number of animals eating during electrical stimulation of the lateral hypothalamus. A quantal dose-response analysis yielded an ED50 of 0.323 mg/kg for pimozide. Because this dose is within the range of pimozide doses found to be effective in disrupting feeding in other tests, it seems likely that the neural substrate mediating stimulation-induced feeding is similar to that involved in deprivation-induced feeding.

Neuroanatomical boundaries of the reward-relevant opiate-receptor field in the ventral tegmental area as mapped by the conditioned place preference method in rats.

The conditioned place preference produced by morphine microinjected into the ventral tegmental area was studied in rats. Cannula placements were varied along the rostrocaudal plane to determine the approximate anatomical focus of morphine's rewarding effect. Microinjections within a 1.4-mm range produced a significant change in place preference suggesting that morphine injected into this zone is rewarding. Injection sites rostral and caudal to this zone were ineffective as were injections ventral to this region. The approximate anatomical boundaries of the reward-relevant opiate-receptor field within the ventral tegmental area correspond well with the distribution of the A10 dopamine-containing cell bodies.

Neural basis of psychomotor stimulant and opiate reward: evidence suggesting the involvement of a common dopaminergic system.

Data are reviewed that suggest a common neural system may be involved in the rewarding properties of psychomotor stimulant and opiate drugs. This neural system corresponds to elements in the ventral tegmental dopamine system with cell bodies in the ventral tegmentum and axon terminals in the nucleus accumbens. Several lines of evidence have shown that psychomotor stimulant reward involves a drug action in the nucleus accumbens and that opiate reward involves a drug action in the ventral tegmentum. Activation of the ventral tegmental system at either synaptic element can produce reinforcement by an enhancement of dopaminergic neurotransmission in the nucleus accumbens. Although additional brain systems may be involved in the rewarding actions of these compounds, their ability to activate the ventral tegmental dopamine system appears to make an important contribution to their net reinforcing impact.

Concurrent heroin self-administration and intracranial self-stimulation in rats.

In a two-lever testing chamber, rats lever pressed for lateral hypothalamic brain stimulation or intravenous heroin reinforcers on a concurrent FR1 FR1 schedule of reinforcement. Responding for stimulation did not alter the rate of heroin self-administration, and responding for heroin caused increased responding for stimulation. Discontinuing heroin injections, or administering 3 mg/kg of naloxone, disrupted responding for both reinforcers, while changing the unit dose of heroin did not appreciably affect response rates for stimulation. This experiment demonstrates that rats are able to lever press during the period between successive self-administered heroin infusions, suggesting that the pausing normally seen between infusions is not due to debilitation, stereotyping, or sedation.