Modulation of neuropeptide FF (NPFF) receptors influences the expression of amphetamine-induced conditioned place preference and amphetamine withdrawal anxiety-like behavior in rats

Peptides 33 (2012) 156–163

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Modulation of neuropeptide FF (NPFF) receptors influences the expression of amphetamine-induced conditioned place preference and amphetamine withdrawal anxiety-like behavior in rats J.H. Kotlinska a,∗ , E. Gibula-Bruzda a , D. Koltunowska a , H. Raoof b , P. Suder b , J. Silberring b,c a

Department of Pharmacology and Pharmacodynamics, Medical University, Lublin, Poland Department of Biochemistry and Neurobiology, Faculty of Materials Science and Ceramics, AGH University of Science and Technology, Krakow, Poland c Centre for Polymer and Carbon Materials, Polish Academy of Science, Gliwice, Poland b

a r t i c l e

i n f o

Article history: Received 27 July 2011 Received in revised form 6 December 2011 Accepted 6 December 2011 Available online 16 December 2011 Keywords: Amphetamine Conditioned place preference Withdrawal anxiety Elevated plus-maze test NPFF RF9

a b s t r a c t Many data indicate that endogenous opioid system is involved in amphetamine-induced behavior. Neuropeptide FF (NPFF) possesses opioid-modulating properties. The aim of the present study was to determine whether pharmacological modulation of NPFF receptors modify the expression of amphetamine-induced conditioned place preference (CPP) and amphetamine withdrawal anxiety-like behavior, both processes relevant to drug addiction/abuse. Intracerebroventricular (i.c.v.) injection of NPFF (5, 10, and 20 nmol) inhibited the expression of amphetamine CPP at the doses of 10 and 20 nmol. RF9, the NPFF receptors antagonist, reversed inhibitory effect of NPFF (20 nmol, i.c.v.) at the doses of 10 and 20 nmol and did not show any effect in amphetamine- and saline conditioned rats. Anxiety-like effect of amphetamine withdrawal was measured 24 h after the last (14 days) amphetamine (2.5 mg/kg, i.p.) treatment in the elevated plus-maze test. Amphetamine withdrawal decreased the percent of time spent by rats in the open arms and the percent of open arms entries. RF9 (5, 10, and 20 nmol, i.c.v.) significantly reversed these anxiety-like effects of amphetamine withdrawal and elevated the percent of time spent by rats in open arms at doses of 5 and 10 nmol, and the percent of open arms entries in all doses used. NPFF (20 nmol) pretreatment inhibited the effect of RF9 (10 nmol). Our results indicated that stimulation or inhibition of NPFF receptors decrease the expression of amphetamine CPP and amphetamine withdrawal anxiety, respectively. These findings may have implications for a better understanding of the processes involved in amphetamine dependence. © 2011 Elsevier Inc. All rights reserved.

1. Introduction Although psychostimulants, such as amphetamine, its derivatives and related compounds are currently prescribed for treatment of attention-deficit hyperactivity disorder (ADHD) [11,62] and narcolepsy [80], the main research interest is focused on a hunt for medications to treat amphetamine abuse and dependence. Amphetamine is misused because it produces feelings of euphoria and relief from fatigue, improves performance on some simple tasks, increases activity levels, and reduces appetite (develops anorexia) [47]. Chronic abuse of amphetamine results in psychological dependence that requires periodic or continu-

∗ Corresponding author at: Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland. Tel.: +48 81 5357391; fax: +48 81 5288918. E-mail addresses: [email protected], [email protected] (J.H. Kotlinska). 0196-9781/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2011.12.002

ous administration of the drug to produce overwhelming pleasure or to avoid discomfort, such as dysphoria. The dysphoric state of amphetamine withdrawal has been recognized as depressive syndrome, including anhedonia, depression, anxiety, and social inhibition in early drug abstinence. Successful treatments for amphetamine withdrawal remain elusive, as the exact molecular basis of the expression of such withdrawal syndromes has not been fully elucidated [48]. Amphetamine acts by inhibiting reuptake of dopamine, norepinephrine, and serotonin by presynaptic terminals, via interactions with membrane transporters involved in neurotransmitter vesicular storage and reuptake [3,88]. The rewarding/reinforcing effects of amphetamine are mediated via stimulation of the mesocorticolimbic dopamine system [3,37,39,56], although other neurotransmitters like glutamate (e.g. [31,35,79,85]), gammaaminobutyric acid (GABA) [34] or norepinephrine [86] may also be involved in amphetamine reward/reinforcement and addiction. It is well known that functional interaction between dopamine and endogenous opioid system plays a pivotal role in various

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aspects of addiction [see 81 for rev.]. It has been postulated that amphetamine activates endogenous opioid systems [27,64,70] and mu opioid receptors (MOR) are not only involved in amphetamine euphoria [15] but also in the amphetamine-induced inhibitory control deficits [93]. The importance of functional opioid–dopamine interaction in amphetamine abuse supports preclinical and clinical studies with opioid antagonists – naloxone or naltrexone. Thus, opioid antagonists attenuate amphetamine-induced increases of locomotor activity [1,92], locomotor sensitization [32], and the amphetamine-induced response rates for intracranial self-stimulation [71]. Naltrexone decreases amphetamine self-administration in rhesus monkeys [44] and reinstatement of amphetamine self-administration in rats, without suppressing general behavior, thus implicating a functional role of opioid receptors in modulation of the amphetamine seeking behavior [33]. Naltrexone significantly blunted the subjective effects [42,43] and craving for amphetamine in the amphetamine-dependent individuals [42]. These data are in accordance with clinical reports suggesting that heroin is very often mixed with psychostimulants. Such mix of heroin and cocaine is known as a “speedball” [20]. Amphetamines, mainly methamphetamine, are also abused as a component of “speedball” combination [30,54]. Users of psychostimulant/opioid mix have reported that these drugs enhance each other euphoric effects and/or ameliorate each other’s unpleasant effects [41]. However, such psychostimulant/opioid combination is dangerous and leads to many cases of intoxication [55]. The clinical consequences of the combined drug abuse is even worse than those caused by single, addictive drugs [see 22,83]. Neuropeptide FF (NPFF, FLFQPQRF) is an endogenous peptide acting as a modulator of opioid functions [96]. Although NPFF does not interact with opioid receptors [29] but with its own G protein-coupled receptors called NPFF1 and NPFF2 [7,21,36], a close relationship between NPFF and opioid system has been clearly demonstrated, particularly in pain perception, opioid tolerance and dependence [25,26,57,74]. At the cellular level, stimulation of NPFF receptors inactivates opioid effects. For example, biochemical experiments indicated that a selective agonist of NPFF2 receptor, dNPA counteracted morphine-induced increase of c-Fos expression in the nucleus accumbens (NAC) shell and the ventral pallidum in mice [63]. In addition, stimulation of NPFF receptors in cells (SH-SY5Y) transfected with NPFF2 receptor modified the G-protein environment of MOR by favoring its interaction with ␣s, ␣i2, and ␤ subunits [45,77]. On the other hand, Roumy et al. [69] suggested that physical interaction between NPFF2 receptors and MOR (NPFF/opioid receptor heteromers) could be responsible for antiopioid activity of NPFF agonists. Generally, a molecular mechanism of NPFF-opioid interaction needs further evaluation. NPFF receptors are distributed in various brain structures [28] important for analgesic-, locomotor-, and motivational effects of opioids in rodents and mammals. Thus, microinjection of NPFF analogs to the dorsal raphe nucleus or parafascicular nucleus of the thalamus (where NPFF receptors are present) attenuated analgesia induced by morphine injection to these structures in rats [17,18]. Co-localization of NPFF binding sites, particularly NPFF2 receptors and opioid receptors was revealed on both soma of non dopaminergic cells in the ventral tegmental area (VTA) and on fibers afferent to the VTA. The intra-VTA injection of NPFF suppressed hyperlocomotion induced by morphine in rats [61]. Recently, an abundant presence of NPFF (NPFF1 and NPFF2) receptors on the dopaminergic and GABAergic neurons in VTA and less content in NAC has been revealed [94]. Injection of NPFF to the VTA or NAC attenuated morphine-induced reward in rats [94]. However, the mechanism of the above mentioned antiopioid effects of NPFF seems to be indirect and associated with modulation/reduction of excitatory effect of opioids on serotoninergic [17,18] or dopaminergic [61,94] neurotransmissions.

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Published data indicated that supraspinal administration of NPFF receptors agonists modulates effects of same addictive drugs. Thus, exogenously applied NPFF or an analog of NPFF – dansyl-RFamide precipitated abstinence syndrome in the nicotine dependent rats [58]. NPFF administration reduced sensitization to hyperlocomotor effects of morphine [51] and heroin [13], as well as to cocaine [52]. Intracerebroventricular (i.c.v.) injection of NPFF potentiated [10] but PFR(Tic)amide, a “super agonist” of NPFF receptors blocked behavioral sensitization to locomotor activity induced by amphetamine [9]. These discrepancies in effects of various NPFF receptors agonists on amphetamine sensitization was explained by differential activation of NPFF1 receptors by these compounds [9]. The aim of the present study was to examine whether modulation of NPFF receptors is able to modify the expression of amphetamine-induced conditioned place preference (CPP) and anxiety-like behavior during amphetamine withdrawal in rats, the two processes relevant to drug addiction/abuse.

2. Materials and methods Male Wistar rats (220–250 g, HZL, Warszawa, Poland) were chosen as the strain sensitive to rewarding effects of drugs [4]. The animals were housed six per cage with standard food (AgropolMotycz, Poland) and water ad libitum. The animals were kept under a 12/12 h light-dark cycle and were adapted to the laboratory conditions for at least one week. The rats were handled once a day for 5 days before the beginning of the experiment. The experiments were carried out according to the National Institute of Health Guidelines for the Care and Use of Laboratory Animals, the European Community Council Directive for Care and Use of Laboratory Animals, and approved by the Local Ethics Committee.

2.1. Drugs and surgery d-Amphetamine sulfate (Sigma, St. Louis, MO, USA) was dissolved in saline (0.9% NaCl) and injected intraperitoneally (i.p.). NPFF was synthesized by the solid-phase method using Fmoc chemistry. This peptide was purified by the high performance liquid chromatography (HPLC) using a semi-preparative reverse-phase C18 column. The purity of the peptide was greater than 98% and was tested by HPLC and electrospray ionization mass spectrometry. RF9 (C26H38N6O3) was purchased from Tocris Bioscience, Bristol, UK. NPFF and RF9 were dissolved in saline (0.9% NaCl), and injected intracerebroventricularly (i.c.v.) in a volume of 5 ␮l/animal. At least five days before the experiments, the animals were prepared for i.c.v. injections with the aid of a stereotaxic apparatus (Stoelting, Wood Dale, IL, USA). Rats were anesthetized with pentobarbital (50 mg/kg, i.p., Vetbutal, Biowet, Pulawy, Poland) and placed in a stereotaxic instrument. The animals were implanted with cannula (internal diameter 0.39 mm; outside diameter 0.71 mm; Milanowek, Poland). The coordinates for the i.c.v. injections were taken from bregma (1.5 mm lateral, 1.0 mm caudal, and 3.5 mm ventral), according to the atlas of Paxinos and Watson [65]. The correctness of the i.c.v. injections was verified histologically after experiments using 5 ␮l of methylene blue. The results obtained from rats with incorrect cannula placement were rejected. In the present study, NPFF was given at the doses of 5, 10, and 20 nmol, i.c.v., and an antagonist of NPFF receptors, RF9 was introduced at the doses of 10 and 20 nmol, i.c.v. in the expression of amphetamine-induced CPP test. RF9 at the doses of 5, 10, and 20 nmol, i.c.v., and NPFF at the dose of 20 nmol, i.c.v. were administered in the elevated plus maze test during amphetamine withdrawal anxiety. RF9 at the doses of 5, 10, and 20 nmol, and

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NPFF at the dose of 20 nmol were given in the rotarod performance test. 2.2. The amphetamine-induced CPP procedure in rats 2.2.1. Apparatus The apparatus to carry out the CPP procedure consisted of 8 rectangular boxes (60 cm × 35 cm × 30 cm), each one divided into three compartments: two large compartments (25 cm × 35 cm) were separated by removable guillotine doors from a small central gray area (10 cm × 10 cm). The two large compartments were distinguished by color of the walls; one compartment was painted black, while the other compartment was painted white. The boxes were kept in a soundproof room with a neutral masking noise, and with a dim 40 lx illumination. The animals’ behavior was observed on a monitor through a digital video camera system. The time spent by animals in the two large compartments of the apparatus was recorded by a video tracking software (Karnet, Lublin, Poland). 2.2.2. Place preference conditioning The CPP procedure was performed according to the method described earlier [53] and consisted of a pre-conditioning phase (pre-test, 2 day), a conditioning phase (4 days) and testing phase (1 day). During the pre-conditioning phase, the baseline preference of rats was determined. Each rat was placed in the central gray area, the guillotine doors were raised and each rat was allowed to freely move for 15 min between three compartments. The time spent in each compartment was recorded only on the second day, as the first day served as a habituation to the chambers. Because the white compartment was the less-preferred side for most animals during pre-test thus, to establish conditioning, we paired amphetamine (1 mg/kg, i.p.) with the initially non-preferred white compartment (drug-associated) every four days of the conditioning phase. In the morning sessions the amphetamine-paired rats received saline and were confined to the vehicle-paired (black) compartment for 30 min. After an interval of 4–6 h, the same rats received amphetamine (1 mg/kg) and were confined to the white compartment of the apparatus for 30 min. Control rats received saline injection before their exposure to the white or black compartments during conditioning. On day 7, one day after the last conditioning trial, animals were placed in the neutral (gray) area of the CPP apparatus. The guillotine doors were removed and rats were allowed a free access to all compartments for 15 min. The time spent in the drug-paired and saline-paired compartments was recorded for each rat. To investigate the influence of NPFF on the expression of amphetamine-induced CPP, rats that had developed amphetamineinduced CPP were pre-treated with NPFF (5, 10, and 20 nmol, i.c.v.), 5 min before their placement in the CPP apparatus. The time spent by each animal in the white compartment was recorded for 15 min. An antagonist of NPFF receptors, RF9 at the dose of 10, and 20 nmol, i.c.v., was given 5 min before NPFF (20 nmol) to evaluate involvement of NPFF receptors in the observed effect. Furthermore, to clarify the role of NPFF receptors in this study, an additional experiment was performed where RF9 at the doses of 10, and 20 nmol, i.c.v. was given to rats that had developed amphetamine-induced CPP (expression of CPP).

days before the experiment, each rat was handled for 5 min every day. The plus-maze experiment was initiated by placing the rat in the center of the plus-maze facing an open arm, after which the number of entries and time spent in each of the two arms were recorded for a period of 5 min. An “arms entry” was recorded when the rat entered the arm with all four paws. The maze was carefully cleaned with tap water after each test session [50]. The open arms activity was quantified as (a) the time spent in the open arms as a percent of the total time spent on exploring both the open and closed arms, and (b) the number of entries into the open arms as a percentage of the total number of entries into both open and closed arms; (c) locomotor activity of rats measured as the total number of entries into the closed arms of the plus-maze apparatus. 2.3.2. Induction of anxiety-like effect of amphetamine withdrawal The induction of anxiety-like effect of amphetamine withdrawal was based on the method described by Vuong et al. [87]. At the beginning of the experiment, rats were randomly divided into two experimental groups. Saline was given intraperitoneally (i.p.) for 14 consecutive days to one group (control) and amphetamine (2.5 mg/kg, i.p.) was distributed to another group, once daily. During experiments the rats were given free access to water and food. On the 15th day of the experiment, 24 h after amphetamine withdrawal (the last injection), an anxiety-like behavior of the animals was tested in the elevated plus maze test for 5 min. RF9 (5, 10, and 20 nmol) was administered 5 min before placing rats onto the central platform of the maze (facing on open arm). NPFF (20 nmol) was given 5 min before RF9 to clarify an involvement of NPFF receptors in amphetamine withdrawal anxiety-like behavior. 2.4. Rotarod performance test To evaluate the possible muscle-relaxant or ataxic effects [78] of RF9 (5, 10, and 20 nmol) and NPFF (20 nmol), the rats were tested on the rotarod apparatus (Multiserv, Lublin, Poland). On the day preceding the experiment, the rats were preselected on the rotating rod (6 cm in the diameter, 50 cm in length, subdivided into four areas by the disks 25 cm in diameter, at a constant rotating speed – 9 rpm), in order to evaluate their performance. The rats that held onto the rotating rod for at least 2 min were selected for the experiment. In order to reveal the influence of RF9 and NPFF on motor coordination, the latency of falling off the rotarod was determined 5 min after injection. The animals that did not fall off the rotarod within 1 min were given the maximum score of 60 s. 2.5. Statistical analysis For CPP paradigm, the data are expressed as means ± S.E.M. of scores (i.e. the differences between post-conditioning and preconditioning time spent in the drug-associated compartment). The statistical significance of drug effects in the tests was assessed by the analysis of variance (one-way ANOVA), and the significance of a difference between individual groups was determined by a Tukey–Kramer multiple comparisons test. Data are expressed as mean (±S.E.M.). P < 0.05 was considered statistically significant for all tests.

2.3. An anxiety-like effect of amphetamine withdrawal in rats 3. Results 2.3.1. Elevated plus-maze apparatus The plus-shaped maze was made of wood and positioned on a height of 50 cm above the floor in a quiet laboratory surrounding. Two opposite arms were open (50 cm × 10 cm) and the other two were enclosed with walls (50 cm × 10 cm × 40 cm). The level of illumination was approximately 100 lx at floor level of the maze. Three

3.1. Effect of NPFF on the expression of CPP induced by amphetamine in rats The data were expressed as a change in time, i.e. testing minus pre-testing time (in seconds) spent in a drug-associated (white)

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Fig. 1. Influence of NPFF (5, 10, and 20 nmol, i.c.v.) on the expression of amphetamine-induced CPP, and RF9 (10 and 20 nmol, i.c.v.) on the effect of NPFF (10 nmol, i.c.v.). Data were expressed as a score, i.e. post-conditioning minus pre-conditioning time (s) spent in the drug-associated compartment. Results are expressed as mean ± SEM, (N = 10–11). * P < 0.05; ** P < 0.01. (ch) SAL/AMPH – administration of saline/amphetamine during acquisition of CPP.

compartment. One-way ANOVA indicated significant differences between groups [F(6, 71) = 2.522; P = 0.0286] in the CPP paradigm during the testing phase. Post hoc analysis (Tukey–Kramer test) showed that administration of amphetamine (1 mg/kg) during conditioning, induced a significant preference for the drug-associated compartment in the testing phase (P < 0.05). On the test day, the acute administration of NPFF (5, 10, and 20 nmol, i.c.v.) attenuated the expression of amphetamine-induced CPP with significant results at the dose of 10 (P < 0.01), and 20 nmol (P < 0.01). The effect of NPFF at the dose of 20 nmol on amphetamine CPP was attenuated by i.c.v. pre-treatment with RF9 at the doses of 10 (P < 0.05) and 20 nmol (P < 0.05) (Fig. 1). Furthermore, one-way ANOVA showed a significant effect of amphetamine treatment [F(3, 86) = 3.903; P < 0.05] and no interaction between acute administration of RF9 at the doses of 10 and 20 nmol, i.c.v. and amphetamine-conditioned rats on the test day(Fig. 2). Acute administration of NPFF (5 and 20 nmol) or RF9 (10 and 20 nmol) to the saline-conditioned group during test phase did not change the time spent by rats in the drug-associated compartment [F(4, 51) = 0.03511; P > 0.05], in comparison with control (saline-pretreated) group (data not shown). 3.2. Effects of RF9 on anxiety-like effect measured during withdrawal from chronic amphetamine administration in the plus-maze test One-way analysis of variance (ANOVA) revealed significant differences between groups on the percent of time spent by rats in the open arms of the plus-maze [F(8, 71) = 4.45; P < 0.001]. As shown

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Fig. 2. Influence of RF9 (10 and 20 nmol, i.c.v.) on the expression of amphetamineinduced CPP. Results are expressed as mean ± SEM, (N = 21–22). *P < 0.05. (ch) SAL/AMPH – administration of saline/amphetamine during acquisition of CPP.

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Fig. 3. Influence of RF9 (5, 10, and 20 nmol, i.c.v.) on anxiety-like behavior in amphetamine withdrawal rats (24 h after the last amphetamine administration) and NPFF (20 nmol, i.c.v.) on the effect of RF9 (10 nmol, i.c.v.) measured in the elevated plus maze test. (A) Percent of the time spent in the open arms; (B) percent of the open arms entries; (C) locomotion measured as a total number of closed arms entries. Results are expressed as mean ± SEM (N = 7–9). * P < 0.05; ** P < 0.01; *** P < 0.001. (ch) SAL/AMPH – administration of saline/amphetamine during development of dependence (14 days).

in Fig. 3A, amphetamine withdrawal (24 h after the last (14 days) amphetamine treatment at the dose of 2.5 mg/kg, i.p.) reduced the percent of time spent by rats (anxiety-like effect) in the open arms of the plus-maze apparatus (P < 0.05). Acute administration of NPFF receptors antagonist–RF9 (5, 10, 20 nmol, i.c.v.) inhibited an anxiety-like effect of amphetamine withdrawal and increased the time spent by rats in open arms. In this test, RF9 induced an inverted U-shaped dose-response effect with significant result at the dose of 5 nmol (P < 0.01), and a maximal effect at the dose of 10 nmol (P < 0.01). NPFF (20 nmol, i.c.v.) given alone to amphetamine withdrawal rats did not change the rats’ behavior but given 5 min before RF9 (10 nmol), it counteracted the effect of RF9 (P < 0.05). Furthermore, NPFF and RF9 at the doses used in this experiment, given alone to the saline treated rats, did not change the percent of time spent by rats in the open arms (Fig. 3A).

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When the percentage of entries in the open arms was measured (Fig. 3B), there were significant differences between groups [F(8, 71) = 4.266; P < 0.001). Amphetamine withdrawal decreased the percent of entries into the open arms (P < 0.05). RF9 (5, 10, and 20 nmol, i.c.v.) inhibited the anxiety-like effect of amphetamine withdrawal and elevated the percentage of the open arms entries. The results were significant at the doses 5 (P < 0.001) and 10 nmol (P < 0.01). Acute injection of NPFF (20 nmol) to the amphetaminewithdrawal rats did not change the percentage of the open arms entries but significantly counteracted the effect of RF9 (10 nmol) (P < 0.5). NPFF and RF9, given alone, at the doses used in this experiment, did not change the percentage of the open arms entries the control (saline-treated) rats (Fig. 3B). Locomotor activity of rats measured as closed arms entries was not statistically significant between groups [F(8, 71) = 0.5936; P > 0.05]. Amphetamine withdrawal did not produce changes in locomotion of rats. RF9 (5, 10, and 20 nmol, i.c.v.) and NPFF (20 nmol, i.c.v.), given 5 min before the test, did not influence locomotor activity of amphetamine withdrawal-, or saline-treated rats. Locomotor activity of amphetamine withdrawal rats was not changed neither when the rats were pretreated with both NPFF (20 nmol, i.c.v.) nor RF9 (10 nmol, i.c.v.) (Fig. 3C). 3.3. Influence of NPFF and RF9 on the rotarod performance test Neither NPFF at the dose of 20 nmol, i.c.v. nor NPFF receptors antagonist–RF9 at the doses of 5, 10, and 20 nmol, i.c.v. affected coordination of animals in the rotarod performance test [F(4, 45) = 1.654, P > 0.05) (data not shown). 4. Discussion Our study indicated that acute administration of NPFF to the rats’ cerebral ventricle attenuates the expression of amphetamineinduced CPP. This effect was reversed by RF9, an antagonist of NPFF receptors. i.c.v. administration of RF9 to amphetamine-conditioned rats did not modify the expression of amphetamine CPP. Furthermore, RF9 reversed the expression of amphetamine withdrawal induced anxiety-like behavior in the elevated plus-maze test. The anxiolytic-like effect of RF9 was attenuated by NPFF. Acute injection of NPFF or RF9 to saline-treated rats neither changed the time spent by rats in the drug-paired compartment of CPP apparatus, nor rats’ behavior in the elevated plus-maze test or rotarod performance test. Midbrain dopamine, preferentially in the NAC, is thought to mediate the reinforcement processes induced by many drugs of abuse [8,75]. Amphetamine increases dopaminergic transmission in the NAC, a terminal region of the mesocorticolimbic pathway [3] and the expression of the amphetamine-produced CPP is mediated by dopamine receptor activation in the NAC [37,39]. More detailed data suggest that rewarding mechanism of amphetamine action on dopaminergic transmission in the NAC may be a sum of two different events: the direct effect of amphetamine on dopamine transporters localized on dopaminergic nerve terminals, and the action of endogenous opioids released by amphetamine in the VTA [70]. Behavioral data support an involvement of the opioid system in amphetamine reward and indicate that naloxone [82] blocked the acquisition of amphetamine-induced CPP in rats, and priming injection of amphetamine effectively reinstated the extinguished morphine CPP in mice [16] and rats [89]. Furthermore, amphetamine increased the rewarding (CPP experiments) or discriminative stimulus effects of morphine [24], and produced reinstatement of heroin self-administration in rats [12,76]. NPFF receptors are located in the VTA and NAC [94]. Intra-VTA administration of NPFF or stable NPFF2 receptor agonist, dNPA

significantly attenuated the morphine induced increase of dopamine turnover rate in the NAC [46,94]. In the VTA, NPFF receptors are localized on dopaminergic and GABAregic neurons [94]. Opioid receptors in the VTA are also located on GABAergic interneurons [14,59]. Disinhibition of GABAergic neurons in VTA by opiates may produce an increase of the neuronal activity of dopamine mesocorticolimbic pathway. This mechanism could be one of the mechanisms of opiate reward/reinforcement [95]. Intra-VTA or intra-NAC injections of NPFF clearly blocked the acquisition of morphine CPP in rats. NPFF given alone did not cause any change in dopamine turnover in these structures [94]. These data suggest the possible inhibitory effect of NPFF on morphine-induced activation of dopaminergic neurotransmission in mesocorticolimbic pathway. Taking into account the above, we can suggest that, in our study, NPFF decreased the expression of amphetamine-induced CPP by affecting dopamine release. Because activation of dopaminergic transmission in the NAC mediates the expression of amphetamine CPP [37,39], the inhibitory influence of NPFF on dopamine release in this structure could be responsible for this effect. Previously published data indicated an inhibitory effect of NPFF on the expression of morphine– [51], and cocaine-induced CPP [52] in rats. Furthermore, the stable analog of NPFF, 1DMe blocked the acquisition of morphine-induced CPP in mice [60]. Taken together, our experiment and published data suggest that NPFF receptors may play a role in negative and tonic regulation of the rewarding pathway activated by addictive drugs. The inhibitory effect of NPFF on the expression of amphetamine CPP was reversed by RF9, an antagonist of both types of the NPFF receptors (NPFF1 and NPFF2 ) [74]. RF9 or NPFF injected to salinetreated rats did not change the time spent by rats in the drug-paired compartment of CPP apparatus. Our data also demonstrated that acute injection of RF9 to the cerebral ventricle of amphetamineconditioned rats did not modify the expression of amphetamine CPP. These results may support an involvement of NPFF receptors in the expression of amphetamine-induced CPP. However, currently published data show that chronic subcutaneous RF9 injection increased the development of rewarding effect of subeffective, but not effective, dose of morphine in CPP test, without producing any rewarding effect itself [19]. In addition, the putative antagonist of NPFF receptors, dansyl-PQRamide, after chronic intraperitoneal administration, was able to induce a significant rewarding effect in the CPP test in rats [40]. However, other experiments indicated that dansyl-PQRamide itself, in contrast to RF9, was able to induce behavioral effects [see 23]. RF9 did not increase the action of the effective dose of morphine in CPP test [19]. In our study, the amphetamine-induced CPP has already been developed (expression) before application of RF9. Perhaps because of this fact RF9 did not affect this amphetamine effect. In a biased design of CPP paradigm, drugs that increase fear or anxiety can produce false-positive or negative effects. NPFF and RF9 given alone did not induce changes in the rats’ behavior in the elevated plus maze test. There is an evidence that chronic administration of amphetamine decreased proenkephalin mRNA level in the central nucleus of the amygdala [84], the structure of mesolimbic system responsible for the control of anxiety. However, Hiroi and White [38] indicated that neither acquisition nor expression of the amphetamine-induced CPP is mediated by the central or basolateral amygdaloid nucleus. Furthermore, amphetamine injections into the NAC affected neither acquisition/expression of conditioned fear nor baseline startle response [72]. Thus, the compounds used in our study probably did not affect anxiety/fear behavior which could influence the interpretation of obtained data. On the other hand, drug-induced CPP is a form of associative learning [91], therefore a compound that produces cognitive impairment may modulate/inhibit conditioned reward. Although the cognitive effects of NPFF have been poorly studied, Betourne

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et al. [6] indicated that stable agonist of NPFF receptors, 1DMe, mildly impairs both short-term and long-term spatial processing, without affecting contextual fear memory. Because CPP paradigm is a form of contextual learning, it seems that NPFF receptors do not play a major role in memory processing in this task. Generally, our results regarding CPP expression suggest that NPFF attenuated amphetamine-associated cue (that has already been developed in CPP paradigm), which may motivate to maintenance and relapse of amphetamine abuse, and also for amphetamine craving. It has been argued that negative emotional components of withdrawal, mainly anxiety, may be of greater motivational relevance in maintaining drug seeking behavior and compulsive drug use than these of somatic signs [49,90]. There is a limited number of reports concerning the amphetamine withdrawal anxiety in animals [5,87]. Vuong et al. [87] indicated, that amphetamine-induced anxiety measured 24 h after the final amphetamine injection is a time that reflects expectation of a subsequent amphetamine injection. Therefore, the model of induction of amphetamine-induced anxiety described by Vuong et al. [87] was applied in the present study. Amphetamine is an active reuptake inhibitor of serotonin, dopamine and norepinephrine, and all these neurotransmitters are thought to be important in the neuronal processes controlling anxiety [2,68,73]. Recently published data indicate that corticotrophin-releasing factor (CRF) antagonist reversed anxietylike behavior of rats during amphetamine withdrawal [87]. Our present study demonstrate that RF9, antagonist of NPFF receptors reduced anxiety-like effect of amphetamine withdrawal measured in the plus-maze test. Thus, RF9 elevated (the inverted U-shaped dose–effect) the percent of time spent in open arms and a number of arm entries of amphetamine withdrawal rats but did not change the locomotor activity of these animals. RF9 did not change behavior of the saline-treated rats in the elevated plus-maze test. The maximal anxiolytic effect of RF9 (10 nmol) was reversed by NPFF pretreatment. Therefore, our results suggest that NPFF receptors modulation may modify the amphetamine withdrawal anxiety in the plus-maze test. The inverted U-shaped dose–effect of RF9 was also observed in other study [23] and was a result of different involvement of NPFF1 and NPFF2 receptors. Such observation may also explain our data. However, the exact mechanism of such outcome is difficult to explain. As mentioned above, chronic administration of amphetamine (2.5 mg/kg twice a day for 5 days) decreased proenkephalin mRNA level in the central nucleus of the amygdala (at 24 h of withdrawal) [84], the structure of mesolimbic system responsible for the control of anxiety. Published data reported that injection of the selective DOR agonist, [d-Pen 2,5]-enkephalin (DPDPE) into the central amygdala reduces anxiety-like behavior in the plus-maze test and suggests that DORs in this area are important for regulating anxious states [66,67]. Thus, RF9 could improve the opioid system tone through blocking antiopioid NPFF-dependent function. In conclusion, our data demonstrate modulatory influence of the NPFF receptors on the expression of amphetamine CPP and withdrawal anxiety. These results may have implications in better understanding of the processes that occur in amphetamine dependent patients, and may therefore initiate targeted drug development for this group.

Acknowledgment This work was partially financed by the grant no. 3048/B/H03/2009/37 from the Polish Ministry of Higher Education.

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