[Effects of NMDA and metabotropic glutamate receptors antagonists in working memory task in rats].

Glutamate, major excitatory neurotransmitter in mammalian CNS, acts via ionotropic and metabotropic receptors. In agreement with the results of in vitro studies that pointed at close interactions between ionotropic NMDA and metabotropic glutamate mGlu5 receptors, blockade ofmGlu5 receptors was reported to enhance behavioral effects of NMDA receptor channel blockers. The present study aimed to study the effects of a highly selective mGluR5 antagonist MTEP, alone and in combination with NMDA receptor channel blocker MK-801, in rats trained to perform a delay-non-match-to-position task (working memory test). Acute administration of MK-801 (0.1 mg/kg) produced specific working memory impairment expressed as proactive interference (poor performance in the current trial due to the interfering influence of the experience in past trials). However, administration of MTEP (5.0 mg/kg), either alone or in combination with MK-801, had no appreciable effects. While these data clearly indicate little or no involvement of mGlu5 receptors in the mechanisms of working memory, present results demonstrate a robust experimental approach to study cognitive deficits associated with psychotomimetic drug treatment.

[Anhedonia, depression, anxiety, and craving in opioid dependent patients stabilized on oral naltrexone or naltrexone implant]. / Angedoniia, depressiia, trevoga i vlechenie k upotrebleniiu narkotikov u patsientov s opioidnoi zavisimost'iu pri kursovom lechenii peroral'noi ili implantiruemoi formoi naltreksona.

AIM: To assess the relationship between long-term naltrexone treatment and anxiety, depression and craving in opioid dependent individuals. MATERIAL AND METHODS: Opioid dependent patients (n=306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Inventory, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the post hoc Tukey test. RESULTS AND CONCLUSION: Anhedonia, depression, anxiety, and craving for opiates were elevated at baseline but gradually reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. There were no significant between-group differences prior to treatment dropout as well as between those who relapsed and who continued on naltrexone. CONCLUSION: These data do not support concerns that naltrexone treatment of opioid dependence precipitates anhedonia, depression, anxiety or craving for opiates.

Overcoming opioid blockade from depot naltrexone (Prodetoxon).

AIM: To describe a situation in which an opioid-dependent patient overcame naltrexone blockade. DESIGN, CASE REPORT, SETTING: Addiction treatment center in St Petersburg, Russia. PARTICIPANT: Patient with naltrexone implant. INTERVENTION: Detoxification. MEASUREMENTS: Clinical observations. CONCLUSIONS: It is possible, but very difficult, to overcome naltrexone blockade by using large doses of heroin.

[A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine]. / Farmakogeneticheskii analiz vliyaniya genov dofaminovoi i opioidnoi sistem na effektivnost' kombinirovannoi terapii naltreksonom i guanfatsinom bol'nykh opioidnoi zavisimost'yu.

AIM: To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial. MATERIAL AND METHODS: Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention. All enrolled participants were genotyped for polymorphisms in the following genes: mu- (OPRM1), kappa-opioid receptors (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (SLC6A3, DAT1) and alpha-2-adrenoreceptor (ADRA2A) a pharmacological target of guanfacine. RESULTS: The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone monotherapy. Regardless of treatment, several gene polymorphisms were associated with higher chance to complete the treatment program: allele Т DRD4 - 521 С/Т (rs1800955) (р=0.039; OR (95% CI)=3.7 (1.1-12.7); log-rank test: р=0.01); allele С DRD2 С957Т (rs6277) (р=0.03; HR=0.6 (0.34-0.95); genotype combination: DRD4 VNTR (LL) + OPRM1 A118G (rs1799971) (AA), р=0.051; DRD2 C957T (ТТ) + OPRM1 (rs1074287) (СС), р=0.025; DRD2 - 141С (II) + OPRM1 (rs510769) (АА), р=0.035; DBH Fau(СС) + OPRM1 (rs1074287) (СС), р=0.0497. Regardless of treatment several polymorphisms were associated with high risk of relapse: allele Т (rs510769) OPRM1 (р=0.053), allele А (rs1799971, A118G) OPRM1 (р=0.056), allele S exon III 48 bp DRD4 VNTR (р=0.001; HR=3.1 (ДИ 95% 1.57-6.18); genotype combinations: DRD4 - 521 С/Т (ТТ) + DRD2 Nco I (TT), р=0.026; DRD4 -521 С/Т (ТТ) + DRD2 -141 С (II), р=0.011; DRD4 - 521 С/Т (ТТ) + OPRM1 A118G (rs1799971) (AA), р=0.011; DRD2 Nco I(ТТ) + ADRA2A (СС), р=0.012; DRD2 Nco I(ТТ) + OPRM1 A118G (AA), р=0.02. The effects dependent on the treatment group were as follows: 1) in the N+G group, patients with the DRD4 -521 С/Т TT genotype had higher probability of completion of treatment program in comparison with other genotypes (CC and CT) (log-rank test: p=0.002); 2) in NP + GP group, patients with the OPRM1 rs510769 T allele had higher risk of relapse compared to the genotype GG (p=0.008) (FDR p<0.0125). CONCLUSION: The additive effect of opioid receptor genes and dopaminergic system genes on outcomes of treatment opioid dependence with oral naltrexone and guanfacine was shown. Pharmacological effects of naltrexone and guanfacine were associated with genetic variants of the DRD4 - 521C/T polymorphism, since its effect was shown only in the N+G group. The effect of the OPRM1 rs510769 polymorphism was demonstrated in the double placebo group that was associated with personality traits (temperament, character) and determined compliance. Genetic analysis is useful for determining potential responders to treatment of opioid dependence; genotyping can increase the efficacy of pharmacotherapy.

[Morphine-induced Straub tail reaction as a model of spasticity in mice: effects of serotonergic compounds]. / Vyzvannaia morfinom reaktsiia Shtrauba kak model' spastichnosti u myshei: éffekty serotoninergicheskikh soedinenii.

AIM: To adopt and validate the Straub tail reaction (SR) for comparative assessment of spastic effects of serotonergic compounds. MATERIAL AND METHODS: To measure the muscle relaxant activity, the morphine-induced Straub-tail assay was used. SR was graded according to modified intensity-score basis in a scale decribed by Kameyama et al. (1978). Subcutaneous injections of different doses of morphine (10-60 mg/kg) induced a dose-dependent SR with maximum response obtained 15-30 min after the morphine administration. RESULTS AND CONCLUSION: The centrally acting muscle relaxant baclofen (3-10 mg/kg) reduced SR induced by morphine (40 mg/kg) at all used doses; tizanidine decreased the intensity of SR at highest doses tested (0.6 and 1 mg/kg). Dantrolene (20-100 mg/kg), a peripherally acting muscle relaxant, did not affect SR. Effects of serotonergic agents depended on the specific mechanism of action. SR appears to be available for rapid evaluation of the effect of antispasticity drugs.

[A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence].

OBJECTIVE: Authors studied the effect of α-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts. MATERIAL AND METHODS: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment. The secondary outcomes were perceived stress (Perceived Stress Scale) and craving. RESULTS: At the end of six months, 20 (26.7%) patients in the N+G group and 15 (19.7%) (p=0.26 to N+G) in N+GP group were retained in treatment compared to 5 (6.7%) in the NP+G group (p=0.002 to N+G group and p=0.017 to N+GP group) and 8 (10.7%) in the double placebo group (p=0.013 to N+G group). There is no significant difference in retention between the N+G group and N+GP group at the end of treatment. CONCLUSION: Guanfacine had significant craving and stress reducing effect. Naltrexone was more effective than placebo for relapse prevention in opioid dependent patients. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone alone. Guanfacine moderately reduced both stress and craving.

[Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach]. / Stabilizatsiia remissii u bol'nykh opiinoi narkomaniei implantom naltreksona: farmakogeneticheskii aspekt.

AIM: To evaluate the effect of opioid receptor genes and dopamine system genes polymorphisms on treatment outcomes of opioid dependence with implantable and oral naltrexone. MATERIAL AND METHODS: Authors carried out a randomized double-blind, double-dummy, placebo-controlled clinical trial. Three hundred and six patients with opioid dependence were randomized into 3 equal treatment groups. The first group received implantation of 1000 mg naltrexone every 2 months during 6 months + oral naltrexone placebo; the second group - placebo implant every 2 months + oral naltrexone (50mg/day) and the third group - placebo implant + oral naltrexone placebo. It was genotyped polymorphisms in the following genes: mu-opioid receptor (OPRM1), kappa-opioid receptor (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (DAT1). RESULTS: Regardless of treatment several polymorphisms of these genes were associated with high risk of relapse: an allele L (2R) DRD4 120bp (p=0.05; OR (95% CI)=3.3(1.1-10.1)); an allele С DRD2 NcoI (р=0,051; OR (95% CI)=2,86 (1,09-7,52)); the genotype 9.9 DAT VNTR 40bp (р=0,04; OR (95% CI)=1,4 (1,3-1,5)); on the contrary, (СС+СТ)-(ТТ)) variants of OPRK1-DRD2Ncol increased a chance to complete treatment program (р=0,004; OR (95% CI)=7.4 (1.8-30.4)), Kaplan-Meier survival analysis (р=0,016). The probability of completing treatment program by the carriers of these variants was higher in the oral naltrexone group (p=0.016), lower in the double placebo group (p=0.015), but did not influence on treatment outcomes in the naltrexone-implant group. CONCLUSION: Naltrexone-implant is a highly effective medication for treatment of opioid dependence and its effectiveness exceeds that of oral naltrexone and placebo. The study has shown the joint influence of opioid receptor genes and genes of dopaminergic system on treatment outcomes of opioid dependence. Genetic analysis is useful for determining potential responders to naltrexone treatment of opioid dependence.

Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance.

Recent evidence suggests that acute administration of opioid analgesic drugs (such as morphine or heroin) produces delayed hyperalgesia. This hyperalgesic response is likely to result from hyperactivation of NMDA receptors triggered by stimulation of opioid receptors and may mediate acute tolerance. In support of this hypothesis, blockade of NMDA receptors attenuates opioid-induced delayed hyperalgesia and prolongs the duration of antinociceptive activity of morphine. Furthermore, the NMDA receptor-induced hyperalgesia is likely an unconditioned response to opioid receptor stimulation that becomes spatiotemporally associated with environmental cues accompanying repeated opioid exposure. This hypothesis conforms to the traditional Pavlovian requirement for conditioned and unconditioned responses to be qualitatively similar. In support of the role of NMDA receptor hyperactivation in morphine tolerance, NMDA receptor antagonists have been shown to block development of analgesic tolerance induced by repeated exposures to morphine. The view of the conditioned nature of opioid tolerance may be significantly extended by assuming that upon repeated drug administration an early-onset effect of a drug may become a predictive stimulus for a later-onset effect and, consequentially, it may become empowered to elicit the later-onset effect itself. Such 'intra-drug' conditioning hypothesis is well in line with the current experimental evidence but further studies will be needed to verify it directly.

Opioid blockade attenuates acquisition and expression of cocaine-induced place preference conditioning in rats.

Endogenous opioid systems have been implicated in experimental cocaine addiction. One aspect of this involvement may be the modulation of the motivational properties of cocaine by endogenous opioids. The present study assessed the effect of opioid blockade with naloxone (NLX) on cocaine's motivational properties using the conditioned place preference procedure. Treatment with doses of NLX that did not induce place aversion (0.01-1.0 mg/kg-1, SC), dose-dependently attenuated place preference induced by cocaine (10 or 20 mg/kg-1, IP). This effect of NLX was present when administered during acquisition of cocaine-induced place preference and when administered before expression of cocaine's motivational effects. These data support the notion that the (conditioned) motivational properties of cocaine are modulated through activation of opioid systems by endogenous opioid peptides. Furthermore, it is suggested that an interaction between endogenous opioid systems and dopaminergic systems in the brain might be of importance in the motivational facilitation of experimental cocaine addiction.

Classical conditioning of electrical self-stimulation of ventral tegmental area to brief visual stimuli in rats.

Two groups of rats with bipolar electrodes implanted unilaterally into the left ventral tegmental area were trained to lever-press for the response contingent electrical stimulation. After preliminary lever-press training, two types of daily sessions were held on 10 consecutive days: type T+, current intensity set at the Threshold level and each response was accompanied by the visual signal (stimulus lights above the lever briefly went off): and type ST-, current set at the Sub Threshold level and no visual stimuli. On day 11, combination of the subthreshold current intensities and stimulus lights previously associated with the threshold stimulation (session type ST+) resulted in a significantly elevated response rates compared to the performance under the subthreshold current without visual stimuli (session type ST-). The extinction and recovery of this phenomenon are also demonstrated.

Analgesic and reinforcing effects of morphine in mice. Influence of Bay K-8644 and nimodipine.

The aim of the present work was to clarify the role of calcium influx through L-type calcium channels in the rewarding and analgesic effects of morphine. Therefore the effects of Bay K-8644 and nimodipine, dihydropyridine calcium agonist and antagonist, respectively, on the analgesic and rewarding effects of morphine in mice were studied. Morphine-induced analgesia was measured with the aid of writhing test, hot plate test and tail clip test. The rewarding properties of morphine were studied using i.v. self-administration in drug-naive mice. Bay K-8644 potentiated morphine-induced analgesia in all the tests. The influence of nimodipine on morphine analgesia was more complicated and depended on the dose of morphine and test used. In self-administration experiments morphine exhibited the bell-shaped concentration-response curve. Bay K-8644 produced a shift of the curve to the left, while nimodipine had the opposite action indicating, respectively, facilitating and inhibitory influence on morphine rewarding effect. It is concluded that nimodipine exhibits partial antagonistic properties towards the rewarding action of morphine and slightly potentiates morphine-induced analgesia while Bay K-8644 increases either the rewarding or the analgesic effects of morphine.

Kappa-opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice.

Modulation of the reinforcing effects of cocaine and morphine by the kappa-opioid receptor agonist U50,488H (trans-3,4-dichloro-N-methyl-N-(2-1-pyrrolidinyl)-cyclohexyl-benzeace tamide) was studied by using the method of intravenous (i.v.) self-administration in drug-naive Wistar rats and DBA/2 mice. Self-administration of cocaine (by rats) and morphine (by mice) was readily initiated and showed an inverted U-shaped unit dose-response curve. Treatment with the kappa-opioid receptor agonist U50,488H dose dependently decreased the intake of both cocaine and morphine when offered in doses that readily initiated and sustained self-administration behavior. Interestingly, treatment with U50,488H induced self-administration behavior with lower sub-threshold doses of cocaine and morphine. With regard to the inverted U-shaped relation between the dose of the drug and the number of self-infusions, it seems that activation of the kappa-opioid receptor with U50,488H produced an almost parallel shift to the left, indicating an increased sensitivity of the animals for the reinforcing effects of cocaine and morphine. These data demonstrate an involvement of kappa-opioid systems in the neurobiological mechanisms underlying drug addiction in general, and sensitivity for drug reward in particular. Furthermore, the dual effect of kappa-opioid receptor agonists on drug self-administration may prompt further research into the mechanisms underlying the role of endogenous opioids in drug self-administration.

Modulation of cocaine intravenous self-administration in drug-naive animals by dihydropyridine Ca2+ channel modulators.

The dihydropyridine Ca2+ channel blocker nimodipine and the dihydropyridine Ca2+ channel activator BayK 8644 (1,4-dihydropyridine-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-py ridine- 5-carboxylate) were administered to drug-naive mice and rats that were tested for intravenous cocaine self-administration. A range of cocaine doses was tested to investigate the nature of the effect. The results indicate that nimodipine and BayK 8644 shifted the dose-response curve for cocaine's reinforcing action to the right and left, respectively. Thus, the Ca2+ channel blocker nimodipine decreases the sensitivity of mice and rats to the reinforcing effects of cocaine while the Ca2+ channel activator BayK 8644 makes the animals more sensitive to cocaine reward. The results suggest that a dihydropyridine-sensitive mechanism is implicated in the initiation of cocaine self-administration.

Effects of NMDA receptor antagonists on cocaine-conditioned motor activity in rats.

NMDA receptor antagonists have been reported to affect learned behaviors conditioned with abused drugs, with the outcome dependent, in part, on the class of NMDA receptor antagonist used. The present study tested the ability of various site-selective NMDA receptor antagonists to modify cocaine-conditioned motor activity. Two procedures were used for independently assessing drug effects on spontaneous activity and expression of cocaine-conditioned behavior. In the conditioning experiments, rats were administered i.p. injections of cocaine (30 mg/kg) or saline paired with distinctive environments. Spontaneous horizontal activity was dose-dependently enhanced by dizocilpine (0.03-0.3 mg/kg) and memantine (1-30 mg/kg), but not by D-CPPene (3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494; 1-10 mg/kg), ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2, 3-quinoxalinedione; 3-56 mg/kg), or eliprodil (3-30 mg/kg). Higher doses of memantine, D-CPPene (1-10 mg/kg), eliprodil (3-30 mg/kg), or ACEA-1021 reduced vertical activity. Following five cocaine-environment pairings, rats displayed significant increases in motor activity when exposed to the cocaine-paired environment. The following antagonists were administered prior to the conditioning test: dizocilpine (MK-801; 0.03-0.1 mg/kg), memantine (1-10 mg/kg), D-CPPene (0.3-3 mg/kg), ACEA-1021 (3-10 mg/kg), and eliprodil (1-10 mg/kg). Of these, memantine, ACEA-1021 and, to the lesser degree, eliprodil attenuated expression of cocaine-conditioned motor activity at doses that did not significantly affect spontaneous motor activity. These results show that cocaine-conditioned behaviors can be selectively modulated by some, but not all, NMDA receptor antagonists.

Subchronic morphine increases amphetamine-induced potentiation of brain stimulation reward: reversal by DNQX.

The ability of morphine and amphetamine to potentiate brain stimulation reward was studied in rats with monopolar electrodes in the medial forebrain bundle. Animals received seven daily injections of morphine (3 mg/kg, s.c.) or saline followed 10 min later by either DNQX (100 mg/kg, i.p.) or its vehicle. On the 8th day the self-stimulation (SS) response was examined 60 min or 30 min after the administration of either morphine (3 mg/kg, s.c.) or amphetamine (1.5 mg/kg, s.c.), respectively. It was found that the subchronic administration of morphine sensitizes animals to subsequent amphetamine-, but not morphine-induced activation of SS, which may be prevented by the coadministration of DNQX, an antagonist of the non-NMDA subtype of glutamate receptors.

Caffeine place conditioning in rats: comparison with cocaine and ethanol.

The present study employed the place conditioning technique to compare rewarding potential of caffeine with that of cocaine and ethanol. In Experiment 1 caffeine, cocaine and ethanol place conditioning were estimated independently, whereas in Experiments 2 and 3 the preference of the external cues associated with caffeine vs. cocaine and caffeine vs. ethanol was assessed in a single test. Caffeine (1.5 mg/kg, i.p.) cocaine (5 mg/kg, i.p.) and ethanol (1.2 g/kg, i.g.) did produce secondary reinforcing effects comparable in magnitude (Experiment 1). In Experiments 2 and 3 animals had the opportunity 'to compare' rewarding effects of two drugs. Data showed that the preference of cocaine-paired cues was absolutely (100%) higher than those of caffeine, whereas reinforcing actions of caffeine and ethanol seemed to be equal. The proposed modification of conditioned place preference procedure may be useful for the comparison of rewarding values of different drugs with presumed addictive potential.

Enhancement of morphine self-administration in drug naive, inbred strains of mice by acute emotional stress.

The primary reinforcing effect of morphine was compared in two genetically inbred strains of mice (C57BL/6 and DBA/2) using the intravenous self-administration procedure in drug naive animals. The morphine self-administration differed between the mouse strains. DBA/2 but not C57BL/6 acquired self-administration of morphine with a bell-shaped unit dose-response curve. Acute physical stress induced by electrical footshocks did not significantly affect the self-administration in both strains. Acute emotional stress induced by forcing mice to witness another mouse being subjected to acute physical stress caused a shift of the bell-shaped unit dose-response curve of morphine self-administration to the left in the DBA/2 mice. The C57BL/6 mice, which initially failed to demonstrate stable self-administration, started to self-administer morphine after emotional but not physical stress. Emotional distress may increase the individual sensitivity to the rewarding effects of morphine and may render an individual more susceptible to development of drug dependence.

Influence of buprenorphine, butorphanol and nalbuphine on the initiation of intravenous cocaine self-administration in drug naive mice.

The influence of different mixed mu-kappa-opioid receptor agonists-antagonists on cocaine reinforcement was studied using the method of initiation of intravenous cocaine self-administration in naive mice. Self-administration of cocaine was readily initiated according to an inverted U-shaped unit dose-response curve. Buprenorphine, butorphanol and nalbuphine tested against the optimal unit dose of cocaine (0.8 microg per infusion), inhibited initiation of cocaine self-administration in a dose-dependent manner. When tested against a scale of cocaine unit doses (0.2 -1.6 microg per infusion) buprenorphine (0.1 mg/kg, s.c.) and nalbuphine (2 mg/kg, s. c.) produced a shift of the optimal cocaine dose from 0.8 to 0.4 microg/inf, while butorphanol (1 mg/kg, s.c.) shifted the optimal unit dose of cocaine to the right along the cocaine unit doses axis. Co-administration of naloxone (0.1 mg/kg, s.c.) significantly reduced the effect of buprenorphine but failed to influence the effect of nalbuphine and butorphanol on cocaine intake. Taken together, these results suggest that nalbuphine is capable of affecting cocaine's reinforcing properties in the same manner as buprenorphine during the initiation phase of cocaine self-administration behavior, while butorphanol causes the opposite effect. Although the exact opioid profile of action of the mixed opioid receptor agonists-antagonists is as yet not precisely known, the present findings suggest that multiple opioid receptor systems (i.e. mu and kappa) play a role in reinforcing properties of cocaine and that a co-operative interaction between mu- and kappa-opioid systems may be of importance during initiation of cocaine self-administration.

Systems of reinforcement and drug dependence.

Experimental data are presented in support of the hypothesis on the role of positive and negative reinforcing systems in the mechanism of drug dependence. Drugs with abuse potential (DAP) may change the manner of response to negative emotional stimuli, activate positive emotional reactions in animals, and possess primary reinforcing properties. Reward and punishment systems respond sensitively to withdrawal from DAP or antagonist administration. Catecholaminergic and peptidergic processes are of importance in the mechanisms of the emotionally positive action of DAP.