Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory in rats

https://doi.org/10.1016/j.bbr.2020.112659Get rights and content

Highlights

  • Females and adolescent-onset rats escalate METH intake more than their counterparts.

  • Self-administration history did not impact novel objection recognition memory.

  • mPFC D1R or GluN2B receptor expression was not altered by adolescent-onset METH use.

Abstract

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h self-administration sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (NOR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats with a history of METH self-administration exhibited modest deficits in OiP compared to their adult-onset counterparts, but there was no sex difference and self-administration groups did not differ from naïve control rats. All rats displayed intact novel object recognition memory. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and modest dysfunction in PFC-dependent cognition.

Introduction

Most drug use begins during adolescence and those who initiate their use earlier in life appear to experience worse outcomes compared to those who start late in adolescence or during adulthood. For example, earlier onset of cocaine and other drug use has been associated with greater deficits in cognition in a battery of neuropsychological tests, a higher risk for psychosocial problems, and an increased risk for substance use disorder (SUD; [[1], [2], [3]]). Female users also tend to experience worse outcomes, including a more rapid transition from initial to problematic drug use [[4], [5], [6]]. Use of amphetamines, and especially the methylated derivative, methamphetamine (METH), may be particularly problematic for these populations. Compared to males, females tend to initiate METH use earlier, are more sensitive to its acute behavioral and subjective effects, are more likely to have psychiatric problems associated with their drug use, and have worse treatment outcomes [[7], [8], [9], [10]]. In laboratory rats, females [11] and those beginning drug use during adolescence [12] develop compulsive-like METH seeking more readily as evidenced by greater and more rapid escalation of METH intake during extended access self-administration sessions. Together, these studies suggest that age-of-onset and sex may be factors that confer vulnerability to adverse outcomes of METH use, including a greater likelihood to develop compulsive METH-taking behavior and a heightened susceptibility to METH-induced cognitive dysfunction.

One hypothesized explanation for this heightened vulnerability is that drug use early in life may induce delays or other significant perturbations in normal brain development. METH, like nearly all other drugs of abuse, has potent effects in corticolimbic brain regions, such as the nucleus accumbens and prefrontal cortex (PFC). These regions continue to reorganize and mature throughout late childhood and adolescence, with the PFC not reaching its mature, adult-like state until individuals are in their mid- to late twenties [13]. Moreover, this continued development is protracted compared to subcortical regions such as the nucleus accumbens [14]. Studies using rodent models of adolescence have revealed a developmental shift in dopamine and glutamate signaling that occurs during adolescence. Specifically, dopamine D1 receptor (D1R) expression on PFC projections to the accumbens peaks during adolescence before pruning and relative decreases in expression occur as rats reach adulthood [15]. This D1R remodeling may precede the late adolescent emergence of GluN2B-containing NMDA receptor transmission in the PFC, which has been shown to be mediated by D1R signaling [16]. These ontogenetic changes are likely important mechanisms for developing adult-like cognition. In adults, intact D1R and NMDAR transmission in the medial prefrontal cortex (mPFC) are needed for certain forms of recognition memory. Pharmacological blockade of D1Rs in the mPFC impaired object-in-place (OiP) recognition memory, while sparing both novel object (NOR) and object location recognition memory [17]. Non-selective NMDAR blockade in the mPFC impairs OiP [18]. Although the role of different NMDAR subunits in OiP memory is not entirely clear, GluN2B function in the PFC has been implicated in working memory [19]. Thus, drugs of abuse taken during adolescence may disrupt the ontogeny of D1R and/or GluN2B signaling in the developing PFC leading to greater deficits in OiP memory compared to adult-onset drug use, while sparing NOR memory.

Exposure to amphetamines during adolescence has been shown to influence the development of certain aspects of dopamine and glutamate signaling, and in turn cognitive functioning, though most of the published work to date has investigated age-of-onset or sex separately. In male rodents exposed to amphetamine non-contingently during adolescence, presynaptic sites on dopamine fiber inputs into the PFC are significantly reduced [20,21], and dopamine-mediated inhibition of pyramidal cells in the PFC is significantly impaired at four- and twelve weeks after the last drug injection [22,23]. We have previously reported that these drug-induced neuroadaptations in the dopamine system are region specific, with reduced expression of D1Rs in the mPFC but no change in the NA after adolescent AMPH exposure [24]. Moreover, the drug-induced changes in pyramidal cell function are associated with significant disruptions in cognitive function, including impaired working memory [25], reduced impulse control [26] and reductions in behavioral flexibility [27]. A more recent study that examined the potential for age of exposure-dependent effects of METH on conditioned fear learning and extinction used only male rats and found adult-exposed animals to have deficits in extinction retrieval that were not apparent in their adolescent-exposed counterparts [28]. The impact of adolescent amphetamine exposure on glutamate signaling has not been published to date, but a recent study demonstrated reduced expression of phosphorylated GluN2B in the infralimbic PFC after adolescent cocaine exposure in male rats [29]. Notably, most of the aforementioned studies employed non-contingent experimenter administered injections, and it is currently unknown whether psychostimulant-induced reductions in PFC D1Rs and GluN2B expression occur with contingent drug-taking during adolescence. Moreover, since most of these studies assessed adolescent drug exposure without including an adult-exposed comparison group, it is unclear whether observed adaptations are due to disruptions in the developmentally regulated processes specific to adolescence, or if they occur regardless of age of drug exposure.

The current study sought to address these gaps by using a methamphetamine (METH) self-administration paradigm to investigate the hypothesis that adolescent-onset METH-taking would disrupt the ontogenetic trajectories of D1R and GluN2B in the PFC in a sex-dependent fashion. To this end, we trained Sprague-Dawley rats of both sexes to self-administer METH or a non-drug reinforcer, saccharin, under short access (ShA) conditions beginning during adolescence or adulthood, followed by an extended period of long access (LgA) METH self-administration. One and two weeks following cessation of self-administration, rats were tested on object recognition memory tasks to assess METH-induced memory impairments. Seven days later, tissue was collected to assess NMDAR subunits and D1R protein expression in the PFC and NA. In line with previous work [11,12], we hypothesized that females and adolescent-onset rats would escalate their METH intake more rapidly during LgA compared to their male and adult-onset counterparts. Importantly, if METH-taking during adolescence indeed disrupted the ontogeny of D1R and GluN2B function in the PFC, we expected that adolescent-onset rats would experience greater deficits in PFC-dependent recognition memory and display greater reductions in D1R and GluN2B protein expression in the PFC, with no changes in the NA, as we found previously [24]. We further predicted that these METH-induced neuroadaptations may be more pronounced in females. Finally, we hypothesized that the effects would be specific to METH as a reinforcer, such that these patterns would not be evident in rats that self-administered the non-drug reinforcer, saccharin.

Section snippets

Subjects

Subjects were a total of 81 male and 84 female Sprague-Dawley rats that were born in-house on postnatal day (P) 1 from breeders originally obtained from Envigo (Indianapolis, IN, USA). Several rats were lost from the study due to issues with catheter patency (adolescent: males = 5, females = 3; adult: males = 3, females = 1), illness (adolescent: males = 3, females = 5), or other technical problems (adolescent females n = 2; adult: male n = 1; females = 1), yielding final subject totals of 69

Body weights

Separate two-way ANOVAs by sex and age-of-onset revealed significant main effects of postnatal day [Adolescent-onset: females F(49,1262) = 90.08, p < 0.0001; Adult-onset: males F(45,1211) = 9.12, p < 0.0001, females F(45,1435) = 5.27, p < 0.0001], which was due to the expected weight gain as Sprague-Dawley rats age under ad libitum access to food (Fig. 2). In adolescent-onset males, two-way ANOVA revealed a significant reinforcer by postnatal day interaction [F(49,1167) = 1.58, p = 0.0076,

Discussion

Adolescence is characterized by considerable development of D1R and GluN2B neurotransmission in the PFC [15,16,43], which may constitute a window of vulnerability to drug-induced neuroadaptations [44,45]. This vulnerability may partly explain why adolescent-onset drug users suffer worse outcomes of their drug use compared to adult-onset users. We tested this hypothesis in the current study by investigating PFC-dependent cognition and receptor expression in rats with a history of METH or

Funding

This work was supported by funding from the National Institutes of Health (DA 029815), the University of Illinois Campus Research Board, and an National Science Foundation Research Experiences for Undergraduates award (NSF REU award) (1559908/1559929).

Declaration of Competing Interest

All authors report they have no conflicts of interest.

Acknowledgements

The authors thank Jessica Alvarez (supported by an NSF/REU award), Erika Carlson, Qingrou (JoJo) Gu, Kate Hamblen, Kristen Hughes, Adrianna Jelen, Shawn Kurian, Karen Lai, Jacob O’Russa, Sarah Rahman, Brittany Rhed, Tugba Serbest, and Ashley Wehrheim for excellent technical assistance. Experimental data and representative band images for all groups can be found on our project portal on the Open Science Framework (https://osf.io/bv7yk/).

References (73)

  • K. Paul et al.

    Repeated exposure to amphetamine during adolescence alters inhibitory tone in the medial prefrontal cortex following drug re-exposure in adulthood

    Behav. Brain Res.

    (2016)
  • S. Kang et al.

    D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence

    Neuroscience

    (2016)
  • S. Kang et al.

    Timing of amphetamine exposure in relation to puberty onset determines its effects on anhedonia, exploratory behavior, and dopamine D1 receptor expression in young adulthood

    Neuroscience

    (2016)
  • L.K. Sherrill et al.

    Age-dependent effects of repeated amphetamine exposure on working memory in rats

    Behav. Brain Res.

    (2013)
  • L.R. Hammerslag et al.

    Effects of amphetamine exposure in adolescence or young adulthood on inhibitory control in adult male and female rats

    Behav. Brain Res.

    (2014)
  • E.R. Hankosky et al.

    Age of exposure-dependent effects of amphetamine on behavioral flexibility

    Behav. Brain Res.

    (2013)
  • S.A. Jablonski et al.

    Determinants of novel object and location recognition during development

    Behav. Brain Res.

    (2013)
  • S.L. Dix et al.

    Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition

    Behav. Brain Res.

    (1999)
  • A.I. Ramsaran et al.

    Ontogeny of object-in-context recognition in the rat

    Behav. Brain Res.

    (2016)
  • J.M. Gulley et al.

    The effects of abused drugs on adolescent development of corticolimbic circuitry and behavior

    Neuroscience

    (2013)
  • P. Melo et al.

    Methamphetamine mimics the neurochemical profile of aging in rats and impairs recognition memory

    Neurotoxicology

    (2012)
  • C.M. Reichel et al.

    Methamphetamine-induced changes in the object recognition memory circuit

    Neuropharmacology

    (2012)
  • N. Liu et al.

    Single housing-induced effects on cognitive impairment and depression-like behavior in male and female mice involve neuroplasticity-related signaling

    Eur. J. Neurosci.

    (2019)
  • O. Ben-shahar et al.

    Changes in levels of D1, D2, or NMDA receptors during withdrawal from brief or extended daily access to IV cocaine

    Brain Res.

    (2007)
  • C.M. Reichel et al.

    Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate N-methyl-d-aspartate receptor expression

    Drug Alcohol Depend.

    (2014)
  • K. Sarantis et al.

    Synergistic interactions of dopamine D1 and glutamate NMDA receptors in rat hippocampus and prefrontal cortex: involvement of ERK1/2 signaling

    Neuroscience

    (2009)
  • J. McKellar et al.

    Pretreatment and during treatment risk factors for dropout among patients with substance use disorders

    Addict. Behav.

    (2006)
  • S.L. Simon et al.

    The effect of relapse on cognition in abstinent methamphetamine abusers

    J. Subst. Abuse Treat.

    (2004)
  • A. Poudel et al.

    Age of onset of substance use and psychosocial problems among individuals with substance use disorders

    BMC Psychiatry

    (2017)
  • N.J. Piazza et al.

    Telescoping of alcoholism in women alcoholics

    Int. J. Addict.

    (1989)
  • L.M. Mayo et al.

    Gender differences in the behavioral and subjective effects of methamphetamine in healthy humans

    Psychopharmacology (Berl.)

    (2019)
  • C.M. Reichel et al.

    Sex differences in escalation of methamphetamine self-administration: cognitive and motivational consequences in rats

    Psychopharmacology (Berl.)

    (2012)
  • J.N. Giedd

    Structural magnetic resonance imaging of the adolescent brain

    Ann. N. Y. Acad. Sci.

    (2004)
  • K.L. Mills et al.

    The developmental mismatch in structural brain maturation during adolescence

    Dev. Neurosci.

    (2014)
  • H.C. Brenhouse et al.

    Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence

    J. Neurosci.

    (2008)
  • G. Savalli et al.

    Regionally selective requirement for D1/D5 dopaminergic neurotransmission in the medial prefrontal cortex in object-in-place associative recognition memory

    Learn. Mem.

    (2015)
  • Cited by (0)

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