Adolescent amphetamine exposure elicits dose-specific effects on monoaminergic neurotransmission and behaviour in adulthood

International Journal of Neuropsychopharmacology (2012), 15, 1319–1330. f CINP 2011 doi:10.1017/S1461145711001544 ARTICLE Adolescent amphetamine exposure elicits dose-specific effects on monoaminergic neurotransmission and behaviour in adulthood Benoit Labonte1, Ryan J. McLaughlin1,2, Sergio Dominguez-Lopez1, Francis Rodriguez Bambico1, Ilaria Lucchino1,3, Rafael Ochoa-Sanchez1, Marco Leyton1 and Gabriella Gobbi1 1 Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada Department of Psychology, University of British Columbia, Vancouver, BC, Canada 3 Department of Physiology and Pharmacology, University ‘ La Sapienza ’, Rome, Italy 2 Abstract Despite the growing non-medical consumption of amphetamine (Amph) during adolescence, its long-term neurobiological and behavioural effects have remained largely unexplored. The present research sought to characterize the behavioural profile and electrophysiological properties of midbrain monoaminergic neurons in adult rodents after Amph exposure during adolescence. Adolescent rats were administered vehicle, 0.5, 1.5, or 5.0 mg/kg.d Amph from postnatal day (PND) 30–50. At adulthood (PND 70), rats were tested in an open-field test (OFT) and elevated plus maze (EPM), paralleled by in-vivo extracellular recordings of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) neurons from the dorsal raphe nucleus, ventral tegmental area, and locus coeruleus, respectively. 5-HT firing in adulthood was increased in rats that had received Amph (1.5 mg/kg.d) during adolescence. At this regimen, DA firing activity was increased, but not NE firing. Conversely, the highest Amph dose regimen (5.0 mg/kg.d) enhanced NE firing, but not DA or 5-HT firing rates. In the OFT, Amph (1.5 mg/kg.d) significantly increased the total distance travelled, while the other doses were ineffective. In the EPM, all three Amph doses increased time spent in the open arms and central platform, as well as the number of stretch-attend postures made. Repeated adolescent exposure to Amph differentially augments monoaminergic neuronal firing in a dose-specific fashion in adulthood, with corresponding alterations in locomotion, risk assessment (stretch-attend postures and central platform occupancy) and risk-taking behaviours (open-arm exploration). Thus, adolescent Amph exposure induces long-lasting neurophysiological alterations that may have implications for drug-seeking behaviour in the future. Received 1 August 2011 ; Reviewed 25 August 2011 ; Revised 12 September 2011 ; Accepted 16 September 2011 ; First published online 3 November 2011 Key words : Amphetamine, adolescence, drug abuse, in-vivo electrophysiology, monoamine. Introduction Amphetamine (Amph) and psychostimulants are among the most widely abused illicit drugs. The estimated percentage of adolescents who ever used Amph is 4.5 % in Canada, 10.3 % in the USA, and from 1 % to 9 % in Europe (UNODC, 2010). In the USA, fulltime college students who were non-medical users of Amph, compared to non-Amph users, showed a higher intake of other illicit drugs such as marijuana Address for correspondence : G. Gobbi, M.D., Ph.D., Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, QC H3A 1A1, Canada. Tel. : 514-398-1290 Fax : 514-398-4866 Email : and cocaine as well as higher consumption of alcohol, benzodiazepines and painkillers (SAaMHSAOoA, 2009). The behaviourally activating effects of Amph have long been thought to be due to its actions on the dopamine (DA) system (Creese & Iversen, 1974 ; Kalivas & Stewart, 1991 ; Sessions et al. 1980 ; Vanderschuren & Kalivas, 2000), although recent evidence suggests that norepinephrine (NE) and serotonin (5-HT) contribute also (Rothman & Baumann, 2006 ; Rothman et al. 2001). Interestingly, the locus coeruleus (LC), dorsal raphe nucleus (DRN), and ventral tegmental area (VTA), midbrain nuclei that are responsible for the output of NE, 5-HT, and DA, respectively, have been shown to interact with each other in an intricate manner (Guiard et al. 2008b). 1320 B. Labonte et al. Therefore, it might be expected that alterations in this complex network might be responsible for the behavioural effects induced by repeated Amph exposure. Adolescence is a critical developmental period characterized by neurobiological processes that profoundly influence behaviour later in adulthood. Adolescence also represents a period of increased impulsivity, risk taking, and novelty seeking, which further predisposes adolescents to seek out drugs of abuse (Spear, 2000). Indeed, the use of drugs usually begins during this developmental stage, with early use patterns predicting the development of substance use and mood disorders in adulthood (Chambers et al. 2003 ; Chen et al. 2009 ; Laviola et al. 1999). Repeated psychostimulant consumption during adolescence might interfere with this developmental neuroplasticity, leading to long-lasting behavioural alterations. Despite the growing use and misuse of Amph during adolescence, its long-term effects on monoaminergic signalling and emotional responding remain poorly understood. Only a handful of studies have examined the effects of adolescent psychostimulant exposure in adulthood, and in most instances these were following a priming injection of the psychostimulant, thus preventing any evaluation of basal responding in the absence of drug (Caster et al. 2005 ; Estelles et al. 2007). Moreover, studies examining the effect of adolescent Amph exposure on monoamine function have been largely restricted to analyses of extracellular release in terminal subfields (Kuczenski & Segal, 1997, 1989 ; Kuczenski et al. 1995) or immediate early gene induction in monoamine cell bodies (McPherson & Lawrence, 2006) ; no research to date has formally characterized the effect of adolescent Amph exposure on monoaminergic neural firing under psychostimulant-free conditions. Given this, the first objective of the present study was to characterize the long-term effects of repeated adolescent Amph administration on basal 5-HT, DA, and NE firing properties from the DRN, VTA, and LC, respectively. The second objective was to determine whether repeated adolescent Amph exposure significantly alters measures of emotionality and risk assessment in the elevated plus maze (EPM) and open field test (OFT). Method Animals Twelve pregnant Sprague–Dawley female rats (Charles River, Canada) were housed individually in polycarbonate cages and maintained under standard laboratory conditions [12-h light/dark cycle (lights on 07 : 30 hours), temperature 20¡2 xC]. Water and food were available ad libitum. All procedures were approved by the McGill University Animal Care Center and the Canadian Office of Controlled Substances. On postnatal day 21 (PND 21), male pups were weaned, and randomly divided into four groups of animals receiving 0.5, 1.5, or 5.0 mg/kg i.p. of d-amphetamine sulfate (Amph ; Sigma Aldrich, USA), or vehicle (0.9 % saline). Litterma (...truncated)