Antagonism of the kappa opioid receptor attenuates THC-induced place aversions in adult male Sprague-Dawley rats.

RATIONALE: Prior research with transgenic mice in which the kappa opioid receptor (KOR) has been suppressed or activated suggests that the aversive effects of THC are mediated by activity of this receptor subtype. If the activity of the KOR system is responsible for mediating the THC's aversive effects, then selective antagonism of the KOR by norBNI should block such aversive effects. To test this hypothesis, rats were pretreated with norBNI 24h prior to place conditioning with THC to assess its effect on the acquisition of THC-induced place aversions. METHODS: In Experiment 1, rats pretreated with norBNI (0 or 15mg/kg) were exposed 24h later to one side of a place conditioning chamber and injected with THC (0, 0.56, 1 and 3.2mg/kg). On the next day, they were injected with vehicle and placed on the opposite side of the chamber. This was repeated for a total of five cycles followed by a test of the animal's aversion to the THC-paired side. In Experiment 2, rats were pretreated with norBNI (0 or 30mg/kg) prior to place conditioning 24h later with THC (0 or 3.2mg/kg). RESULTS: In Experiment 1, THC produced dose-dependent place aversions that were unaffected by norBNI (15mg/kg). In Experiment 2, THC induced significant place aversions that were fully attenuated by norBNI (30mg/kg). CONCLUSIONS: Although 15mg/kg norBNI was ineffective in antagonizing the aversive effects of THC, 30mg/kg norBNI blocked the ability of THC to induce a place aversion. The results of the latter assessment are consistent with prior research with transgenic manipulations of the KOR and provide further evidence for the role of the KOR system in the aversive properties of THC.

Cadherin 13: human cis-regulation and selectively-altered addiction phenotypes and cerebral cortical dopamine in knockout mice.

The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5 choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

Adolescent delta-9-tetrahydrocannabinol (THC) exposure fails to affect THC-induced place and taste conditioning in adult male rats.

BACKGROUND: Adolescent initiation of drug use has been linked to problematic drug taking later in life and may represent an important variable that changes the balance of the rewarding and/or aversive effects of abused drugs which may contribute to abuse vulnerability. The current study examined the effects of adolescent THC exposure on THC-induced place preference (rewarding effects) and taste avoidance (aversive effects) conditioning in adulthood. METHODS: Forty-six male Sprague-Dawley adolescent rats received eight injections of an intermediate dose of THC (3.2mg/kg) or vehicle. After these injections, animals were allowed to mature and then trained in a combined CTA/CPP procedure in adulthood (PND ~90). Animals were given four trials of conditioning with intervening water-recovery days, a final CPP test and then a one-bottle taste avoidance test. RESULTS: THC induced dose-dependent taste avoidance but did not produce place conditioning. None of these effects was impacted by adolescent THC exposure. CONCLUSIONS: Adolescent exposure to THC had no effect on THC taste and place conditioning in adulthood. The failure to see an effect of adolescent exposure was addressed in the context of other research that has assessed exposure of drugs of abuse during adolescence on drug reactivity in adulthood.

Effect of norbinaltorphimine on ∆9-tetrahydrocannabinol (THC)-induced taste avoidance in adolescent and adult Sprague-Dawley rats.

RATIONALE: The aversive effects of ∆(9)-tetrahydrocannabinol (THC) are mediated by activity at the kappa opioid receptor (KOR) as assessed in adult animals; however, no studies have assessed KOR involvement in the aversive effects of THC in adolescents. Given that adolescents have been reported to be insensitive to the aversive effects induced by KOR agonists, a different mechanism might mediate the aversive effects of THC in this age group. OBJECTIVES: The present study was designed to assess the impact of KOR antagonism on the aversive effects of THC in adolescent and adult rats using the conditioned taste avoidance (CTA) procedure. METHODS: Following a single pretreatment injection of norbinaltorphimine (norBNI; 15 mg/kg), CTAs induced by THC (0, 0.56, 1.0, 1.8, and 3.2 mg/kg) were assessed in adolescent (n = 84) and adult (n = 83) Sprague-Dawley rats. RESULTS: The KOR antagonist, norBNI, had weak and inconsistent effects on THC-induced taste avoidance in adolescent rats in that norBNI both attenuated and strengthened taste avoidance dependent on dose and trial. norBNI had limited impact on the final one-bottle avoidance and no effects on the two-bottle preference test. Interestingly, norBNI had no effect on THC-induced taste avoidance in adult rats as well. CONCLUSIONS: That norBNI had no significant effect on THC-induced avoidance in adults, and a minor and inconsistent effect in adolescents demonstrates that the aversive effects of THC are not mediated by KOR activity as assessed by the CTA design in Sprague-Dawley rats.

Measures of the aversive effects of drugs: A comparison of conditioned taste and place aversions.

The present experiments directly compared the ability of the conditioned taste and place aversion designs (CTA and CPA, respectively) to measure the aversive effects of lithium chloride (LiCl) in male Sprague-Dawley rats. In the CTA assessment (Experiment 1), rats were given one of two novel tastes paired with LiCl (0, 0.18, 0.32, 0.56 or 1mEq/kg) and the alternate novel taste paired with vehicle the next day. This was repeated three times, followed by a final two-bottle test. In the CPA assessment (Experiment 2), rats were given LiCl at the same doses and placed on one side of an unbiased two-chambered apparatus, followed by vehicle injection and placement on the opposite side on alternating days. This was repeated three times followed by free access to both sides in an assessment of relative preference. LiCl induced robust, dose-dependent taste aversions with rats receiving 0.32mEq/kg or greater consuming a smaller percentage of the drug-paired taste than that of controls. LiCl did not induce place aversions at any dose with LiCl- and vehicle-treated subjects displaying comparable preferences for the drug-paired side. The basis for the differences of the two designs in indexing LiCl's aversive effects was discussed.

Effect of preexposure on methylphenidate-induced taste avoidance and related BDNF/TrkB activity in the insular cortex of the rat.

RATIONALE: Exogenous brain-derived neurotrophic factor (BDNF) in the insular cortex (IC) is known to influence conditioned taste avoidance (CTA) learning, but little is known of its endogenous role in the phenomenon. Preexposure to many abusable compounds attenuates their ability to induce CTA, thus providing a possible platform from which to further elucidate the endogenous role of IC BDNF in CTA. OBJECTIVES: The role of IC BDNF in CTA learning was examined by assessing the effect of preexposure to methylphenidate (MPH) on MPH-induced CTA, followed by expression between preexposure groups of BDNF in the IC, central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). METHODS: Following preexposure to MPH (18 mg/kg), CTAs induced by MPH (0, 10, 18, and 32 mg/kg) were assessed in adult male Sprague-Dawley rats (n = 64). In separate groups (n = 31), differences in BDNF and tropomyosin-related kinase receptor-B (TrkB) were assessed using Western blots following similar preexposure and conditioning procedures. RESULTS: Preexposure to MPH significantly blunted MPH-CTA compared to preexposure to vehicle. Unexpectedly, there were no significant effects of MPH on BDNF activity following CTA, but animals preexposed to MPH exhibited decreased activity in the CeA and enhanced activity in the IC and NAc. CONCLUSIONS: Preexposure to MPH attenuates its aversive effects on subsequent presentations, and BDNF's impact on CTA learning may be dependent upon its temporal relation to other CTA-related intracellular cascades.