Kyle J. Frantz

Behavioral and neurochemical responses to cocaine in periadolescent and adult rats.

Although recreational drug use by human adolescents is a well-known and long-standing problem, relatively little is known regarding differences in behavioral and physiological responses to abused substances in adolescent vs adult animals. The present study compared effects of the psychomotor stimulant, cocaine, in periadolescent (postnatal days 37–52) and adult (postnatal days 75–90) male Wistar rats. Locomotion and motor stereotypy were recorded after acute and repeated cocaine injections (0, 10, or 20 mg/kg cocaine, intraperitoneal (i.p.), four injections spaced 5 days apart). Spontaneous acquisition of intravenous (i.v.) cocaine self-administration was investigated in two dose groups (∼0.37 or 0.74 mg/kg/infusion) over 14 days. Dopamine levels in the nucleus accumbens were recorded under basal conditions (no net flux method) and after cocaine administration (∼0.37, 0.74, and 2.92 mg/kg/i.v. infusion or 20 mg/kg i.p.) using in vivo microdialysis. The locomotor data are in partial agreement with previous reports of hyposensitivity to acute cocaine in periadolescent vs adult rats; periadolescents were less active overall than adults. Moreover, adult rats exhibited significant locomotor sensitization after repeated injection of 10 mg/kg cocaine, whereas periadolescents required the high dose of 20 mg/kg cocaine to demonstrate sensitization. Neither age group showed sensitization of motor stereotypies. No age-related difference was observed in acquisition of cocaine self-administration, or in basal or cocaine-stimulated nucleus accumbens dopamine. These experiments imply a developmental dissociation between the motor activating and reinforcing effects of cocaine. Similarities in dopamine levels across age groups suggest that age-specific motor responses to cocaine are not mediated by dopamine in the nucleus accumbens.

New perspectives on adolescent motivated behavior: Attention and conditioning

Adolescence is a critical transition period, during which fundamental changes prepare the adolescent for becoming an adult. Heuristic models of the neurobiology of adolescent behavior have emerged, promoting the central role of reward and motivation, coupled with cognitive immaturities. Here, we bring focus to two basic sets of processes, attention and conditioning, which are essential for adaptive behavior. Using the dual-attention model developed by Corbetta and Shulman (2002), which identifies a stimulus-driven and a goal-driven attention network, we propose a balance that favors stimulus-driven attention over goal-driven attention in youth. Regarding conditioning, we hypothesize that stronger associations tend to be made between environmental cues and appetitive stimuli, and weaker associations with aversive stimuli, in youth relative to adults. An attention system geared to prioritize stimulus-driven attention, together with more powerful associative learning with appetitive incentives, contribute to shape patterns of adolescent motivated behavior. This proposed bias in attention and conditioning function could facilitate the impulsive, novelty-seeking and risk-taking behavior that is typical of many adolescents.

Locomotion elicited by MK801 in developing and adult rats: temporal, environmental, and gender effects.

The effects of environmental novelty on locomotion elicited by an N-methyl-D-aspartate (NMDA) receptor antagonist, (+)MK-801 hydrogen maleate [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine], were investigated. Male and female rats aged 10, 20, 30 or 54-68 days were injected s.c. with MK801 and placed in activity monitors either immediately (no-delay) or after a 60 min delay (delay). In the no-delay condition, MK801 induced an inverse U-shaped dose-response effect on locomotion; peak activation occurred with 0.1 mg/kg and ataxia occurred with higher doses. The introduction of a novel environment 60 min after drug injection shifted the dose-effect function of MK801 to the left; i.e., in rats 20 days of age and older, the activity induced by 0.1 mg/kg MK801 was potentiated in the delay condition. For the 0.5 mg/kg dose, 20-day-olds showed activation in the no-delay condition but ataxia in the delay condition. This dose induced ataxia followed by activation in 30-day-olds and adult males or ataxia in adult females, regardless of delay condition. Age-, gender-, and novelty-dependent variations in MK801-induced locomotion may reflect differences in limbic-motor circuitry.

The locomotor effects of a putative dopamine D3 receptor agonist in developing rats

Dopamine receptors have been categorized into subfamilies D1 and D2, each with separate roles in dopamine-mediated behaviors. Of the D2 subfamily, the dopamine D3 receptor has been cloned, but the behavioral effects of selectively stimulating the D3 receptor are largely unknown. The purpose of this study was to quantify the locomotor responses of developing rats to the putative dopamine D3 receptor agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT). One of three doses of 7-OH-DPAT (0.01, 0.10, 1.00 mg/kg) or saline was injected subcutaneously into rats at the age of 10,20,30, or 60 days. Five minutes after the injection, rats were placed in automated activity monitors which recorded locomotor behavior at 5 min intervals for 2 h. The high dose of 7-OH-DPAT increased locomotor activity in rats of all ages. The medium and low doses increased activity in 10- and 20-day-old rats but not in 30- or 60-day-old rats. The level of drug-induced activation peaked at 20 days of age. In 30- and 60-day-old rats, but not 10- and 20-day-old rats, a period of locomotor suppression preceded the activation in response to the high dose of 7-OH-DPAT. In rats aged 20 days and older, the middle and low doses decreased locomotion early in the test session, but activation did not ensue. This dose-response pattern across ontogeny closely resembles that induced by quinpirole, an agonist at the dopamine D2 receptor subfamily.

The locomotor effects of quinpirole in rats depend on age and gender

Periadolescence in the rat [postnatal day (PND) 35-50] is an important but understudied period of neurobehavioral development. In this experiment, an ongoing survey of the effects of quinpirole in developing rats was completed by the addition of periadolescent rats to the range of ages tested. PND40 or 50 rats were injected subcutaneously with the dopamine D2/D3 receptor agonist, quinpirole (0.0, 0.02, 0.2, or 2.0 mg/kg), and their locomotor activity was recorded. Periadolescent rats showed adult-like locomotor responses to either the 0.2 or 2.0 mg/kg doses of quinpirole, i.e., the responses were biphasic with respect to time: early suppression of locomotion followed by later activation within a single test session. In younger female rats (PND40) but older male rats (PND50), the lowest dose of quinpirole suppressed activity early in the test session but did not increase it later. In male rats, the magnitude of locomotor activation declined with age. Taken together with previous data from this laboratory, these results suggest that periadolescent rats exhibit locomotor responses that fall along a continuum from a high level of activation just after weaning to a low level of activation in early adulthood.

Age-dependent morphine intake and cue-induced reinstatement, but not escalation in intake, by adolescent and adult male rats.

Despite increasing rates of opioid abuse by human adolescents, few laboratory experiments address adolescent vulnerability to opiates. We examined intravenous morphine self-administration after adolescent- vs. adult-onset, followed by extinction and cue-induced reinstatement. Adolescent male Sprague-Dawley rats [postnatal day (P) 35 at start] and adults (P91) acquired lever pressing maintained by 0.375 mg/kg/infusion morphine on a fixed ratio one schedule of reinforcement. Subjects were subsequently divided into short or long daily access conditions (ShAcc, 1-h vs. LgAcc, 8-h; 18 sessions). After extinction, cue-induced reinstatement was recorded over 1 h. During the first six 1-h acquisition sessions and continuing throughout ShAcc conditions, adolescent-onset rats self-administered less morphine than adults, an effect commonly interpreted as higher drug sensitivity. In contrast under LgAcc conditions, escalation of morphine intake was similar across ages. Extinction of drug-seeking was similar across ages, although rats from LgAcc conditions pressed more than ShAcc conditions. Notably, cue-induced reinstatement was less robust in rats that began morphine self-administration during adolescence vs. adulthood. Although increased sensitivity of younger rats to morphine reinforcement under ShAcc conditions might help explain opioid abuse by human adolescents, lower rates of reinstatement in younger rats might suggest that adolescent development includes some protective factors that dampen the long-term impact of early drug intake.

The locomotor effects of MK801 in the nucleus accumbens of developing and adult rats.

This developmental study was an investigation of locomotion induced by the NMDA receptor antagonist, (+)MK-801 hydrogen maleate [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine], at doses of 0, 3 or 10 microg injected bilaterally into the nucleus accumbens of rats at 11, 21, 31, or 61-66 days of age. During a 2-h test session, only a few 11-day-old pups responded to either dose of MK801; they displayed short bouts of obstinate progression. In contrast, 21- and 31-day-olds were not affected by 3 microg MK801 but exhibited robust activation after 10 microg MK801. The activation was greatest in 21-day-olds and also occurred after mid-striatal injections in 21- but not 31-day-old rats. Adult rats injected with MK801 were not robustly activated, but they maintained their initial level of activity throughout the test session, instead of habituating to the test monitor, as controls did. Ontological changes in MK801-induced activity are likely to reflect maturation of glutamate transmission in the nucleus accumbens.

Effects of the putative dopamine D3 receptor antagonist PNU 99194A on motor behavior and emotional reactivity in C57BL/6J mice

Due to the regional expression of D3 dopamine receptors in limbic areas of the brain, there has been considerable interest in the potential role of this receptor subtype in mediating emotional behavior. Previous studies in habituated rats have shown that the putative dopamine D3 receptor antagonist 5,6-dimethoxy-2-(di-n-propylamino)indan (PNU 99194A) increased locomotor behavior. The present study examined the effects PNU 99194A on motor and emotional behaviors in C57BL/6J mice. Motor behavior was assessed in both habituated and nonhabituated mice. Emotional behavior was assessed using the elevated plus-maze and a social context involving an isolated C57BL/6J mouse and a nonaggressive conspecific. In mice habituated to the activity chamber prior to drug administration, PNU 99194A increased locomotion and rearing at lower doses (5, 10 mg/kg) whereas higher doses (20, 30 mg/kg) reduced these behaviors early in the test session. Thigmotaxis was increased independently of the effects on motor behavior. In mice exposed to the activity chamber for the first time, PNU 99194A produced a weak motor activation at lower doses and an initial decrease in motor behavior at higher doses that was followed by an increase in locomotion later in the test session. PNU 99194A had no systematic effects on activity in the elevated plus-maze, but dose-dependently increased flight reactivity in the social reactivity paradigm. These and previous findings raise questions about the role of dopamine D3 receptors in mediating motor behavior and emotional reactivity as well as the pharmacology of this putative dopamine D3 receptor antagonist.

A Role For The Prefrontal Cortex In Heroin-Seeking After Forced Abstinence By Adult Male Rats But Not Adolescents

Adolescent drug abuse is hypothesized to increase the risk of drug addiction. Yet male rats that self-administer heroin as adolescents show attenuated drug-seeking after abstinence, compared with adults. Here we explore a role for neural activity in the medial prefrontal cortex (mPFC) in age-dependent heroin-seeking. Adolescent (35-day-old at start; adolescent-onset) and adult (86-day-old at start) male rats acquired lever-pressing maintained by heroin using a fixed ratio one reinforcement schedule (0.05 and 0.025 mg/kg per infusion). Following 12 days of forced abstinence, rats were tested for heroin-seeking over 1 h by measuring the number of lever presses on the active lever. Unbiased stereology was then used to estimate the number of Fos-ir+ and Fos-ir− neurons in prelimbic and infralimbic mPFC. As before, adolescents and adults self-administered similar amounts of heroin, but subsequent heroin-seeking was attenuated in the younger rats. Similarly, the adolescent-onset group failed to show significant neural activation in the prelimbic or infralimbic mPFC during the heroin-seeking test, whereas the adult-onset heroin self-administration group showed two to six times more Fos-ir+ neurons than their saline counterparts in both mPFC subregions. Finally, the overall number of neurons in the infralimbic cortex was greater in rats from the adolescent-onset groups than adults. The mPFC may thus have a key role in some age-dependent effects of heroin self-administration.

Time-dependent increases in cue-induced reinstatement of sucrose seeking after sucrose self-administration in adolescence.

Previously we reported that time-dependent increases in cue-induced reinstatement of cocaine seeking were attenuated in rats self-administering cocaine as adolescents, compared with adults (Li and Frantz (2009)). Now using sucrose self-administration, we report time-dependent increases in cue-induced reinstatement of sucrose seeking are similar across age groups, suggesting that age differences in reinstatement of cocaine seeking depend on specific effects of cocaine, not a compromised ability among younger rats to associate cues with rewards.