Neonatal -methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor ...
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International Journal of Neuropsychopharmacology (2013), 16, 377–391. f CINP 2012 ARTICLE
doi:10.1017/S1461145712000144
Neonatal (+)-methamphetamine exposure in
rats alters adult locomotor responses to
dopamine D1 and D2 agonists and to a glutamate
NMDA receptor antagonist, but not to serotonin
agonists
Devon L. Graham, Robyn M. Amos-Kroohs, Amanda A. Braun, Curtis E. Grace,
Tori L. Schaefer, Matthew R. Skelton, Michael T. Williams and Charles V. Vorhees
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Division of Neurology, Cincinnati Children’s Research Foundation, Cincinnati, OH and Department of Pediatrics,
University of Cincinnati College of Medicine, Cincinnati, OH, USA
Abstract
Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but
its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal
days (PD) 11–20 (stage that approximates human development from the second to third trimester) with
Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge
doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to
Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1
agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist
quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-D-aspartic acid
(NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge
with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the
first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and
glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many
of its long-term adverse effects.
Received 6 September 2011 ; Reviewed 5 October 2011 ; Revised 6 January 2012 ; Accepted 30 January 2012 ;
First published online 6 March 2012
Key words : Development, locomotor activity, methamphetamine, MK-801, p-chloroamphetamine,
quinpirole, quipazine, SKF82958.
Introduction their primary drug of abuse, up from 8 % in 1994
(Terplan et al. 2009). Effects in exposed children
The majority of methamphetamine (Meth) users are of
documented thus far include reduced birth weight,
reproductive age (Kuczkowski, 2007 ; Substance
height and head circumference (Chomchai et al. 2004 ;
Abuse & Mental Health Services Administration,
Dixon & Bejar, 1989 ; Little et al. 1988 ; Smith et al.
2009). Since approximately half are women and some
2008) and withdrawal symptoms shortly after birth
are pregnant, the likelihood is high that some children
(Chomchai et al. 2004 ; Dixon, 1989 ; Oro & Dixon,
are exposed in utero to Meth, yet the consequences of
1987). Later changes include growth reduction (Smith
such exposures are largely unknown. A recent study
et al. 2003), neuroanatomical changes shown with
found that, among pregnant women seeking treatment
magnetic resonance imaging (Chang et al. 2004 ; Cloak
in 2006, nearly one in four (24 %) reported Meth as
et al. 2009), elevated physiological stress (Smith et al.
2008) and learning and memory deficits (Chang et al.
Address for correspondence : C. V. Vorhees, PhD, Division of
2009 ; Struthers & Hansen, 1992).
Neurology (MLC 7044), Cincinnati Children’s Research Foundation,
3333 Burnet Ave., Cincinnati, OH 45229-3039, USA.
We developed a preclinical model of mid- to late-
Tel. : 513 636 8622 Fax : 513 636 3912 prenatal exposure that shows related findings.
Email : charles.vorhees@cchmc.org Developmental Meth exposure in rats also causes378 D. L. Graham et al.
weight reductions, elevated physiological stress and brain (Scheetz & Constantine-Paton, 1994). NMDA
learning and memory deficits (Grace et al. 2008 ; receptors have been implicated in the maturation of
Vorhees et al. 1994, 2007, 2008, 2009 ; Williams et al. cortical circuitry (Grutzendler et al. 2002) as well as the
2002, 2003a, b, c). The most sensitive exposure period stabilization of synaptic connections (Parrish et al.
for these effects is post-natal days (PD) 11–20, an in- 2007) and contribute to Meth neurotoxicity in mice
terval that corresponds to late second to third tri- (Sonsalla et al. 1998). As with 5-HT receptors, little is
mester in humans based on neurogenesis rates across known about how developmental Meth exposure
species (Clancy et al. 2001, 2007a, b ; Rice & Barone, alters NMDA levels or function. However, studies by
2000). However, the mechanisms that lead to cognitive Slamberova and colleagues have demonstrated that
deficits remain unknown. early exposure to Meth results in increased sensitivity
A number of neurotransmitters and their receptors to NMDA-induced seizures later in life (Slamberova
have been shown to be altered by Meth. For instance, & Rokyta, 2005a, b ; Slamberova et al. 2009), thus im-
the cholinergic system is altered (increased M1 mAChR plicating Meth-induced alterations to this receptor
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number) in mice with developmental Meth-induced system.
novel object and novel place recognition deficits (Siegel Based on such evidence, we hypothesized that de-
et al. 2010). Histamine and its receptors are also altered velopmental Meth treatment induces alterations in
by Meth use and is involved in the cognitive deficits DA, 5-HT and glutamatergic receptor function. The
following both developmental and adult exposure to purpose of the experiments was to test this using
the drug (Acevedo & Raber, 2011 ; Noda et al. 2010). locomotor activity as the outcome following drug
The GABAergic (Zhu et al. 2006) and norepinephrine challenge with selective agonists and/or antagonists
(Graham et al. 2008) systems are also vulnerable to for a subset of the receptors previously implicated in
Meth toxicity. However, research has focused primar- the effects of Meth in adults.
ily upon dopamine (DA), serotonin (5-HT) and gluta-
mate in adult animals. For instance, adult Meth
Materials and method
exposure affects all three of these systems in both ro-
dents and humans (Cadet & Krasnova, 2009). These Animals
same molecules influence the development of neurons
Male and nulliparous female (175–200 g) Sprague–
and associated neurocircuitry at early stages of on-
Dawley (IGS) rats (Charles River Laboratories, USA),
togeny (Thompson et al. 2009). We demonstrated that
were bred in-house after at least 1 wk of acclimatiz-
Meth administration from PD 11–20 produces long-
ation in the vivarium (AAALAC-accredited). The ani-
term reductions in striatal DA and D2-like receptors
mal facility is controlled for temperature (20¡1 xC)
(Crawford et al. 2003). DA receptors are involved in
and humidity (50¡10 %) and is maintained on a
neuronal cell cycle progression (Ohtani et al. 2003),
14:10 h light–dark cycle (lights on 06:00 hours).
GABAergic migration (Crandall et al. 2007) and den-
Throughout the study, rats had access to food and
dritic growth (Song et al. 2002) during development.
filtered water ad libitum. Presence of a sperm plug
While 5-HT is also reduced in neostriatum and en-
was designated embryonic day (ED) 0 and on ED 1
torhinal cortex following developmental Meth ex-
females were transferred to polycarbonate cages
posure (Grace et al. 2010) and 5-HT receptor levels are
(46r24r20 cm) containing woodchip bedding. Day
decreased in adult rats exposed to Meth (McCabe et al.
of birth was designated PD 0 and on PD 1 litters were
1987a), it is not clear if 5-HT receptors are affected
culled to 12 pups, although if a litter contained 95 %
N-methyl-D-aspartic acid (NMDA) subtype, are im- pure) were administered from PD 11–20 to half the
portant in the plasticity and structure of the developing males in each litter (range 3–6), while the remainingDevelopmental methamphetamine receptor changes 379
Table 1. Pharmacological challenges used for measurements of locomotor activity
Doses used Doses used
part A part B
Drug challenge Target receptor (mg/kg) (mg/kg)
MK-801 Glutamate : NMDA 0.1, 0.2, 0.3 0.15, 0.20, 0.25
receptor antagonist
SKF-82958 Dopamine : D1 0.1, 1.0, 2.0 0.5, 1.0, 1.5
receptor agonist
Quinpirole Dopamine : D2 0.5, 1.0, 1.5 1.5, 2.0, 3.0
receptor agonist
Quipazine Serotonin : 5-HT2 0.1, 0.3, 0.5 n.a.
receptor agonist
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p-Chloroamphetamine Serotonin : 5-HT n.a. 2.5, 3.75, 5.0
releasing compound
NMDA, N-Methyl-D-aspartic acid.
half received saline (Sal). Injections were administered To establish dose-effect curves, three doses were
s.c. This dose is similar to those used by some chronic utilized, such that one PD 11–20 Sal- and one Meth-
users (Melega et al. 2007) when scaled to take into ac- treated pair from each litter were administered one
count species differences in size and metabolic rate of the three different doses per drug (Table 1).
between humans and rats (Mordenti & Chappell,
1989). Using Mordenti & Chapell’s formula 48, a PD 11 Drug challenges (part A)
rat weighing 25 g and receiving a dose of 10 mg/kg
Meth would be equivalent to an adult woman taking a The following challenges were used : (1) MK-801, a
dose of 58 mg Meth, or y1 mg/kg (assuming a human glutamatergic NMDA receptor antagonist, at doses of
body weight of 60 kg). This is within the range of 0.1, 0.2 or 0.3 mg/kg (Bubenikova-Valesova et al. 2007 ;
human addiction (Melega et al. 2007). In rodents, it has Jacobs et al. 2000 ; Su et al. 2007) ; (2) SKF-82958, a DA
been demonstrated that maternal and fetal blood levels D1 receptor agonist, at doses of 0.1, 1.0 or 2.0 mg/kg
of Meth are similar (White et al. 2009) and in pregnant (Maneuf et al. 1997) ; (3) quinpirole, a DA D2/3 receptor
ewes Meth reaches an initially higher peak in maternal agonist, at doses of 0.5, 1.0 or 1.5 mg/kg (Stuchlik
than in fetal plasma (Burchfield et al. 1991) but by 1 and et al. 2007) ; or (4) quipazine, a non-selective serotonin
2 h post-treatment, foetal plasma Meth concentrations 5-HT2/3 receptor agonist, was given of 0.1, 0.3 or
exceed maternal levels. Given this, direct treatment of 0.5 mg/kg (Antri et al. 2005 ; Ichiyama et al. 2008). All
pups is a reasonable approximation of human third drugs were obtained from Sigma-Aldrich (USA).
trimester-equivalent exposure, given that the equiva- Following each challenge, animals were placed back in
lent states of brain development in the rat occur post- the locomotor chambers and activity was recorded
natal (Clancy et al. 2007a, b). All drugs were delivered for an additional 3 h. Dependent measures analysed
in a volume of 3 ml/kg normal Sal. Animals were were horizontal and regional (central vs. peripheral)
weaned on PD 28 and housed in pairs. distance travelled and were analysed in 10-min inter-
vals. However, since no differential patterns were
Locomotor activity found between central and peripheral distance vs. total
horizontal distance, regional data are not presented.
Animals underwent locomotor activity testing at PD Chambers were cleaned with 70 % ethanol between
60–70. Each rat was tested only once. On the day of subjects. At least 16 rats were used per challenge dose
testing, rats were weighed and placed in the locomotor (n=16 per treatmentrchallengerdose).
chambers (41 cmr41 cm ; AccuScan Electronics, USA)
for 1 h to habituate them to the test environment. Rats
Drug challenges (part B)
were removed, administered one of the pharmaco-
logical challenge drugs and returned to the test Once basic patterns of effects were established in part
chamber for an additional 3 h. One challenge drug at A, effective doses of those showing effects were re-
one dose level was assigned to each rat within a litter. fined in part B and, in the case of 5-HT, a different380 D. L. Graham et al.
drug was tested since no effect of quipazine was found (a)
in part A. New litters were treated with Meth or Sal 5000
from PD 11–20 as above and locomotor activity tested 4000 kg
as in part A. The challenge drugs were : (1) MK-801 at g/
3000 m
1
doses of 0.15, 0.2 or 0.25 mg/kg ; (2) SKF-82958 at ad- 0.
2000
justed doses of 0.5, 1.0 (same) or 1.5 mg/kg ; (3) quin-
1000
pirole at adjusted doses of 1.5, 2.0 (same) or 3.0 mg/
kg ; or (4) p-chloroamphetamine (PCA), a 5-HT re- 0
Horizontal beam interruptions
(b)
leaser, at doses of 2.5, 3.75 or 5.0 mg/kg (Callaway et al.
5000
1993 ; Sugita et al. 1994) (Table 1). As before, at least 16
4000 kg
rats were used for each treatmentrchallengerdose g/
3000 m
group with no more than one rat per group per chal- 3
0.
lenge dose level taken from any given litter to control 2000
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for litter effects. 1000
0
Data analyses (c)
5000
Data were analysed using mixed linear factorial 4000 kg
g/ Sal
analysis of variance (ANOVA ; SAS v. 9.2 ; SAS m Meth
3000 5
0.
Institute, USA). Pre-challenge and post-challenge data
2000
were analysed separately for each drug at each dose.
1000
In order to account for litter effects, litter was a block
factor in a completely randomized block design with 0
20 40 60 x 20 40 60 80 100 120 140 160 180 x
treatment as the fixed factor within blocks and interval
Time (min)
as the repeated measure factor. Significant interactions
were further analysed using slice-effect ANOVAs by Fig. 1. Locomotor activity and quipazine : activity
interval. Where significant treatment effects were (least square mean¡S.E.M.) before (1 h) and after (3 h)
found in part A, these were used to make predictions quipazine challenge. (a) 0.1, (b) 0.3 and (c) 0.5 mg/kg
about direction of change in part B. In these cases, quipazine treatment groups. Quipazine was administered
analyses used pre-planned comparison methods (for s.c. to adult rats treated on post-natal days 11–20 with
methamphetamine (Meth) or saline (Sal). A significant
MK-801 and SKF-82958). Degrees of freedom were by
interaction (treatmentrinterval) was found pre-
the Kenward–Roger method. Significance was set at
challenge with the low dose condition at 1 interval
pj0.05 ; data are presented as least square (LS) means (20 min) in which the Meth group was less active than
and LS S.E.M. the Sal group (a). Post-challenge, no differential
response to quipazine was found at any dose level.
n=15–16 per group per challenge dose level. *** pDevelopmental methamphetamine receptor changes 381
(a) (a)
5000 6000
kg 5000 Sal
4000 g/ kg
m 4000 g/ Meth
5 Sal m
3000 2. Meth 0.
1
3000
2000
2000
1000 1000
0 0
Horizontal beam interruptions
(b)
Horizontal beam interruptions
(b)
6000
5000
5000
4000 kg kg
g/ 4000 g/
m m
3000 75 0.
2
3. 3000
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2000 2000
1000 1000
0 0
(c)
(c) 6000
5000
5000
4000 4000 kg
g /kg g/
3000 m 3000 m
0 0 .3
5. 2000
2000
1000
1000
0
0 20 40 60 x 20 40 60 80 100 120 140 160 180 x
20 40 60 x 20 40 60 80 100 120 140 160 180 x
Time (min)
Time (min)
Fig. 3. Locomotor activity and MK-801 (part A) : activity (least
Fig. 2. Locomotor activity and p-chloroamphetamine (PCA) : square mean¡S.E.M.) before and after MK-801 challenge. Pre-
activity (least square mean¡S.E.M.) before and after PCA challenge, there were no significant group differences as a
challenge. There were no significant pre-challenge group function of post-natal days 11–20 methamphetamine (Meth)
differences in the low or high PCA conditions, but there was a vs. saline (Sal) treatment in the different dose groups. (a) 0.1,
main effect of treatment in the mid-dose condition in which (b) 0.2 and (c) 0.3 mg/kg MK-801 given s.c. A significant
the methamphetamine (Meth)-treated group was less active treatment main effect and treatmentrinterval interaction
than the saline (Sal)-treated group but the effect was no were uncovered at the 0.2 mg/kg challenge dose and a
longer present during the final habituation interval prior to complex treatmentrinterval interaction at the 0.3 mg/kg
PCA administration. In the high dose pre-challenge animals challenge dose that is not marked as the curves crossed one
there was a significant interaction with the Meth-treated another and no slicerinterval analyses of variance were
animals showing less activity than Sal-treated animals at the significant for this condition. n=17–19 per group per
last interval. Post-challenge PCA had no differential effect on challenge dose level. * p382 D. L. Graham et al.
was found following administration of MK-801 at (a)
the mid-level dose (0.2 mg/kg ; Fig. 3 b), with the 6000
Meth-treated group showing significantly reduced 5000 kg
g/
m
hyperactivity (F1,40.8=8.72, pDevelopmental methamphetamine receptor changes 383
(a) (a)
6000 5000
kg
5000 4000 g/
m
4000 g /kg 3000 1.
5
m
3000 5
0. 2000
2000
1000
1000
0
0
Horizontal beam interruptions
(b)
(b)
Horizontal beam interruptions
5000 Sal
6000 Sal kg Meth
5000 Meth 4000 g/
m
0
kg 3000 2.
4000 g/
m 2000
0
3000 1.
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2000 1000
1000 0
0 (c)
(c) 5000
6000 4000 kg
5000 g/
3000 m
0
4000 kg 3.
g/ 2000
3000 m
5
1. 1000
2000
0
1000 20 40 60 x 20 40 60 80 100 120 140 160 180 x
0 Time (min)
20 40 60 x 20 40 60 80 100 120 140 160 180 x
Time (min) Fig. 6. Locomotor activity and quinpirole (part B) : activity
(least square mean¡S.E.M.) before and after quinpirole. Pre-
Fig. 5. Locomotor activity and quinpirole (part A) : activity challenge, there were no significant group differences as a
(least square mean¡S.E.M.) before and after quinpirole. Pre- function of post-natal days 11–20 methamphetamine (Meth)
challenge, there were no significant group differences as a vs. saline (Sal) treatment. Post-challenge, a main effect of
function of post-natal days (PD) 11–20 methamphetamine treatment was revealed in the Meth-treated group following
(Meth) vs. saline (Sal) treatment. Post-challenge, there were the moderate dose of quinpirole challenge only in which the
no significant differential effects of quinpirole challenge as a Meth-treated group under-responded to the D2 agonist
function of PD 11–20 Meth vs. Sal treatment. (a) 0.5, (b) 1.0 and compared to the Sal-treated group. (a) 1.5, (b) 2.0 and (c)
(c) 1.5 mg/kg of quinpirole given s.c. n=17–19 per group per 3.0 mg/kg quinpirole given s.c. n=12–15 per group per
challenge dose level. challenge dose level. * p384 D. L. Graham et al.
(a) (a)
5000 5000
kg kg
4000 g/
4000 g/
m m
1 Sal 3000 0.5
3000 0. Meth
2000 2000
1000 1000
0 0
Horizontal beam interruptions
Horizontal beam interruptions
(b) (b)
5000 5000 Sal
kg kg
4000 g/
4000 g/ Meth
m m
0
3000 1.
0 3000 1.
2000 2000
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1000 1000
0 0
(c) (c)
5000 5000
kg
4000 g/ 4000 kg
0
m g/
3000 2. 3000 m
5
1.
2000 2000
1000 1000
0 0
20 40 60 x 20 40 60 80 100 120 140 160 180 x 20 40 60 x 20 40 60 80 100 120 140 160 180 x
Time (min) Time (min)
Fig. 7. Locomotor activity and SKF-82958 (D1 agonist ; part Fig. 8. Locomotor activity and SKF-82958 (D1 agonist ; part B) :
A) : activity (least square mean¡S.E.M.) before and after activity (least square mean¡S.E.M.) before and after
SKF-82958. Pre-challenge group differences were found in SKF-82958. Pre-challenge, there were no significant group
the low and mid-dose SKF-82958 challenge between the differences in any of the groups for any challenge conditions.
post-natal days 11–20 methamphetamine (Meth)-treated vs. Post-challenge, significant interval-by-interval effects from
saline (Sal)-treated groups. In both cases, the Meth-treated post-natal days 11–20 methamphetamine (Meth) vs. saline
group was significantly less active, especially during the last (Sal)-treatment occurred at the mid and high dose challenge
30 min of the 1 h habituation phase. SKF-82958 induced conditions. At these doses, SKF-82958 induced exaggerated
hyperactivity in all groups ; however, neither of the two hyperactivity in the Meth-treated group compared to the
conditions (low and moderate) that showed pre-challenge Sal-treated group. (a) 0.5, (b) 1.0 and (c) 1.5 mg/kg SKF-82958
differences exhibited any differential responses to the given s.c. n=15–17 per group per challenge dose level.
SKF-82958 challenge. By contrast, at the highest challenge * pDevelopmental methamphetamine receptor changes 385
SKF-82928 : post-challenge activity (part B) Quinpirole, a D2 agonist, induced less hyperactivity
in Meth-treated rats, but only at one dose level. By
Post-challenge, all groups at all doses showed marked
contrast, the D1 agonist SKF-82958 resulted in in-
hyperactivity in response to the drug. Pre-planned
creased hyperactivity following developmental Meth
comparisons were used to predict that Meth-treated
treatment at several doses. DA is integral to the
animals would have an increased response to the
mechanism of action of Meth in adults (Hyman et al.
drug. No significant differential effects of prior
2006) and is the major neurotransmitter affected by
Meth treatment were seen following the low dose of
neurotoxic Meth exposure (O ’Callaghan & Miller,
SKF-82958 (0.5 mg/kg ; Fig. 8 a). Significant differences
2002 ; Wilson et al. 1996). Clinical and preclinical data
in the degree of hyperactivity were seen 40–100 min
have shown that adult Meth exposure can induce
following the mid-level dose (1.0 mg/kg), in which
long-lasting decreases in levels of the DA transporter
Meth-treated rats were more hyperactive, as pre-
(Fleckenstein et al. 1997 ; Johanson et al. 2006 ;
dicted from part A, compared to Sal-treated rats
Kokoshka et al. 1998 ; McCann et al. 1998 ; Sekine et al.
(Fig. 8 b). Likewise, Meth exposure resulted in signifi-
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2001 ; Volkow et al. 2001b ; Wilson et al. 1996), the ves-
cantly increased hyperactivity from 100 to 160 min
icular monoamine transporter and DA (Friedman et al.
post-challenge after the highest dose (1.5 mg/kg),
1998 ; Ricaurte et al. 1980 ; Wagner et al. 1979, 1980 ;
showing a shift to the right of the dose–response curve
Wilson et al. 1996).
(Fig. 8 c).
It has been proposed that DA receptors play an
integral role in Meth-induced addiction and neuro-
toxicity (Chapman et al. 2001 ; Self, 1998 ; Wang &
Discussion
McGinty, 1996). One clinical study found that Meth
The results show that developmental exposure to Meth users had elevated D1 protein levels, but only in the
results in long-term alterations in receptor function as nucleus accumbens, following post-mortem examin-
determined by locomotor activity using selective ation (Worsley et al. 2000). Despite this increase, a fol-
pharmacological agents. Neither of the serotonergic low-up study indicated that D1 receptor functionality
agents (quipazine or PCA) induced significant chan- was decreased in Meth users (Tong et al. 2003), sug-
ges in activity in adult rats following developmental gesting that receptor abundance does not correlate
exposure to Meth or Sal. This could be because 5-HT with receptor function. Additionally, adult chronic
receptors are unchanged or, given that there are at Meth users exhibit lower levels of D2 (and D3) receptor
least seven families of 5-HT receptors with multiple availability, a phenomenon that has been linked to
subtypes within each family (Pytliak et al. 2011), we impulsive behaviour (Lee et al. 2009 ; Volkow et al.
may not have tested for the affected receptor. 2001a), while others have shown that this decrease is
Alternatively, 5-HT receptor dysfunction may not be non-significant (Worsley et al. 2000). Animal studies
unmasked with locomotor tests, but may be apparent have revealed that, following a behavioural sensitiza-
with other types of behavioural tests. We have shown tion paradigm, there is no change in the number of D1
that developmental Meth exposure (PD 11–20) results or D2 receptors (Suzuki et al. 1997), while others noted
in sharp reductions in 5-HT and its metabolite 5-HIAA that D1 and D2 receptor levels were decreased 18 h
during and shortly after treatment (Schaefer et al. 2008) following a neurotoxic regimen of Meth (5r15 mg/kg
and, while partial recovery occurs, long-term re- every 6 h ; McCabe et al. 1987b). However, normal
ductions remain (Grace et al. 2010). Thus, neither qui- receptor levels were attained between 7 and 21 d post-
pazine, an agonist of 5-HT2/3 receptor subtypes, nor treatment, indicating that receptor number, not affin-
PCA, a 5-HT releaser, had a significant effect on loco- ity, had changed transiently.
motor activity relative to previous Meth treatment. Less is known about the receptor alterations fol-
However, as previously mentioned, there are a num- lowing early Meth exposure, as the aforementioned
ber of 5-HT receptor subtypes and we only tested one data are gleaned from adult rodent studies and short-
such group directly. Thus, additional experiments term changes in DA levels are not reported to occur
specific for the other 5-HT receptor classes are during PD 11–20 drug administration (Schaefer et al.
necessary before a conclusive statement can be made 2006, 2008). Interestingly, the findings in the present
upon long-term 5-HT receptor dysfunction following study indicate that the D1 and D2 receptors show last-
developmental Meth exposure. These and other data ing functional changes following developmental
indicate that developmental Meth treatment does not Meth treatment although we did not directly assay
result in long-term alterations in 5-HT2/3 receptor or receptor number or affinity. Moreover, it is not clear
serotonergic metabolism. how early Meth exposure induces long-term DA386 D. L. Graham et al.
receptor changes. Only one other study has looked of the NMDA receptor results in an up-regulation
at long-lasting DA receptor changes resulting from of D1 receptors (Pei et al. 2004). Yamamoto and collea-
developmental Meth exposure. We demonstrated that gues found that Meth increases glutamate release
this same post-natal Meth exposure resulted in de- via a D1-mediated mechanism in adult rats (Mark
creases in dorsostriatal D2 receptor binding and pro- et al. 2004). While it is not known whether a similar
tein kinase A (PKA) activity (a modulator of the D1 mechanism occurs during developmental Meth treat-
receptor) when examined in adulthood (PD 90 ; ment, it is clear that developmental treatment has
Crawford et al. 2003). We had posited that this re- multiple effects on dopaminergic and glutamatergic
duction in PKA activity was attributable to D1 receptor systems.
desensitization. Since Meth-treated rats later chal- In addition to the above, age of exposure is pivotal
lenged with SKF-82958 exhibited greater activity than to understanding the effects we observed. The treat-
Sal-treated rats, it does not appear likely that the de- ment period encompassed critical stages of cortical
velopmental Meth treatment results in long-term D1 and limbic development, roughly equivalent to late
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receptor desensitization ; in fact the opposite appears second to third trimester brain development in hu-
more likely. This is based on the assumption that mans (Clancy et al. 2007a, b ; Rice & Barone, 2000). DA
striatal D1 receptors are affected, as this brain region is receptor mRNA is highly expressed embryonically,
highly innervated with DA receptors and plays a indicating a role in neurogenesis ; however, DA re-
dominant role in locomotor activity (Holschneider & ceptors do not appear to be functionally active until
Maarek, 2008 ; Kalivas et al. 1999). In addition, it is PD 14–21 (Schambra et al. 1994). Likewise, while
known that activation of D1 receptors in other brain NMDA receptors are expressed pre-natally, they are
regions such as the medial prefrontal cortex and orbi- not functionally active until after birth, with receptor
tofrontal cortex also play a role in motor inhibition binding and expression peaking between PD 7 and PD
(Diaz et al. 2004 ; Heijtz et al. 2007 ; Pellis et al. 2006). 20 (Insel et al. 1990 ; Luo et al. 1996 ; Monyer et al. 1994).
Therefore, we suggest that early Meth treatment sen- During these stages, NMDA receptors are most
sitizes DA D1 receptors while desensitizing D2 re- susceptible to toxic insult (Haberny et al. 2002 ; Scheetz
ceptors (Crawford et al. 2003 ; Schaefer et al. 2006, 2008 ; & Constantine-Paton, 1994). By contrast, expression of
Williams et al. 2003a). Whether the smaller D2 receptor 5-HT receptors, including 5-HT2/3 receptors, peaks
change was a direct effect of Meth exposure or an during the embryonic period and maximal ligand
indirect effect via the Meth-induced change in D1 re- binding occurs during the late embryonic–early post-
ceptor sensitivity cannot be determined from the natal period (e.g. ED 17–PD 13 for 5-HT2 subtypes ;
present data. Bell et al. 1992 ; Johnson & Heinemann, 1995 ; Miquel
This study further demonstrated that early Meth- et al. 1995 ; Roth et al. 1991 ; Wu et al. 1999). As such, the
treated rats showed marked changes following adult dosing regimen used here (PD 11–20) aligns with
exposure to the NMDA receptor antagonist, MK-801, vulnerable periods of DA and NMDA receptor devel-
resulting in decreased activation relative to Sal-treated opment more than with that of 5-HT receptors. One
controls. In adult animals, Meth causes the release of in vitro study noted that the activation of NMDA re-
extracellular glutamate (Nash & Yamamoto, 1992), ceptors produced more toxicity in brain slices from
which can contribute to Meth-induced neurotoxicity younger rats (PD 21¡2) than from adults relative to
via excitotoxicity and reactive nitrogen species (Cadet other glutamate receptor subtypes (Sanganahalli et al.
& Brannock, 1998 ; Dawson et al. 1993 ; Garthwaite, 2006). We have demonstrated that PD 11–20 Meth ex-
1991 ; Imam et al. 2001). NMDA itself is able to de- posure results in enduring deficits in Cincinnati water
crease DA uptake in vitro and DA levels in vivo and maze (CWM) learning (Grace et al. 2010 ; Vorhees et al.
Meth potentiates the latter effect when co-adminis- 2008, 2009). This maze assesses route-based egocentric
tered (Sonsalla et al. 1998). Others have found that learning, a form of navigation that relies on the use
administration of MK-801 attenuates the DA depleting of self-movement cues and signposts to determine
effects of Meth and the inhibitory effect of Meth on location within a given space (Byrne, 1982 ; di Fiore &
tyrosine hydroxylase (Miller & O’Callaghan, 1995 ; Suarez, 2007). As such, it is possible that the CWM is
Sonsalla et al. 1989). It is known that glutamatergic and mediated via the neostriatum, particularly the caudate
dopaminergic systems interact and this association nucleus (Cook & Kesner, 1988), a region rich in DA
is significant in Meth-induced neurotoxicity. NMDA projections. It is plausible that Meth exposure during
receptors are localized on DA nerve terminals this stage permanently altered DA and glutamate
(Krebs et al. 1991) and NMDA receptors regulate D1 receptors critical for the formation or integration of
receptors via physical interaction, such that activation route-based information.Developmental methamphetamine receptor changes 387
In sum, the results identified several long-term for selective long-term dysfunction of serotonin pathways
receptor changes in the DA and glutamate systems in brain. Synapse 15, 198–208.
important for locomotion following post-natal Meth Cadet JL, Brannock C (1998). Free radicals and the
treatment. The changes observed in Meth-treated pathobiology of brain dopamine systems. Neurochemistry
International 32, 117–131.
offspring in their adult functional response to a D1 re-
Cadet JL, Krasnova IN (2009). Molecular bases of
ceptor agonist was opposite to that after a D2 receptor
methamphetamine-induced neurodegeneration.
agonist or an NMDA receptor antagonist. Since this International Review of Neurobiology 88, 101–119.
exposure also causes later cognitive deficits, the func- Callaway CW, Wing LL, Nichols DE, Geyer MA (1993).
tional changes seen here may be indirectly related to Suppression of behavioral activity by norfenfluramine and
the cognitive effects, but further experiments will be related drugs in rats is not mediated by serotonin release.
required to test this connection since locomotor be- Psychopharmacology (Berlin) 111, 169–178.
haviour only was assessed here. Chang L, Cloak C, Jiang CS, Farnham S, et al. (2009). Altered
neurometabolites and motor integration in children
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exposed to methamphetamine in utero. Neuroimage 48,
Acknowledgements 391–397.
Chang L, Smith LM, LoPresti C, Yonekura ML, et al. (2004).
We thank Mary Moran, Lindsey Burns, Brian
Smaller subcortical volumes and cognitive deficits in
Hoffman, Emily Hautman and Holly Johnson for children with prenatal methamphetamine exposure.
technical assistance. Supported by NIH grants Psychiatry Research : Neuroimaging 132, 95–106.
DA006733 (C.V.V.), ES015689 (M.T.W.) and training Chapman DE, Hanson GR, Kesner RP, Keefe KA (2001).
grant T32 ES007051 (D.L.G., R.M.A.K., A.A.B., C.E.G., Long-term changes in basal ganglia function after a
T.L.S.). neurotoxic regimen of methamphetamine. Journal of
Pharmacology and Experimental Therapeutics 296, 520–527.
Chomchai C, Na MN, Watanarungsan P, Yossuck P, et al.
Statement of Interest (2004). Methamphetamine abuse during pregnancy and its
health impact on neonates born at Siriraj Hospital,
None.
Bangkok, Thailand. Southeast Asian Journal of Tropical
Medicine and Public Health 35, 228–231.
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