Nicotine-induced place preferences following prior nicotine exposure in rats

The motivational properties of morphine and nicotine were investigated in an automated conditioned place preference (CPP) procedure using a two-compartment apparatus. The accuracy of the photocell recording system was assessed by correlation with direct observation. In a counterbalanced conditioning design, graded doses of morphine (0.1-3.2 mg/kg SC) produced dose-related CPP. Under similar conditions, a dose of nicotine (0.6 mg/kg SC) previously reported to produce CPP failed to show an effect. Increasing the number of conditioning trials from 4 to 12 did not facilitate CPP with nicotine. After pretreatment with nicotine (0.4 mg/kg SC) daily for 7 days prior to conditioning, nicotine (0.4-0.8 mg/kg) produced increasing magnitudes of CPP. Locomotor activity was assessed during both conditioning and extinction tests. During conditioning, nicotine but not morphine decreased activity in the first conditioning trial, but by the fourth trial, marked stimulation was apparent following administration of either drug. Activity in the drug-paired compartment was not increased during tests for CPP carried out in the undrugged state following 4 conditioning trials with either morphine or nicotine, but there was evidence for conditioned hyperactivity after 12 conditioning trials with nicotine. The results suggest that motivational properties of nicotine can be detected in counterbalanced CPP procedures, but only in subjects with a history of nicotine exposure. The CPP produced by morphine or nicotine does not appear to be an artefact associated with conditioned changes in locomotor activity.     

Isradipine produces neither a conditioned place preference nor aversion

Isradipine (ISR) has been reported to block cocaine-induced conditioned place preference. Using this procedure, the pairing of this L-type calcium blocker, at doses of 2.5, 5.0 and 10 mg/kg, with a preferred (cue-distinct) environment was investigated. In a separate experiment, ISR injection (10 mg/kg) was paired with the less-preferred environment to determine whether ISR produces a place preference. Testing in the non-drugged state revealed that ISR conditioning failed to affect side preference in both experiments. The neutral affective properties of ISR may be relevant to the development of cocaine use/abuse treatment regimens.     

Effects of dopamine D1 and D2 receptor antagonists on cocaine-induced place preference conditioning in preweanling rats

The effects of dopamine D1 and D2 receptor antagonists on the reward processes of 10- and 17-day-old rats were assessed using the conditioned place preference paradigm. Conditioning and testing were conducted in a three-compartment chamber, with each end compartment having its own distinct tactile and odor cues (almond and lemon). During six experiments, 10- and 17-day-old rats (age at initial conditioning) were injected intraperitoneally with either saline, the dopamine D1 receptor antagonist R(+/-)-SCH 23390 hydrochloride (0.01-1.0 mg/kg), or the dopamine D2 receptor antagonists (+/-)-sulpiride (1-100 mg/kg) or S(-)-eticlopride hydrochloride (0.1-0.5 mg/kg) 30 min prior to being injected with cocaine hydrochloride (20 mg/kg) or saline. After the latter injections, rats were immediately confined in the lemon-scented (nonpreferred) compartment for 30 min. On the alternate conditioning day, rats were injected with saline and confined in the almond-scented compartment. On the third day (i.e., the test day), rats were given saline and allowed free access to the entire chamber for 15 min. The results showed that the dopamine D1 receptor antagonist SCH 23390 blocked the cocaine-induced place preference conditioning of both 10- and 17-day-old rats. Surprisingly, the dopamine D2 receptor antagonists sulpiride and eticlopride blocked the place preference conditioning of 10-day-old rats, while leaving the 17-day-old rats unaffected. These results indicate that dopamine D1 receptors are critically involved in the reward processes of preweanling rats, but that the importance of dopamine D2 receptors changes across ontogeny.     

Intracerebroventricular ethanol-induced conditioned place preferences are prevented by fluphenazine infusions into the nucleus accumbens of rats.

The rewarding properties of centrally administered ethanol (EtOH) were examined using a conditioned place preference (CPP) test. Male rats subjected to bilateral intracerebroventricular (icv) infusions of EtOH (0-240 nmol) produced a dose-dependent preference for the drug-paired environment that was potentiated by concurrent intravenous (iv) administration of heroin (0.025 mg/kg). The role of mesolimbic dopamine (DA) pathways in the development of EtOH reward was then examined by challenging EtOH-treated rats with bilateral intra-accumbens shell applications of a DA receptor antagonist. Fluphenazine (10 or 50 μg/side), infused immediately prior to daily place conditioning trials, was found to reliably attenuate the development of CPPs produced by icv EtOH administration. When fluphenazine was administered into the nucleus accumbens shell prior to the final test trial only (i.e., in already conditioned rats), intra-accumbens shell DA receptor blockade was found to prevent the expression of CPPs produced by icv EtOH. In summary, rats form reliable learned preferences for EtOH-paired locations (CPPs) that are potentiated by iv heroin and whose acquisition and expression rely on intact DA functionality within the nucleus accumbens. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Place conditioning with the dopamine D1-like receptor agonist SKF 82958 but not SKF 81297 or SKF 77434

While self-administration and place conditioning studies have shown that dopamine D2-like receptor agonists produce reward-related learning, the effects of dopamine D1-like receptor agonists remain equivocal. The present study tested three dopamine D1-like receptor agonists for their ability to induce a place preference. Like control rats treated with amphetamine (2.0 mg/kg i.p.), rats treated with SKF 82958 (+/- -6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1-phenyl-1H- 3-benzazepine hydrobromide; 0.05 but not 0.01, 0.025, 0.075, or 0.10 mg/kg s.c. and/or i.p.) during conditioning showed a significant increase in the amount of time spent on the drug-paired side during the drug free test. Neither SKF 81297 (+/- -6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; 0.25, 0.50, 1.0, 2.0, and 4.0 mg/kg i.p.) nor SKF 77434 (+/- -7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; 0.20, 1.0, 5.0, and 10.0 mg/kg i.p.) produced place conditioning. Significant increases in locomotion were seen at some doses of all drugs. Results show for the first time that systemic administration of a dopamine D1-like receptor agonist produces a place preference and are consistent with previous findings showing that dopamine D1-like receptor activation produces reward-related learning.     

Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies

The association of propofol with excitatory motor activity, such as myoclonic jerking and opisthotonus, in humans and in animals suggests that it may aggravate clinical seizure activity in some circumstances, although evidence suggests that under other circumstances, propofol inhibits seizure activity. In the current study, we assessed the effect of sedating doses of propofol on lidocaine-induced seizure activity in spontaneously breathing rats receiving no other anesthetics. Adult Sprague-Dawley male rats, 300-400 g, were divided into a control group and three experimental groups representing three graded levels of propofol sedation. The control rats then received a lidocaine infusion at the rate of 150 mg x kg(-1) x h(-1), resulting in a slow, progressive increase in systemic lidocaine concentrations. At the onset of electroencephalographic (EEG) seizure activity, arterial lidocaine concentrations were obtained. The treated rats received propofol according to three different dose schedules: Dose 1 = 10 mg x kg(-1) x h(-1) after a 2.5-mg/kg bolus; Dose 2 = 20 mg x kg(-1) x h(-1) after a 5-mg/kg bolus; Dose 3 = 40 mg x kg(-1) x h(-1) after a 10-mg/kg bolus. After 30 min, a steady level of sedation, dependent on the dose of propofol, was achieved. The lidocaine infusion was then started, and systemic lidocaine levels were obtained at the onset of EEG seizure activity. The lidocaine was continued until the onset of death by cardiac arrest. Plasma lidocaine was measured by gas chromatography. Analysis of variance and Dunnett's t-test were used for comparisons with the control values. Continuous propofol sedation increased the seizure dose of lidocaine from 37.7 +/- 3.5 mg/kg (mean +/- SEM) to 52.5 +/- 2.6 mg/kg (Dose 1, P < 0.05) and 67.9 +/- 8.6 mg/kg (Dose 2, P < 0.05), and completely abolished lidocaine seizures at Dose 3. The lethal dose of lidocaine, 89.4 +/- 10.5 mg/kg control versus 108.7 +/- 10.3 mg/kg (Dose 1), 98.3 +/- 10.1 mg/kg (Dose 2), and 93.5 +/- 10.4 mg/kg (Dose 3) did not differ among groups. The lidocaine levels at seizure threshold were increased in the propofol-treated rats: 16.9 +/- 0.5 microg/mL control versus 19.2 +/- 0.7 microg/mL (Dose 1, P = not significant) and 23.7 +/- 1.8 microg/mL (Dose 2, P < 0.05). Continuous propofol sedation in spontaneously breathing rats receiving no other anesthetics exerts a protective effect against lidocaine-induced seizures in a monotonic, dose-dependent fashion. The cardiac arrest dose of lidocaine is unaffected by propofol under these conditions. IMPLICATIONS: The i.v. anesthetic drug propofol, given to rats to produce sedation, was found to suppress seizure activity caused by overdosage of the local anesthetic lidocaine.     

Verapamil suppresses d-amphetamine-induced place preference conditioning

The effect of pretreatment with (+/-)-verapamil (5, 10 or 15 mg/kg, i.p.) on place preference induced with d-amphetamine (1 mg/kg, i.p. 40 min after verapamil) was studied in male rats. Place preference conditioning was performed using two-compartment shuttle boxes and 8 alternating stimulant/saline sessions. Verapamil dose-dependently suppressed amphetamine-induced place preference. No significant changes in place preference were observed following 8 alternating verapamil (no stimulant)/saline sessions, irrespective of whether verapamil injections were paired with the originally less or the originally more preferred compartment. It appears that verapamil effectively suppresses the reinforcing properties of d-amphetamine in the paradigm used.     

Competition between novelty and cocaine conditioned reward is sensitive to drug dose and retention interval.

The conditioned rewarding effects of novelty compete with those of cocaine for control over choice behavior using a place conditioning task. The purpose of the present study was to use multiple doses of cocaine to determine the extent of this competition and to determine whether novelty’s impact on cocaine reward was maintained over an abstinence period. In Experiment 1, rats were conditioned with cocaine (7.5, 20, or 30 mg/kg ip) to prefer one side of an unbiased place conditioning apparatus relative to the other. In a subsequent phase, all rats received alternating daily confinements to the previously cocaine paired and unpaired sides of the apparatus. During this phase, half the rats had access to a novel object on their initially unpaired side; the remaining rats did not receive objects. The ability of novelty to compete with cocaine in a drug free and cocaine challenge test was sensitive to cocaine dose. In Experiment 2, a place preference was established with 10 mg/kg cocaine and testing occurred after 1, 14, or 28 day retention intervals. Findings indicate that choice behaviors mediated by cocaine conditioning are reduced with the passing of time. Taken together, competition between cocaine and novelty conditioned rewards are sensitive to drug dose and retention interval. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A morphine-paired environment alters c-Fos expression in the forebrain of rats displaying conditioned place preference or aversion.

The question of whether a common mechanism mediates both aversive and rewarding drug-paired cues is still unclear. In this study, we used a place preference conditioning paradigm to train rats to associate 1 chamber with morphine and the other chamber with saline. On the test day, rats were divided into those displaying conditioned place preferences (CPP) versus conditioned place aversion (CPA). After the test, all rats were killed and c-Fos immunocytochemistry was performed. For the control group, rats were treated with the same procedure except that the injections of morphine or saline had no association with the chambers. Compared with the control group, the CPP and CPA groups showed a significant increase of c-Fos expression in the dorsomedial striatum, central medial nucleus of the thalamus, and the basolateral amygdala. However, we saw no difference between CPP and CPA rats in any brain region examined. These results suggest that a morphine-paired environment can elicit neural activity in brain regions that are involved in emotional learning. Morphine-conditioned place preference and aversion may share a common neural circuitry elicited by a morphine-paired environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in gastric mucosa and Helicobacter pylori infection in young health volunteers

The effect of microinjection of a GABAB receptor agonist, baclofen, into the ventral tegmental area on the rewarding effect of morphine was investigated using the conditioned place preference paradigm in rats. Morphine (1-8 mg/kg, s.c.) caused a dose-related place preference for the drug-associated place. In contrast, microinjection of baclofen (0.1-1 nmol/side) into the ventral tegmental area did not produce a significant preference for either compartment of the test box. Pretreatment with baclofen (0.1-1 nmol/side) into the ventral tegmental area dose dependently suppressed the morphine (8 mg/kg, s.c)-induced place preference. This suppression of the morphine (8 mg/kg, s.c.)-induced place preference by baclofen (1 nmol/side), but not with the GABAA receptor antagonist bicuculline (1 nmol/side). The present results suggest that a decrease in GABAB neurotransmission in the ventral tegmental area, which may be produced via inhibition of a tonic GABAergic input by morphine, may be involved in the expression of the rewarding effect of morphine.     

Place conditioning in a three- or four-choice apparatus: Role of stimulus novelty in drug-induced place conditioning.

Examined in a series of 4 experiments the suggestion (M. T. Scoles and S. Siegel, 1986) that drug-induced place preference conditioning may be due to interference with habituation. In each experiment, rats had the opportunity to select among a drug-paired chamber, a saline-paired chamber, and a novel (or relatively novel) chamber. The drugs included the positively reinforcing drugs amphetamine, apomorphine, morphine, and nicotine and the aversive drug lithium chloride. The rats preferred chambers that were paired with amphetamine, apomorphine, and morphine more than chambers that were novel; however, they also consistently preferred novel chambers to familiar saline-paired chambers. There was no evidence of place conditioning with nicotine. The drug-induced place preference, but not the novelty preference, occurred after a single conditioning trial in a 3-choice apparatus but not a 4-choice apparatus. Lithium chloride established a place aversion after 1–3 conditioning trials. Measures of activity revealed that the rats were least active while in their most preferred chamber and most active while in their least preferred chamber. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blood lead of intravenous drug users

Ethanol, morphine, cocaine and amphetamine were examined in place conditioning. After determination of initial preferences, animals were conditioned with ethanol (1 g/kg), morphine (5 mg/kg), cocaine (5 mg/kg) and amphetamine (5 mg/kg) alone or with combinations of these drugs plus naloxone (1 mg/kg). Naloxone prevented the ability of all drugs used to produce a place preference. The reinforcing properties of ethanol and morphine were reduced by sodium nitroprusside at a dose equal to 1/10 of LD50 given before preference testing. Molsidomine (1/10 LD50 and 1/20 LD50) altered the expression of the conditioned place preference produced by ethanol but not by morphine. Results of the present study suggest the involvement of endogenous opioids and probably of nitric oxide in the rewarding actions of drugs of abuse.     

Morphine influences on classical aversive conditioned heart rate in rats.

Investigated in 3 experiments the effects of morphine and the morphine antagonist naloxone on the development of a classical aversive heart rate (HR) conditioned response (CR) to a tone conditioned stimulus (CS) paired with an electric shock unconditioned stimulus (US). In Exp I, groups of rats received either 0.25, 5 or 10 mg/kg, sc, of morphine. Three other groups were given 0.1, 5, or 10 mg/kg of naloxone. All morphine groups showed attenuation HR responses to the CS on preconditioning CS-alone trials. During conditioning, the 10-mg/kg morphine group showed a markedly decremented bradycardia CR and tachycardia unconditioned response (UR), whereas the 5-mg/kg morphine group showed a normal CR in combination with a decremented UR. In the Exp II, 1 mg/kg naloxone given after conditioning failed to reverse the CR and UR losses produced by 10 mg/kg of morphine given prior to conditioning. 10 mg/kg of morphine produced only a minor reduction in a HR CR established in a drug-free state, but the tachycardia UR was severely reduced. Exp III showed that 1 mg/kg of naloxone was effective in reversing analgesia induced by 10 mg/kg of morphine. 10 mg/kg dose of morphine interfered with the learning of a HR CR, perhaps principally by reducing the aversive or emotional consequences of the shock US. Direct cardiovascular effects of morphine seemed to interfere with the performance of the tachycardia UR, but not with the performance of the bradycardia CR. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Music-induced context preference following cocaine conditioning in rats.

Traditional models of drug-seeking behavior have shown that exposure to associated environmental cues can trigger relapse. These learned associations take place during repeated drug administration, resulting in conditioned reinforcement. Although considerable investigation has occurred regarding simple conditioned stimuli, less is known about complex environmental cues, particularly those that may be salient in human addiction. Recent studies indicate that music can serve as a contextual conditioned stimulus in rats and influence drug-seeking behavior during abstinence. The purpose of the present study was to further assess the effectiveness of music as a conditioned stimulus in rats, to determine rats' preferences for two contrasting pieces of music, and to determine rats' preferences for music versus silence. To this end, we created an apparatus that gave instrumental control of musical choice (Miles Davis vs. Beethoven) to the rats themselves. After determining baseline musical preference, animals were conditioned with cocaine (10 mg/kg) to the music they initially preferred least, with alternating conditioning sessions pairing saline with the music preferred most. The animals were subsequently tested in a drug-free state to determine what effect this conditioning had on musical preference. The results indicate that music serves as an effective contextual conditioned stimulus, significantly increasing both musical preference and locomotor activity after repeated cocaine conditioning. Furthermore, we found that rats initially favor silence over music, but that this preference can be altered as a result of cocaine-paired conditioning. These findings demonstrate that, after repeated association with reward (cocaine), music can engender a conditioned context preference in rats; these findings are consistent with other evidence showing that musical contextual cues can reinstate drug-seeking behavior in rats. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Relationship between auditory intensity discrimination in noise and olivocochlear efferent system activity in humans

The intravenous (i.v.) steroid anesthetic, eltanolone, compares favorably to propofol with respect to its induction characteristics. This double-blind investigation was designed to compare the induction and recovery profile of eltanolone (versus propofol) when it was used for both induction and maintenance of ambulatory anesthesia. Eighty-three consenting ASA physical status I-III outpatients undergoing minor gynecologic or urologic procedures lasting 10-40 min were randomly assigned to one of three anesthetic treatment groups. All patients received midazolam, 2 mg i.v., and fentanyl, 50 micrograms i.v., before induction of anesthesia. The control group (Group 1) was induced with propofol, 2.4 mg/kg i.v. (18-60 yr or ASA physical status I or II) or 1.6 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus doses of 0.6 mg/kg i.v. in combination with N2O 67% for maintenance of anesthesia. In Group 2, anesthesia was induced with eltanolone, 0.75 mg/kg i.v., (18-60 yr and/or ASA physical status I or II) or 0.5 mg/kg i.v. (61-80 yr and/or ASA physical status III), and maintained with intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. Group 3 received eltanolone, 1.0 mg/kg i.v. (18-60 yr and/or ASA physical status I or II), or 0.75 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. In addition to recording the induction and recovery times and side effects, psychomotor testing was performed before and at 30-min intervals after anesthesia. Induction times (57 +/- 23, 67 +/- 26, and 61 +/- 22s, respectively) were similar in all three groups. Although eltanolone produced no pain on injection (versus 52% in the propofol group), 10% of the eltanolone-treated patients (versus none in the propofol group) developed transient cutaneous (rash-like) reactions. The total dose of study medication used during the anesthetic period was 9.2 +/- 3.7 mg.kg-1.h-1 in the propofol group compared with 3.3 +/- 1.4 mg.kg-1.h-1 and 3.3 +/- 1.9 mg.kg-1.h-1 in Groups 2 and 3, respectively. Early recovery times were significantly shorter after propofol anesthesia. However, times to ambulation, micturition, and being judged "fit for discharge," as well as recovery of cognitive function, were similar in all three groups. Although ethanolone seems to be a safe and effective i.v. anesthetic, these data suggest that it is unlikely to replace propofol in the ambulatory setting. Implications: Eltanolone is an investigational steroid anesthetic that causes less pain on injection and less cardiovascular depression than propofol (the most widely used intravenous anesthetic in the outpatient setting). Unfortunately, emergence from anesthesia after ambulatory surgery is slower with eltanolone compared with propofol. Therefore, it is unlikely that eltanolone will replace propofol for outpatient anesthesia.     

Lesions of the nucleus accumbens in rats reduce opiate reward but do not alter context-specific opiate tolerance.

Bilateral electrolytic lesions of the nucleus accumbens in rats eliminated the capacity of 10 mg/kg morphine to produce a conditioned place preference (Experiment 1). However, these lesions did not alter the capacity to establish context-specific tolerance to the analgesic effects of 5 mg/kg of morphine (Experiment 2). This latter finding indicates that rats with nucleus accumbens lesions are not impaired in associating the effects of morphine with a particular location. Thus, the failure of morphine to produce a conditioned place preference in these lesioned rats probably cannot be attributed to an inability to associate the effects of morphine with a particular chamber, i.e., the initially nonpreferred chamber. Rather, morphine may fail to establish a conditioned place preference in these rats because nucleus accumbens lesions disrupt a pathway that is critical in mediating the rewarding effects of opiates. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

LSD produces place preference and flavor avoidance but does not produce flavor aversion in rats.

The hedonic properties of lysergic acid diethylamide (LSD) were assessed using the place conditioning, taste reactivity, and taste avoidance tests. LSD produced a conditioned place preference, but only at the highest dose tested (0.2 mg/kg). A single preexposure to the conditioning chamber (latent inhibition) prevented the establishment of a place preference. When paired with sucrose, doses of 0.05 to 0.2 mg/kg of LSD produced taste avoidance, but no dose of LSD produced an aversion to the taste as assessed by the taste reactivity test. These results suggest that LSD, like other rewarding drugs, produces taste avoidance by a mechanism other than that produced by emetic drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse

The sedative and anesthetic effects of ethanol and propofol when these drugs are coadministered are not known. Accordingly, we investigated the nature of the pharmacological interaction between ethanol and propofol during hypnosis and anesthesia in the mouse. Propofol, ethanol, and mixtures of the two were administered through the tail vein in male CD-1 mice (n = 162). The loss of righting response occurring 10 s after injection and persisting at least 10 s thereafter was defined as hypnosis, and lack of a motor response to tail clamping 60 s after injection was defined as anesthesia. The 50% effective dose (ED50) values for the hypnotic and anesthetic actions of the drugs were determined with quantal dose-response curves, using probit analysis. The pharmacological interactions were identified by the locations of ED50 values on their corresponding hypnosis and anesthesia isoboles. For each drug alone, the hypnotic and anesthetic ED50 values with 0.95 confidence intervals were 16.70 (11.98, 23.20) mg/kg and 25.02 (20.27, 31.29) mg/kg for propofol and 0.88 (0.81, 0.95) g/kg and 1.80 (1.45, 2.23) g/kg for ethanol, respectively. For the drugs in combination, the ED50 values for hypnosis with 0.95 confidence intervals were 6.98 (6.50, 7.49) mg/kg propofol with 0.61 (0.57, 0.66) g/kg ethanol, and for anesthesia were 10.55 (9.76, 11.42) mg/kg propofol with 0.93 (0.86, 1.05) g/kg ethanol, respectively. When plotted isobolographically, we found these combinations to be behaviorally additive both for hypnosis and anesthesia. Although a finding of synergism would have excluded the possibility of an identical mechanism of action for the drugs, elucidation of the molecular basis of the additivity must await further studies.     

Genetic variation among Trypanosoma cruzi populations

Four experiments examined the effect of naloxone pretreatment on the expression and extinction of ethanol-induced conditioned place preference (experiments 1, 2, 4) or conditioned place aversion (experiments 1, 3). DBA/2 J mice received four pairings of a distinctive tactile (floor) stimulus (CS) with injection of ethanol (2 g/kg) given either immediately before or after 5-min exposure to the CS. A different stimulus was paired with injection of saline. Pre-CS injection of ethanol produced conditioned place preference, whereas post-CS injection of ethanol produced conditioned place aversion. Both behaviors extinguished partially during repeated choice testing after vehicle injection. Naloxone (10 mg/kg) had little effect on the initial expression of conditioned place preference, but facilitated its extinction. Moreover, repeated naloxone testing resulted in the expression of a weak conditioned place aversion to the CS that initially elicited a place preference. In contrast, naloxone (1.5 or 10 mg/kg) enhanced expression of conditioned place aversion, thereby increasing its resistance to extinction. A control experiment (experiment 4) indicated that repeated testing with a different aversive drug, lithium chloride, did not affect rate of extinction or produce an aversion to the CS previously paired with ethanol. These findings do not support the suggestion that naloxone facilitates the general processes that underlie extinction of associative learning. Also, these data are not readily explained by the conditioning of place aversion at the time of testing. Rather, naloxone's effects appear to reflect a selective influence on maintenance of ethanol's conditioned rewarding effect, an effect that may be mediated by release of endogenous opioids. Overall, these findings encourage further consideration of the use of opiate antagonists in the treatment of alcoholism.     

Elevated novelty seeking and peculiar d-amphetamine sensitization in periadolescent mice compared with adult mice

Novelty seeking as well as amphetamine sensitization were studied in adult (postnatal day "PND" > 60) and periadolescent (PND 3343) mice treated with saline or amphetamine (2 or 10 mg/kg once per day) for 3 days in a familiar environment. After a 48-hr wash-out period, mice were challenged with either saline or amphetamine (2 mg/kg) in the same environment. When given a choice, animals showed a preference for a novel environment, an effect more marked in periadolescents. Acute amphetamine strongly increased novelty seeking in adults, whereas it had an opposite effect in periadolescents. Adult mice in the chronic amphetamine 2 group showed a conditioned preference for the drug-paired compartment, whereas an aversion characterized adult mice in the amphetamine 10 group. Periadolescents in the latter group exhibited a greater sensitization of the locomotor response, but did not show the compulsive licking typical of adults. This appears to be a useful model to study psychobiological risk factors involved in vulnerability to addiction during human adolescence.