d-Amphetamine conditioned place preference in developing mice: Relations with changes in activity and stereotypies.

Conditioned place preference (CPP) with both visual and tactile cues, hyperactivity, and stereotypies produced by d-amphetamine (1–20 mg/kg) were studied in CD-1 mice at 2, 3, and 4 wks from birth. CPP was shown from the youngest age onward in female mice and from 3 wks in male mice. Hyperactivity was much more pronounced in postweanlings (3 and 4 wks) than in preweanlings. Stereotypies (at 3.3 and 10 mg/kg) occurred from the youngest age and tended to peak at 3 wks. Stereotypies may indicate a sickness experience or "poor welfare" due to an aversive component of amphetamine's action. Therefore, the delayed development of fully fledged amphetamine CPP, relative to cocaine CPP, may be due to an age-dependent diminution of the positive hedonic value of the former drug by negative effects that are minimal or absent in the case of the latter drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats.

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABAB receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six-day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2 mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABAB receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole

Three cases of isolated one-and-a-half syndrome with facial nerve palsy related to infarction are presented. Magnetic resonance imaging in cases 1 and 2 was unremarkable, whereas magnetic resonance angiography demonstrated pathophysiologically significant vertebral basilar disease. Case 3 is unique due to its association with giant cell arteritis. Ipsilateral adduction improved to a greater extent than abduction in each case, perhaps providing insight into the exact localization of these lesions or selective vulnerability of the ocular motor structures within the pons. This combination of clinical findings, termed the 8-1/2 syndrome (cranial nerve 7 + 1-1/2), allows precise localization, and magnetic resonance angiography appears to be the imaging study of choice.     

The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats

(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate, (MK-801) a potent noncompetitive antagonist of central NMDA receptors, has been hypothesized to have rewarding properties indicative of abuse potential. To test this hypothesis, the effects of MK-801 on the acquisition of a conditioned place preference and on locomotor activity were assessed and compared with d-amphetamine. Both MK-801 (0.03 and 0.1 mg/kg, SC) and d-amphetamine (1.0 mg/kg, SC) administration resulted in the acquisition of a conditioned place preference. However, while both amphetamine and the higher dose of MK-801 produced a behavioral activation during the training period the lower dose of MK-801 did not. These results suggest that MK-801, at doses that produce behavioral activation and below, is rewarding and therefore may have abuse potential.     

Differential effects of 7-OH-DPAT on amphetamine-induced stereotypy and conditioned place preference

Cost-effectiveness and cost per successful treatment has been evaluated in 186 outpatients randomised to treat moderate to severe migraine attacks either with subcutaneous sumatriptan 6 mg (n = 97) or with their current therapy (n = 89) during an open, multicentre study of 3 months. Within 2 hours, headache severity decreased to none/mild in 86% of all attacks in the sumatriptan group (STG) compared to 25% in the customary group (CTG). Migraine was alleviated earlier in the STG than in the CTG (median 3.78 vs. 13.39 hours, p < 0.0001). The direct and total cost of treatment was 133 and 2012 BF, respectively, in the CTG and 1400 and 2522 BF, respectively, in the STG. Measuring the effectiveness of earlier pain relief with sumatriptan, the incremental cost-effective ratios for direct and total cost were 132 and 53 BF per hour of relieved pain, respectively. For this price, significantly more sumatriptan patients improved their quality of life by more than 20% (61.6 vs. 20.6% patients, p < 0.001) and less sumatriptan patient consulted a medical professional (11.3 vs. 29.2% patients, p < 0.01), used less medication for adverse events (6.2 vs. 22.5%, p < 0.001) and suffered less from associated migraine symptoms. The median number of hours of diminished work-efficiency (3 vs. 7 hours, p < 0.01) or of suspension of non-professional activity (10 vs. 24 hours, p < 0.001) was also significantly lower in the STG. The total cost per successfully treated patient was lower in the STG. Sumatriptan is more effective, provides a better quality of life, reduces health care resource utilisation, and improves work productivity as compared to the CTG, thereby resulting in a favourable cost-effectiveness ratio.     

A role for α?-adrenergic receptors in extinction of conditioned fear and cocaine conditioned place preference.

Previous work has demonstrated an important role for adrenergic receptors in memory processes in fear and drug conditioning paradigms. Recent studies have also demonstrated alterations in extinction in these paradigms using drug treatments targeting β- and α2-adrenergic receptors, but little is known about the role of α?-adrenergic receptors in extinction. The current study examined whether antagonism of α?-adrenergic receptors would impair the consolidation of extinction in fear and cocaine conditioned place preference paradigms. After contextual fear conditioning, injections of the α?-adrenergic receptor antagonist prazosin (1.0 or 3.0 mg/kg) following nonreinforced context exposures slowed the loss of conditioned freezing over the course of 5 extinction sessions (Experiment 1). After cocaine place conditioning, prazosin had no effect on the rate of extinction over 8 nonreinforced test sessions. Following postextinction reconditioning, however, prazosin-treated mice showed a robust place preference, but vehicle-treated mice did not, suggesting that prazosin reduced the persistent effects of extinction (Experiment 2). These results confirm the involvement of the α?-adrenergic receptor in extinction processes in both appetitive and aversive preparations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blockade of morphine-induced place preference by diazepam in mice

We assessed the efficacy of combined laparoscopic and minilaparotomy for outpatient microsurgical reversal of extensive tubal sterilization in 11 women undergoing the procedure and followed for a mean of 24.7 months. All patients desired reversal of extensive tubal sterilization, and had 4 cm or less of the longer oviduct remaining. The mean operating time was 110 minutes, and the mean total cost was $5067. There were no major complications. Two women were treated for uncomplicated cystitis within 1 month of surgery. Five (45%) of 11 women delivered viable infants; one patient had two ectopic pregnancies. These preliminary data suggest that outpatient combined laparoscopy and minilaparotomy may be effective in patients who desire restoration of fertility after extensive tubal sterilization.     

The effects of the naltrexone implant on rodent social interactions and cocaine-induced conditioned place preference

It is well known that excessive thyroid hormone in the body is associated with bone loss. However, the mechanism by which thyroid hormone affects bone turnover remains unclear. It has been shown that it stimulates osteoclastic bone resorption indirectly via unknown mediators secreted by osteoblasts. To determine if interleukin-6 (IL-6) or interleukin-11 (IL-11) could be the mediator(s) of thyroid hormone-induced bone loss, we studied the effects of 3,5,3'-tri-iodothyronine (T3) on basal and interleukin-1 (IL-1)-stimulated IL-6/IL-11 production in primary cultured human bone marrow stromal cells. T3 at 10(-12)-10(-8) M concentration significantly increased basal IL-6 production in a dose-dependent manner. It also had an additive effect on IL-1-stimulated IL-6 production, but failed to elicit a detectable effect on basal or IL-1-stimulated IL-11 production. Treatment with 17beta-estradiol (10(-8) M) did not affect the action of T3 on IL-6/IL-11 production. These results suggest that thyroid hormone may stimulate bone resorption by increasing basal and IL-1-induced IL-6 production from osteoblast-lineage cells, and these effects are independent of estrogen status.     

The development of a conditioned place preference to morphine: effects of microinjections into various CNS sites

This study examined the neural substrates underlying the development of a conditioned place preference (CPP) to morphine (2 mg/kg x 3 pairings) by testing whether lesions of 7 different neural sites block a morphine-induced CPP. Lesions of the pedunculopontine tegmental nucleus (PPTg), the periaqueductal gray (PAG), or the fornix reduced the preference for a morphine-paired compartment. When they were retested following morphine administration, fornix- or PAG-lesioned animals exhibited a CPP indicating that lesions did not block morphine-induced reward or the ability to associate this effect with salient environmental cues. PPTg-lesioned animals did not express a CPP during state-dependent testing, suggesting that the lesions may attenuate the rewarding effect of the drug. Lesions of the mesolimbic dopamine system, the ventral pallidum, the lateral nucleus of the amygdala, or the caudate putamen had no effect on a morphine-induced CPP.     

The development of a conditioned place preference to morphine: Effects of lesions of various CNS sites.

This study examined the neural substrates underlying the development of a conditioned place preference (CPP) to morphine (2 mg/kg?×?3 pairings) by testing whether lesions of 7 different neural sites block a morphine-induced CPP. Lesions of the pedunculopontine tegmental nucleus (PPTg), the periaqueductal gray (PAG), or the fornix reduced the preference for a morphine-paired compartment. When they were retested following morphine administration, fornix- or PAG-lesioned animals exhibited a CPP indicating that lesions did not block morphine-induced reward or the ability to associate this effect with salient environmental cues. PPTg-lesioned animals did not express a CPP during state-dependent testing, suggesting that the lesions may attenuate the rewarding effect of the drug. Lesions of the mesolimbic dopamine system, the ventral pallidum, the lateral nucleus of the amygdala, or the caudate putamen had no effect on a morphine-induced CPP. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delayed extinction and stronger reinstatement of cocaine conditioned place preference in adolescent rats, compared to adults.

Adolescence is a transitional period during development that is associated with a greater likelihood of addiction to drugs than any other age. One possibility for this observation is that learned associations between the rewarding experience of drugs and drug-related cues may produce greater motivational salience, and thus are more difficult to extinguish. Using an unbiased place-conditioning paradigm with two doses of cocaine (10 mg/kg or 20 mg/kg), the authors show here that adolescents require 75 ± 17% more extinction trials than adults to extinguish cocaine place-preferences. Furthermore, once extinguished, adolescents display a greater preference for a previously cocaine-paired environment upon drug-primed reinstatement compared with adults. These results suggest that adolescent vulnerability to addiction involves robust memories for drug-associated cues that are difficult to extinguish. Therefore, drug-addicted adolescents may have a higher risk of relapse than adults, leading to greater prevalence of addiction in this population. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphine, MDMA, MDA, and nexus produce a conditioned place preference in newly hatched chickens.

The current study was undertaken to determine whether morphine and three amphetamine-related designer drugs would produce a conditioned place preference in newly hatched chickens (Gallus gallus). MDMA (3,4-methylenedioxymethamphetamine) and Nexus (4-bromo-2,5-dimethoxyphenethylamine) produced a place preference at intermediate doses; MDA (3,4-methylenedioxyamphetamine) produced a place preference only at the highest dose; and morphine produced a place preference only at the lowest dose tested. A second experiment was then conducted in which the same drugs were administered outside the context of the place preference apparatus. With the exception of Nexus, none of the drugs caused in a change in preference for the initially preferred side, suggesting that the place preference seen with Nexus in Experiment 1 was of a dissociative nature (i.e., not a true conditioned place preference). Results suggest that the newly hatched chicken may be an inexpensive, alternative species for studying drug-conditioned place preferences, but the results also emphasize the importance of conducting the proper control experiments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Facilitation of ejaculation induced by 8-OH-DPAT does not produce conditioned place preference in male rats.

The serotonin 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) produces a drastic facilitation of ejaculation characterized by a significant reduction in the number of pre-ejaculatory intromissions and a shortening of ejaculation latency. In the present study, the authors evaluated whether this facilitation of ejaculation can induce a reward state assessed by conditioned place preference. Males treated with 0.1 or 1.0 mg/kg of 8-OH-DPAT showed a clear facilitation of ejaculation but did not develop conditioned place preference. These results clearly indicate that the pharmacological facilitation of ejaculation and the reduction of the number of intromissions does not necessarily make sex rewarding. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treatment with a serotonin-depleting regimen of MDMA prevents conditioned place preference to sex in male rats.

Among young adults, 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular drug of abuse, and anecdotal evidence indicates that repeated use of MDMA may result in impairments in sexual function and decreased sex drive in human users. There has been little investigation of the effects of MDMA on sexual function in rodents. In the present study, the authors determined that in male rats (Rattus novegicus) tested in a sexually na?ve or a sexually experienced state, administration of a serotonin (5-HT)-depleting regimen of MDMA did not produce a change in mount, intromission, and ejaculation latency or in mount and intromission frequency compared with such latency and frequency in vehicle-treated control rats. In contrast to vehicle-treated rats, MDMA-treated rats did not form a conditioned place preference (CPP) to sex. Failure of MDMA-treated rats to form CPP to sex may be due to MDMA-induced impairments in circuits mediating sexual reward. (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)     

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)     

Dorsal hippocampus inhibition disrupts acquisition and expression, but not consolidation, of cocaine conditioned place preference.

Cocaine abusers may experience drug craving upon exposure to environmental contexts where cocaine was experienced. The dorsal hippocampus (DHC) is important for contextual conditioning, therefore the authors examined the specific role of the DHC in cocaine conditioned place preference (CPP). Muscimol was used to temporarily inhibit the DHC and was infused before conditioning sessions or tests for CPP to investigate acquisition and expression of cocaine CPP, respectively. To investigate consolidation, rats received intra-DHC muscimol either immediately or 6 hr after conditioning sessions. Inhibition of DHC, but not the overlying cortex, disrupted acquisition and expression of cocaine CPP. It is interesting to note that there was no effect of postconditioning DHC inhibition. The findings suggest that the DHC is important for both acquisition and recall, but not consolidation, of context-cocaine associations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP+ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP+ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.     

Amphetamine and morphine produce a conditioned taste and place preference in the house musk shrew (Suncus murinus).

Rats have been shown to avoid consuming a flavor, but prefer a location, previously paired with amphetamine or morphine. A series of 4 experiments evaluated the hedonic properties of amphetamine and morphine in the house musk shrew (Suncus murinus), an insectivore that (unlike rats) is capable of vomiting when exposed to toxins. Unlike rats, amphetamine (20 mg/kg) and morphine (20 mg/kg) produced both a conditioned sucrose (0.3 M) and saccharin (0.1%) preference in shrews (administered intraperitoneally), when measured by both a 1-and a 2-bottle test. At the same dose, both drugs also produced a place preference in shrews. These results suggest that the potential of rewarding drugs to produce taste avoidance may vary on the basis of the ability of the species to vomit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A study examining intravenous ethanol-conditioned place preference in C57BL/6J mice

The reinforcing effects of intravenous (I.V.) ethanol were examined in C57BL/6J (C57) mice with a conditioned-place-preference (CPP) paradigm. Before CPP testing, adult mice underwent jugular catheterization. On the following day, subjects were acclimated to a two-compartment CPP chamber. A 15-min nondrug pretest was conducted to determine compartment preference. For the treatment group, I.V. ethanol [30% (v/v), 3.4 microl/min, 25 min] was paired with the nonpreferred compartment, whereas I.V. saline was paired with the preferred compartment. The control group received I.V. saline in both compartments. Two conditioning sessions were conducted per day (0900 and 1500), and the order of the infusions was counterbalanced across subjects. The drug-free posttest was identical to the pretest, except that it occurred on the day after the final drug/compartment pairing. The entire procedure required 6 days. After just two pairings with ethanol, with a cumulative ethanol dose of only 0.82 g/kg/day, significant CPP was noted in the treatment group, whereas no change in compartment preference was noted for the control group. A separate group of C57 mice were trained to discriminate intraperitoneal ethanol (1.5 g/kg) from saline using a two-lever drug discrimination paradigm. After training was complete, these mice also underwent jugular catheterization. Substitution testing was conducted with I.V. ethanol [30% (v/v), 6.4 microl/min, 12 min] and saline. The results indicate that the subjective effects of ethanol did not differ according to the route of administration. Together, these experiments provide evidence that ethanol is rewarding for C57 mice, as indexed by ethanol CPP, and that the subjective effects of intravenously and intraperitoneally administered ethanol are similar.