Electrolytic lesions of the nucleus accumbens enhance locomotor sensitization to nicotine in rats.

Electrolytic lesions of the medial core of the nucleus accumbens (NAc) in male Long-Evans rats increased spontaneous locomotion, enhanced the locomotor stimulating effect of acute 5.0 mg/kg cocaine, enhanced the development and subsequent expression of locomotor sensitization produced by repeated injections of 0.4 mg/kg nicotine but not 7.5 mg/kg cocaine, and enhanced the expression of conditioned locomotion. Given that 6-hydroxydopamine lesions of the NAc typically have effects on locomotor-related processes that are opposite of those produced by electrolytic and excitotoxic lesions, these data are consistent with a hypothesis that the NAc output, especially from the core, inhibits a variety of such processes and that the DA input to the NAc enhances these processes by inhibiting this inhibitory output. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitization to cocaine in pigeons: Interaction with an operant contingency.

A 2-part study with pigeons investigated the role of an explicit operant contingency in determining how cocaine interacts with locomotor activity. In Part 1, pigeons pecked on a fixed-ratio-20 schedule of food presentation. In Part 2, different pigeons were studied without opportunity to peck for food. After determination of cocaine's initial effects, pigeons were exposed to daily administrations of a locomotion-increasing dose of cocaine. Locomotor sensitization was evident in the pigeons of Part 2, and tolerance developed to cocaine's effects on key pecking in the pigeons of Part 1. Locomotor sensitization was generally not evident in the pigeons of Part 1. These results suggest that explicitly conditioned operant behavior may compete with behavior sensitized by prolonged exposure to cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential involvement of enkephalins in analgesic tolerance, locomotor sensitization, and conditioned place preference induced by morphine.

In this study, the authors investigated the role of enkephalins in morphine-induced conditioned place preference, locomotor sensitization, and analgesic tolerance. Both preproenkephalin wild type (ppENK [+/+]) and knockout (ppENK [-/-]) mice showed similar preference for the morphine-paired chamber over the vehicle-paired chamber, indicating morphine induced comparable conditioned place preference in ppENK (+/+) and ppENK (-/-) mice. Sensitization developed to the motor stimulatory action of morphine after its repeated administration, but the magnitude of this response was not altered in ppENK (-/-) mice. However, as shown previously, ppENK (-/-) mice displayed blunted morphine analgesic tolerance. Taken together, the results suggest that enkephalins may be important for the development of analgesic tolerance but not for conditioned place preference or behavioral sensitization induced by morphine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Day-by-day maturation of the long-term expression of cocaine sensitization acquired before weaning in the rat.

This study aimed to identify the ontogenetic period during which long-term expression of behavioral sensitization to cocaine begins to emerge. Rat pups aged 4, 8, 12, or 16 days received a pretreatment of 4 daily injections of 15 mg/kg sc: cocaine paired with the test chamber for 45 min. Pups were then tested for sensitization in that context after abstinence intervals ranging from 2 to 10 days. On test days, pups were videotaped, and their behavior was scored later. Sensitization was detected after intervals of 2, 4, 5, or 9 days in pups aged 4–7, 8–11, 12–15, or 16–19 days during pretreatment, respectively. These results suggest that the mechanisms for long-term retention of sensitization mature incrementally in the rat, starting to emerge gradually after the 1st week of age, whereas those relevant to short-term retention and initiation of sensitization are present earlier. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

U-69593, a kappa opioid receptor agonist, decreases cocaine-induced behavioral sensitization in female rats.

This study was designed to investigate if the kappa opioid system regulates the locomotor response to cocaine in the female rat and to determine if the effect is dependent on estradiol treatment. Adult rats were ovariectomized (OVX) and half received an estradiol (OVX-EB) implant. After a week, rats were injected for 5 consecutive days with vehicle or with the kappa opioid receptor (KOPr) agonist U-69593 (0.16, 0.32, and 0.64 mg/kg) 15 min prior to cocaine injection (15 mg/kg). Following a 7-day drug-free period, rats were challenged with cocaine (Day 13). The locomotor response to cocaine was measured on Days 1, 5, and 13. U-69593 (0.32 mg/kg) decreased cocaine-induced locomotor activity in drug-na?ve OVX rats and in those that received the OVX-EB implant. These results indicate that the acute effects of U-69593 are independent of estradiol treatment. Repeated exposure to U-69593 (0.32 mg/kg) prior to cocaine decreased the development of behavioral sensitization in OVX-EB-implanted rats. This decrease in cocaine-induced hyperlocomotion persisted after 1 week of cocaine withdrawal. These data indicate that the KOPr system participates in estradiol modulation of cocaine-induced behavioral sensitization in the female rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Environmental and pharmacological factors in the development of noncontingent tolerance to cocaine in pigeons.

Previous research with rats and monkeys has shown that tolerance to behavioral effects of cocaine developed if the drug was administered before behavioral test sessions but not if it was administered after sessions, a finding known as contingent tolerance. In contrast, a recent experiment using pigeons found that they showed tolerance resulting from postsession drug administration (noncontingent tolerance). The 4 experiments reported in this article were conducted to examine that result more fully. Experiment 1 found that immediate presession administration of cocaine to pigeons reliably led to tolerance to effects on food-reinforced operant key pecking and that immediate postsession administration of cocaine also led to tolerance in half the subjects, those whose key pecking was not suppressed by postsession dosing. Experiment 2 showed that eating in the home cage under the effects of postsession cocaine was not necessary for tolerance to develop to effects of postsession cocaine and that the majority of subjects developed tolerance from postsession cocaine administration. Experiment 3 found that mere drug exposure in the home cage without exposure to an experimental session did not reliably produce tolerance during the behavioral session. Experiment 4 showed that tolerance from postsession cocaine administration could be observed even when daily dosing was discontinued during dose–response curve assessment. Therefore, the combined results showed that pigeons often developed tolerance to effects of cocaine during the behavioral session when cocaine was administered postsession and that this tolerance was not the result of feeding under effects of the drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characterization of the role of medial prefrontal cortex dopamine receptors in cocaine-induced locomotor activity.

Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D?-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D? receptor agonist PD 168,077 or the selective D? receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D?, and D? receptors. These results suggest that D? receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

One-trial cocaine-induced behavioral sensitization in preweanling rats: Role of contextual stimuli.

Using a one-trial procedure, preweanling rats exhibit robust sensitization regardless of whether drug pretreatment and testing occur in the same or different environments. The purpose of the present study was to determine whether one-trial context-specific and context-independent sensitization of preweanling rats could be dissociated by varying the pretreatment dose of cocaine, by varying the pretreatment drug, or by minimizing interoceptive cues. In Experiments 1a and 1b, rats were pretreated with a broad dose range of cocaine (0–40 mg/kg) before placement in a novel activity chamber or the home cage. In Experiment 2, rats were pretreated with a locomotor-enhancing drug (e.g., methylphenidate, U50,488, or MK-801) before placement in a novel activity or anesthesia chamber. In Experiment 3, rats were anesthetized with isoflurane before cocaine administration to minimize the effects of interoceptive and injection cues. In all experiments, rats were challenged with cocaine on the test day (24 hr later), with locomotion being measured in activity chambers. Results showed that (a) the pretreatment dose of cocaine (10–40 mg/kg) did not differentially affect context-specific and context-independent sensitization; (b) cross-sensitization between methylphenidate and cocaine was observed in the context-specific condition, but not when using a context-independent procedure; and (c) sensitization was evident if injection and interoceptive cues were minimized. One possibility is that associative processes do not modulate the one-trial sensitization of preweanling rats. Alternatively, “unitization” may cause preweanling rats to treat the different environments as equivalent, thus permitting robust sensitization even when drug pretreatment and testing occur in different environments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neonatal amygdala lesions: Co-occuring impact on social/fear-related behavior and cocaine sensitization in adult rats.

Neurodevelopmental abnormalities of temporal-limbic structures may underlie both adult psychiatric syndromes and increased addiction vulnerability, leading to high frequencies of "dual diagnosis" disorders. Although the amygdala is implicated in various mental disorders and drug addiction, no studies have explored the impact of early developmental damage to the amygdala on phenotypes relating to mental illness and addictions as co-occurring processes. We tested rats with neonatal amygdala lesions (NAML) vs. SHAM-operated controls in a battery of tests-novel field activity, elevated plus maze (EPM), and social interaction (SI) at baseline and after odor and restraint stress-followed by measures of cocaine sensitization (15 mg/kg vs. saline × 5 days + challenge session 2 weeks later) and remeasurement of SI. NAMLs showed increased novelty-related locomotion, less fear responding in the EPM, and resistance to predator-odor--but not to restraint-induced suppression of SI. NAMLs also had elevated cocaine sensitization profiles, and cocaine history differentially affected subsequent SI in NAMLs compared with SHAMs. NAMLs may provide models for understanding a shared neurobiological basis for and complex interactions among psychiatric symptoms, drug exposure history, and addiction vulnerability. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Psychomotor stimulant effects of cocaine in rats and 15 mouse strains.

Relative to intravenous drug self-administration, locomotor activity is easier to measure with high throughput, particularly in mice. Therefore its potential to predict differences in self-administration between genotypes (e.g., targeted mutations, recombinant inbred strains) is appealing, but such predictive value is unverified. The main goal of this study was to evaluate the utility of the locomotor assay for accurately predicting differences in cocaine self-administration. A second goal was to evaluate any correlation between activity in a novel environment, and cocaine-induced hyperactivity, between strains. We evaluated locomotor activity in male and female Sprague–Dawley rats and 15 mouse strains (129S1/SvImJ, 129S6/SvEvTac, 129X1/SvJ, A/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, SJL/J, SPRET/EiJ, and outbred Swiss Webster and CD-1/ICR), as well as cocaine self-administration in BALB substrains. All but BALB/cJ mice showed locomotor habituation and significant cocaine-induced hyperactivity. BALB/cJ mice also failed to self-administer cocaine. BALB/cByJ mice showed modest locomotor habituation, cocaine-induced locomotion, and cocaine self-administration. As previously reported, female rats showed greater cocaine-induced locomotion than males, but this was only observed in one of 15 mouse strains (FVB/NJ), and the reverse was observed in two strains (129X1/SvJ, BALB/cByJ). The intriguing phenotype of the BALB/cJ strain may indicate some correlation between all-or-none locomotion in a novel environment, and stimulant and reinforcing effects of cocaine. However, neither novelty- nor cocaine-induced activity offered a clear prediction of relative reinforcing effects among strains. Additionally, these results should aid in selecting mouse strains for future studies in which relative locomotor responsiveness to psychostimulants is a necessary consideration. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Anisomycin disrupts a contextual memory following reactivation in a cocaine-induced locomotor activity paradigm.

In experiments examining the potential reconsolidation of drug-associated contextual memories, rats were given a single pairing of cocaine with a specific context, and the ability of the protein synthesis inhibitor anisomycin administered following a context-only memory retrieval trial to impair conditioned locomotor sensitization was tested. Rats receiving 150 mg/kg anisomycin immediately following a 5-min reexposure to the cocaine-conditioned context showed decreased activity compared with the vehicle control group in response to a low-dose cocaine challenge during a subsequent test for conditioned sensitization. This effect was not seen when anisomycin was administered following a 30-min reexposure to the context or when anisomycin was administered 25 min after a 5-min reexposure. These results are consistent with a growing literature suggesting that following retrieval, associative contextual memories may undergo a transient protein synthesis-dependent reconsolidation phase that normally serves to maintain memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estrogen effects on the hyperactivity induced by (+)-MDMA and cocaine in female rats.

This study compared the effects of estrogen (E) on the hyperactivity induced by (+)-3,4-methylenedioxymethamphetamine (MDMA) with E effects on cocaine-evoked hyperactivity in female rats. Sprague-Dawley rats were ovariectomized (OVX); half of them received a 17β-estradiol (E?) implant (OVX + E). Three weeks later, rats received saline, (+)-MDMA (1, 2, or 4 mg/kg) or cocaine (5, 10, or 20 mg/kg), and locomotor activity was monitored. OVX + E rats exhibited greater locomotor hyperactivity in response to both psychostimulants than did OVX rats. The enhanced response to cocaine appeared within 5 min following drug injection whereas the enhanced response to (+)-MDMA was delayed for approximately 30 min. The differential effects of E on hyperactivity may be due to the unique profiles of dopamine (DA) and serotonin (5-HT) in response to (+)-MDMA and cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance.

The relationship between the effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on acute responses to ethanol and its ability to block ethanol sensitization and tolerance was examined in DBA/2J mice. Cross-sensitization between these drugs was also studied. Repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol's locomotor stimulant effects; rearing was similarly affected. There was evidence for cross-sensitization between ethanol and 0.25 mg/kg MK-801. MK-801 potentiated ethanol's ataxic effects in the grid test, but had no effect on tolerance to this effect. MK-801's effects on ethanol sensitization appeared to be related to its own behavioral effects, rather than NMDA receptor blockade per se. Further, these studies demonstrate dissociation between ethanol sensitization and tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gestational methylmercury exposure selectively increases the sensitivity of operant behavior to cocaine.

Developmental methylmercury (MeHg) exposure alters dopamine neurotransmitter systems, but the selectivity of this and the effects of low, environmentally relevant MeHg exposure regimens are poorly understood. In previous reports, some including littermates of animals studied here, chronic, low-level exposures affected performance on reversal tasks and enhanced reinforcer efficacy. Using high- and low-rate operant behavior under a fixed interval (FI) schedule, sensitivity was examined to drugs that target noradrenergic and dopaminergic neurotransmitter systems. Female rats were exposed in utero to 0, 0.5, or 5 ppm of mercury, as MeHg, via maternal drinking water. Selenium (Se) is thought to attenuate MeHg's neurotoxicity, so animals consumed a diet containing 0.06 or 0.6 ppm of Se. At 11 months, they lever-pressed under a FI 120” schedule of sucrose reinforcement. Acute dose-effect curves were generated with cocaine, desipramine, SKF-38393, quinpirole, SCH-23390, and sulpiride. As compared with unexposed animals, those exposed to 5 ppm mercury, regardless of Se exposure, were 2 to 3 times more sensitive to the rate-reducing effects of high doses of cocaine and did not show increased responding earlier in the interval following moderate cocaine doses. Cocaine's effects in the 0.5 ppm Hg groups depended on dietary Se: low Se diet resulted in a rightward shift in the DEC compared to controls, whereas a high Se diet did not. No differential effects of MeHg were seen with the other drugs. Gestational MeHg exposure produces irreversible sensitivity to dopamine, but not norepinephrine, reuptake inhibitors and not to drugs that target D1 or D2 receptors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The many facets of the locomotor response to a novel environment test: Theoretical comment on Mitchell, Cunningham, and Mark (2005).

Several animal studies have shown that there is a positive correlation between locomotor activity in response to a novel environment and acquisition of drug self-administration behavior. This finding led to the assumption that animals with heightened reactivity to novel environments are more sensitive to the rewarding effects of drugs compared with animals with reduced reactivity. But are these individuals really more responsive to drugs, or could they have enhanced sensitivity to rewards in general or even simply be better learners? In the previous issue of this journal, J. M. Mitchell, C. L. Cunningham, and G. P. Mark (2005) (see record 2005-03585-010), investigated these important matters. They reported that the locomotor response to a novel environment does not predict responding for cocaine but reflects overall differences in the ability to learn operant tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Insulin receptor substrate-2 in the ventral tegmental area regulates behavioral responses to cocaine.

Neurotrophic factor signaling modulates cellular and behavioral responses to drugs of abuse. Among other biochemical adaptations, chronic exposure to abused drugs decreases the expression of insulin receptor substrate-2 (IRS-2; a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of IRS-2, the authors show that overexpression of IRS-2 in the VTA results in an enhanced preference for environments previously paired with cocaine, as measured by the place conditioning paradigm, whereas blockade of IRS-2 activity results in avoidance of cocaine-paired compartments. In addition, IRS-2 overexpression leads to enhanced cocaine-induced locomotor activity, and blockade of IRS-2 expression significantly blunts behavioral responses to cocaine. These results demonstrate that levels of IRS-2 in the VTA regulate responsiveness to the behavioral effects of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrolytic lesions of the nucleus accumbens core (but not the medial shell) and the basolateral amygdala enhance context-specific locomotor sensitization to nicotine in rats.

We previously demonstrated that lesions of the nucleus accumbens (NAc) core enhanced locomotion and locomotor sensitization to repeated injections of nicotine in rats (Kelsey & Willmore, 2006). In this study, we compared the effects of separate lesions of the NAc core, NAc medial shell, and basolateral amygdala on context-specific locomotor sensitization to repeated injections of 0.4 mg/kg nicotine. Electrolytic lesions of the NAc core increased locomotion, and lesions of the core (but not the shell) and the basolateral amygdala enhanced context-specific locomotor sensitization by enhancing the development of sensitization in paired rats and decreasing expression in unpaired rats relative to sham-operated rats when challenged with an injection of 0.4 mg/kg nicotine in the locomotor chambers. These data are consistent with findings that the NAc core and the basolateral amygdala share a variety of behavioral functions and anatomical connections. The findings that lesions of these structures enhance context-specific locomotor sensitization while typically impairing other reward-related behaviors also indicate that the processes underlying locomotor sensitization and reward are not identical. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intravenous cocaine discrimination in humans.

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20 mg/70 kg cocaine. During the first session, saline and cocaine injections were alternated twice, with each separated by 1 hr. The injections were identified by letter codes. During the next 3 sessions, 12 trials were conducted, with saline and cocaine administered 6 times each in pseudorandom order. Thirty minutes following each injection, participants were asked to identify the injection by letter code. Seven of the 10 learned the discrimination (at least 10 trials correct). To evaluate sensitivity, the investigators tested participants with different doses of cocaine in test sessions. In the next phase, methamphetamine (5 and 10 mg/70 kg) and pentobarbital (50 and 100 mg/70 kg) were given intravenously during test sessions to determine whether the discrimination exhibited pharmacological class selectivity. During the evaluation of sensitivity and selectivity, training sessions were interspersed. As dose of cocaine increased, the number of participants identifying the test dose as cocaine increased, demonstrating sensitivity. The higher doses of methamphetamine and pentobarbital substituted for cocaine. The physiological and subjective effects of cocaine and methamphetamine were stimulant-like and dose related. Pentobarbital produced no physiological changes but increased Visual Analog Scale ratings of Sedation, Good Drug Effect, and High. This failure to demonstrate pharmacological selectivity may be related to participants' learning a drug-vs.-no-drug discrimination, and thus it may be necessary to alter training procedures in future studies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strain differences in maintenance of cocaine self-administration and their relationship to novelty activity responses.

The authors previously demonstrated that Fischer 344 (F344) and Lewis inbred rats differ in acquisition of cocaine self-administration. Other studies show that acquisition and maintenance of drug self-administration are predicted by locomotor activity in a novel environment among outbred Sprague-Dawley rats. The present study was designed to determine whether this relationship extended to F344 and Lewis rats. In Experiment 1, F344, Lewis, and Sprague-Dawley rats were trained to self-administer cocaine and tested with several doses under fixed- and progressive-ratio schedules of reinforcement. Self-administered infusions and ineffective active lever presses--those emitted during infusion and time-out periods--were assessed. In Experiment 2, separate sets of rats of each strain were examined for locomotor responses (distance traveled and center time) under novelty conditions. Results show that F344 rats self-administer more cocaine than Lewis or Sprague-Dawley rats under both schedules and emit more ineffective lever presses--a possible measure of craving. Strain comparisons of locomotor responses suggest that center time, not activity, relates to self-administration behavior. Maintenance studies of cocaine self-administration rather than acquisition may better reflect vulnerability to addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)