Resistance of androgen-mediated aggressive behavior in mice to flutamide,an antiandrogen

The effects of ethanol (0.4, 0.8, 1.6, and 2.4 g/kg p.o.) on behavior of aggressive, timid, and sociable male mice treated with the drug on paired interactions with non-aggressive males given water were investigated. Under control interactions, aggressive mice attacked their partners, timid mice showed defensive-escape activities though their partners were completely non-aggressive, and sociable mice intensively investigated their partners. A low dose of ethanol (0.4 g/kg) increased while higher doses (0.8 to 2.4 g/kg) reduced aggressive activities in aggressive mice. Ethanol (0.8 g/kg) also evoked aggressive behavior in non-aggressive timid mice but no dose of ethanol stimulated aggression in non-aggressive sociable mice. Ethanol altered timid defensive-escape activities only in the highest dose of 2.4 g/kg: this dose increased defences and escapes in aggressive males while it reduced defensive upright postures in timid mice. However, 2.4 g/kg of ethanol reduced also another upright movement (exploratory rearing) in timid mice. Sociable activities were not increased by any dose of ethanol tested. By contrast, 0.4 g/kg of ethanol reduced sniffing and following partners in sociable mice. Thus, ethanol exhibited relatively strong aggression-stimulating effects in aversively disposed subjects while the drug was not able to supress timid defensive escape behavior and to stimulate active non-aggressive contacts between strange male mice.     

Effect of selective blockade of mu(1) or delta opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats.

This study examined the effects of a nonselective opiate antagonist and antagonists selective for the mu(1) versus delta opioid receptor on ethanol-seeking behavior induced by alcohol-related environmental stimuli in an animal model of relapse. Rats were trained to self-administer ethanol (10% w/v) or water on an FR 1 schedule in 30-min daily sessions. The availability of ethanol was signaled by an olfactory discriminative stimulus (S(+)). A different olfactory stimulus (S(-)) signaled water availability. In addition, each lever-response resulting in delivery of ethanol was paired with illumination of a visual cue for 5 s (SC(+)), whereas a 5-s white noise (SC(-)) was associated with water. The rats were then subjected to a 20-day extinction phase where lever presses had no programmed consequences. Reexposure to the S(+)/CS(+) stimulus condition in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of S(-)/CS(-). Subsequently, ethanol-seeking behavior associated with the S(+)/CS(+) stimulus condition was studied in rats treated with the nonselective opiate antagonist naltrexone (0.25-1 mg/kg, SC), the delta selective antagonist naltrindole (1-5 mg/kg, IP), and the mu(1) selective antagonist naloxonazine (1-15 mg/kg, IP). Naltrexone (1 mg/kg) and naltrindole (5 mg/kg) selectively inhibited alcohol-seeking behavior. Naloxonazine (15 mg/kg) also reduced ethanol-seeking behavior but produced some nonselective behavioral suppression as well. The results provide evidence that selective blockade of either mu(1) or delta opioid receptors inhibits ethanol-seeking behavior elicited by drug-related environmental stimuli. Moreover, the data suggest that drugs aimed at the delta opioid receptor may offer advantages in the treatment and prevention of relapse compared with agents that also block the mu(1) receptor.     

Effects of alcohol on attack and defensive-submissive reactions in rats

The effects of alcohol on fighting behavior in pairs of rats were studied when either the dominant or the subordinate animal was given the drug. Intense fighting episodes, consisting of all major acts and postures of attack, threat, defense, and submission, were generated between two otherwise isolated male Sprague-Dawley rats in a situation in which the accustomed food reinforcement was omitted. Alcohol (10% w/v) was administered intraperitoneally 10 min prior to the fighting test. A low dose (0.5 g/kg), when given to the dominant animal, increased the frequency of biting attack and prolonged the display of the aggressive posture. Higher doses of alcohol (1.0, 1.5 g/kg) suppressed attack behavior and, when given to the subordinate animal, impaired defensive upright postures. In a further experiment, animals without fighting or drug experience were subjected to attack by a non-treated dominant animal. When treated with alcohol (1.0, 1.5 g/kg) naive rats were more frequently attacked and injured, but reacted more readily to initial attacks by submissive-supine postures. The results demonstrate differential effects of alcohol depending on the type of drug recipient (dominant, experienced subordinate, or naive). The drug had greater effect on attack behavior than on defensive-submissive reactions.     

Free-choice responding for ethanol versus water in alcohol preferring (P) and unselected Wistar rats is differentially modified by naloxone,bromocriptine, and methysergide

The role of opioids, dopamine and serotonin in ethanol (EtOH) reward and preference was investigated in non-deprived, Alcohol-Preferring (P), and genetically heterogenous Wistar rats. Operant responding for ethanol was initiated using sweet-solution substitution procedures. The rats were then trained in 30-min daily sessiosn to respond for ethanol (10% v/v) versus water under a two-lever, free-choice contingency. All testing was conducted in the absence of water and food deprivation or addition of sweeteners to the ethanol drinking solution. Rats of both strains developed stable preferences in responding for ethanol over water and consumed ethanol at quantities sufficient to produce pharmacologically relevant mean blood alcohol concentrations (P-Rats: 98±19.6 mg%; unselected Wistars: 41.7±8.5 mg%). InP-rats, systemic naloxone (NAL; 0.125, 0.25 and 0.5 mg/kg) pretreatments resulted in a dose-dependent suppression in responding for both ethanol and water, but did not alter ethanol preference (expressed as percent ethanol of total intake). In contrast, bromocriptine (BRO; 1.0, 2.0 and 4.0 mg/kg) produced a significant, dose-dependent shift in preference from ethanol toward water by inhibiting responding for ethanol while enhancing water consumption. Inunselected Wistar rats, NAL and BRO treatments produced changes in ethanol preference patterns similar to those observed in P-rats. However, compared to P-rats, these changes were smaller and not consistently dose dependent. No changes in ethanol preference and water or ethanol intake were observed with methysergide (MET; 2.5, 5.0, 10.0 mg/kg) in either strain of rat. Together, the results suggest a possible involvement of dopaminergic mechanisms in the reinforcing properties of ethanol. In contrast, the response decrements observed with naloxone may reflect a more general depression in consummatory behavior.This is publication number 5768 BCR from the Research Institute of Scripps Clinic, La Jolla, California     

Testosterone modulates the effects of ethanol on male mouse aggression

In a series of three experiments, we evaluated the degree to which the effects of acutely administered ethanol on aggressive behavior of male CFW mice toward a male intruder interact with, and depend on, androgen levels. In the first experiment, mice were tested at 15 min after 0, 0.1, 0.3, 1.0, 1.7, or 3.0 g/kg of ethanol PO. The highest dose (3.0 g/kg) significantly suppressed aggression by the male residents. In the second experiment, aggressive behavior was suppressed from 5 to 60 min after 3.0 g/kg ethanol administration PO. The third experiment evaluated the role of testosterone in these effects in another set of male mice that were castrated and then implanted with a 7.5-mm or 2.5-mm silastic capsule of testosterone (T) or a silastic capsule containing cholesterol as a control. The castrated mice with 2.5-mm T capsules or cholesterol capsules had lower baseline levels of aggression than intact mice or castrated males with 7.5-mm T capsules, but they demonstrated an alcohol dose-response pattern similar to that of the intact males. The castrated males with 7.5-mm T capsules had a different dose-response curve than the other males. Doses of 1.0 and 1.7 g/kg ethanol PO significantly enhanced aggression; 5.6 g/kg was required to suppress aggression. Ethanol effects on aggressive behavior did not require T or changes in T level, but T levels altered behavioral sensitivity to ethanol.     

Effects of SR141716 and WIN 55,212-2 on tolerance to ethanol in rats using the acute and rapid procedures

Rationale Our previous findings have shown rapid cross-tolerance between ethanol and Δ⁹-tetrahydrocannabinol and that intraperitoneal (i.p.) injection of cannabinoid receptor type 1 (CB1R) antagonist SR141716 (SR) does not interfere with tolerance to either of these drugs in mice. Objectives This study investigates the effects of SR, alone or in combination with the CB receptor agonist WIN 55,212-2 (WIN), on the development of acute and rapid tolerance to the incoordinating effect of ethanol in rats. Materials and methods Male Wistar rats received SR, through i.p. (0.5–2.0 mg/kg) or intracerebroventricular (i.c.v.) injections (0.5–4.0 μg), alone or together with WIN (1.0 μg, i.c.v.), in combination with ethanol (2.7 g/kg, i.p.). Another group received WIN (1.0 μg, i.c.v.) in combination with ethanol (2.3 g/kg), and the rats were tested for motor coordination. Rapid tolerance was assessed 24 h later by administering ethanol to all animals and retesting them under the same dose regimen. Acute tolerance was evaluated for 75 min after ethanol (3.0 g/kg, i.p.) in animals treated with SR or WIN (i.c.v.). Results The reduced motor impairment on day 2 (i.e., rapid tolerance) was blocked by SR (i.p. and i.c.v.). WIN (1.0 μg, i.c.v.) facilitated rapid tolerance and also prevented the blockade of rapid tolerance by SR (1.0 μg, i.c.v.). In the acute tolerance procedure, SR did not affect the motor incoordination induced by ethanol. Conclusions The results suggest that the endocannabinoid system may contribute to the development of rapid tolerance to ethanol.     

Ethanol locomotor sensitization, but not tolerance correlates with selection for alcohol preference in high- and low-alcohol preferring mice

Rationale: Some theories have advanced a role for both locomotor sensitization and tolerance in the reinforcing properties of drugs. The present studies used selected lines of mice to assess genetic correla- tions among ethanol drinking, ethanol locomotor sensitization, and tolerance to the depressant effects of ethanol. Objectives: Ethanol-naive high- and low-alcohol preferring (HAP and LAP) selected lines of mice were tested for locomotor sensitization to ethanol and acquisition of acute functional tolerance to ethanol using the static dowel test. Methods: For the locomotor sensitization study, mice received four i.p. injections of one of five doses of ethanol (0–3.5 g/kg) at 48-h intervals. On the sensitization test day, 48 h after the last drug administration day, all mice received a 2.0-g/kg ethanol injection. Other mice from the same lines were subjected to a two-injection (3.75 g/kg total), acute functional tolerance procedure assessing disruption of balance on a static dowel. Results: Lines differed neither in the acute locomotor activating nor depressant effects of ethanol. Additionally, neither line’s response to the depressant effect of 3.5 g/kg ethanol changed with repeated injection. However, locomotor sensitization was seen in HAP but not LAP mice that had received 2.75 g/kg or 3.5 g/kg ethanol during repeated administration. Both HAP and LAP mice acquired equivalent acute functional tolerance, as measured by an increase in blood ethanol concentration between the first and second recovery measures. Conclusions: Overall, these findings imply that high ethanol consumption in mice appears to be genetically related to ethanol locomotor sensitization. Additionally, ethanol locomotor sensitization does not appear to be related to tolerance to the depressant effects of ethanol. These findings support a role for sensitization in high alcohol-seeking behavior in mice. Received: 28 October 1999 / Accepted: 20 January 2000     

Effects of the NMDA receptor channel blockers memantine and MRZ 2/579 on morphine withdrawal-facilitated aggression in mice

Rationale: Opioid withdrawal is known to facilitate aggressive behavior in laboratory rodents. Aggression develops as the somatic signs disappear and thus may reflect protracted withdrawal-related behavioral alterations. Antagonists acting at the NMDA receptor are known to attenuate the expression of morphine withdrawal syndrome in laboratory animals. Objective: The present study aimed to evaluate the effects of low-affinity NMDA receptor channel blockers (memantine and MRZ 2/579) on aggression facilitated by morphine withdrawal in mice. Methods: Significant increases in aggressive behavior were observed 48 h after repeated morphine administration (8 days, b.i.d., 10–80 mg/kg, SC) was discontinued. Separate groups of mice were treated intraperitoneally with vehicles or different doses of memantine (1, 3, 10 or 30 mg/kg) or MRZ 2/579 (1, 3 or 10 mg/kg) 48 h after the last morphine injection. Results: Both compounds dose-dependently reduced the expression of aggressive behavior while having no significant effect upon the intensity of non-aggressive social contacts. Memantine significantly diminished the occurrence of all recorded components of aggressive behavior (attacks/bites, threats, tail rattling) while MRZ 2/579 affected mainly the appetitive events of aggressive bursts (threats, tail rattling). For both compounds, anti-aggressive effects occurred at dose levels that did not produce motor impairment in the Rotarod test. Conclusions: Taken together with the evidence on the lack of selective anti-aggressive effects of these drugs in morphine-naive mice, attenuation of the aggression observed in the present study may be due to specific interaction with morphine withdrawal-triggered processes. Received: 2 May 1999 / Final version: 17 November 1999     

Involvement of catecholamines in acute tolerance to ethanol in mice

The percentage of mice able to remain on a rolling drum for 45 s was recorded at 1.25 min and 30 min after administration of ethanol (2.4 g/kg). Though there was no significant difference in brain ethanol levels at the two test times, performance was markedly different with significantly fewer mice able to remain on the drum at 1.25 min than at 30 min. This phenomenon, known as acute tolerance, was antagonised by pretreating mice with haloperidol (0.4 mg/kg), FLA-63 (25 mg/kg), diethyldithiocarbamate (400 mg/kg), phenoxybenzamine (40 mg/kg), phentolamine (20 mg/kg), yohimbine (3 mg/kg) and clozapine (1 mg/kg), but not by spiperone (0.16 mg/kg), -methyl-p-tyrosine (300 mg/kg) or phenobarbitone (10 mg/kg). The relative potencies of the effective blocking agents suggest that ₂-receptors may play an important role in mediating acute ethanol tolerance.     

Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

Rationale

Higher doses of benzodiazepines and alcohol induce sedation and sleep; however, in low to moderate doses these drugs can increase aggressive behavior.

Objectives

To assess firstly the effects of ethanol, secondly the effects of flunitrazepam, a so-called club drug, and thirdly the effects of flunitrazepam plus alcohol on aggression in mice and rats.

Methods

Exhaustive behavioral records of confrontations between a male resident and a male intruder were obtained twice a week, using CF-1 mice and Wistar rats. The salient aggressive and non-aggressive elements in the resident's repertoire were analyzed. Initially, the effects of ethanol (1.0 g/kg), and secondly flunitrazepam (0; 0.01; 0.1; and 0.3 mg/kg) were determined in all mice and rats; subsequently, flunitrazepam or vehicle, given intraperitoneally (0; 0.01; 0.1; and 0.3 mg/kg) was administered plus ethanol 1.0 g/kg or vehicle via gavage.

Results

The most significant finding is the escalation of aggression after a moderate dose of ethanol, and a low dose of flunitrazepam. The largest increase in aggressive behavior occurred after combined flunitrazepam plus ethanol treatment in mice and rats.

Conclusions

Ethanol can heighten aggressive behavior and flunitrazepam further increases this effect in male mice and rats.     

Behavioral correlations of gradual forced administration of psychoactive drugs

The study was aimed at evaluating the behavioral correlations of the forced administration of psychoactive drugs. Wistar rats received the following drugs in elevated doses (over 4 days, i. p.): (i) physiological saline (control; 0.1-0.2-0.4-0.8 ml/rat), (ii) psychostimulant amphetamine (0.5-1.0--2.0-4.0 mg/kg); (iii) opioid analgetic fentanyl (0.00625-0.0125--0.025-0.05 mg/kg), (iv) ethanol 40% solution (0.5-1.0--2.0-4.0 g/kg), (v) barbiturate sodium ethaminal (2.5-5--10-20 mg/kg); and(vi) synthetic glucocorticoid dexamethasone (0.5-1.0--2.0-4.0 mg/kg). The forced regime of drug administration led to gradual load of the organism and prevented drug tolerance. The dynamics of self-stimulation reaction of the lateral hypothalamus was registered every day over drug administration period and revealed the following regularities: (I) dose-dependent effect of psychostimulant amphetamine and opioid analgetic fentanyl; (II) dexamethasone modulated self-stimulation, increasing (2 day, 1 mg/kg) or decreasing it (3 day, 2 mg/kg); (III) ethanol (1-2 g/kg) activated self-stimulation slightly; (IV) sodium ethaminal slightly inhibited self-stimulation and increased the thresholds of self-stimulation. In 24 h and 72 h after the last administration of drugs, the rat behavior was assessed in open field, elevated plus maze, resident-intruder paradigm, and Porsolt's test. In the open field, significant signs of post-intoxication exposure of psychoactive drugs were revealed, which were registered for 24-72 h after drug withdrawal. The withdrawal of drugs was accompanied with reduction (in 24 h) and subsequent recovery (in 72 h) of the vertical motor activity, exploration behavior, and emotionality. The anxiety indexes were increased up to the 3rd day after withdrawal. The antidepressant effect was also increased. The system of aggression-defense was restored only in rats treated with ethanol. The indexes of individual behavior and communicability in the post-intoxication period were decreased as well. It is suggested that the forced regime of drug administration in increasing doses with subsequent withdrawal of drug injections is a suitable method to evaluate the behavioral elements of drug dependence.     

Effects of alcohol dependence on shock-induced fighting: action of muscimol and homotaurine.

We have applied the electroshock-induced fighting behavior to the study of experimental alcohol dependence. Adult Wistar rats were intoxicated chronically with ethanol (10 g/kg/24 h) for 13 days. Electroshock-induced fighting behavior was studied during chronic intoxication and withdrawal in comparison with normal rats receiving a water-carbohydrate solution isocaloric to ethanol. Rats were divided into groups receiving respectively muscimol (0.25 mg/kg), a GABAA agonist; homotaurine (140 mg/kg) a GABA mimetic; and physiological saline (10 ml/kg), intraperitoneally. During chronic intoxication, rats showed an increase in defensive-fighting behavior. Withdrawal accentuated the aggressive behavior and muscimol and homotaurine inhibited it. These results confirm the relevance of the electroshock-induced defensive fighting behavior test in chronic intoxication with alcohol, but to show the involvement of GABAergic transmission in the behavioral effects of alcohol withdrawal, additional experiments with other GABA mimetics and with GABA antagonists should be considered.     

Effects of drug-state change on discrimination performance

A single dose of d-amphetamine (0.25, 0.50, or 1.00 mg/kg), administered in 5 successive sessions, did not seriously impede the discrimination performance of male Holtzman rats under cued reinforcement conditions. A 2.00 mg/kg dose, however, produced a total cessation of operant behavior. In 2 postdrug (saline) sessions, groups previously treated with 0.50 or 1.00 mg/kg demonstrated an initial decrement and subsequent recovery in performance. A second experiment demonstrated that rats administered either saline or 0.50 mg/kg d-amphetamine for 5 successive sessions showed a decrement and subsequent recovery in performance when switched to the opposite treatment condition for the next 2 sessions. These data may be explained in terms of a change in drug state.     

Aggressiveness induced by marihuana and other psychotropic drugs in REM sleep deprived rats

In 96 hr REM sleep deprived rats given 5–40 mg/kg of Δ⁹-THC and several alcoholic extracts of marihuana induce dose dependent aggressive behavior. The aggressiveness appears after the first application of the drugs and is observable for at least 4 hr following the injection. The rats also develop a high degree of irritability. LSD-25 (0.02–0.08 mg/kg), mescaline (80 mg/kg), d-amphetamine (1.0 to 4.0 mg/kg) and ethanol (0.8–1.6 g/kg) failed to elicit either aggressiveness or irritability in the REM sleep deprived rats. On the other hand, 8 and 16 mg/kg of d-amphetamine induced aggressiveness which was, however, far below that observed in the marihuana treated animals. These data add further support to the previous findings that the acute effects of marihuana can be dramatically changed from depression, as observed in normal rats, to irritability and aggressiveness as observed in stressed animals.     

Intraspecies aggression in rats: Effects of d-amphetamine and chlordiazepoxide

d-Amphetamine sulfate and chlordiazepoxide hydrochloride, administered to either the dominant or subordinate rat, altered several components of fighting behavior in a dose-dependent biphasic manner. Stereotypic sequences of attack, threat, defense, and submission were generated between pairs of previously isolated Sprague-Dawley rats by extinction of a food-reinforced response. Low doses of amphetamine (0.05, 0.1 mg/kg) and chlordiazepoxide (2.5, 5.0 mg/kg) given i.m. to the dominant rat 30 min prior to 15 min tests increased attack bites and leaps and the display of aggressive postures and threats, whereas higher doses of both drugs (0.5, 1.0 mg/kg amphetamine; 20 mg/kg chlordiazepoxide) suppressed attacks and threats. Amphetamine and chlordiazepoxide, administered to the subordinate rat, caused a more prolonged display of submissive-supine and defensive-upright postures; chlordiazepoxide (10.0, 20.0 mg/kg) prolonged immobile crouching whereas amphetamine (0.5, 1.0 mg/kg) greatly reduced this response. Drugged subordinate rats also provoked more attacks and threats by the non-drugged opponents. The multi-response analysis of fighting reveals that various elements of aggressive and defensive-submissive behavior patterns are differentially sensitive to drug action. The results indicate that amphetamine and chlordiazepoxide can facilitate or inhibit attack or defense depending on the dose level and which of the opponents was injected, but do not reverse dominance-subordination relationships.     

Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate–putamen-binding sites

Rationale Higher doses of benzodiazepines induce sedation. However, in low to moderate doses, benzodiazepines can increase aggressive behavior both after acute and chronic administration. The determinants for increasing aggression after chronic intake of flunitrazepam, a so-called date rape drug, in violence-prone individuals are incompletely understood. Objectives The aim of this study is to assess the effects of acute and chronic treatment with flunitrazepam on male aggression in resident rats. We also examined possible changes in binding to benzodiazepine receptors throughout the brain of rats that display aggressive behavior after repeated flunitrazepam treatment using quantitative receptor autoradiography. Materials and methods The behaviors of the male Wistar resident rats (n = 35) toward a male intruder were recorded for 10 min twice a week. The salient aggressive and non-aggressive elements in the resident rat’s behavior were analyzed. Initially, the dose-dependent effects of flunitrazepam (0.01, 0.03, 0.1, 0.18, and 0.3 mg/kg) or vehicle were determined in all rats; subsequently, 0.3 mg/kg per day flunitrazepam was administered for 42 days (n = 15), and a parallel group was treated with vehicle (n = 20). After the chronic treatment, the flunitrazepam (0, 0.01, 0.03, 0.1, 0.18, and 0.3 mg/kg) effects were again assessed. Results The most significant finding is the escalation of aggression after chronic treatment with flunitrazepam. A previously sedative 0.3 mg/kg dose of flunitrazepam engendered very high levels of attack bites, sideways threats, and aggressive postures (total aggression) after 6 weeks of daily administration. Individual differences emerged, and these were associated with decreased binding to benzodiazepine receptors, mainly in the limbic structures such as the cingulate cortex (cingulate areas 1 and 2) and caudate–putamen (posterior part) of aggressive animals, suggesting that these areas are pivotal in the control of emotional and aggressive behavior. Conclusions Chronic flunitrazepam produces changes in receptor binding in discrete areas of the cingulate cortex and caudate–putamen that are proposed to be part of the mechanisms for increased expression of aggressive behavior.     

Involvement of adenosine receptor activities in aggressive responses produced by clonidine in mice

A behavioral study was made of the mechanisms underlying the aggressive behavior induced by high doses of clonidine in mice. The frequency of clonidine-induced aggressive responses such as attacking and biting was increased dose-dependently from 10 to 50 mg/kg. Aggressive behavior induced by clonidine at doses of 10–30 mg/kg was potentiated under conditions of isolation and food deprivation for 24 h. Clonidine (30 mg/kg)-induced aggressive behavior was attenuated by adenosine (10 mg/kg IP) or dipyridamole (10 mg/kg IP), but markedly antagonized by combined pretreatment with both drugs. The behavior was strongly reduced by potent adenosine analogs, such as N⁶-cyclohexyl adenosine (CHA, 0.1 and 0.2 mg/kg IP) and N⁶-(l-phenyl isopropyl) adenosine (l-PIA, 0.2 mg/kg IP), but conversely was potentiated by phentolamine (10 mg/kg IP) or theophylline (10 mg/kg IP). Diazepam (2.5 mg/kg IP) and Ro 15-1788 (2.5 mg/kg IP), a benzodiazepine receptor antagonist, also blocked the aggressive behavior. The inhibition by CHA (0.2 mg/kg IP) or diazepam (2.5 mg/kg) of clonidine-induced aggression was not antagonized by additional pretreatment with bicuculline (2 mg/kg IP). The aggressive response to apomorphine (8 mg/kg IP) was not affected by those drugs which inhibited the response to clonidine. The results suggest that the aggressive behavior evoked by high doses of clonidine, but not that by apomorphine, involves a blockade of adenosine receptors.     

Noradrenergic role in the self-administration of ethanol

Involvement of noradrenergic and/or dopaminergic processes of the brain in self-administration behavior toward ethanol was assessed in rats allowed to lever-press for 25 mg/kg intragastric doses on a CRF schedule. Initial access to infusions of saline for establishing an operant baseline was followed by one 10-hr session on acquisition contingencies for ethanol and then one extinction session on saline. Prior to a reacquisition session, rats were treated with either (a) saline, (b) alpha-methyl-p-tyrosine (AMT; 225 mg/kg), (c) 1-phenyl-3(2-thiazolyl)-2-thiourea (U-14,624; 600 mg/kg or 300 mg/kg), or (d) haloperidol (3.5 mg/kg). Only the saline- pretreated control group and the haloperidol-treated rats reacquired lever-press behavior. Groups treated in like fashion, but pressing for a sweet milk reinforcer, all showed reacquisition. Thus, the effects of AMT and U-14,624 are attributed to an interference with the reinforcing effects of ethanolinfusions. Brain levels of norepinephrine were depeleted by both compounds, dopamine was depleted only by AMT, and serotonin was elevated by 600 mg/kg of U-14,624 but unaffected by 300 mg/kg. These results suggest that a cerebral noradrenergic system plays an important role in the reinforcing effect of ethanol without an involvement of dopaminergic systems     

Ethanol-mediated operant learning in the infant rat leads to increased ethanol intake during adolescence

Recent studies indicate that the infant rat has high affinity for ethanol ingestion and marked sensitivity to the drug's reinforcing effects [Spear, N.E., Molina, J.C. Fetal or infantile exposure to ethanol promotes ethanol ingestion in adolescence and adulthood: a theoretical review. Alcohol Clin Exp Res 2005; 29: 909–29.]. A novel operant technique was developed to analyze reinforcing effects of ethanol delivery during the third postnatal week. The impact of this ethanol-reinforcement experience upon subsequent ethanol consumption during adolescence (postnatal weeks 5–6) was also examined. In Experiment 1, pups (postnatal days 14–17) were given an explicit contingency between nose-poking behavior and intraoral delivery of either water or 3.75% v/v ethanol (paired groups). Yoked controls (pups receiving either reinforcer independently of their behavior) were also included. Paired subjects reinforced with ethanol exhibited rapid and robust operant conditioning leading to blood ethanol concentrations in the 25–48 mg% range. In Experiment 2, a higher ethanol concentration (7.5% v/v) provided significant reinforcement. During adolescence, animals originally reinforced with 3.75% v/v ethanol exhibited greater ingestion of ethanol than control animals without prior ethanol reinforcement. These results indicate that, without extensive initiation to ethanol, infant rats rapidly learn to gain access to ethanol and that this experience has a significant impact upon later ethanol intake patterns.     

Long term reduction of male agonistic behavior in mice following early exposure to ethanol

A system was developed to study the ability of early (pre- and neonatal) ethanol input to induce long lasting neural and behavioral changes. Ethanol was administered to C57B1/10Bg and DBA/1 Bg offspring through their parents who received 10% ethanol as their only liquid supply either before and during pregnancy, or from delivery until 14 days post partum, or during both periods. Thus the offspring received ethanol transplacentally and/or through the mother's milk. The present paper is concerned with the male agonistic behavior at age 50 days of the treated offspring as compared with their pair fed controls. Early ethanol input resulted in a 23% increase in latency to attack in C57 mice and 58% in DBA, as well as a 49% (C57) and 38% (DBA) decrease in time spent fighting. The sensitive period to ethanol effect was apparently postnatal. Prenatal administration had no effect on agonistic behavior. DBA offspring were more aggressive than C57 and the scores of C57 offspring were more variable, thus indicating a lower phenotypic buffering in this strain.