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Doi:10.1016/s0091-3057(03)00068-6

Pharmacology, Biochemistry and Behavior 75 (2003) 173 – 179 Dimenhydrinate produces a conditioned place preference in rats Alison G. Halperta, Mary C. Olmsteada, Richard J. Beningera,b,* aDepartment of Psychology, Queen’s University, Kingston, Ontario, Canada K7L 3N6 bDepartment of Psychiatry, Queen’s University, Kingston, Ontario, Canada K7L 3N6 Received 14 October 2002; received in revised form 1 March 2003; accepted 4 March 2003 Dimenhydrinate (DMH; trade names Gravol and Dramamine) is a compound of diphenhydramine (DP) and 8-chlorotheophylline in equimolar ratios. DMH has been reported to be abused by humans for its euphoric and hallucinogenic properties but few studies haveevaluated its reinforcing effects in animals. To evaluate the hypothesis that DMH and its constituents DP and 8-chlorotheophylline arerewarding in animals, rats were tested for conditioned place preference (CPP). The paradigm consisted of pre-exposure (three 15-minsessions of access to both sides of the chamber), conditioning [eight 30-min pairings of one side with drug (four sessions) and, on alternatedays, the other side with vehicle (four sessions)] and test phases (three 15-min sessions of access to both sides of the chamber). Significantpreferences for the drug-paired location were found on test session one after conditioning with 60.0, but not 25.0, 40.0 or 50.0 mg/kg ofDMH, and after conditioning with 37.8 but not 27.0 or 32.4 mg/kg of DP. No preference was found after conditioning with 23.0, 27.6 or 32.2mg/kg of 8-chlorotheophylline. All three drugs stimulated locomotor activity during conditioning sessions and DMH and DP showedsensitization over conditioning sessions. DMH doses that showed sensitization (25.0 and 40.0 mg/kg) were lower than the dose (60.0 mg/kg)that produced a CPP revealing a dissociation of locomotor stimulating versus rewarding effects. Results reveal that DMH and DP haverewarding properties, although the molar equivalent dose – response curve for DP appeared to be further to the right than that for DMH.
Future investigations into the neurotransmitter systems modulating this effect are awaited.
D 2003 Elsevier Science Inc. All rights reserved.
Keywords: 8-Chlorotheophylline; Conditioned place preference; Dimenhydrinate; Diphenhydramine; Dramamine; Gravol; Locomotor activity; Reward;Sensitization DMH is composed of the antihistaminergic agent diphen- hydramine (DP), sold under the trade name Benadryl, plus Dimenhydrinate (DMH), an over-the-counter antiemetic the methylxanthine 8-chlorotheophylline in equimolar ratios known by the trade names Gravol or Dramamine, has been reported to be abused by humans. For example, street drug subjective effects of large doses of DMH are believed to users will self-administer 750 – 1250 mg (15 – 25 tablets) of be due to its antihistaminergic component DMH to experience euphoria and hallucinations 1992). Animal behavioral paradigms such as self-adminis- Sigmundson, 1969; Malcolm and Miller, 1972; Rowe et al., 1997). Psychiatric patients will tolerate up to 5000 mg (100 tablets) in a single dosage to experience the drug’s anti- that antihistamines are rewarding in animals (review: depressant, anxiolytic or locomotor-activating effects pert et al., 2002). Although DP acts at the H1 receptor and Mellor, 1990; Gardner and Kutcher, 1993; Oliver and and Serafiin, 1996), the antidepressant, anxiolytic or Stenn, 1993). Thus, there is considerable evidence suggest- euphoric effects seen after its administration suggest that it ing that DMH has rewarding effects in humans.
may interact, either directly or indirectly, with other neuro-transmitter systems as well. Specifically, DP may antagon-ize muscarinic receptors modulateserotonin functioning potentiate * Corresponding author. Department of Psychology, Queen’s Univer- sity, Kingston, Ontario, Canada K7L 3N6. Tel.: +1-613-533-2486; fax: +1- E-mail address: beninger@psyc.queensu.ca (R.J. Beninger).
receptors Thus, the rewarding effects of DMH 0091-3057/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved.
doi:10.1016/S0091-3057(03)00068-6 A.G. Halpert et al. / Pharmacology, Biochemistry and Behavior 75 (2003) 173–179 administration may be attributable to the action of its were arranged so that the configuration was different for each of the four chambers. Two Plexiglas guillotine doors could be The other component of DMH, 8-chlorotheophylline, is used to close the tunnel off from the separate compartments an adenosine antagonist. Adenosine has a general inhibitory and a Plexiglas lid covered each chamber. Six photocells effect on neuronal activity and when adenosine activity is were located in each chamber: two (height 5 cm) trisected diminished, there is a resultant increase in neurotransmis- each compartment into equal sections and two (height 3 cm) sion. Thus, psychomotor stimulant effects are seen follow- similarly trisected the tunnel. An 80C188EB-based Experi- ing theophylline administration both in mice ment Control Board using custom-made software written in ECBASIC used information from these photocells to record amount of theophylline present in a standard dose of DMH the amount of time spent in each compartment, as well as the does not have stimulatory effects in humans number of beam breaks created by each rat. The chambers 1962), the behavioral effects induced by higher doses of this were indirectly lit by 7.5-W light bulbs, ventilated with a small fan and housed in wooden boxes that were insulated There are several possible neuropharmacological mech- with sound-attenuating Styrofoam (for further details of the anisms underlying the behavioral effects following DMH administration. Whether the behavioral effects are due to theantihistaminergic actions of DP, the stimulant actions of 8- chlorotheophylline or a synergism of the two have yet to bedetermined.
DMH, DP and 8-chlorotheophylline (Sigma-Aldrich The notion that DMH has abuse liability is supported Canada, Oakville, ON) each were dissolved in dimethylsulf- both by human case studies and by animal experimentation oxide (DMSO). DMH was tested at 25.0, 40.0, 50.0, and 60.0 mg/kg. Due to the appearance of side effects such as research was to determine whether DMH, or either of its convulsions, higher DMH doses were not tested. The doses components DP and 8-chlorotheophylline, has rewarding of DP and 8-chlorotheophylline were selected to correspond value in the rat, assessed by the CPP paradigm. It was with the amount of each component present in 50.0, 60.0 hypothesized that a dose-dependent preference for the drug- and 70.0 mg/kg of DMH. Thus, DP was tested at 27.0, 32.4 paired location would be found for DMH.
and 37.8 mg/kg and 8-chlorotheophylline was tested at 23.0,27.6 and 32.2 mg/kg. On drug conditioning days, rats wereadministered the appropriate drug and dose plus DMSO solution. On the vehicle days, the rats were given DMSOalone. All drugs were injected intraperitoneally with 1.0 ml/ Male Wistar rats (N = 120) weighing from 250 to 350 g were housed in pairs and had water and food freely availablein their home cages. They were kept on a reversed 12-h All experiments were conducted between 0900 and 1900 light – dark schedule and were tested in the dark portion of h. Each dose of DMH, DP or 8-chlorotheophylline was the cycle. Handling of the animals occurred daily for 5 days evaluated in the CPP using a group of 12 randomly assigned immediately prior to the commencement of each experi- experimentally naı¨ve rats. The experiment consisted of three ment. The rats were treated according to the regulations of phases, a pre-exposure phase of three sessions, a condition- the Canadian Council on Animal Care and the experimental ing phase of eight sessions and a test phase of three protocol was approved by the Queen’s University Animal sessions; sessions were separated by 24 h.
During the 15-min pre-exposure sessions the tunnel was open. The compartment into which a rat was placed to begin a session was constant for all pre-exposure sessions for eachrat but counterbalanced among the rats, so that in each The CPP apparatus consisted of four chambers, each with group six rats began in the left compartment and six in the two distinct compartments (38 Â 27 Â 36 cm) and a connect- right. No drugs were administered during this phase.
ing tunnel (8 Â 8 Â 8 cm). One compartment had urethane- On conditioning sessions 1, 3, 5 and 7, rats were injected sealed walls and the other had 1.0-cm-wide black-and-white with their respective drug 15 min prior to being placed into vertical stripes. The floors of the compartments were also one compartment of the chambers for 30 min and on distinct: one had steel mesh flooring and the other had conditioning sessions 2, 4, 6 and 8, they were injected with stainless steel rods. The mesh floor was in the right compart- the vehicle solution and placed into the other compartment.
ment in two of the chambers and in the left in the others.
The compartments were separated from each other and from Similarly, the stripes were in the right compartment in two of the tunnel with the use of the guillotine doors during the the chambers and in the left in the others. The floors and walls conditioning sessions. The drug-paired compartments were A.G. Halpert et al. / Pharmacology, Biochemistry and Behavior 75 (2003) 173–179 counterbalanced across rats so that the start compartmentwas the drug-paired compartment for half the rats and thevehicle-paired compartment for the other half. Activity wasassessed during conditioning sessions.
The 15-min test sessions followed. The rats were placed into the start compartments used in the pre-exposure ses-sions. The amount of time spent in each compartment wasmeasured for the pre-exposure sessions and the test sessions.
An alpha level of .05 was used for all statistical tests.
Preference for the drug-paired compartment was assessed bycomparing the amount of time in this location during thefirst test session to the amount of time spent in thiscompartment over the average of the three pre-exposuredays. Each dose for each drug tested served as an individualexperiment and was evaluated with a planned paired t test.
For each compound tested, a three-variable mixed-designanalysis of variance (ANOVA), with sessions and phases aswithin factors and dose as a between factor, was alsoconducted to evaluate the possible decay of the CPP effectover test sessions and to test for a dose effect.
Activity data consisted of total counts for each of eight conditioning sessions, four with drug and four without. Foreach compound, these data were analyzed using a three-variable mixed-design ANOVA with repeated measures onday and condition (drug vs. vehicle) and independentgroups. Significant main effects or interactions were fol-lowed by tests of simple effects and pairwise comparisonswhere appropriate.
On average, rats spent approximately half of the session time on the drug-paired side during pre-exposure, showingno significant bias towards either side. For example, theDMH 25.0 mg/kg group spent a mean time of 414.3 s on theto-be-drug-paired side and 428.6 s on the to-be-vehicle- Fig. 1. Mean ( ± S.E.M.) difference in time (s) spent on the drug-paired sidefrom the average of the three pre-exposure sessions to the first test session paired side during the average of the pre-exposure sessions; for groups treated with DMH (A), DP (B) or 8-chlorotheophylline (C) these values did not differ significantly. Tunnel time from during conditioning. * Significant ( P < .05) change in time spent on the the pre-exposure phase for each drug and dose was com- pared to the tunnel time for the relevant first test sessionsand no differences were found. For example, for the 25.0-mg/kg DMH group, respective mean tunnel times were 57.1 between 10 and 90 s The change in time was and 59.2 s. Thus, observed differences in time spent in the significant at 60.0 mg/kg [t(11) = 2.57, P < .05], but not at drug-paired side from pre-exposure to test were not affected 25.0 mg/kg [t(11) < 1.00, P>.05], 40.0 mg/kg [t(11) = 2.13, P>.05] or 50.0 mg/kg [t(11) = 1.23, P>.05]. The Session  shows the differences in time spent on the drug- Phase  Dose ANOVA yielded only a significant phase paired side between the pre-exposure and the first test effect [ F(1,44) = 10.98, P < .05], indicating that for all doses session for each dose of DMH, DP and 8-chlorotheophyl- combined more time was spent on the drug-paired side after line. After conditioning with DMH, increases in time spent conditioning (the data for the individual pre-exposure ses- on the drug-paired side were seen for all doses, ranging sions and for test sessions 2 and 3 are not shown).
A.G. Halpert et al. / Pharmacology, Biochemistry and Behavior 75 (2003) 173–179 Conditioning with DP yielded increases in time spent in itization to the stimulant effects of DMH over the four the drug-paired location that ranged between 29 and 77 s conditioning sessions. Activity during vehicle sessions was While the change in time spent on the drug-paired similar in the different dose-groups and generally decreased side was not significant for the 27.0 mg/kg [t(11) = 1.48, P>.05], or 32.4 mg/kg doses [t(11) = 1.24, P>.05], 37.8 mg/ The three-variable ANOVA revealed a significant kg showed a significant effect [t(11) = 2.63, P < .05]. The three-way interaction of Day  Condition  Dose-group doses used were equivalent to the amount of DP found in [ F(9,120) = 1.98, P < .05], showing that the relationship 50.0, 60.0 and 70.0 mg/kg DMH, respectively. The three- among dose-groups differed across conditions and days.
way Session  Phase  Dose ANOVA for the experiments Tests of simple interaction effects for each condition revealed with DP revealed a significant phase effect [ F(1,44) = 10.98, a significant Day  Dose-group interaction for the drug P < .05]; thus, overall the rats preferred the drug-paired condition [ F(9,132) = 2.56, P < .01], but not for the vehicle compartment after conditioning with DP.
condition. For the vehicle condition, there was a significant After administration of 8-chlorotheophylline, the changes effect of days [ F(3,120) = 10.33, P < .001], showing that the in time spent on the drug-paired side ranged from a decrease decline in activity over days of the four dose-groups com- of 41 s to an increase of 30 s None of the effects was significant [t’s(11) = 0.59, 1.04 and À 1.18, all P>.05].
Further analyses of the drug-condition data revealed a These doses were equivalent to the amount of 8-chlorotheo- significant effect of days for the 25.0 mg/kg DMH group phylline contained in 50.0, 60.0 and 70.0 mg/kg of DMH, [ F(3,30) = 10.63, P < .001]. The day effect was near sig- respectively. There were no significant effects found in the nificance for the 40.0-mg/kg group [ F(3,27) = 2.61, P=.072], three-way Session  Phase  Dose ANOVA.
and not significant for the 50.0 and 60.0 mg/kg groups.
In summary, preference for the drug-paired location was Furthermore, in tests of simple main effects of groups at each found after conditioning with 60.0 mg/kg of DMH. While day, dose-groups only differed significantly on Day 4 location preference was also seen after testing with DP, the [ F(3,40) = 3.88, P < .02]. Newman – Keuls post hoc com- dose – response curve appeared to be shifted to the right; parisons of groups on Day 4 revealed that the 40.0 mg/kg thus, a DP dose of 37.8 mg/kg, corresponding to the amount dose-group differed from the 60.0 mg/kg dose-group of DP found in 70 mg/kg of DMH, but not a DP dose of ( P < .01); the corresponding difference for the 25.0 versus 32.4 mg/kg, corresponding to a DMH dose of 60.0 mg/kg, 60.0-mg/kg dose-groups was near significance (.05 < produced a CPP. No preference was recorded after condi- P < .06). These analyses confirm that DMH stimulated locomotor activity during conditioning sessions at lowerdoses (25.0 and 40.0 mg/kg) but not at the higher doses (50.0 and 60.0 mg/kg) and that the stimulant effect wasseen as a sensitization to the drug effect over the 4 days of DMH stimulated locomotor activity at lower doses but not at the highest dose Increases were seen in The activity data for the groups conditioned with DP are later conditioning sessions suggesting that there was sens- shown in In general, activity was higher in the drug Fig. 2. Mean ( ± S.E.M.) activity counts (per 30 min) during each of the four conditioning sessions on the drug-paired side (left panels) and on the vehicle-paired side (right panels) for groups treated with DMH (A), DP (B) or 8-chlorotheophylline (C). ANOVA revealed significantly higher activity on the drug-paired side for each drug treatment. Groups treated with DMH or DP during conditioning also showed significant sensitization, motor activity increasing fromsession to session. * Significantly ( P < .05) different from 60.0 mg/kg in Newman – Keuls post hoc test following significant simple main effect of groups onconditioning day 4 following significant interaction in ANOVA of groups over days of conditioning with drug.
A.G. Halpert et al. / Pharmacology, Biochemistry and Behavior 75 (2003) 173–179 condition than in the vehicle condition and the stimulant further emphasizes the dissociation of locomotor and place effect seemed to show sensitization like that seen in the DMH experiments, the highest levels of activity being seen A change in the amount of time spent in the tunnel on Drug Day 4 of the conditioning phase. In contrast, the between preconditioning and test days could alter the vehicle-treated groups showed a gradual decrease in activity significance in the amount of time spent in the drug-paired location. Upon examination of tunnel times for all experi- The three-variable ANOVA revealed a main effect of drug ments, it was concluded that this variable did not signific- condition [ F(1,30) = 14.77, P < .001], confirming that activ- antly influence the place preference results. The vehicle, ity was higher on drug versus vehicle days. The ANOVA DMSO, can impair acquisition of conditioned autoshaped also yielded a significant Day  Condition interaction [ F(3,90) = 9.27, P < .001]. This interaction occurs when possible behavioral effects of DMSO associated with a dose-groups are combined and reflects the general increase particular compartment, DMSO was administered on both in activity seen over drug days versus the general decrease in drug and vehicle conditioning days. Neither a change in activity seen over vehicle days. Individual two-way ANOVA tunnel time nor possible behavioral effects of DMSO done separately on the drug and vehicle conditions both confounded the significant findings in the present study.
yielded only significant days effects [ F(3,90) = 3.72, P < .02,and F(3,90) = 11.13, P < .001, respectively]. These analyses confirm that DP stimulated activity and that the stimulanteffect showed sensitization over days; however, there were The place preference induced by DMH supports the hypothesis that DMH has rewarding properties. This finding 8-Chlorotheophylline also seemed to produce higher is consistent with case studies in which doses exceeding the levels of activity than vehicle but there was no evidence recommended daily intake were self-administered to achieve of a sensitization effect such as that seen with DMH and Miller, 1972; Rowe et al., 1997). The CPP paradigm can be effects of days [ F(3,99) = 4.19, P < .01], and condition used to identify rewarding drug states, as has been shown in [ F(1,33) = 18.75, P < .001]. The days effect reflects the experiments using cocaine, morphine, amphetamine and a generally downward trend in activity over days in both conditions and the condition effect confirms that treatment fore, the finding that DMH administration can induce a CPP with 8-chlorotheophylline enhanced locomotor activity. As suggests that DMH may have rewarding properties similar to was the case with DP, there were no significant effects of those associated with other drugs of abuse.
The antihistaminergic component of DMH, DP, also In summary, DMH, DP and 8-chlorotheophylline produced a place preference, but at a higher dose (37.8 enhanced locomotor activity. DMH and DP produced sens- mg/kg) than that (32.4 mg/kg) found in the rewarding dose itization, the stimulant effect being apparent on the latter of DMH. Antihistamines have been shown to induce a conditioning days. Differential dose effects were only seen with DMH; for DMH lower but not higher doses stimulated substituted for cocaine in drug substitution studies et al., 2001; Rumore and Schlichting, 1985). These reports,coupled with the present findings, suggest that DP, and antihistamines in general, have rewarding properties. Therewarding effects of DMH may reflect its antihistaminergic The present study demonstrated that high doses of DMH and its component DP can produce a CPP, suggesting that 8-Chlorotheophylline did not produce a place preference.
they are rewarding. No preference was seen after condition- Theophylline can increase schedule-controlled responding ing with 8-chlorotheophylline. Activity counts were in- creased by lower doses of DMH and by DP and 8- man, 1988), possibly reflecting its stimulant effects. On the chlorotheophylline. DMH (25.0 and 40.0 mg/kg) and DP other hand, methylxanthines, including 8-chlorotheophyl- produced sensitization, the locomotor stimulant effect line, produced dose-dependent increases in the reinforce- increasing from session to session. For DMH, there was a ment threshold in intracranial self-stimulation paradigms dissociation between place conditioning and locomotor stimulation; the dose (60.0 mg/kg) that produced a CPP pounds produce a decrease in threshold. 8-Chlorotheophyl- did not produce locomotor stimulation and the doses (25.0 line alone does not seem to have rewarding properties.
and 40.0 mg/kg) that produced locomotor stimulation did Consideration of the CPP results for the three compounds not produce a CPP. Locomotor activity was also increased together suggests that 8-chlorotheophylline may synergize by DP and 8-chlorotheophylline but there was no significant with DP to enhance the rewarding properties of DP. Thus, effect of dose. In the case of 8-chlorotheophylline, this result the dose of DMH that was rewarding, 60.0 mg/kg, contained A.G. Halpert et al. / Pharmacology, Biochemistry and Behavior 75 (2003) 173–179 32.8 mg/kg of DP. However, 32.8 mg/kg of DP alone did histamine antagonism. Psychomotor stimulation is seen fol- not produce a CPP although a higher dose, 37.8 mg/kg, did.
lowing theophylline administration, and correlates with the A 60.0-mg/kg dose of DMH also contains 27.6 mg/kg of 8- agent’s ability to antagonize adenosine receptor sites chlorotheophylline. This dose of 8-chlorotheophylline did et al., 1981). DMH and both of its components, DP and 8- not produce a CPP. A DMH dose (60 mg/kg) that contained chlorotheophylline, have significant effects on locomotion.
an ineffective rewarding dose of DP (32.4 mg/kg) and an Lower doses of DMH and DP (all doses combined) ineffective rewarding dose of 8-chlorotheophylline (27.6 produced sensitization. Slight locomotor stimulation was mg/kg) produced a significant rewarding effect in the CPP produced by these compounds in the first conditioning test. Thus, 8-chlorotheophylline and DP synergize in DMH session and generally greater effects were seen from session to session. Sensitization has been reported for a number of The rewarding effects of DMH are likely due to the locomotor stimulants including amphetamine and cocaine antihistaminergic actions of DP but may also be potentiated and doses that produce sensitization generally by the methylxanthine, 8-chlorotheophylline. Drugs of abuse are believed to induce their rewarding properties finding of a dissociation between DMH doses that produce through actions on the mesolimbic DA system sensitization of the locomotor response and those that and Berridge, 1993). This may indicate that the rewarding produce a CPP suggests that the underlying mechanisms properties elicited by DMH and DP administration are due mediating the two processes may be different. Further to either a direct or an indirect interaction with the DA studies are needed to characterize the nature of these system. Neurochemical evidence supports this notion; H1 antagonists can both inhibit DA reuptake in the striatum In the present experiment, the drug doses capable of eliciting a motor response did not correspond to the doses capable of producing rewarding effects. While the reinfor- transmitter systems, such as the cholinergic, serotonergic, cing properties of some drugs of abuse are related to their adrenergic, opioid and adenosine systems are modulated by the administration of antihistamines, but whether these this was not the case for DMH, DP or 8-chlorotheophylline.
interactions influence the agent’s rewarding capacity is This finding supports a previous experiment where doses of undetermined. Rewarding effects of the antihistamines DP that substituted for amphetamine in pigeons did not DMH and DP may be the result of their ability to stimulate produce stimulatory effects and doses of DP that produced convulsions in monkeys did not substitute for amphetamine Theophylline is an adenosine receptor antagonist. While modulation of this system is not generally associated with elucidate the neurochemical mechanisms responsible for reward, there is evidence that adenosine A1 receptor ant- agonism will increase striatal extracellular DA levels et al., 1986) and A2 receptor antagonism will produce a placepreference 8-Chlorotheo- phylline may indirectly potentiate the rewarding effect of DPthrough its interactions with the adenosine system. There- The present study confirmed the hypothesis that DMH fore, rewarding properties observed after DMH administra- has rewarding properties, like drugs of abuse. This appears tion may be due to the antihistamine-induced increases in to be due to the action of its antihistaminergic component, DA transmission, which may be further potentiated by the DP, though administration of DP alone had a dose – response methylxanthine’s indirect influence on this neurotransmitter curve that was shifted to the right. The abuse potential of system. This notion is in line with the anecdotal evidence DMH may be related to its influence on mesolimbic DA that DMH abuse is reported more often than DP abuse.
transmission; antihistamines directly increase DA levels inthis system while methylxanthines indirectly enhance DA activity via adenosine antagonism. Thus, 8-chlorotheophyl-line may potentiate the rewarding effects of DP making The agents evaluated in this experiment were all capable DMH (a compound made up of DP and 8-chlorotheophyl- of eliciting motor effects. DMH increased activity at lower doses; DP and 8-chlorotheophylline also increased activity There was a dissociation between doses of DMH, DP and but statistical analyses revealed no significant differences 8-chlorotheophylline that produced increased activity and among the doses tested. These results are in line with previous those that produced reward. The stimulatory and rewarding reports of the stimulating effects of antihistamines and effects of DMH and its components may be modulated methylxanthines. For example, antihistamine administration through different neurotransmitter mechanisms and further studies are needed to elucidate these putative mechanisms.
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Source: http://queensu.ca/psychology/Beninger/Publications/peerreview/Beninger_prp_22.pdf

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