No tolerance to antiaggressive effect of d-amphetamine in mice

Agonistic, locomotor, and stereotyped behavior were measured in male Swiss-Webster mice in their home cage, normally shared with a female, while confronting an intruder mouse. Acute administration of d-amphetamine (2, 4, 8 mg/kg, IP) to resident mice decreased the frequency of attacks toward an untreated intruder, increased the resident's locomotor activity, and induced a small amount of stereotyped behavior. Redetermination of dose-effect functions during chronic treatment (8 or 16 mg/kg/day) indicated that tolerance did not develop to the antiaggressive effect of d-amphetamine. By contrast, the chronically treated mice showed sensitization to amphetamine-induced stereotypies and a diminished sensitivity to the drug's enhancement of locomotor activity. Subsequent tests with cocaine indicated no differences between amphetamine-maintained and saline control animals, providing no evidence for cross-tolerance or cross-sensitization between cocaine's and amphetamine's effects on attack, locomotion, and stereotypies.     

An observational method for quantifying the behavioural effects of dopamine agonists: Contrasting effects of d-Amphetamine and apomorphine

A novel means of measuring and analysing behavioural effects of dopamine agonists is described and illustrated by a comparison of the effects of d-amphetamine and apomorphine in the rat. d-Amphetamine (0–15 mg/kg IP) produced significant dose- and time-dependent changes in responses such as locomotion, rearing and sniffing, but not in licking or gnawing. In contrast, apomorphine (0–5 mg/kg SC) produced significant increases in licking and gnawing, as well as in locomotion and sniffing, but no changes in rearing. The results are discussed in comparison with those obtained by other methods, such as photocell beam interruptions or stereotypy rating scales, and may be of importance in elucidating the functions of the forebrain dopamine projections.     

An analysis of some discriminative properties of d-amphetamine

Male albino rats were trained and tested on a two-lever discrimination task based upon the presence or absence of d-amphetamine (1.0 mg/kg). This compound was found to produce strong discriminative cues (i.e., 90% correct choice behavior). A dose-effect function was then ascertained and the discriminative ED₅₀ (following training with 1.0 mg/kg) was found to be 0.23 mg/kg d-amphetamine.In order to determine the effective duration of d-amphetamine action, the interval between injection and testing was varied; it was found that the discriminative effects of the drug began to dissipate between 60 and 90 min post-injection.In an attempt to compare the discriminative cues of other drugs with those of d-amphetamine, injections of LSD (0.04 and 0.08 mg/kg), psilocybin (0.50 and 1.0 mg/kg), THC (0.50 and 1.0 mg/kg), mescaline (5.0 and 10.0 mg/kg), and caffeine (6.0 and 20.0 mg/kg) were given during extinction. In all cases, the rats responded predominantly on the saline-related lever. Only methamphetamine (1.0 mg/kg) produced d-amphetamine-like responding.Finally, alpha-methyl-para-tyrosine (AMPT), a compound which depletes brain catecholamines (CA), was found to disrupt the d-amphetamine-saline discrimination.     

Long-term d-amphetamine in rats: Lack of change in post-synaptic dopamine receptor sensitivity

Treatment of rats with d-amphetamine (5 mg/kg) once daily for 25 days did not change locomotor responses, on day 7 of withdrawal, to dopamine (DA) or d-amphetamine into the nucleus accumbens. Nor was there a change in ³H-spiperone binding of caudate nucleus membranes. There was no effect of treatment on the locomotor response of rats to 1.0, 1.5 or 2.0 mg/kg d-amphetamine IP. However, d-amphetamine-treated rats were significantly less sensitive to 0.5 mg d-amphetamine. Although 1, 2 or 3 mg/kg apomorphine produced the same degree of stereotypy in both treatment groups, there was a significant difference in the response of the two groups to 0.5 mg apomorphine, d-amphetamine-treated animals being less sensitive than vehicle-treated animals. No change was found in brain DA levels with or without synthesis inhibition. The present data do not support the hypothesis that chronic treatment of rats with d-amphetamine can produce supersensitive post-synaptic DA receptors.     

Discriminative stimulus properties of cocaine in pigeons

The present study was designed to assess the discriminative stimulus properties of cocaine in pigeons. Six pigeons were trained to discriminate IM injections of cocaine (2 mg/kg) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. Cocaine, d-amphetamine, and l-cathinone substituted completely for the training dose of cocaine in all pigeons. When nicotine (0.25–4.0 mg/kg), apomorphine (0.03–1.0 mg/kg), procaine (4–32 mg/kg), and lidocaine (4–16 mg/kg) were substituted, both partial substitutions and individual differences between pigeons were observed. Oxazepam (0.5–4.0 mg/kg) and pentobarbital (2–8 mg/kg) failed to substitute for the training dose of cocaine. Discriminative stimulus control by cocaine was greatest when the drug was administered 10–40 min prior to the session and the effects disappeared after 2 h. The substitution results indicate drug class specificity of the cocaine cue but, in addition, suggest its multidimensional nature.     

Failure of naloxone to modify the effects of chlorpromazine and d-amphetamine on avoidance behavior in the squirrel monkey

Lever-pressing by squirrel monkeys was maintained under a continuous avoidance schedule in which each response postponed for 30 s the delivery of an electric shock to the tail. Dose-response curves were determined for chlorpromazine (0.03–0.3 mg/kg) and d-amphetamine (0.03–1.0 mg/kg) administered alone and administered concomitantly with 1.0 or 10 mg/kg of aaloxone. The dose-response curves for chlorpromazine and d-amphetamine were similar to those previously reported for monkeys under other schedules of shock-maintained behavior: Chlorpromazine decreased responding in a dose-related manner while d-amphetamine increased responding at low doses and disrupted behavior at the highest dose. Naloxone did not modify the effects of chlorpromazine, and d-amphetamine. These results suggest that interactions observed previously between naloxone and nonopiate drugs on behavior in pigeons and rodents are not general phenomena in all animal species.     

Intruder-evoked aggression in isolated and nonisolated mice: Effects of psychomotor stimulants and l-Dopa

Adult male Swiss-Webster mice were housed either singly (isolated) or with a female (nonisolated). Aggressive behavior was evoked by introducing a group-housed male mouse (intruder) into the home cage of the isolated or nonisolated mouse (resident). d-Amphetamine, methamphetamine, methylphenidate, cocaine, and l-dopa decreased attack and threat behavior by resident mice, the isolates requiring 2–4 times higher drug doses for the antiaggressive effects than the nonisolates. d-Amphetamine, methamphetamine, and methylphenidate caused intruder mice to be more frequently attacked by their nontreated resident opponents, to escape more often, to assume the defensive upright posture less, and to move about more often. l-Dopa nonspecifically decreased all elements of agonistic and nonagonistic behavior, while the amphetamines and methylphenidate suppressed attacks, increased escapes, decreased upright postures, and increased nonagonistic locomotion. By contrast, cocaine's antiaggressive effects were remarkably specific, i.e., not accompanied by changes in other behavioral elements.     

The effects of pimozide and phenoxybenzamine pretreatments on amphetamine and apomorphine potentiation of the acoustic startle response in rats

A series of three experiments investigated the individual roles of neurons containing dopamine (DA) and norepinephrine (NE) in modulating the amplitude of the acoustic startle response (ASR) in rats. Experiment I investigated the effects of 0.1, 0.5, and 2.5 mg/kg pimozide or 5, 10, and 20 mg/kg phenoxybenzamine alone on startle amplitude. Experiments II–III investigated the effects of pretreatment with either 2.5 mg/kg pimozide or 10 mg/kg phenoxybenzamine on the potentiation of startleamplitude by either d-amphetamine (8 mg/kg), l-amphetamine (32 mg/kg), or apomorphine (3 mg/kg). Treatment with pimozide (2.5 mg/kg given 85 min before testing) and phenoxybenzamine (10 mg/kg, given 25 min before testing) resulted in a significant reduction in startle amplitude, supporting the conclusion that neurons containing NE and DA both tonically facilitate the ASR. The startlepotentiating effect of d- and l-amphetamine and apomorphine were totally blocked by pretreatment with pimozide (2.5 mg/kg, injected 2 h before these drugs), which supports the hypothesis that these agents potentiate startle at least in part by acting through dopaminergic neural systems. Phenoxybenzamine pretreatment (10 mg/kg, given 0.5 h before) also blocked the startle-potentiating effects of l-amphetamine and apomorphine, which suggests that noradrenergic neural systems are also involved in the potentiation of ASR by these agents, possibly through the interaction of dopaminergic and noradrenergic neural systems. The potentiating effect of d-amphetamine on ASR magnitude was not attenuated by phenoxybenzamine.     

Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0–3.0 mg/kg but had little systematic effect on rate at doses of 0.03–0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03–0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.     

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.     

Separation of the associative and non-associative effects of brain serotonin released by p-chloroamphetamine: Dissociable serotoninergic involvement in avoidance learning,pain and motor function

p-Chloramphetamine (PCA, 0.63–5 mg/kg IP) injected 30–60 min before testing produced a dose-related impairment of avoidance acquisition, prolonged reaction time in the hot-plate test and increased locomotor activity. Pretreatment with the selective serotonin (5-HT) uptake inhibitor zimeldine (10 mg/kg IP) blocked these behavioural effects. Degeneration of brain 5-HT neurons by a high neurotoxic dose of PCA (2×10 mg/kg IP) or inhibition of tryptophan hydroxylase by p-chlorophenylalanine (300 mg/kg IP) also blocked the behavioural effects of PCA. There was a complete blockade of the PCA-induced avoidance deficit following pretreatment with metergoline, a central 5-HT receptor blocking agent. On the other hand, metergoline failed to block the hot-plate analgesia and the increased locomotion caused by PCA. Depletion of brain NA and DA by the tyrosine hydroxylase inhibitor H44/68 did not counteract the PCA effect on avoidance or hot-plate performance, but reduced the locomotor stimulating effect. The selective NA neurotoxin DSP4 (50 mg/kg IP) or the opiate antagonist naloxone (1 mg/kg) failed to affect the PCA-induced modulations of the behaviours studied. In addition, PCA administration in doses that caused avoidance deficits, did not result in motor impairment as assessed by the tread mill test. The above results support the hypothesis that the PCA-induced impairment of active avoidance acquisition does not involve changes in nociception or altered locomotor activity. It is concluded that behavioural processes related to serotonergic neurotransmission can be independently modified, suggesting differences in the underlying 5-HT mechanisms.     

Interactions of naloxone with morphine,amphetamine and phencyclidine on fixed interval responding for intracranial self-stimulation in rats

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle-lateral hypothalamus (MFB-LH) and were trained to lever-press for brain self-stimulation on a fixed interval: 60 s schedule of reinforcement. The effects of graded doses of naloxone (0.1–30 mg/kg), morphine (0.3–5.6 mg/kg), naloxone plus morphine,d-amphetamine (0.03–1.0 mg/kg), naloxone plusd-amphetamine, phencyclidine (0.3–5.6 mg/kg), and naloxone plus phencyclidine were tested. Naloxone produced a significant decrease in rates at 30 mg/kg. Naloxone (0.1–1.0 mg/kg) plus morphine blocked the dose-dependent decrease produced by morphine alone. In contrast, naloxone (1.0–10 mg/kg) plusd-amphetamine attenuated the graded increase in response rates produced byd-amphetamine. Naloxone (1.0–10 mg/kg) plus phencyclidine did not reliably change the increase in response rates produced by phencyclidine alone. The use of the fixed interval schedule of brain self-stimulation to study these drug interactions is novel, and further demonstrates that the highly reinforcing aspects of brain stimulation, known to be influenced by dopamine, may also be modulated by the endogenous opiate system.     

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.     

On the role of noradrenaline in psychostimulant-induced psychomotor activity and sensitization

Rationale Psychostimulant drugs exert their behavioral effects primarily through enhancement of monoaminergic neurotransmission. Augmented dopamine activity is thought to play a critical role in the psychomotor stimulant effects of amphetamine and cocaine, as well as in the development of long-term behavioral sensitization evoked by repeated exposure to amphetamine. However, despite the fact that brain dopamine and noradrenaline systems are closely interconnected, the extent to which noradrenergic transmission contributes to these behavioral effects of psychostimulants is a relatively unexplored issue. Objectives By inhibiting noradrenergic neurotransmission with the α₂-adrenoceptor agonist clonidine, the α₁-antagonist prazosin and the β-antagonist propranolol, we investigated the involvement of noradrenaline neurotransmission in the psychomotor stimulant and long-term sensitizing effects of d-amphetamine and cocaine in rats. Methods Clonidine (0.003–0.1 mg/kg), prazosin (0.1–3.0 mg/kg) and propranolol (1.0–3.0 mg/kg) were administered prior to d-amphetamine (1.0 mg/kg), cocaine (15 mg/kg) or apomorphine (1.0 mg/kg) and psychomotor activity was measured. In separate studies, clonidine (0.03 mg/kg), prazosin (1.0 mg/kg) or propranolol (3.0 mg/kg) were co-administered with d-amphetamine (2.5 mg/kg) or cocaine (30 mg/kg) for 5 days, and locomotor sensitization was assessed 3 weeks post-treatment. Results The psychomotor stimulant effect of d-amphetamine, but not that of cocaine or apomorphine, was dose-dependently inhibited by clonidine and prazosin, and enhanced by propranolol. Clonidine, prazosin, and propranolol did not influence the induction of sensitization by amphetamine or cocaine. Conclusions Enhancement of synaptic noradrenaline concentrations contributes to the psychomotor stimulant effect of d-amphetamine, but not cocaine or apomorphine. In addition, noradrenergic neurotransmission is not critically involved in the induction of psychostimulant sensitization.     

Altered sensitivity to d-methylamphetamine,apomorphine, and haloperidol in rhesus monkeys depleted of caudate dopamine by repeated administration of d-methylamphetamine

The long-term neurochemical and behavioral effects of repeated d-methylamphetamine (d-MA) administration were investigated using four male rhesus monkeys trained to lever-press for food on a DRL-40 s schedule of reinforcement. Dose-response curves for d-MA (0.0625–2.0 mg/kg), apomorphine (0.025–0.4 mg/kg), and haloperidol (0.005–0.04 mg/kg) on responding showed that repeated d-MA administration (0.5–16.0 mg/kg/day) decreased sensitivity to d-MA and to apomorphine but increased sensitivity to haloperidol. At 3–6 months after the last injection of d-MA, a 48.1% decrease in caudate dopamine (DA) was observed, with the frontal cortex, midbrain, and ponsmedulla showing no significant change. A trend toward increasing concentrations of norepinephrine was noted in the same brain areas, but only in the frontal cortex did this change reach significance. Specific binding of 3H-spiroperidol to caudate membrane preparations was not changed, while the V _max of the caudate DA re-uptake process declined 32%, with no change in K _m. These results suggest that exposure of DA neurons in the caudate nucleus to high concentrations of d-MA can lead to nerve terminal degeneration.     

The effect of p-chloroamphetamine on motility in rats after inhibition of monoamine synthesis,storage, uptake and receptor interaction

The effect of PCA on motility was investigated after s.c. injection to rats in a familiar cage. The doses 1, 2, 5 and 10 mg/kg induced increasing hypermotility. PCA 1 and 2 mg/kg produced various normal behavioral items, but 5 and 10 mg/kg induced mainly abnormal jerky locomotion and head movements.The effect of PCA 5 mg/kg was investigated in rats treated s.c. with various drugs affecting central monoamines. Pretreatment with the 5HT-synthesis inhibitor H 69/17 200 mg/kg, the tyrosinehydroxylase inhibitor H 44/68 250 mg/kg twice and reserpine 7.5 mg/kg inhibited PCA-hyperactivity. H 44/68 250 mg/kg once and the dopamine -hydroxylase inhibitor FLA 63 did not influence the effect of PCA.Simultaneous administration of imipramine 3.1 mg/kg, chlorimipramine 0.9 mg/kg, desipramine 26 mg/kg, amitriptyline 15 mg/kg, doxepine 1.8 mg/kg, chlorpromazine 0.1 mg/kg, haloperidol 0.01 mg/kg, spiramide 0.01 mg/kg and chlorpheniramine 3.9 mg/kg antagonized PCA-hypermotility. Protriptyline 50 mg/kg, clozapine 20 mg/kg and benztropine 10 mg/kg showed no PCA-antagonism.These results indicate that 5HT and DA release are involved in PCA-hyperactivity and that 5HT-membrane blockers inhibit uptake of PCA into brain 5HT neurons thus preventing 5HT release.     

A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine

Rats were trained to discriminate fenfluramine (1.0 mg/kg) from saline in a two-lever drug discrimination task. The dose-response curve for this discrimination was orderly with an ED₅₀ of about one-half of the training dose (0.52 mg/kg). In substitution tests, indirect (p-chloroamphetamine) and direct (quipazine, MK-212, lisuride) serotonin (5-HT) agonists substituted for fenfluramine. Since none of these compounds have been reported to be hallucinogenic and the potent hallucinogen LSD did not substitute completely, it was suggested that the discriminative stimulus properties of fenfluramine are not related to its ability to produce hallucinations in humans. The fenfluramine cue, like the quipazine cue, was antagonized by the 5-HT antagonists cyproheptadine and methiothepin. Unlike quipazine, fenfluramine was also partially antagonized by the 5-HT uptake inhibitor, fluoxetine, and the 5-HT synthesis inhibitor, p-chlorophenylalanine. Thus, the fenfluramine cue differs from that of quipazine in that it is mediated via indirect actions on 5-HT receptors. Since the indirect dopamine (DA) agonist d-amphetamine failed to substitute and the DA antagonist haloperidol failed to block the fenfluramine cue, a mediating role for DA was not indicated. Another indirect DA agonist, cocaine, substituted partially for fenfluramine, a result which paralleled that seen with fluoxetine. Both of these partial substututions were reduced by cyproheptadine; therefore, it was concluded that these effects may be due to the common ability of cocaine, fluoxetine, and fenfluramine to inhibit 5-HT uptake.Portions of this research were presented at the Ninth Annual Meeting of the Society for Neuroscience Atlanta, Georgia, November 2–6, 1979     

Effects of nimodipine on the discriminative stimulus properties ofd-amphetamine in rats

The discriminative stimulus (DS) properties ofd-amphetamine (AMP) are thought to be mediated by enhanced release of catecholamines, which may involve neuronal calcium influx through voltage sensitive channels. The present study examined the influence of nimodipine, a calcium channel blocker, on the DS properties of AMP. Rats (N=8) were trained to discriminate AMP (0.5 mg/kg, IP) from saline in a two-lever, food-reinforced, drug discrimination paradigm. Nimodipine alone (2.0–5.6 mg/kg, IP) did not substitute for AMP. When given in combination with AMP, 2.0 mg/kg nimodipine increased by less than 2-fold the AMP dose necessary to induce AMP-appropriate responses. Higher doses of nimodipine combined with AMP did not increase the magnitude of this effect. Nimodipine enhanced the effects of AMP on response rate. Haloperidol (0.125 mg/kg) increased by approximately 4-fold, whereas diazepam (0.5 or 1.0 mg/kg) and morphine (5.0 mg/kg) increased by approximately 2-fold the AMP dose necessary to induce AMP-appropriate responses. The interaction with AMP was associated with enhanced reduction of response rate in the tests with diazepam and morphine but not haloperidol. These results suggest that nimodipine attenuates the DS properties of AMP, probably in a non-specific way, due to the ability of nimodipine itself to induce a discriminable internal state.     

p-Chloroamphetamine (PCA), 3,4-methylenedioxymethamphetamine (MDMA) andd-fenfluramine pretreatment attenuatesd-fenfluramine-evoked release of 5-HT in vivo

Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA andd-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect ofd-fenfluramine might also be sensitive to lesions produced by PCA, MDMA andd-fenfluramine itself. Basal and 5-HT release evoked byd-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA,d-fenfluramine, or vehicle. In frontal cortex of vehicle controls,d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reducedd-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg×8) andd-fenfluramine (12.5 mg/kg×8) pretreatment reducedd-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked byd-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA andd-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data fromd-fenfluramine challenge tests is discussed.     

Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists

One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT_1A receptors. The present experiments tested the hypothesis that activating 5-HT_1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT_1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1–0.3 mg/kg, IP) or flesinoxan (0.1–1.0 mg/kg, IP). The 5-HT_1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, IP) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, PO) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03–0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT_1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT_1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT_1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission. Received: 26 January 1998/Final version: 10 March 1998