NEUROPSYCHOPHARMACOLOGY 1993-VOL. 9, NO.4 303

Beta-Adrenergic Antagonists Attenuate Somatic and Aversive Signs of Opiate Withdrawal Glenda C. Harris, Ph.D. and Gary Aston-Jones, Ph.D.

The current studies were designed to evaluate the somatic responses to either naloxone-precipitated or effectiveness of {3-adrenergic antagonists on opiate abstinence-induced withdrawal from morphine. In withdrawal symptoms utilizing a variety of paradigms. addition, propranolol (10 mglkg) significantly reduced a Male Sprague-Dawley rats were made moderately withdrawal-induced conditioned place aversion, while dependent on morphine with daily incremental injections. atenolol was effective only at the highest dose tested (20 Both the nonselective {3-antagonist propranolol and the mglkg). These data indicate that {3-adrenergic antagonists selective {3I-antagonist atenolol, in the dose range of 5 to might be effective in the treatment of opiate addictions. 20 mglkg, were found to significantly reduce many of the [Neuropsychopharmacology 9:303-311, 1993J

KEY WORDS: Morphine; Opiate dependence; Opiate withdrawal produces a marked increase in the ftring withdrawal syndrome; Beta-adrenergic antagonists; of noradrenergic locus ceruleus (LC) neurons (Aghaja­ Propranolol; Atenolol nian 1978; Akaoka and Aston-Jones 1991) and a corre­ sponding increase in circulating levels of 3-methoxy-4- Withdrawal from chronic opiate use in humans has hydroxyphenethylene glycol, the principle metabolite been described as a mixture of anxiety and dysphoria of norepinephrine (NE) (Korf et al., 1974). Direct corre­ that is accompanied by a variety of physical symptoms lations have been reported between the time course of such as chills, nausea, and diarrhea (Jaffe, 1985). The the increased activity of LC neurons and the presence aversiveness of these symptoms, and their precipita­ of overt somatic symptoms during naloxone-precipi­ tion by drug-conditioned environmental cues, is specu­ tated withdrawal (Rasmussen et al. 1990). Furthermore, lated to contribute to the high incidence of relapse the region of the LC has been reported to be one of the among former addicts attempting to abstain from opi­ most sensitive sites in the brain for producing overt so­ ate use (Childress et al. 1986). matic signs of opiate withdrawal following local ad­ There is considerable evidence indicating that cen­ ministration of an opiate antagonist (Maldonado et al. tral noradrenergic systems are hyperactive during with­ 1992). The a2-adrenergic agonist clonidine prevents drawal from chronic opiates and may contribute to the the withdrawal-induced increase in LC activity (Aghaja­ opiate withdrawal syndrome. Naloxone-precipitated nian 1978), the increase in NE metabolites (Crawley et al., 1979), and a majority of the withdrawal symptoms (Tseng et al. 1975; Meyer and Sparber 1976), even when microinjected into the LC (Taylor et al. 1988). From the Department of Mental Health Sciences, Hahnemann If NE release is important for the manifestation of University, Philadelphia, Pennsylvania. Address correspondence to: Gary Aston-Jones, Ph.D., Department some or all of the opiate withdrawal syndrome, then of Mental Health Sciences, Hahnemann University, Philadelphia, blockade of postsynaptic al- and/or �-adrenergic re­ Pennsylvania 19102. ceptors should reduce the severity of some or allof the Received March 29, 1993; revised July 21, 1993; accepted August 23,1993. withdrawal symptoms. In the few studies that have

© 1993 American College of Neuropsychopharmacology Published by Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0893-133X/93/$6.00 304 G.c. Harris and G. Aston-Jones NEUROPSYCHOPHARMACOLOGY 1993-VOL. 9, NO.4

tested this hypothesis, it was reported that al antago­ Chronic Drug Treatment nists reduce some signs of withdrawal (Cicero et al. Rats receiving chronic morphine treatment were in­ 1974; Valeri et al. 1989), but it was reported in these jected intraperitoneally (IP) once daily at 4:00 PM. On studies and others that the J3-antagonist, propranolol, Day 1, the dose was 10 mg/kg and the doses were in­ had no effect on the somatic signs of precipitated opi­ creased incrementally by 10 mg/kg every day until rats ate withdrawal (Jhamandas et al. 1973; Cicero et al. 1974; received 80 mg/kg, after which they were maintained Chipkin et al. 1975). Recently, we found that J3-adren­ at 60 mg/kg per day for the duration of the experiment. ergic antagonists were effectivein reducing abstinence­ At the dose level of 60 mg/kg per day, animals main­ induced anxiety-like behaviors in both chronic mor­ tained their weight or gained small amounts of weight. phine- and cocaine-treated rats (Harris and Aston-Jones At higher doses (80 to 90 mg/kg/day) animals appeared 1993). These data indicated that J3-adrenergic antago­ to be sick and lost considerable amounts of weight nists could be useful in the treatment of addiction. Fur­ within a week. thermore, previous reports have noted the effectiveness of J3-antagonists in treating alcohol withdrawal symp­ toms (Carlsson, 1976). In the human literature, there Measurement of Somatic Responses to Withdrawal have been conflicting reports on the effectivenessof pro­ Rats were tested in the morning, approximately 16 pranolol in treating heroin addicts. Two reports have hours after the previous morphine injection, in the rat indicated that propranolol was effective in reducing colony room. Each rat was placed alone in a 24- x 45- withdrawal symptoms (Roehrick and Gold 1987) and x 21-cm Plexiglas chamber, the floor of which was cov­ alleviating craving (Grosz 1972), whereas two other ered with commercially available corn cob bedding ma­ reports concluded that the effectiveness of proprano­ terial. No more than two rats were scored at the same lol was too limited to warrant further investigation (Hol­ time. Fifteen minutes prior to a 0.5 mg/kg IP dose of lister and Prusmack 1974; Resnick et al. 1976). naloxone, rats were pretreated with saline (n = 10), pro­ The purpose of the present experiments was to pranolol (2 mg/kg [n = 6]; 5 mg/kg [n = 8]; 10 mg/kg reevaluate the effectivenessof propranolol in treating [n = 8]; 15 mg/kg [n = 7]; 20 mg/kg [n = 7], IP) or opiate withdrawal symptoms using a variety of para­ atenolol (5 mg/kg [n = 6]; 10 mg/kg [n = 9]; 15 mg/kg digms. We tested the effectiveness of propranolol on [n = 7]; 20 mg/kg [n = 6], IP). Additional experiments the somatic signs of naloxone-precipitated withdrawal were performed to determine if the amount of time af­ (as in the previous studies) and also on somatic signs ter the last morphine injection influencedthe findings. of abstinence withdrawal. Furthermore, we have used In these experiments, rats (n = 17) were given morphine place-conditioning paradigms to determine if J3-adren­ (30 mg/kg) on the morning of the test day and given ergic antagonists are effective in blocking the devel­ naloxone 2 hours later. In these experiments, saline, opment of withdrawal-induced place aversions. The propranolol, or atenolol (10 mg/kg; n = 6 for each group) J3-adrenergic antagoniststhat were used in this study was injected 15 minutes prior to naloxone. include the nonselective J3112-antagonist, propranolol, The behavioral rating scale employed was similar as well as the selective J31-antagonist, atenolol. to that reported by Blasig et al. (1973). Instances of the following behaviors were counted for 30 minutes after naloxone administration: wet dog shakes (whole-body METHODS shaking), teeth chatter (grinding of teeth, grossly cal­ culated as number of episodes, maximal count of 1 per Subjects 30 seconds), writhing (abdominal stretching), eye The subjects were 135 male Sprague-Dawley rats weigh­ twitching (rapid closing of the eye lid), diarrhea (num­ ing between 200 and 250 g, purchased from Taconic ber of episodes), and jumping (leaping onto the edge Farms (Germantown, NY). Rats were housed in accor­ of the chamber). In addition, every 10 minutes animals dance with National Institutes of Health guidelines with were scored for the presence or absence of the follow­ food and water available ad lib. A 12-hour light/dark ing behaviors: vocalizing on touch, ptosis (drooping of cycle was in effect throughout the experiment. the eye lids), rhinorrhea, lacrimation, and piloerection. These parameters were distinctive and easily measured so that blind observations were not necessary. Nonethe­ Drugs less, several animals in some of the groups were scored

Morphine sulfate was provided by the National Insti­ by blind observers (propranolol 5 mg/kg, n = 2; pro­ tute on Drug Abuse and was dissolved in saline. Pro­ pranolol 10 mg/kg, n = 3; atenolol 10 mg/kg, n = 3; pranolol and atenolol were purchased from Sigma atenolol 15 mg/kg, n = 2; vehicle, n = 2). As the mean Chemical Company (St. Louis, MO) and were dissolved scores for animals scored blind were nearly identical in distilled water. to scores for those not scored blind, the data from both NEUROPSYCHOPHARMACOLOGY 1993-VOL. 9, NO.4 /l-Adrenergic Antagonists and Opiate Withdrawal 305

observation methods were pooled to form one score for Day 4: Test Phase. Rats were given free access to both each particular drug treatment group. compartments and the amount of time spent on each For similar measures during abstinence with­ side was recorded for 20 minutes. drawal, other rats were placed in the Plexiglas test chamber 1 hour prior to the daily morphine injection Data Analysis (23 hours after the last morphine injection) and scored using the same rating scale that was used to measure Data for somatic measures of precipitated and absti­ precipitated withdrawal signs. Rats were observed for nence withdrawal experiments were analyzed using a 30 minutes to obtain data on baseline measurements one-way analysis of variance (ANOVA) (on dose) for of withdrawal signs. Following this period, rats were each withdrawal measure. Post-hoc follow-up tests on injected with saline (n = 10), propranolol (5 mg/kg [n = signifIcant interactions were done using Newman­

8], 10 mg/kg [n = 6], or atenolol (5 mg/kg [n = 6], 10 Keuls' tests. The data from the place-aversion experi­

mg/kg [n = 6], IP). Fifteen minutes after these injec­ ment were analyzed using the nonparametric Kruskal­ tions, rats were again scored for the incidence of with­ Wallis test. An aversion score was calculated for each drawal behaviors for 30 minutes. subject by subtracting the amount of time spent on the naloxone paired side prior to conditioning (day 1) from the amount of time spent on that side after condition­ ing (day 4). Post-hoc comparisons were made using the Measurement of Place Aversion Mann-Whitney U test. The place conditioning apparatus was a 70- x 30- x 45-cm box divided equally into two compartments. The frrst compartment had a smooth clear Plexiglas floor, RESULTS black spots on the rear wall, and an almond scent. The second compartment had a rough opaque Plexiglas Naloxone-Precipitated Withdrawal floor,black stripes on the rear wall, and an orange scent. The most prominent somatic signs of precipitated with­ Scents were applied sparingly to walls on opposite ends drawal were wet dog shakes, teeth chatter, writhing, of the apparatus. A separate group of rats (n = 22) was vocalization on touch, ptosis, eye twitch, and diarrhea. used in these experiments. All rats were tested in the Only a few animals (n = 4) exhibited rhinorrhea or morning 16 hours to 18 hours after the last morphine piloerection and none showed jumping or lacrimation. injection. Only the most consistent signs of withdrawal (listed Day 1: Preconditioning Phase. On the frrstday, each above) were included in the data analysis. Figure lA rat was allowed to freely explore both compartments and B shows the instances of withdrawal behaviors fol­ of the box, and the amount of time spent on each side lowing pretreatment with propranolol or atenolol, was recorded for 20 minutes. Any rat showing a strong respectively. All doses of each drug signifIcantly re­ preference for either side (>13 minutes) was removed duced allsomatic withdrawal measures. Vehicle-treated from the study; only two animals had to be eliminated animals typically became inactive and laid supine on for this reason. the bottom of the cage following precipitated with­ drawal. In contrast, animals treated with J3-blockers Days 2 and 3: Conditioning Phase. On day 2, rats were typically remained active during the entire observation injected with either saline, propranolol (10 mg/kg IP) period after naloxone and continued to explore the test or atenolol (10 or 20 mg/kg, IP) 15 minutes prior to an cage. Animals given J3-blockersin the range of 5 mg/kg injection of either saline or 0.2 mg/kg of naloxone (IP). to 15 mg/kg were signifIcantly more likely to be given The environment to be paired with naloxone was a rating of active (p < .01) than were the vehicle-injected chosen in a quasirandom order so that equal numbers animals. of animals in each group were assigned to be given nal­ The J3-blockers appeared to be less effective at at­ oxone in the two different sides. Immediately follow­ tenuating somatic withdrawal symptoms in animals ing the naloxone or saline injection, rats were confmed given naloxone 2 hours as compared to 16 hours after to one side of the box by means of an opaque Plexiglas a morphine injection (Fig. 2). These differences reached divider for 20 minutes. On day 3, rats were given the statistical signifIcancefor measures of wet dog shakes, same pretreatment as on day 2 and confmed to the op­ teeth chatter, and writhing for the propranolol-treated posite compartment following either a saline or nalox­ group (p < .01). However, only wet dog shakes in the one injection. Animals within each group were coun­ 2-hour group were not attenuated compared to vehicle­ terbalanced so that half of the animals in each group treated animals. Similarly, in the atenolol-treated received the naloxone injection on day 2 and the other groups, there were signifIcantlymore wet dog shakes, half on Day 3. ptosis, and writhing in the animals subjected to with- 306 C.c. Harris and C. Aston-Jones NEUROPSYCHOPHARMACOLOGY 1993-VOL. 9, NO.4

A 20 • Vehicle 20 • 2 hr post-morphine Propranolol 2 mg/kg m 16 hr post·morphine 'II • - C • Propranolol 5 mg/kg 15 II> :I ... ¢ fa Propranolol 10 mg/kg v¢ U m'" 0 Propranolol 15 mg/kg 10 ¢ ca ... ra Propranolol 20 mg/kg � II> 10 5 (\I,c ... 8 '1:1:1 :z 0

�c(\I II> � � = '" = r Q,I 0 20 i 0 '" "'U .. .. 011 .. III .. Ol:i-f Propranolol 10 mg/kll Pre·treatment ...: � I: .!:! 'iii .. .. 0 ] .c 15 1; :s 'OJ .. (J)Cj 0 ..c .c . u ci: .. rI) U ;: 0 � .. -'" 011 � ;> .. is = Q,I 10 0 -= ;.. Q .. (;oj �,Q � � = e � ... = 5 ..c"CIZ ::::= 0 B 20 �� • Vehicle Atenolol 5 mglkg � � • C AtenolollO mglkg 20 II> :I • ... ¢ Pre·treatment U � Atenolol 15 mg/kg Atendolol 10 mg/kg a 15 mes 0 Atenolol20 mg/kg :a: ca ... � II> 10 (\I,c 10 ... e '1:1:1 :z �c 5 COl 11/ � 0

0 '" .. 011 .. III 01 .. .!! I: 'iii .. ..:.:01 .!:! 0 ] ..c 1; 'OJ .. .c ..c :si: u Ii: 'i rI) U 0 E- til 011 ..c � ;> .. is 0 ;.. Figure 2. Mean number of counts (± SEM) for each with­ Q (;oj - i drawal behavior measured during naloxone-precipitated with­ .. E- � drawal 2 hours or 16 hours after the previous morphine in­ jection. Propranolol and atenolol (10 mg/kg) were less effective Figure 1. Mean number of counts (± the SEM) for each be­ at reducing withdrawal elicited by naloxone given 2 hours havior measured during naloxone-precipitated withdrawal. compared to 16 hours after the last morphine injection. Sig­ The response to different doses of propranolol is shown in nifIcancelevels refer to 2-hour versus 16-hour data within each A, and B shows the response to atenolol doses. When com­ drug group. ** P < .01, * P < .05. pared to the vehicle-treated group, the drug-treated groups were signifIcantly different on the following measures: wet dog shakes: propranolol, p < .05 for each dose; atenolol, atenolol on somatic signs of abstinence withdrawal. The p < .01 for each dose; teeth chatter, writhing, vocalization on touch, ptosis, and eye twitch: propranolol and atenolol p < primary somatic symptoms elicited by abstinence in all .001 at each dose; diarrhea; propranolol and atenolol p < .01 of the animals prior to treatment were wet dog shakes, at each dose. teeth chatter, writhing, and eye twitching. There was no signmcant difference between any of the groups in the number of abstinence signs measured prior to treat­ drawal 2 hours postmorphine compared to 16 hours ment with vehicle or the I)-blockers. There was no postmorphine (p < .01). Again, however, only wet dog signmcant differencein the number of any signs mea­ shakes in the 2-hour group were not attenuated by this sured pre- versus postinjection with vehicle treatment. I)-antagonist relative to vehicle-treated animals. For both doses of propranolol, however, there was a signmcant decrease in the number of abstinence signs Abstinence Withdrawal seen following the injection, relative to levels seen Figure 3 shows the effects of vehicle, propranolol, or preinjection or after vehicle injections. NEUROPSYCHOPHARMACOLOGY 1993-VOL. 9, NO.4 /1-Adrenergic Antagonists and Opiate Withdrawal 307

• Pre-injection I:2l Post-injection 10 10

8 Propranolol S mg/kg 8 Vehi cle Propranolol 10 mglkg 6 6

4 4 * 2 2

o "'I til o o � ... � ! .. ... n � ... t '" • I ... i ..i t 10 10

8 8 Atenolol 10 mg/kg Vehicle Atenolol S mg/kg 6 6

4 4 *

2 2

0 o � :!. � � i "'I t:I � n n ! ... o'i i '" VJ i ... � ... I l­ " II t

Figure3. Mean number of counts (± SEM) for each withdrawal behavior measured during abstinence-induced withdrawal before (pre) and after (post) injections of vehicle, propranolol, or atenolol. There was a significant decrease in withdrawal signs following propranolol treatment at both 5 mg/kg and 10 mg/kg doses as compared to pretreatment values: wet dog shakes, teeth chatter, p < .01; writhing, eye twitch, p < .05. This was also true for atenolol treatment at 5 mg/kg and 10 mg/kg doses: wet dog shakes, p < .05, teeth chatter and eye twitchs: p < .01, atenololl0 mg/kg: writhing, p < .05. When compared to vehicle-treated animals, propranolol and atenolol animals also showed a significant decrease in withdrawal signs postinjection (propranolol 5 mg/kg and 10 mg/kg: wet dog shakes, writhing, p < .01; teeth chatter, p < .05; propranolol 5 mg/kg: eye twitch, p < .05; atenolol 5 mg/kg and 10 mg/kg: wet dog shakes and teeth chatter, p < .01, eye twitch, p < .05).

Similar results were seen with both doses of ate no- with naloxone (Fig. 4), spending an average of only 2 101. There was a signifIcant decreasein abstinence with­ minuteson that side. Administrationof propranolol (10 drawal signs following atenolol treatment relative to mg/kg) signifIcantly reducedthis aversion (Z = - 2.88, preinjection measures and atenolol-treated animals ex­ P < .004, Fig. 4), whereas the same concentration of hibited signifIcantly fewer signs than vehicle-treated atenolol was not signifIcantly effective. A higher con­ animals posttreatment. centration of atenolol (20 mg/kg) signifIcantly reduced

the withdrawal aversion (Z = - 2.88, P < .004; Fig. 4). In one group of chronically morphine treated Place Aversion animals (n = 4), propranolol (10 mg/kg) was tested on There was no signifIcantpreference for either compart­ its own in the place-conditioning apparatus. Testing ment before naloxone treatment (day 1), and all rats was done in the morning before animals exhibited ab­ spent approximately equal amounts of time on both stinence withdrawal. These experiments were con­ sides. After conditioning, the rats treated with saline ducted in a similar manner to that used for place­ on day 2 or 3 showed a strong aversion to the side paired aversion conditioning with the 4-day protocol. On days 308 G.c. Harris and G. Aston-Jones NEUROPSYCHOPHARMACOLOGY 1993-VoL. 9, NO.4

indicating a central site of origin for many withdrawal symptoms (Maldonado et al. 1992). However, it is pos­ 0+----- sible that peripherall3-adrenergicreceptors become in­ volved in the somatic withdrawal reaction following activation by a central sympathetic cascade. For pro­ ....c- S pranolol, the most effectivedoses for alleviating somatic signs of opiate withdrawal were in the range of 5 mg/kg 5 - to 10 mg/kg. Lower doses and higher doses had reduced tn� effectiveness. In contrast, atenolol was equally effec­ c: Q tive at each dose tested from 5 mg/kg to 20 mg/kg. It .� couldbe that at the higher doses, propranolol has other � effects that interfere with its ability to decrease with­ < -10 drawal symptoms. For example, unlike atenolol, pro­ • Vehicle pranolol binds to serotonin receptors and can act as a � Propranolol 10 mglkg local anesthetic (Gilman et al. 1985; Middlemiss et al. • Atenolol 10 mglkg 1977). III Atenolol 20 mglkg When animals were given naloxone 2 hours after �------15 a morphine injection, both propranolol and atenolol were less effective in reducing withdrawal symptoms Figure 4. A version scores, calculated by subtracting the than in animals given naloxone 16- hours after the last amount of time spent in the naloxone-paired environment morphineinjection. A major differencebetween 2- and postconditioning from the amount of time spent in the same environment prior to conditioning. Treatments refer to the 16-hour postmorphine treatment is the concentration injections given to each group 15 minutes prior to condition­ of circulating morphine, which is presumably much ing on both days 2 and 3. SignifIcance levels refer to the lower in the latter. The severity of withdrawal might vehicle-treated group, ** p < .01. be linked to the number of activated opiate receptors that are subsequently blocked by naloxone. Therefore, the l3-blockers may have been less efficacious 2 hours after morphine because the withdrawal reaction was 2 and 3, an injection of propranolol was paired with more severe. However, there was no signilicant in­ one side of the apparatus while a vehicle injection was crease in withdrawal behaviors in animals withdrawn paired with the other side. Propranolol was found to 2 hours versus 16 hours after morphine when they were have no signifIcantvalence of its own. The mean change not given a l3-blocker.The failure to fmd increased with­ in the amount of time spent on the propranolol side drawal behaviors in the vehicle-treated 2-hour group was 0.30 ± 0.60 minutes after conditioning. may reflect a ceiling effect that prevented withdrawal behaviors from increasing in measurable intensity be­ yond that seen in the 16-hour group. DISCUSSION The fmdings in the place-aversion study are con­ These data indicate that l3-adrenergic antagonists can sistent with those of a previous study that showed that be effective in alleviating many of the somatic signs of the pairing of a distinctive environment with naloxone both naloxone-precipitated and abstinence-induced in opioid-dependent rats can produce an aversion to opiate withdrawal. Both propranolol and atenolol that environment (Hand et al. 1988). In the current signifIcantly reduced all of the somatic signs of with­ study, l3-adrenergicantagonists were found to be effec­ drawal measured in the current experiment. Further­ tive in reducing this aversion. One possible explana­ more, propranolol was also found to be effective in tion for these results is that propranolol itself is aver­ blocking the development of a conditioned place aver­ sive and by pairing both sides of the apparatus with sion to an environment associated with naloxone ad­ propranolol, both sides of the apparatus became equally ministration in morphine-dependent animals. aversive. However, in a separate test, itwas found that Both l3-blockersappeared to be equally effectivein propranolol had no signilicant valence on its own, attenuating the somatic symptoms of withdrawal. Be­ thereby indicating that propranolol could not have cause atenolol acts preferentially at peripheral 131-re­ influenced the results by being either aversive or re­ ceptors and enters the brain in only limited amounts warding. A second possibility could be that the l3-block­ (Gilman et al. 1985; Agon et al. 1991), this may indicate ers caused the animals to forget what had happened that peripheral131-receptors play a primary role in the to them during the conditioning phase. This possibil­ initiation of some withdrawal symptoms. It has been ity is also not likely because similar doses used in a shown that central injections of methylnaloxonium can previous study (Harris and Aston-Jones 1993) did not elicit powerful somatic withdrawal reactions, thereby cause animals to forget an aversive electric shock. NEUROPSYCHOPHARMACOLOGY 1993-VOL. 9, NO.4 (3-Adrenergic Antagonists and Opiate Withdrawal 309

A lower dose of naloxone was used in these experi­ reported previously (Jhamandas et al. 1973; Cicero et ments for precipitating withdrawal (compared to the al. 1974; Chipkin et al. 1975). This discrepancy may somatic withdrawal studies) to produce mild somatic reflect the different methods used to induce morphine symptoms of withdrawal while maintaining place aver­ dependence. In both the Cicero et al. (1974) and Chip­ sions. Previous research has indicated that the brain kin et al. (1975) studies, morphine pellets were used areas most sensitive for producing aversion are differ­ to allow for continuous morphine treatment. In the ent from those producing somatic responses to with­ studies by Jhamandas et al. (1973) and Chipkin et al. drawal. In a recent review by Koob et al. (1992), it was (1975) animals were given multiple daily injections of stated that the regions of the LC and periaqueductal morphine in the dose range of 200 mg/kg to 300 mg/kg gray were the most sensitive sites for producing somatic per day. In the current study, animals were given mor­ symptoms of withdrawal, whereas the nucleus accum­ phine injections once daily and maintained at a moder­ bens was the most sensitive site for producing with­ ate dose of 60 mg/kg per day. This dosing regimen main­ drawal aversions. It is possible that interactions between tained healthy animals throughout the experimental the LC and the nucleus accumbens influence with­ phase. In addition, although naloxone precipitated a drawal aversions. For example, it has been reported that substantial withdrawal syndrome in these animals, in­ naloxone-precipitated withdrawal decreases extracel­ dicating that they were dependent, it did not consis­ lular dopamine levels in the accumbens and that this tently elicit certain characteristic signs such as rhinor­ effect can be blocked by pretreatment with the adren­ rhea, lacrimation, and jumping that have been reported ergic agonist, clonidine (Pathos et al. 1991). It has been to occur with more intensive treatment regimens. Data speculated that the decreased dopamine levels in the from the current study, when viewed with the data from accumbens could be the neural substrate responsible these previous studies, indicate that J3-blockersmay be for the withdrawal-induced place aversions (Acquas et most effectivein reducing opiate withdrawal in moder­ al. 1991; Pathos et al. 1991; Rossetti et al. 1992). Fur­ ately dependent subjects. Additional studies would be thermore, it is thought that clonidine alleviates some required, comparing the abilityof propranolol to allevi­ withdrawal signs by decreasing central noradrenergic ate withdrawal signs in animals with different levels output (Taylor et al. 1988). of morphine dependence, to determine ifthis hypoth­ In the current place-conditioning experiments, pro­ esis is true. Thishypothesis is, however, consistent with pranolol was so effectivein preventing the development previous clinical studies. In the two papers that found of place aversion that animals spent equal amounts of propranolol to be effective in the mitigation of with­ time in each environment, regardless of any associa­ drawal in human opiate addicts (Grosz 1972; Roehrick tions with naloxone. Atenolol was much less effective and Gold 1987), the patients were already in various than propranolol in reducing place aversions, produc­ stages of detoxifIcation, whereas in the other studies ing signifIcant effects only at the highest dose. This with negative results, the patients were just beginning differencemay reflect atenolol's much more limited ac­ detoxifIcation. Differences in the level of dependence cess to the central nervous system after systemic ad­ in the human subjects between these studies could ex­ ministration (Agon et al. 1991) and may indicate that plain the discrepancies in their flndings. blockade of central J3-receptors is necessary to block The current study also found that propranolol was place-aversion development. In a previous study, it was effective in reducing signs of abstinence withdrawal, found that high doses of methylnaloxonium (10 mg/kg) a milder form of withdrawal than that produced by nal­ were required to produce place aversion when given oxone. None of the previous studies examined absti­ systemically, but only small concentrations (50 ng) were nence withdrawal, and, therefore, it is unknown ifpro­ required to produce the same effectwhen administered pranolol would be effective in alleviating abstinence centrally (Hand et al. 1988). The present data are con­ signs with the more intensive morphine treatment reg­ sistent with these results and may also indicate that imens. aversive aspects of opiate withdrawal are mediated at The present results indicate that J3-blockersmay be central locations. Although there are a substantial useful in treating patients who have mild opiate addic­ number of J3-adrenergic receptors in the accumbens, tions or who are trying to reduce or eliminate main­ J3-receptors are also located throughout much of the cen­ tenance doses of methadone. Currently, clonidine is tral nervous system (Rainbow et al. 1984). Additional the only non opiate pharmaceutical treatment that is experiments directly comparing central with peripheral generally effective in such patients. Clonidine, how­ J3-antagonist administration would be necessary to ever, produces drowsiness, restlessness, and hypoten­ confIrm exactly where propranolol was working to al­ sion (Charney et al. 1981). In the current study, pro­ leviate withdrawal aversion. pranolol was effective at a low dose range, and, The flnding in the current study that the J3-antag­ therefore, the high doses that have been tried in pa­ onists were effectivein reducing naloxone-precipitated tients in the past may not be necessary. Lower doses opiate withdrawal signs is contrary to what has been of propranolol would not produce drowsiness, restless- 310 G.c. Harris and G. Aston-Jones NEUROPSYCHOPHARMACOLOGY 1993-VOL. 9, NO.4

ness, or severe hypotension and may be preferred over ditioning factors in the development of drug dependence. clonidine. Alternatively, propranolol may be useful as Psychiatr Clin North Am 9:413-425 an adjunct to clonidine therapy, as was reported in an Chipkin RE, Dewey WL, Harris LS, Lowenthal W (1975): earlier paper (Roehrick and Gold 1987). Effectof propranolol on antinociceptive and withdrawal Previously, we have shown propranolol and ateno- characteristics of morphine. Pharmacol Biochem Behav 3:843-847 101 to be very effective in alleviating anxiety-like be­ haviors in animals withdrawing from opiates (Harris Cicero TJ, Meyer ER, Bell RD (1974): Effects of phenoxyben­ zamine on the narcotic withdrawal syndrome in the rat. and Aston-Jones 1993). Former addicts often report Neuropharmacology 13:601-607 anxiety and conditioned withdrawal reactions when Crawley IN, Laverty R, Roth RH (1979): Clonidine reversal they returnto a drug-associated environment (Childress of increased norepinephrine metabolite levels during et al. 1986). These reactions may precipitate a relapse morphine withdrawal. Eur J Pharmacol 57:247-250 to drug taking behaviors. Thus, propranolol might be Gilman AG, Goodman LS, RaIl TW, Murad F (eds) (1985): an effectivetreatment to prevent the occurrence of such Goodman and Gilman's The Pharmacological Basis of anxieties and conditioned withdrawal reactions. The Therapeutics, 7th ed. New York, Macmillan, pp 192-202 present results indicate that, in addition, l3-adrenergic Grosz HJ (1972): Narcotic withdrawal symptoms in heroin antagonists may alleviate somatic symptoms and other users treated with propranolol. Lancet 2:564-566 aversive components of opiate withdrawal. The con­ Hand TH, Koob GF, Stinus L, Le Moal M (1988): Aversive stellation of these effectsindicates that these agents may properties of opiate receptor blockade: Evidence for ex­ be benefIcial in helping addicts overcome their opiate clusively central mediation in naive and morphine­ dependency. It is hoped that future research efforts dependent rats. Brain Res 474:364-368 might be directed to test these hypotheses in opiate­ Harris Gc, Aston-Jones G (1993): Beta-adrenergic antagonists addicted individuals. attenuate withdrawal anxiety in cocaine- and morphine­ dependent rats. Psychopharmacology (In press)

Hollister LE, Prusmack JJ (1974): Propranolol in withdrawal from opiates. Arch Gen Psychiatry 31:695-698

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