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1.
Psychopharmacology (Berl) ; 237(8): 2469-2483, 2020 Aug.
Article En | MEDLINE | ID: mdl-32445054

RATIONALE: MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral effect ultimately relies on monoamine neurotransmission is of dispute. OBJECTIVE: The purpose of this study was to determine whether these psychopharmacological effects and underlying neural mechanisms vary according to sex and age. METHODS: Across four experiments, male and female preweanling and adolescent rats were pretreated with vehicle, the monoamine-depleting agent reserpine (1 or 5 mg/kg), the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), or both AMPT and PCPA. The locomotor activity of preweanling and adolescent rats was then measured after saline or MK801 (0.3 mg/kg) treatment. RESULTS: As expected, MK801 increased the locomotor activity of all age groups and both sexes, but the stimulatory effects were significantly less pronounced in male adolescent rats. Preweanling rats and adolescent female rats were more sensitive to the effects of DA and 5-HT synthesis inhibitors, as AMPT and PCPA caused only small reductions in the MK801-induced locomotor activity of male adolescent rats. Co-administration of AMPT+PCPA or high-dose reserpine (5 mg/kg) treatment substantially reduced MK801-induced locomotor activity in both age groups and across both sexes. CONCLUSIONS: These results, when combined with other recent studies, show that NMDA receptor open-channel blockers cause pronounced age-dependent behavioral effects that can vary according to sex. The neural changes underlying these sex and age differences appear to involve monoamine neurotransmission.


Dizocilpine Maleate/pharmacology , Dopamine/physiology , Excitatory Amino Acid Antagonists/pharmacology , Locomotion/physiology , Serotonin/physiology , Sexual Maturation/physiology , Adrenergic Uptake Inhibitors/pharmacology , Age Factors , Animals , Animals, Newborn , Dopamine Antagonists/pharmacology , Female , Locomotion/drug effects , Male , Rats , Rats, Sprague-Dawley , Serotonin Antagonists/pharmacology , Sex Factors , Sexual Maturation/drug effects
2.
Behav Brain Res ; 379: 112267, 2020 02 03.
Article En | MEDLINE | ID: mdl-31593789

Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d-amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.


Behavior, Animal/drug effects , Biogenic Monoamines/metabolism , Excitatory Amino Acid Antagonists/pharmacology , Ketamine/pharmacology , Locomotion/drug effects , Neurotransmitter Uptake Inhibitors/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Synaptic Transmission/drug effects , Adrenergic Uptake Inhibitors/pharmacology , Age Factors , Animals , Cocaine/pharmacology , Dextroamphetamine/metabolism , Dopamine Uptake Inhibitors/pharmacology , Drug Interactions , Excitatory Amino Acid Antagonists/administration & dosage , Female , Ketamine/administration & dosage , Male , Neurotransmitter Uptake Inhibitors/administration & dosage , Rats , Rats, Sprague-Dawley , Reserpine/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Sex Characteristics
3.
Behav Brain Res ; 379: 112302, 2020 02 03.
Article En | MEDLINE | ID: mdl-31655095

The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2 h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40 mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism.


Central Nervous System Stimulants/pharmacology , Cocaine/pharmacology , Dextroamphetamine/pharmacology , Dopamine Agents/pharmacology , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Fenclonine/analogs & derivatives , Ketamine/pharmacology , Locomotion/drug effects , Serotonin Agents/pharmacology , alpha-Methyltyrosine/pharmacology , Age Factors , Animals , Behavior, Animal/drug effects , Central Nervous System Stimulants/administration & dosage , Cocaine/administration & dosage , Dextroamphetamine/administration & dosage , Dopamine Agents/administration & dosage , Drug Interactions , Enzyme Inhibitors/administration & dosage , Excitatory Amino Acid Antagonists/administration & dosage , Female , Fenclonine/administration & dosage , Fenclonine/pharmacology , Ketamine/administration & dosage , Male , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Serotonin Agents/administration & dosage , alpha-Methyltyrosine/administration & dosage
4.
Psychopharmacology (Berl) ; 235(7): 1967-1980, 2018 07.
Article En | MEDLINE | ID: mdl-29671013

RATIONALE: Ontogenetic differences in the behavioral responsiveness to cocaine have often been attributed to the maturation of dopaminergic elements (e.g., dopamine transporters, D2High receptors, receptor coupling, etc.). OBJECTIVE: The purpose of this study was to determine whether ontogenetic changes in cocaine pharmacokinetics might contribute to age-dependent differences in behavioral responsiveness. METHODS: Male and female neonatal (PD 5), preweanling (PD 10 and PD 20), and adult (PD 70) rats were injected (IP) with cocaine or saline and various behaviors (e.g., locomotor activity, forelimb paddle, vertical activity, head-down sniffing, etc.) were measured for 90 min. In a separate experiment, the dorsal striata of young and adult rats were removed at 10 time points (0-210 min) after IP cocaine administration. Peak cocaine values, cocaine half-life, and dopamine levels were determined using HPLC. RESULTS: When converted to percent of saline controls, PD 5 and PD 10 rats were generally more sensitive to cocaine than older rats, but this effect varied according to the behavior being assessed. Peak cocaine values did not differ according to age or sex, but cocaine half-life in brain was approximately 2 times longer in PD 5 and PD 10 rats than adults. Cocaine pharmacokinetics did not differ between PD 20 and PD 70 rats. CONCLUSIONS: Differences in the cocaine-induced behavioral responsiveness of very young rats (PD 5 and PD 10) and adults may be attributable, at least in part, to pharmacokinetic factors; whereas, age-dependent behavioral differences between the late preweanling period and adulthood cannot readily be ascribed to cocaine pharmacokinetics.


Cocaine/pharmacokinetics , Corpus Striatum/drug effects , Dopamine Uptake Inhibitors/pharmacokinetics , Motor Activity/drug effects , Age Factors , Animals , Animals, Newborn , Behavior, Animal/drug effects , Behavior, Animal/physiology , Corpus Striatum/metabolism , Dopamine/pharmacology , Dopamine Antagonists/pharmacology , Female , Male , Motor Activity/physiology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/physiology
5.
Psychopharmacology (Berl) ; 234(18): 2683-2696, 2017 Sep.
Article En | MEDLINE | ID: mdl-28589265

RATIONALE: Ketamine is used by preadolescent and adolescent humans for licit and illicit purposes. OBJECTIVE: The goal of the present study was to determine the effects of acute and repeated ketamine treatment on the unconditioned behaviors and conditioned locomotor activity of preadolescent and adolescent rats. METHODS: To assess unconditioned behaviors, female and male rats were injected with ketamine (5-40 mg/kg), and distance traveled was measured on postnatal day (PD) 21-25 or PD 41-45. To assess conditioned activity, male and female rats were injected with saline or ketamine in either a novel test chamber or the home cage on PD 21-24 or PD 41-44. One day later, rats were injected with saline and conditioned activity was assessed. RESULTS: Ketamine produced a dose-dependent increase in the locomotor activity of preadolescent and adolescent rats. Preadolescent rats did not exhibit sex differences, but ketamine-induced locomotor activity was substantially stronger in adolescent females than males. Repeated ketamine treatment neither caused a day-dependent increase in locomotor activity nor produced conditioned activity in preadolescent or adolescent rats. CONCLUSIONS: The activity-enhancing effects of ketamine are consistent with the actions of an indirect dopamine agonist, while the inability of ketamine to induce conditioned activity is unlike what is observed after repeated cocaine or amphetamine treatment. This dichotomy could be due to ketamine's ability to both enhance DA neurotransmission and antagonize N-methyl-D-aspartate (NMDA) receptors. Additional research will be necessary to parse out the relative contributions of DA and NMDA system functioning when assessing the behavioral effects of ketamine during early ontogeny.


Anesthetics, Dissociative/pharmacology , Conditioning, Psychological/drug effects , Dopamine Agonists/pharmacology , Ketamine/pharmacology , Locomotion/drug effects , Age Factors , Animals , Conditioning, Psychological/physiology , Dose-Response Relationship, Drug , Female , Locomotion/physiology , Male , Rats , Rats, Sprague-Dawley , Sex Factors
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