ABSTRACT
Previous findings showed allocentric and egocentric learning deficits in rats after MDMA treatment from postnatal days (PD) 11-20 but not after treatment from PD 1-10. Shorter treatment periods (PD 1-5, 6-10, 11-15, or 16-20) resulted in allocentric learning deficits averaged across intervals but not for any interval individually and no egocentric learning deficits individually or collectively. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. In the present experiment rat litters were treated on PD 1-10, 6-15, or 11-20 with 0, 10, or 15 mg/kg MDMA q.i.d. at 2-h intervals. Two male/female pairs/litter received each treatment. One pair/litter received acoustic startle with prepulse inhibition, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent inhibition paradigm. The other pair/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity retest with MK-801 challenge. MDMA impaired CWM learning following PD 6-15 or 11-20 exposure. In MWM acquisition, all MDMA-treated groups showed impairment. During reversal and shift, the PD 6-15 and PD 11-20 MDMA-treated groups were significantly impaired. Reductions in locomotor activity were most evident after PD 6-15 treatment while increases in acoustic startle were most evident after PD 1-10 treatment. After MK-801 challenge, MDMA-treated offspring showed less locomotion compared to controls. Region-specific changes in brain monoamines were also observed but were not significantly correlated with behavioural changes. The results show that PD 11-20 exposure to MDMA caused the largest long-term cognitive deficits followed by PD 6-15 exposure with PD 1-10 exposure least affected. Other effects, such as those upon MK-801-stimulated locomotion showed greatest effects after PD 1-10 MDMA exposure. Hence, each effect has a different window of developmental susceptibility.
Subject(s)
Aging/drug effects , Aging/physiology , Behavior, Animal/drug effects , Biogenic Monoamines/metabolism , Hallucinogens/pharmacology , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , Acoustic Stimulation , Animals , Animals, Newborn , Body Weight/drug effects , Conditioning, Psychological/drug effects , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Fear/drug effects , Female , Inhibition, Psychological , Male , Maze Learning/drug effects , Mortality , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Reflex, Startle/drug effects , Swimming/psychologyABSTRACT
Developmental exposure to the dopamine D2/3 receptor agonist quinpirole is reported to induce D2 priming, impair Morris water maze performance, reduce acoustic startle prepulse inhibition (PPI), and alter locomotor activity. We treated rats from postnatal days 1-21 with the dose reported to induce these effects, 1.0 mg/kg/day, and two higher doses, 2.0 and 4.0 mg/kg/day, or saline. Offspring were tested in the Morris water maze, PPI, exploratory locomotor activity, activity after quinpirole and (+)-methamphetamine challenge, elevated zero maze, light-dark box, marble burying, straight channel swimming, and Cincinnati water maze. In the Morris water maze, all quinpirole groups had longer latencies on test days 3-5 of acquisition, but no effects on reversal or shifted-reduced platform trials. The quinpirole 4.0 mg/kg group had significantly reduced mean search distances on probe trials when combined across the 3 phases of testing but not separately. The male 4.0 mg/kg quinpirole group showed a greater increase in methamphetamine-stimulated activity during the first 10 min after drug challenge but not in the remainder of the 2 h test. No quinpirole effects were found for light-dark box, marble burying, exploratory locomotor activity, straight channel, Cincinnati water maze, or locomotor activity after quinpirole challenge. No effects were found on most measures in the elevated zero maze however the quinpirole 4.0 mg/kg females had longer latencies to enter an open quadrant. The results partially support prior Morris maze deficits induced by developmental quinpirole treatment but little evidence of dopamine D2/3 priming was found using locomotor activity with quinpirole or methamphetamine challenge or acoustic startle/PPI. The limited comparability to published data using developmental quinpirole exposure may be attributable to differences in experimental procedures or may be the result of quinpirole having limited effects. The data suggest that caution is warranted concerning the developmental efficacy of quinpirole.
