Self-administration Procedure Research Articles

Relative reinforcing efficacy of high and low affinity NMDA channel blockers in rhesus monkeys

Preclinical self‐administration (SA) procedures provide face validity and in may cases predictive validity regarding the abuse potential of drugs. A number of NMDA channel blocking antagonists are self‐administered off a fixed‐ratio (FR) phencyclidine (PCP) baseline. To assess relative abuse liability, the high affinity channel blockers PCP, ketamine and dextrorphan and the low affinity channel blockers memantine and dextromethorphan were re‐evaluated using a FR/progressive ratio (PR) procedure. Adult rhesus monkeys participated in daily 1‐h FR 20 SA sessions for 3 to 10 μg/kg/infusion PCP. Test drug solutions serving as positive reinforcers under the FR schedule were evaluated under a PR schedule in which the ratio for each infusion was increased by 10 or 20 (dependent on subject) during each subsequent session. One or more doses of all of the channel blockers, high affinity and low affinity, served as positive reinforcers of behavior under the FR schedule. Under a PR schedule, the high affinity compounds demonstrated much greater break points than the low affinity channel blockers, suggesting a higher reinforcing efficacy and abuse potential for the former compounds. Overall this approach appears to provide a refinement on previous substitution procedures for evaluating the abuse liability of NMDA antagonist drugs that is most predictive of human abuse potential. Supported by NIDA grant DA‐01442.

Operant Self‐Administration Models for Testing the Neuropharmacological Basis of Ethanol Consumption in Rats

Operant self-administration procedures are used to assess the neural basis of ethanol-seeking behavior under a wide range of experimental conditions. In general, rats do not spontaneously self-administer ethanol in pharmacologically meaningful amounts. This unit provides a step-by-step guide for training rats to self-administer quantities of ethanol that produce moderate to high blood-alcohol content. Different protocols are used for rats that are genetically heterogeneous versus rats that are selectively bred for high alcohol preference. Also, these protocols have different sets of advantages and disadvantages in terms of the ability to control for caloric intake and taste of solutions in operant testing. Basic self-administration protocols can also be altered to focus on different aspects of the motivational properties of ethanol (for example, those related to dependence). This unit provides multiple protocols that lead to alcohol intake in rats, which can be pharmacologically probed relative to a variety of control conditions.

Modafinil effects on reinstatement of methamphetamine seeking in a rat model of relapse

Modafinil (Provigil) is a wake-promoting drug characterized by cognitive enhancing abilities. Recent clinical data have supported the use of modafinil for treatment of chronic psychostimulant addiction and relapse prevention. We used an intravenous methamphetamine (meth) self-administration procedure to assess the dose-dependent effects of modafinil on reinstatement following abstinence and after extinction on conditioned-cue and meth-primed reinstatement of meth seeking. Modafinil attenuated active lever responding in multiple reinstatement conditions-context-induced, conditioned cue, and meth prime. The most pronounced and consistent effect was on meth-primed reinstatement, and modafinil did not reinstate meth seeking when tested alone. These findings support clinical findings in humans that modafinil may be an effective therapeutic agent for the prevention of relapse in abstinent meth users.

Human sex differences in d‐amphetamine self‐administration

Women and men may respond differently to the effects of stimulants such as amphetamine and cocaine. In order to assess potential sex differences in the reinforcing effects of d-amphetamine, a retrospective-analysis was conducted on data collected from three studies that employed similar d-amphetamine self-administration procedures and used identical subject-rated drug-effect measures. Data from 10 women and 15 men were included in the analysis. In all studies, participants sampled placebo, low (8-10 mg) or high (16-20 mg) dose oral d-amphetamine. Following sampling sessions, participants worked for capsules containing one eighth of the previously sampled dose on a modified progressive-ratio schedule of reinforcement. We hypothesized that women and men would be differentially sensitive to the reinforcing effects of d-amphetamine. A two-way mixed-model analysis of variance (sex and dose) and planned comparisons were used in the statistical analyses. The low dose of d-amphetamine functioned as a reinforcer in women, but not men, whereas the high dose of d-amphetamine functioned as a reinforcer in men, but not women. Men self-administered significantly more capsules under the high dose condition than women. The results of this study suggest that men are more sensitive to the reinforcing effects of a high dose of d-amphetamine than women. Future research is needed that determines prospectively the reinforcing effects of weight-adjusted doses of d-amphetamine in women and men while controlling for menstrual cycle phase.

The hypocretin–orexin system regulates cocaine self‐administration via actions on the mesolimbic dopamine system

Recent evidence suggests that the hypocretin-orexin system participates in the regulation of reinforcement processes. The current studies examined the extent to which hypocretin neurotransmission regulates behavioral and neurochemical responses to cocaine, and behavioral responses to food reinforcement. These studies used a combination of fixed ratio, discrete trials, progressive ratio and threshold self-administration procedures to assess whether the hypocretin 1 receptor antagonist, SB-334867, reduces cocaine self-administration in rats. Progressive ratio sucrose self-administration procedures were also used to assess the extent to which SB-334867 reduces responding to a natural reinforcer in food-restricted and food-sated rats. Additionally, these studies used microdialysis and in vivo voltammetry in rats to examine whether SB-334867 attenuates the effects of cocaine on dopamine signaling within the nucleus accumbens core. Furthermore, in vitro voltammetry was used to examine whether hypocretin knockout mice display attenuated dopamine responses to cocaine. Results indicate that when SB-334867 was administered peripherally or within the ventral tegmental area, it reduced the motivation to self-administer cocaine and attenuated cocaine-induced enhancement of dopamine signaling. SB-334867 also reduced the motivation to self-administer sucrose in food-sated but not food-restricted rats. Finally, hypocretin knockout mice displayed altered baseline dopamine signaling and reduced dopamine responses to cocaine. Combined, these studies suggest that hypocretin neurotransmission participates in reinforcement processes, likely through modulation of the mesolimbic dopamine system. Additionally, the current observations suggest that the hypocretin system may provide a target for pharmacotherapies to treat cocaine addiction.

Genetically correlated effects of selective breeding for high and low methamphetamine consumption

Improved prevention and treatment of drug addiction will require deeper understanding of genetic factors contributing to susceptibility to excessive drug use. Intravenous operant self-administration methods have greatly advanced understanding of behavioral traits related to addiction. However, these methods are not suitable for large-scale genetic experiments in mice. Selective breeding of mice can aggregate 'addiction alleles' in a model that has the potential to identify coordinated effects of multiple genes. We produced mouse lines that orally self-administer high (MAHDR) or low (MALDR) amounts of methamphetamine, representing the first demonstration of selective breeding for self-administration of any psychostimulant drug. Conditioned place preference and taste aversion results indicate that MAHDR mice are relatively more sensitive to the rewarding effects and less sensitive to the aversive effects of methamphetamine, compared to MALDR mice. These results validate the oral route of self-administration for investigation of the motivational effects of methamphetamine and provide a viable alternative to intravenous self-administration procedures. Gene expression results for a subset of genes relevant to addiction-related processes suggest differential regulation by methamphetamine of apoptosis and immune pathways in the nucleus accumbens of MAHDR and MALDR mice. In each line, methamphetamine reduced an allostatic state by bringing gene expression back toward 'normal' levels. Genes differentially expressed in the drug-naï ve state, including Slc6a4 (serotonin transporter), Htr3a (serotonin receptor 3A), Rela [nuclear factor kappaB (NFkappaB)] and Fos (cFos), represent candidates whose expression levels may predict methamphetamine consumption and susceptibility to methamphetamine reward and aversion.

Orbitofrontal and Anterior Cingulate Cortex Neurons Selectively Process Cocaine-Associated Environmental Cues in the Rhesus Monkey

Encounters with stimuli associated with drug use are believed to contribute to relapse. To probe the neurobiology of environmentally triggered drug use, we have conducted single-unit recordings in rhesus monkeys during presentation of two distinct types of drug paired cues that differentially support drug-seeking. The animals were highly conditioned to these cues via exposure during self-administration procedures conducted over a 4 year period. The cues studied were a discriminative cue that signaled response-contingent availability of cocaine, and a discrete cue that was temporally paired with the cocaine infusion (0.1 or 0.5 mg/kg). Two cortical regions consistently activated by cocaine-associated cues in human imaging studies are the orbitofrontal (OFC) and anterior cingulate cortex (ACC), though little is known about cortical neuronal activity responses to drug cues. We simultaneously recorded single-unit activity in OFC and ACC as well as in dorsal striatum in rhesus monkeys during cocaine self-administration. Dorsal striatal neurons were less engaged by drug cues than cortical regions. Between OFC and ACC, distinct functionality was apparent in neuronal responses. OFC neurons preferentially responded to the discriminative cue, consistent with a role in cue-induced drug-seeking. In contrast, the ACC did not respond more to the discriminative cue than to the discrete cue. Also distinct from the OFC, ACC showed sustained firing throughout the 18 s duration of the discrete cue. This pattern of sustained activation in ACC is consistent with a role in reward expectation and/or in mediating behavioral effects of discrete cues paired with drug infusions.

Environmental enrichment reduces cocaine seeking and reinstatement induced by cues and stress but not by cocaine.

Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in drug addiction, in a recent study we suggested that EE can also have 'curative' effects. In fact, we found that cocaine addiction-related behaviors can be eliminated by housing cocaine-treated mice in EE during periods of forced abstinence. However, those results were obtained with two simple models of addiction, conditioned place preference (CPP), and behavioral sensitization. In this study, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of EE on cocaine addiction in a reinstatement model of relapse. Singly housed rats learned to self-administer cocaine during 10 consecutive daily sessions (0.6 mg/injection, 6 h/day). They were then housed three per cage in either standard environments (SE) or EE and were kept abstinent in the animal facility until testing for extinction and reinstatement. We found that 30 days of EE significantly and consistently reduced cocaine seeking during a 6-h extinction session. In addition, EE significantly reduced cue- and stress-induced reinstatement. Surprisingly, given our earlier results in mice with CPP, EE did not reduce cocaine-induced reinstatement regardless of the level of exposure to cocaine and the duration of the period of abstinence and exposure to EE. Altogether, these results support the hypothesis that EE can reduce cocaine-induced craving and highlight the importance of positive life conditions in facilitating abstinence and preventing relapse to cocaine addiction.

Effects of environmental enrichment on sensitivity to cocaine in female rats: importance of control rates of behavior

Environmental enrichment produces functional changes in mesolimbic dopamine transmission and alters sensitivity to psychomotor stimulants. These manipulations also alter the control rate of many behaviors that are sensitive to stimulant administration, which can make comparison of drug effects between isolated and enriched subjects difficult. The purpose of this study was to examine the effects of environmental enrichment on control rates of behavior and on sensitivity to cocaine in tests of locomotor activity, drug self-administration, conditioned place preference, and toxicity. In the locomotor activity test, isolated rats exhibited greater activity after the administration of cocaine, but also had higher control rates of activity. When locomotor activity was expressed as a percentage of saline control values, enriched rats exhibited a greater increase relative to their own control than isolated rats. In the drug self-administration procedure, isolated rats had higher breakpoints on a progressive-ratio schedule of reinforcement when responding was maintained by cocaine; however, isolated rats also had higher breakpoints in saline substitution tests and higher rates of inactive lever responding. When the self-administration data were expressed as a percentage of these control values, enriched rats exhibited a greater increase in responding relative to their own control rates than isolated rats. No differences were observed between isolated and enriched rats under control conditions in the place preference and toxicity studies. In both of these procedures, enriched rats were more sensitive than isolated rats to all the doses of cocaine tested. These data emphasize the importance of considering control rates of behavior in studies examining environmental enrichment and drug sensitivity, and suggest that environmental enrichment increases sensitivity to cocaine across a range of dependent measures when differences in control rates of behavior are taken into account.

The influence of mecamylamine on ethanol and sucrose self-administration

Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to be critically involved in ethanol-related behaviors as well as in neurochemical responses to ethanol. However, discernment of nAChR contribution to ethanol reinforcement and consumption remains incomplete. The current studies examined the influence of the nAChR antagonist mecamylamine (MEC) on operant ethanol self-administration using a procedure that independently assessed appetitive and consumptive processes, and compared these findings to effects of MEC on sucrose self-administration. Male C57BL/6J (B6) mice were trained to respond for 30-min access to a retractable drinking tube containing either 10% v/v ethanol (10E) or 5% w/v sucrose (5S). Once trained, mice were habituated to saline injection and then treated with a series of MEC doses (0–8 mg/kg; i.p.) in a within-subject design. In a separate cohort, MEC was evaluated for its influence on locomotor activity. MEC dose-dependently reduced 10E and 5S self-administration. The suppression in ethanol intake was attributable to a reduction in bout frequency, whereas the attenuation in sucrose intake was due to a decrease in bout size. Doses of MEC (6–8 mg/kg) that altered drinking patterns were also found to impair locomotor activity. Although MEC non-selectively reduced 10E and 5S intakes in mice, there was some specificity in alterations of the underlying drinking pattern for each reinforcer. Assessment of drinking topography within an operant self-administration procedure may provide useful insights regarding the role of nAChR function in the regulation of ethanol consumption.

Rats Self-Administer Intravenous Nicotine Delivered in a Novel Smoking-Relevant Procedure: Effects of Dopamine Antagonists

Attempts to explain tobacco addiction have relied heavily on the assumption that each cigarette puff delivers a bolus of nicotine to the brain within seconds. However, nicotine transits from lungs to brain much more gradually than once thought. Nevertheless, animal self-administration studies continue to use rapid (e.g., <3-s) infusions, as well as high unit doses of nicotine (e.g., 15-30 microg/kg/infusion), each equivalent to one to two cigarettes. Here, we report that nicotine is self-administered across a range of infusion durations (3, 30, 60, and 120 s) in rats. Slow (30-s) infusions were preferred over fast (nominal 3-s) infusions and were self-administered across several reinforcement schedules, at doses as low as 3 microg/kg/infusion, equivalent to one to two puffs. A conventional "fast/high" self-administration procedure (3 s-30 microg/kg/infusion) was then compared with our new "slow/low" procedure (30 s-3 microg/kg/infusion) in rats trained on a progressive ratio schedule and acutely challenged with dopamine receptor antagonists. The D(1) antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) (6-25 microg/kg s.c.) reduced intake in both procedures and in rats self-administering cocaine (0.5 mg/kg/infusion). The D(2) antagonists spiperone (3-30 microg/kg s.c.) and sulpiride (5-20 mg/kg i.p.) increased intake of fast/high nicotine and cocaine, but markedly reduced intake of slow/low nicotine. In a final test, in which only infusion speed was varied, an acute spiperone challenge produced the same differential effect on nicotine self-administration. In conclusion, our new slow/low nicotine self-administration procedure, designed to better mimic smoking-associated nicotine intake, is pharmacologically distinct from the conventional fast delivery/high-dose procedure.

Behavioral Effects of a Synthetic Agonist Selective for Nociceptin/Orphanin FQ Peptide Receptors in Monkeys

Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64-6198 with those of a mu-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001-0.06 mg/kg, s.c.) and alfentanil (0.001-0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01-0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose-response curve of Ro 64-6198-induced antinociception. The apparent pA(2) value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of mu-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans.

Involvement of local serotonin-2A but not serotonin-1B receptors in the reinforcing effects of ethanol within the posterior ventral tegmental area of female Wistar rats.

Previous studies indicated that ethanol could be self-infused into the posterior ventral tegmental area (p-VTA) and that activation of local serotonin-3 (5-HT(3)) receptors was involved. 5-HT(1B) and 5-HT(2A) receptors are involved in the effects of 5-HT and ethanol on VTA dopamine neurons. The current study used the intracranial self-administration (ICSA) procedure to determine the involvement of local 5-HT(1B) and 5-HT(2A) receptors in the self-infusion of ethanol into the p-VTA. Female Wistar rats were implanted unilaterally with a guide cannula aimed at the p-VTA. Seven days after surgery, rats were placed into the two-lever operant conditioning chambers for ICSA tests. The tests consisted of four acquisition sessions with self-infusion of 200 mg% ethanol alone, two or three sessions with co-infusion of the 5-HT(1B) antagonist GR 55562 (10, 100, or 200 microM) or the 5-HT(2A) antagonist R-96544 (10, 100, or 200 microM) with 200 mg% ethanol, and one final session with 200 mg% ethanol alone. During the acquisition sessions, all rats readily self-infused ethanol and discriminated the active from inactive lever. Co-infusion of GR 55562, at all three doses, had no effect on the self-infusion of ethanol. In contrast, co-infusion of R-96544, at the two higher doses, attenuated responding on the active lever for ethanol infusion (p < 0.05). The results suggest that the reinforcing effects of ethanol within the p-VTA are modulated, at least in part, by activation of local 5-HT(2A), but not 5-HT(1B), receptors.

Strain differences in patterns of drug-intake during prolonged access to cocaine self-administration.

The current study examined possible interactions between genetic factors and prolonged drug access by testing the Fischer (F344), Lewis (LEW), and Wistar rat strains in a prolonged access cocaine self-administration (SA) procedure. Before prolonged access, the strains did not differ in breakpoints for food or cocaine with progressive ratio (PR) testing. The LEW and Wistar rats acquired cocaine SA faster than the F344s. With prolonged access to cocaine SA, the LEW and Wistar rats showed comparable within-session patterns that were higher at the outset of each session and decreased to a stable baseline. Alternatively, the F344 rats began sessions with lower intake and increased their rate of intake during the session. The F344 and Wistar rats took more drug per session than the LEW rats but did not differ from each other. Following prolonged access, the strains did not differ in breakpoints for food, but the Wistar rats had higher breakpoints for cocaine than the F344 rats. Possible underpinnings for the observed strain differences are discussed.

The Alcohol Deprivation Effect (ADE) in C57BL/6J mice is observed using operant self-administration procedures and is modulated by CRF-1 receptor signaling

The Alcohol Deprivation Effect (ADE) in C57BL/6J mice is observed using operant self-administration procedures and is modulated by CRF-1 receptor signaling

The Alcohol Deprivation Effect in C57BL/6J Mice is Observed Using Operant Self‐Administration Procedures and is Modulated by CRF‐1 Receptor Signaling

The alcohol deprivation effect (ADE) is characterized by transient excessive alcohol consumption upon reinstatement of ethanol following a period of ethanol deprivation. While this phenomenon has been observed in rats using both bottle drinking (consummatory behavior) and operant self-administration (consummatory and appetitive "ethanol-seeking" behavior) procedures, ADE studies in mice have primarily relied on bottle drinking measures. Furthermore, the neurochemical pathways that modulate the ADE are not well understood. Therefore, we determined whether the ADE can be observed in C57BL/6J mice using operant self-administration procedures and if expression of the ADE is modulated by the corticotropin releasing factor-1 (CRF-1) receptor. C57BL/6J mice were trained in a 2-hour operant self-administration paradigm to lever press for 10% ethanol or water on separate response keys. Between operant sessions, mice had access to ethanol in their homecage. Once stable responding occurred, mice were deprived of ethanol for 4 days and were then retested with ethanol in the operant paradigm for 3 consecutive days. Next, to assess the role of the CRF-1 receptor, mice were given intraperitoneal (i.p.) injection (0, 10, or 20 mg/kg) of the CRF-1 receptor antagonist CP-154,526 30 minutes before ADE testing. Additional experiments assessed (i) ADE responding in which the alternate response lever was inactive, (ii) the effects of CP-154,526 on self-administration of a 1% sucrose solution following 4 days of deprivation, and (iii) ADE responding in which mice did not received i.p. injections throughout the experiment. Mice exhibited a significant increase in postdeprivation lever responding for ethanol with either a water reinforced or inactive alternate lever. Interestingly, i.p. injection of a 10 mg/kg dose of CP-154,526 protected against the ADE while not affecting lever responding for a sucrose solution. Finally, baseline and deprivation-induced increases of ethanol reinforced lever responding were greater in mice not given i.p. injections. The ADE in C57BL/6J mice can be modeled using the operant self-administration paradigm and increased ethanol self-administration associated with the ADE is modulated by CRF-1 receptor signaling.

Self‐administration of cocaine, cannabis and heroin in the human laboratory: benefits and pitfalls

The objective of this review is to describe self-administration procedures for modeling addiction to cocaine, cannabis and heroin in the human laboratory, the benefits and pitfalls of the approach, and the methodological issues unique to each drug. In addition, the predictive validity of the model for testing treatment medications will be addressed. The results show that all three drugs of abuse are reliably and robustly self-administered by non-treatment-seeking research volunteers. In terms of pharmacotherapies, cocaine use is extraordinarily difficult to disrupt either in the laboratory or in the clinic. A range of medications has been shown to significantly decrease cocaine's subjective effects and craving without decreasing either cocaine self-administration or cocaine abuse by patients. These negative data combined with recent positive findings with modafinil suggest that self-administration procedures are an important intermediary step between pre-clinical and clinical studies. In terms of cannabis, a recent study suggests that medications that improve sleep and mood during cannabis withdrawal decrease the resumption of marijuana self-administration in abstinent volunteers. Clinical data on patients seeking treatment for their marijuana use are needed to validate these laboratory findings. Finally, in contrast to cannabis or cocaine dependence, there are three efficacious Food and Drug Administration-approved medications to treat opioid dependence, all of which decrease both heroin self-administration and subjective effects in the human laboratory. In summary, self-administration procedures provide meaningful behavioral data in a small number of individuals. These studies contribute to our understanding of the variables maintaining cocaine, marijuana and heroin intake, and are important in guiding the development of more effective drug treatment programs.

Relationship Between Ethanol’s Acute Locomotor Effects and Ethanol Self‐Administration in Male Long‐Evans Rats

Human studies have suggested an important relationship between ethanol sensitivity and risk of alcoholism. These studies have led some to hypothesize that a low initial sensitivity to ethanol's depressant effects and/or an elevated response to ethanol's stimulant effects may represent important risk factors associated with the development of abusive drinking behavior. Unfortunately, elucidating neurobiologic mechanisms that may underlie these relationships between ethanol sensitivity and ethanol drinking have been hampered by difficulties in modeling some of these interactions in animals. In this study, we re-examined some of these relationships in an outbred strain of rats using continuous access two-bottle choice drinking and a limited-access operant procedure that engenders pharmacologically relevant levels of ethanol intake and permits the discrete assessment of appetitive and consummatory measures of ethanol drinking behavior. Twenty-three male Long-Evans rats were habituated to a locomotor activity box and then tested for their response to a stimulant (0.5 g/kg) and depressant (1.5 g/kg) ethanol dose. Rats were then trained to complete a lever pressing requirement to gain access to 10% ethanol for 20-minute sessions conducted 5 d/wk for 5 weeks. Appetitive behavior was assessed after 2.5 and 4.5 weeks using 20-minute extinction trials in which ethanol was not presented and lever responses were recorded. Home-cage ethanol preference was also assessed prior to and immediately following the 5-week self-administration regimen using a continuous access, two-bottle choice procedure. A significant increase in home-cage ethanol preference was observed following the self-administration procedure, however, neither measure of ethanol preference correlated with average daily ethanol intake during the operant self-administration sessions or with initial sensitivity to ethanol's stimulant or depressant effects. Notably, a significant negative correlation was observed between sensitivity to ethanol's locomotor depressant effect and daily intake during the operant self-administration sessions. No significant relationships were noted between sensitivity to ethanol's locomotor effects and extinction responding. The results of these studies suggest that the well-established relationship between a low level of response to ethanol and increased ethanol consumption reported in human studies can be observed in an outbred rodent strain using a limited-access operant self-administration procedure, but not with home-cage ethanol drinking.

Behavioral Economic Assessment of Price and Cocaine Consumption Following Self-Administration Histories that Produce Escalation of Either Final Ratios or Intake

Various self-administration procedures are being developed to model specific aspects of the addiction process. For example, ‘increased cocaine intake over time’ has been modeled by providing long-access (LgA) to cocaine during daily self-administration sessions under a fixed-ratio (FR1) reinforcement schedule. Additionally, ‘increased time and energy devoted to acquire cocaine’ has been modeled by providing access to cocaine during daily self-administration sessions under a progressive-ratio (PR) schedule. To investigate the distinctiveness of these models, the behavioral economics variables of consumption and price were applied to cocaine self-administration data. To assess changes in consumption and price, cocaine self-administration was tested across a descending series of doses (0.237 – 0.001 mg/inj) under an FR1 reinforcement schedule in order to measure drug intake in the high dose range and thresholds in the low range. Cocaine consumption remained relatively stable across doses until a threshold was reached, at which maximal responding was observed. It was found that a history of LgA training produced an increase in cocaine consumption; whereas a history of PR training produced an increase in the maximal price (Pmax) expended for cocaine. Importantly, the concepts of consumption and price were found to be dissociable. That is, LgA training produced an increase in consumption but a decrease in Pmax, whereas PR training produced an increase in Pmax without increasing consumption. These results suggest that distinct aspects of the addiction process can be parsed using self-administration models, thereby facilitating the investigation of specific neurobiological adaptations that occur through the addiction process.

Maternal separation stress in male mice: long-term increases in alcohol intake

In rodents, prolonged maternal separation has been used as a model of developmentally early environmental stress to influence adult drug intake. The aim of the present study was to evaluate the long-term effects of prolonged maternal separation on alcohol consumption using two different self-administration procedures in mice: operant alcohol self-administration vs. three-bottle choice. From postnatal day (PND) 1 to 14, pups were separated from the dam (maternal separation, MS) daily for 180 min or were left undisturbed, only handled during cage cleaning (animal facility rearing, AFR). On PND 60, they were assigned to one of two experimental manipulations: either a three-bottle choice or operant oral alcohol self-administration. In the three-bottle choice procedure, mice were given access to 6% or 10% alcohol or 0.05% saccharin solution for 2 h/day for 10 days. In the second experiment, mice were reinforced for nose poking by delivery of oral alcohol (6% or 10% in saccharin) or 0.05% saccharin solutions during daily 30-min sessions. Following the acquisition phase, "break points" were determined. Later, mice were allowed 1 h access to the reinforcing solution with no dosage limitation. In the three-bottle choice procedure, MS mice showed higher alcohol intake than AFR at the 10% alcohol concentration. In the operant alcohol self-administration, MS mice achieved higher alcohol intake than AFR at the concentrations 6% and 10% during the 1-h session. The results demonstrate the long-term consequences of MS on alcohol intake in male mice, suggesting early life stress as a risk factor for alcohol consumption and abuse.