Rationale: The rate of acquisition of drug self-administration may serve as a predictor of later drug-taking behavior, possibly influencing vulnerability to initiate drug use. Objectives: The present study examined the effects of perinatal (gestation/lactation) lead exposure on adult rates of acquisition of intravenous (i.v.) heroin self-administration and cocaine self-administration using an automated procedure that included both Pavlovian and operant components. Methods: For Experiment 1, female rats were gavaged daily with 0 or 16 mg lead for 30 days prior to breeding with nonexposed males. Metal administration continued through pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21). Animals born to control or lead-exposed dams received indwelling jugular catheters as adults and subsequently were tested daily in a preparation where sessions included an initial 3-hr autoshaping period followed by a 3- hr self-administration period. During autoshaping, heroin (.018 mg/kg) infusions were paired with the extension and retraction of a lever when a lever press was not made for 15 sec, while infusions occurred during self-administration only when a lever press was executed (FR-1). The criterion for acquisition was a 2-day period during which a mean of 10 infusions/session occurred during self-administration. Animals were given 35 days to reach criterion. Results: Findings from Experiment 1 showed the proportion of rats meeting the lever-press response criterion for heroin when tested as adults was lower among lead-exposed animals. In Experiment 2, cocaine (.20 mg/kg) was presented to animals that underwent the same metal-exposure regimen, surgical procedures and methods with variations only in the number of infusions that were automatically administered during the Pavlovian component. Criterion for cocaine acquisition was a mean of 50 infusions over a two-day. In Experiment 2, a greater proportion of leadexposed animals reached the criterion for cocaine acquisition. Conclusions: Developmentally lead-exposed animals showed a decrease in vulnerability to initiate drug-taking behavior when presented with heroin in the adult phase, relative to controls. In contrast, developmentally lead-exposed animals showed an enhanced vulnerability to reach the criterion for cocaine self-administration. Clinical relevance of developmental exposure to lead and the attendant vulnerability to self-administer drugs of abuse is discussed.

Methamphetamine is gaining mainstream popularity across the United States at the same time that lead exposure remains at elevated levels. Perinatal (gestation/lactation) lead exposure has been found to modify the reward efficacy of various drugs of abuse (e.g., cocaine, opiates) across the phases of initial selection, use, and abuse. Lead-induced changes in sensitivity to methamphetamine have not been examined in animals perinatally exposed to lead. Accordingly, four studies were conducted to examine the effects of perinatal lead exposure on adult self-administration of intravenous (i.v.) methamphetamine across all relevant transition points of drug addiction. Adult female rats were administered a 16-mg lead or a control solution for 30 days prior to breeding with non-exposed males. Exposure continued through pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21). Animals born to control or lead-exposed dams received indwelling jugular catheters as adults (PND 60 and PND 90) and subsequently were randomly assigned to one of the four studies mentioned above, using only one male rat per litter for each study. In Experiment 1, an acquisition study revealed that perinatal exposure to environmentally relevant levels of lead resulted in a smaller percentage of rats reaching the criterion for intravenous (i.v.) methamphetamine (.02 mg/kg) acquisition, relative to non-exposed controls. In Experiment 2, a dose-effect curve yielded a biphasic pattern of attenuation of the self-administration of methamphetamine (.04 mg/kg) in lead-exposed animals. In Experiment 3, lead-exposed animals reached lower breaking points for methamphetamine (.04 mg/kg) in a progressive ratio task, in comparison to control animals. Finally in Experiment 4, a reinstatement study revealed that perinatally leadexposed animals showed a decreased propensity to relapse to methamphetamine (.04 mg/kg) self-administration after a period of forced abstinence. The general attenuation to the rewarding efficacy of methamphetamine observed in animals perinatally exposed to lead may functionally translate into a form of tolerance or counteradaptation. The data collected from these four studies further strengthen the possibility that pollutants in the environment may play a modulatory role in substance abuse.

Rationale: The rate of acquisition of drug self-administration may serve as a predictor of later drug-taking behavior, possibly influencing vulnerability to initiate drug use. Objectives: The present study examined the effects of perinatal (gestation/lactation) lead exposure on adult rates of acquisition of intravenous (i.v.) heroin self-administration and cocaine self-administration using an automated procedure that included both Pavlovian and operant components. Methods: For Experiment 1, female rats were gavaged daily with 0 or 16 mg lead for 30 days prior to breeding with nonexposed males. Metal administration continued through pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21). Animals born to control or lead-exposed dams received indwelling jugular catheters as adults and subsequently were tested daily in a preparation where sessions included an initial 3-hr autoshaping period followed by a 3- hr self-administration period. During autoshaping, heroin (.018 mg/kg) infusions were paired with the extension and retraction of a lever when a lever press was not made for 15 sec, while infusions occurred during self-administration only when a lever press was executed (FR-1). The criterion for acquisition was a 2-day period during which a mean of 10 infusions/session occurred during self-administration. Animals were given 35 days to reach criterion. Results: Findings from Experiment 1 showed the proportion of rats meeting the lever-press response criterion for heroin when tested as adults was lower among lead-exposed animals. In Experiment 2, cocaine (.20 mg/kg) was presented to animals that underwent the same metal-exposure regimen, surgical procedures and methods with variations only in the number of infusions that were automatically administered during the Pavlovian component. Criterion for cocaine acquisition was a mean of 50 infusions over a two-day. In Experiment 2, a greater proportion of leadexposed animals reached the criterion for cocaine acquisition. Conclusions: Developmentally lead-exposed animals showed a decrease in vulnerability to initiate drug-taking behavior when presented with heroin in the adult phase, relative to controls. In contrast, developmentally lead-exposed animals showed an enhanced vulnerability to reach the criterion for cocaine self-administration. Clinical relevance of developmental exposure to lead and the attendant vulnerability to self-administer drugs of abuse is discussed.

Approximately two-thirds of patients will experience pain following spinal cord injury (SCI). This pain can arise as an immediate consequence of SCI, or can develop over time into chronic, neuropathic pain. Individuals are frequently prescribed opioid analgesics, including morphine, for the treatment of pain in both the acute and chronic phases of SCI. Yet, despite the prevalence of opioid use, no studies have examined the addictive potential of opioids, or their secondary effects, following spinal injury. These experiments used a clinically relevant self-administration paradigm to examine both addiction and functional recovery after morphine administration. To assess morphine administration in the acute phase of SCI, animals were placed in operant chambers 24-hours following spinal injury. In the chambers, depression of a reinforced lever resulted in an intravenous infusion of morphine (or vehicle). Animals were placed in the chambers for 7, 12-hour sessions and could administer up to 30 mg of morphine per session. Morphine self-administration was also examined in the chronic phase of injury. Animals were placed into operant chambers for 7, 12-hour sessions beginning 14 or 35 days after injury. The amount of morphine administered, as well as recovery of locomotor function and general health, was compared across subjects with SCI and sham (no injury) controls. In the acute phase of injury, SCI significantly reduced self-administration of morphine, but administration led to decreased recovery of locomotor function and weight loss. In the chronic phase of injury, self-administration did not differ between contused and sham animals. All subjects administered the full amount of morphine available each day. In this phase of injury, morphine administration led to significant weight loss, but did not attenuate recovery of locomotor function. These studies suggest that spinal injury reduced the addictive potential of morphine in the acute, but not the chronic, phase of SCI. However, acute administration of high doses of morphine decreased recovery of locomotor function. Morphine should not be used in this phase of injury for the clinical treatment of pain. In the chronic phase, opioid use must be closely monitored as use may result in addictive behavior.

There are several lines of evidence supporting the existence of a pivotal role of the cannabinoid system in mediating the reinforcing effects of nicotine. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications for our understanding of the neurobiological mechanisms underlying nicotine dependence. Objectives: The current series of experiments, we investigated the effects of activating CB1 receptors, modulating CB2 receptors as well as elevating levels of the endogenous cannabinoid ligand anandamide on nicotine taking and reinstatement of nicotine seeking behaviour. METHODS: In the first series of experiments, we investigated the effects of pretreatment with the CB receptor agonist WIN 55, 212-2 (0.1-1mg/kg), on nicotine self-administration and on the reinstatement of nicotine seeking behaviour. In the next series of experiments, we used a selective CB1 inverse agonist rimonabant (0.3mg/kg) and CB2 antagonist AM630 (5mg/kg) to delineate wether the effects obsereved with WIN 55, 212-2 are CB1 or CB2 meidated. Moreover, we investigated the effect of selective CB2 receptor activation (AM1241 1-10 mg/kg) and inhibition (AM630 1.25-5 mg/kg) on nicotine self-administration under fixed ratio (FR) and progressive (PR) schedules of reinforcement and on reinstatement of nicotine seeking induced by nicotine associated cues and nicotine priming. Finally, the effects of activation of CB receptors through administration of anandamide reuptake inhibitor VDM11 (1-10 mg/kg) on nicotine self-administration and on reinstatement of nicotine seeking were investigated. RESULTS: WIN 55,212-2 enhanced the break points for nicotine self-administration under a PR schedule of reinforcement, reinstated nicotine seeking behaviour and enhanced cue induced reinstatement of nicotine seeking. Neither activation nor blockade of CB2 receptors affected the responding of the animals for nicotine self-administration under FR or PR schedules of reinforcement or for reinstatement of nicotine seeking induced by nicotine associated cues and priming. Pretreatment with VDM11 dose dependently attenuated the reinstatement of nicotine seeking behaviour induced by nicotine associated cues and priming without affecting stable nicotine self administration. CONCLUSION: CB1 but not CB2 receptors appear to play a pivotal role in modulating the reinforcing effects of nicotine. Inhibition of anandamide reuptake could be a potentially useful tool in modulating relapse to smoking

There are several lines of evidence supporting the existence of a pivotal role of the cannabinoid system in mediating the reinforcing effects of nicotine. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications for our understanding of the neurobiological mechanisms underlying nicotine dependence. Objectives: The current series of experiments, we investigated the effects of activating CB1 receptors, modulating CB2 receptors as well as elevating levels of the endogenous cannabinoid ligand anandamide on nicotine taking and reinstatement of nicotine seeking behaviour. METHODS: In the first series of experiments, we investigated the effects of pretreatment with the CB receptor agonist WIN 55, 212-2 (0.1-1mg/kg), on nicotine self-administration and on the reinstatement of nicotine seeking behaviour. In the next series of experiments, we used a selective CB1 inverse agonist rimonabant (0.3mg/kg) and CB2 antagonist AM630 (5mg/kg) to delineate wether the effects obsereved with WIN 55, 212-2 are CB1 or CB2 meidated. Moreover, we investigated the effect of selective CB2 receptor activation (AM1241 1-10 mg/kg) and inhibition (AM630 1.25-5 mg/kg) on nicotine self-administration under fixed ratio (FR) and progressive (PR) schedules of reinforcement and on reinstatement of nicotine seeking induced by nicotine associated cues and nicotine priming. Finally, the effects of activation of CB receptors through administration of anandamide reuptake inhibitor VDM11 (1-10 mg/kg) on nicotine self-administration and on reinstatement of nicotine seeking were investigated. RESULTS: WIN 55,212-2 enhanced the break points for nicotine self-administration under a PR schedule of reinforcement, reinstated nicotine seeking behaviour and enhanced cue induced reinstatement of nicotine seeking. Neither activation nor blockade of CB2 receptors affected the responding of the animals for nicotine self-administration under FR or PR schedules of reinforcement or for reinstatement of nicotine seeking induced by nicotine associated cues and priming. Pretreatment with VDM11 dose dependently attenuated the reinstatement of nicotine seeking behaviour induced by nicotine associated cues and priming without affecting stable nicotine self administration. CONCLUSION: CB1 but not CB2 receptors appear to play a pivotal role in modulating the reinforcing effects of nicotine. Inhibition of anandamide reuptake could be a potentially useful tool in modulating relapse to smoking

Thesis (Ph. D.)--University of Missouri--Columbia, 1996. / "December 1996." Typescript. Vita. Includes bibliographical references (leaves 107-109). Also available on the Internet.

abstract: Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that are used to facilitate acquisition, such as food restriction, prior reinforcement training, or response-contingent co-delivery of a naturally reinforcing light. This study examined whether rats acquire nicotine self-administration in the absence of these facilitators. A new mathematical modeling procedure was used to define the criterion for acquisition and to determine dose-dependent differences in rate and asymptote levels of intake. Rats were trained across 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0, 0.015, 0.03, 0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined by the best fit of a logistic function (i.e., S-shaped) versus a constant function (i.e., flat line) for reinforcers obtained across sessions using a corrected Akaike information criterion (AICc) as a model selection tool. The results showed an inverted-U shaped function for dose in relation to the percentage of animals that acquired nicotine self-administration, with 46% acquiring at 0.015 mg/kg, 73% at 0.03 mg/kg, and 58% at 0.06 mg/kg. All saline rats failed to acquire as expected. For rats that acquired nicotine self-administration, multiple model comparisons demonstrated that the asymptote (highest number of reinforcers/session) and half learning point (h; session during which half the assymptote had been achieved) were justified as free parameters of the reinforcers/session function, indicating that these parameters vary with nicotine dose. Asymptote exhibited an inverted U-shaped function across doses and half learning point exhibited a negative relationship to dose (i.e., the higher the dose the fewer sessions to reach h). These findings suggest that some rats acquire nicotine self-administration without using procedures that confound measures of acquisition rate. Furthermore, the modeling approach provides a new way of defining acquisition of drug self-administration that takes advantage of using all data generated from individual subjects and is less arbitrary than some criteria that are currently used. / Dissertation/Thesis / M.A. Psychology 2011

Rationale. Nicotine is often considered a ‘gateway’ drug because people typically experiment with tobacco before illicit drugs such as cocaine and amphetamine. We have shown that nicotine increases approach to reward-associated stimuli, this is referred to as ‘sign-tracking’, and that this effect persists after nicotine is discontinued. Individuals who are high in sign-tracking also show increased cocaine self-administration. Objectives. The goal of this experiment was to determine whether nicotine enhanced sign tracking could result in greater cocaine self-administration. Method. Rats were randomly assigned to one of 2 groups (NIC or SAL), and injected with their assigned solution (0.4 mg/kg base or placebo, respectively) 15 min before conditioning sessions. During conditioning sessions, a lever/light stimulus was inserted into the chamber for 15 s and immediately followed by sucrose delivery. Approach to the sucrose receptacle was recorded by monitoring head entries and defined as goal tracking. Contact with the lever was recorded and defined as ‘sign-tracking’. After 29 conditioning sessions, the rats were instrumented for cocaine self-administration and were shaped to respond for cocaine on the same lever that served as the CS. After 10 days of acquisition of cocaine self-administration (0.16 mg/inf), demand for cocaine was tested over 6 days using a within session procedure that increased cocaine price every 10 min. Results. We showed increased sign-tracking, but not goal tracking in the NIC group relative to the SAL group. The NIC group also showed increased demand for cocaine during the price manipulation, but the essential value of cocaine did not differ, relative to the SAL group. Conclusion. Our results support a gateway interpretation of substance use – when both the gateway drug (nicotine) and drug-associated rewards (the lever/light) occur together, they can promote future self-administration of illicit drugs such as cocaine.

A simple method for IV self-administration of drugs by mice is described. When morphine (0.5 mg/kg) was made contingent on a nosepoke response, naive mice increased their rate of nosepoking when compared either with animals receiving contingent saline vehicle injectionsor yoked control animals receiving noncontingent morphine.