Baclofen blocks the development of sensitization to the locomotor stimulant effect of amphetamine

The GABAB agonist baclofen (BCF) has recently been reported to block the expression of sensitization to the locomotor effect of amphetamine (AMPH), and to reverse it after repeated administration. The present study was undertaken to investigate whether baclofen could also prevent the development of sensitization to the psychostimulant. Chronic AMPH treatment (1.5 mg/kg i.p. for 10 days) led to an increased locomotor response to AMPH (1.5 mg/kg) when the animals were challenged 3 and 30 days after the end of repeated treatment. Chronic co-administration of BCF (2 mg/kg, i.p.) and AMPH blocked the development of sensitization to the stimulant effect of AMPH. An ancillary experiment excluded that a 'state-dependency' hypothesis could account for the effect of baclofen. Furthermore, a previous repeated treatment with baclofen alone had no influence either on the acute AMPH effect or on the subsequent development of sensitization to AMPH. In conclusion, the results confirm that GABAB receptors play an important role in the acquisition of AMPH behavioural sensitization and further support a potential use of GABAB agonists in the treatment of psychostimulant addiction.     

The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioural sensitisation in mice.

The effects of acute administration of the neurotensin receptor antagonist, SR48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-carbonyl]amino]adamantane-2-carboxylic acid), on amphetamine-induced behavioural sensitisation were studied with the locomotor activity of mice in an open-field as an experimental parameter. The animals were repeatedly pretreated with saline or amphetamine (2.0 mg/kg, i.p. once a day, every other day for 13 days) and 2, 9 and 16 days after the last injection they received an acute i.p. administration of saline or 0.3 mg/kg SR48692 15 min before a challenge i.p. injection of 2.0 mg/kg amphetamine. Locomotor activity of the amphetamine-challenged mice was significantly higher in amphetamine-pretreated animals than in saline-pretreated mice on days 9 and 16 after withdrawal. SR48692 prevented the expression of this behavioural sensitisation. In addition, in saline-pretreated mice, the first two challenge injections of amphetamine sufficed to induce a sensitized locomotor response to the third challenge injection of the drug. SR48692 administration before amphetamine challenge injections prevented the development of this challenge injection-induced sensitisation in saline-pretreated mice but not in amphetamine-pretreated animals. In order to determine the effects of SR48692 on the expression of amphetamine-induced behavioural sensitisation in the absence of this challenge injection-induced sensitisation, the experiment was redone with a single challenge test 9 days after pretreatment. Once again, SR48692 prevented the expression of amphetamine-induced behavioural sensitisation. These results suggest that neurotensinergic transmission has a critical role in both the initiation and expression of locomotor sensitisation to amphetamine.     

The effect of previous exposure to amphetamine on drug-induced locomotion and self-administration of a low dose of the drug

Rationale and objectives: In order to assess directly the relationship between locomotor activity and drug self-administration, the present experiment simultaneously measured these two behaviors in rats with different histories of pre-exposure to amphetamine either following or in the absence of priming injections of the drug. Methods: Different groups of rats were exposed to ten daily injections of either saline (1.0 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.) and, in each of 13 daily sessions starting 10 days later, were given the opportunity to lever press for a low dose of amphetamine (10 μg/kg per i.v. infusion) in a two-lever (active versus inactive) continuous reinforcement task. Animals were administered a priming injection of amphetamine (1.0 mg/kg, i.p.) immediately before testing on the first 8 days, a saline injection (1.0 ml/kg, i.p.) on the next 3 days and amphetamine on the final 2 days of testing. Results: Consistent with previous reports, prior exposure to amphetamine led to an enhanced locomotor response to the priming injection of amphetamine on the first day of testing. Little pressing for drug was observed on this day. Following priming injections on the subsequent test days, evidence for enhanced locomotion by amphetamine-pre-exposed rats diminished and both groups showed comparable and progressive increases in active versus inactive lever pressing. When priming injections were not made, however, only animals previously exposed to amphetamine maintained lever pressing for the drug. Under these conditions, these animals emitted more active lever presses and time-out responses and exhibited higher levels of locomotor activation in proximity to the active drug administering lever than did saline-pre-exposed rats. Conclusions: These results are consistent with the view that previous exposure to amphetamine produces a long-lasting enhancement in the behavioral activation animals will direct toward stimuli associated with the drug. This enhancement was displayed initially as a sensitized locomotor response to amphetamine on the first day of testing and was subsequently observed on those test days when no priming injections were given when animals continued to self-administer a low dose of amphetamine under a simple schedule of reinforcement. The implications of these findings for our understanding of the excessive expression of drug-directed behaviors are discussed. Received: 23 November 1998 / Final version: 19 June 1999     

Mechanism of antinociceptive effect of nimodipine in experimental diabetic neuropathic pain

This study used streptozotocin-(STZ; 50 mg/kg, i.v.) diabetic rats and monitored the weekly thermal nociceptive thresholds for 8-week diabetes. Nimodipine (10 mg/kg i.p.) treatment initiated after 8 weeks of diabetes antagonized the hyperalgesic response in diabetic rats. However, insulin treatment showed a partial response in these animals. Thermal hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5 mg/kg, i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of baclofen (GABAB agonist; 4 mg/kg i.p.) was observed. Five days of treatment with MK-801 (N-methyl-D-aspartate [NMDA] receptor antagonist 0.5 mg/kg i.p.) completely reversed 8-week diabetes-induced thermal hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABAB ergic inhibitory systems might accelerate the increased excitation, thus contributing to the ongoing pain in diabetic rats.     

Effects of serotonergic manipulations on the behavioral sensitization and disinhibition associated with repeated amphetamine treatment

This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.     

The effects of chronic intraperitoneal administration of the GABA B receptor agonist baclofen on food intake in rats

This study was undertaken to examine the effects of repeated administration of the GABA(B) receptor agonist baclofen on food intake in male Wistar rats. In the 1st Experiment, the effects of daily administration of physiological saline and baclofen (2 mg/kg, i.p.) for 27 days were investigated on food intake and body weight in non-deprived rats (n=6 in each group). Baclofen significantly (P<0.05) increased cumulative food intake each day over the treatment period during the 60 min measurement period following administration. Tolerance did not develop to the short-term hyperphagic effect of baclofen over the course of the experiment. In addition, treatment with baclofen did not alter body weight of the animals over the 27 day treatment period when compared with the saline control rats. In the 2nd Experiment, the effects of acute and chronic administration of baclofen (2 mg/kg) were investigated on 24 h food intake in rats. The rats were injected daily for 21 days with either saline (n=6) or baclofen (n=6). Food intake was measured in 30 min time bins for 24 h on treatment Days 1, 12 and 21 following injection. The results showed that while baclofen produced short-term increases in food consumption following injection on treatment Days 1, 12 and 21, the daily (24 h) food intake of the animals was not significantly different from those of control rats. Thus, these data reveal that while chronic administration of baclofen (2 mg/kg) produces short-term increases in feeding without the development of tolerance, daily (24 h) food consumption is not affected. These findings are consistent with the observation that chronic administration of baclofen (2 mg/kg) had no effect on the body weight of these animals.     

Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain

RATIONALE: Sensitisation of the mesoaccumbens dopamine response to nicotine has been implicated in the development of nicotine dependence. This study explored the doses of nicotine that elicit the response in two strains of rats that differ in their baseline levels of activity. METHODS: Male Sprague-Dawley and Lister hooded rats were pretreated with daily subcutaneous injections of (-)-nicotine for 7 days at doses ranging from 0.03 mg/kg to 0.90 mg/kg. Microdialysis studies were performed on day 9 in conscious freely moving rats, placed in an activity box and challenged with 0.4 mg/kg nicotine. RESULTS: The acute administration of nicotine to drug-naive rats stimulated dopamine overflow in the accumbal shell but not the core. Sprague-Dawley rats, pretreated with nicotine (0.03 mg/kg/day and 0.10 mg/kg/day) showed increased basal overflow of dopamine in the accumbal core. Pretreatment with 0.10 mg/kg/day or 0.30 mg/kg/day, but not 0.03 mg/kg/day or 0.90 mg/kg/day, also caused sensitisation of the response to a nicotine challenge on the test day. Sensitisation of the locomotor response to nicotine exhibited a simple dose-response relationship, with the largest sensitisation being observed in animals pretreated with 0.90 mg/kg/day. In Lister hooded rats, pretreatment with nicotine reduced basal dopamine overflow in the accumbal core and did not cause sensitisation to a subsequent challenge with nicotine. CONCLUSIONS: Sensitisation of the mesoaccumbens dopamine response to nicotine is influenced by pre-treatment dose and the strain of rats used. It is not related directly to the expression of sensitised locomotor responses to the drug and, therefore, may be implicated in other psychopharmacological properties of the drug, including dependence.     

Modification of d-amphetamine-induced responses by baclofen in rats

RATIONALE: d-Amphetamine is known to have effects on heart rate, body temperature and locomotor activity. However, it is not known if GABAB receptor stimulation modifies these actions of d-amphetamine. OBJECTIVES: Using telemetry recordings, this study examined the interactions between the GABAB receptor agonist baclofen and d-amphetamine, on heart rate responses, body temperature and locomotor activity, and whether these effects could be blocked by the GABAB receptor antagonist SCH 50911. METHODS: Rats were prepared with telemetry implants, which allowed continuous monitoring of heart rate, core temperature and spontaneous locomotor activity. Drugs were subsequently administered subcutaneously to the animals for simultaneous recording over a period of 180 min. RESULTS: d-Amphetamine alone (0.3, 1.0 and 3.0 mg/kg) produced a dose-related increase in heart rate, but was without any effect on body temperature, whilst at 1.0 mg/kg, it significantly increased locomotor activity. Baclofen increased heart rate without affecting locomotor activity, and, at the highest dose of 10.0 mg/kg, it induced a significant reduction in body temperature. Graded doses of baclofen (3.0-10.0 mg/kg), when co-administered with d-amphetamine (1.0 mg/kg), did not modify the d-amphetamine-induced increase in heart rate, but the combination produced significant reductions of body temperature. The latter was only partially reversed by the GABAB receptor antagonist SCH 50911 (10.0 mg/kg). By contrast, the increase in locomotor activity by d-amphetamine was markedly blocked by baclofen in a dose-related manner, and this effect was abolished by SCH 50911 (10.0 mg/kg). SCH 50911 alone at doses of 3.0, 6.0 and 10.0 mg/kg had no effect on temperature or locomotor activity. Heart rate was increased significantly, but the magnitude of change was small. CONCLUSIONS: The results of the present study suggest that stimulation of GABAB receptors by baclofen completely blocks the locomotor stimulatory effects of d-amphetamine. Baclofen did not significantly modify the increase in heart rate produced by d-amphetamine and decreased body temperature, both alone and in combination with d-amphetamine. GABAB receptor ligands may well have potential as pharmacotherapies in the treatment of amphetamine abuse and dependence.     

Repeated d-amphetamine enhances stimulated mesoamygdaloid dopamine transmission

The mesoaccumbens dopamine pathway exhibits an enhanced dopaminergic response to a challenge injection of d-amphetamine or cocaine after repeated intermittent exposure to that drug. Much research has focused on the potential role of this sensitised response in the enhanced propensity of drug-associated stimuli to elicit relapse. However, the amygdala is acknowledged to play a critical role in stimulus-reward learning, and recent work suggests that the mesoamygdaloid dopamine pathway exerts a significant influence upon amygdala function. In the present study, rats were administered d-amphetamine (1 mg/kg, IP) or vehicle once per day, for 14 days. After 11 untreated days, a locomotor assay showed that prior repeated administration of d-amphetamine led to a markedly enhanced locomotor response to 0.5 mg/kg d-amphetamine. There was no effect of d-amphetamine pretreatment upon the response to a novel environment, or to injection with vehicle. Following a total of 14 days in the home cage, subjects were implanted with microdialysis probes within the amygdala, and for comparison also within the nucleus accumbens. Baseline and d-amphetamine-stimulated (0.5 mg/kg) levels of extracellular dopamine were assessed for each brain region. Results showed that baseline levels of dopamine were very similar in sensitised and control animals. By contrast, prior treatment with d-amphetamine enhanced dopamine overflow in response to a challenge with d-amphetamine both in the nucleus accumbens and amygdala. These results indicate that changes in the pattern of dopamine transmission both in the nucleus accumbens, and the amygdala, accompany the behavioural sensitisation observed after repeated exposure to d-amphetamine. Hence, an enhanced propensity of drug-associated stimuli to elicit relapse may not depend solely upon changes relating to the mesoaccumbens dopamine projection. Received: 24 October 1996/Final version: 28 February 1997     

Apomorphine-induced behavioural sensitization in rats: individual differences, role of dopamine and NMDA receptors

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED₅₀ values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D₂ antagonist), 0.023 mg/kg for SCH 23390 (dopamine D₁ antagonist), 6.42 mg/kg for clozapine (dopamine D₄ antagonist). This supports the involvement of D₁ and D₂ receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D₁ and D₂, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization.     

Effects of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APA) on food intake in rats

It has previously been demonstrated that central administration of the GABAB agonist baclofen increases food intake in non-deprived or satiated animals by action at the central GABAB receptors. It has also been shown that systemic administration of baclofen increases food intake in non-deprived rats. Although baclofen crosses the blood brain barrier from systemic circulation to enter the brain, it is conceivable that it may increase food intake by a peripheral mode of action. This possibility was examined in the present study. The effects of intraperitoneal (i.p.) administration of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APA) were investigated on food intake in non-deprived rats. 3-APA is a potent GABAB agonist that does not penetrate the blood brain barrier. The results show that while baclofen (1-4 mg/kg) increases food intake in a dose-related manner, 3-APA (0.5-2 mg/kg) has no effects on food consumption. The results indicate that a peripheral GABAB mechanism is not involved in the hyperphagia elicited by systemic administration of baclofen and suggests that the drug increases food intake by a central mode of action.     

In vivo effectiveness of CGP7930, a positive allosteric modulator of the GABAB receptor

The present study was aimed at assessing the in vivo effectiveness of the positive allosteric modulator of the gamma-aminobutyric acidB (GABAB) receptor, CGP7930 [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol]. The synergistic potentiation of GABAB receptor functioning, previously observed in different in vitro assays, has been confirmed in the present work, where pretreatment with CGP7930 (10-170 mg/kg, i.p.) resulted in a marked potentiation of the sedative/hypnotic effect of the GABAB receptor agonists, baclofen (40 mg/kg, i.p.) and gamma-hydroxybutyric acid (500 mg/kg, i.p.), in DBA mice. Pretreatment with the GABAB receptor antagonist, SCH 50911 [(S)-5,5-dimethyl-2-morpholine acetic acid; 100 mg/kg, i.p.], resulted in a complete blockade of the sedative/hypnotic effect of the combination of CGP7930 with either baclofen or gamma-hydroxybutyric acid. These results confirm that CGP7930 may constitute an interesting tool for pharmacological studies in the GABAB receptor field.     

Repeated administration of amphetamine induces sensitisation to its disruptive effect on prepulse inhibition in the rat

 Male Sprague-Dawley rats were repeatedly treated with amphetamine (AMP, 1 mg/kg, SC) at 3- day intervals for 15 days and tested for prepulse inhibition of acoustic startle after each treatment. This treatment regimen induced sensitisation in the animals as evidenced by a progressive increase in the disruptive effect of AMP on prepulse inhibition. Persistent changes in brain function was indicated, since an increase in disruptive effect was observed in sensitised animals also after a 22-day-long drug- and test-free period. The development of sensitisation was blocked by pretreatment with haloperidol (HPD, 0.1 mg/kg, SC), which suggests that sensitisation to the disruptive effect of AMP was dependent on dopamine (DA) D₂ receptor activation. Furthermore, the development of sensitisation was blocked by adrenalectomy, which suggests that sensitisation was dependent also on circulating adrenal hormones. Increased DA-ergic activity has been implicated in the pathophysiology of schizophrenia and AMP-induced sensitisation to the neuronal functions that modulate prepulse inhibition may be an experimental model to investigate this hypothesis. Received: 20 May 1997 / Final version: 14 August 1997     

Blockade of group II metabotropic glutamate receptors in the nucleus accumbens produces hyperlocomotion in rats previously exposed to amphetamine

The neurotransmitter glutamate is known to participate in both the induction and expression of locomotor sensitization by psychostimulant drugs like amphetamine. Previously, it was reported that subtype nonselective blockade of metabotropic glutamate receptors (mGluRs) in the nucleus accumbens (NAcc) produces hyperlocomotion in rats previously exposed to amphetamine. The present experiments examined whether group II mGluRs may contribute to this effect. Rats in different groups were administered five injections of either saline or amphetamine (1.0 mg/kg, i.p.), one injection given every third day. Two weeks later, they were tested for 2 h following an injection of either saline or the group II mGluR antagonist LY341495. In one experiment, test injections were administered systemically (saline or LY341495, 1.0 mg/kg, i.p.). Rats previously exposed to amphetamine showed a greater locomotor response to LY341495 on the test compared to controls previously exposed to saline. This hyperlocomotor response was absent in rats tested with a combination of LY341495 and the group II mGluR agonist LY379268 (1.0 mg/kg, i.p.). In a second experiment, different rats were tested following microinjections into the NAcc (saline or LY341495, 0.1, 10 or 100 microg/0.5 microl/side). Again, rats previously exposed to amphetamine showed a greater dose-dependent locomotor response to LY341495 on the test relative to saline-exposed controls. Locomotor activity in saline-exposed rats challenged with LY341495 did not differ from that observed in rats previously exposed and tested with saline in either experiment. These results indicate that group II mGluRs, particularly those found in the NAcc, are well positioned to modulate the expression of locomotor sensitization by amphetamine.     

Involvement of GABAergic neurotransmission in the neurobiology of the apomorphine-induced aggressive behavior paradigm, a model of psychotic behavior in rats

The effect of treatment with the acute GABAA receptor agonist THIP and the GABAB receptor agonist baclofen on apomorphine-induced aggressive behavior was studied in adult male Wistar rats. Both THIP (10 mg/kg i.p.) and baclofen (8 mg/kg i.p.) attenuated the aggressiveness, thereby indicating the involvement of GABAergic neurotransmission in the mediation of apomorphine-induced aggressiveness. On the basis of our data it can be proposed that both GABAA and GABAB receptor subtypes are involved in the neurobiology of apomorphine-induced aggressive behavior, as this phenomenon is evidently subject to the general inhibitory effect of GABAergic neurotransmission.     

Calcium dependence of sensitised dopamine release in rat nucleus accumbens following amphetamine challenge: implications for the disruption of latent inhibition

Repeated amphetamine treatment results in sensitisation both of its behavioural effects, and of its dopamine (DA)-releasing effects on which the former largely depend. Understanding the nature of the sensitised response may help to explain behaviours which emerge only with repeated treatment, such as particular stereotypies and effects on social behaviour in animals, and links between these effects and the emergence of dependence and psychotic symptoms in humans. We show here that a single pretreatment with amphetamine (1mg/kg) is sufficient to sensitise the locomotor response to amphetamine challenge (1mg/kg) 24h later. We have used in vivo microdialysis in the nucleus accumbens in unrestrained rats to demonstrate a corresponding potentiation in the DA response; the marked increase in accumbens dialysate DA following amphetamine (to 427% of basal) was significantly potentiated (to 675% of basal) by the pretreatment, without any alteration in the basal DA. There was also no change in the expected reduction in DA metabolites. Replacement of perfusate calcium by magnesium left the response to acute amphetamine challenge substantially unaffected, as expected from previous reports; however, the potentiation of the DA response by amphetamine pretreatment was prevented. Similarly the potentiated response was attenuated by administration of ondansetron, a 5HT-3 antagonist, (0.01mg/kg) before each amphetamine treatment. The ability of amphetamine to disrupt latent inhibition (L1), which is also disrupted in acute schizophrenia, has been suggested to provide a model of schizophrenia linking underlying cognitive deficits with the DA theory of the disorder. Since LI is disrupted by two systemic administrations of amphetamine 24h apart, but not by one, the present results are consistent with the concept that it is the calcium, and hence impulse, dependence of increased accumbal DA release, rather than its magnitude, which is critical for the disruption of LI.     

Sensitized activation of Fos and brain-derived neurotrophic factor in the medial prefrontal cortex and ventral tegmental area accompanies behavioral sensitization to amphetamine

Behavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. Male Sprague-Dawley rats underwent unilateral intra-VTA infusion of the retrograde tracer Fluorogold (FG), followed by 5 daily injections of either amphetamine (2.5 mg/kg, i.p.) or saline vehicle. Four weeks later, rats were challenged with amphetamine (1.0 mg/kg, i.p.) or saline (1.0 mL/kg, i.p.). Repeated amphetamine treatment produced locomotor sensitization upon drug challenge. Two hours later, rats were euthanized, and mPFC sections were double-immunolabeled for either Fos-FG or Fos-BDNF. Tissue from the VTA was also double-immunolabeled for Fos-BDNF. Amphetamine challenge increased Fos and BDNF expression in the mPFC regardless of prior drug experience, and further augmented mPFC BDNF expression in sensitized rats. Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.     

Behavioural correlates of modified dopaminergic/anticholinergic responses following chronic treatment with neuroleptic agents of differing activity spectra.

An attempt was made to differentiate the mechanisms of action of these “neuroleptic” agents having antidyskinetic properties from the classical neuroleptics by studying the effects of chronic treatment on the responses to a dopamine agonist and cholinergic antagonist. Rats were chronically treated with haloperidol (2 mg/kg i.p.), oxiperomide (8 mg/kg i.p.), pimozide (8 mg/kg p.o.), tiapride (100 mg/kg i.p.), sultopride (100 mg/kg i.p.), sulpiride (100 mg/kg p.o.) and metoclopramide (100 mg/kg i.p.) for 7 consecutive days. On days 1, 3 and 7 after neuroleptic withdrawal rats were assessed for their sensitivity to the stereotypic effects of apomorphine (0.25–1.0 mg/kg s.c.) and the locomotor stimulant effects of dexetimide (0.32–1.25 mg/kg s.c.). A supersensitivity phase to apomorphine, persisting for 1–3 days, was noted in all drug-treated groups and, during this time, the responses to dexetimide were decreased (haloperidol, oxiperomide and pimozide groups), increased (metoclopramide group) or remained similar to control values (sultopride-, sulpiride- and tiapride-treated animals). The responses to dexetimide returned to control values in all treatment groups as the apomorphine sensitivity phase declined. It is suggested that chronic treatment with neuroleptic agents may enhance the sensitivity of those cerebral receptors responsible for mediating the stereotypic effects of apomorphine, and that the relationship between such dopamine function and interacting cholinergic mechanisms may differ for the different groups of neuroleptic agent. However, these differentiations did not directly correlate with the known ability of the neuroleptics to induce or antagonise dyskinetic phenomena.     

Amphetamine-sensitized rats show sugar-induced hyperactivity (cross-sensitization) and sugar hyperphagia

The goal was to determine the locomotor and consummatory effects of sugar in amphetamine-sensitized rats. Following a 30-min locomotor activity baseline using a photocell cage, male rats were administered either 3.0 mg/kg amphetamine or saline i.p. daily for 6 days. On the final day of injections, locomotor activity was measured again to affirm amphetamine sensitization. Experiment 1: Seven days later, half of each group was offered 10% sucrose or water for 1 min in the home cages, followed by a 30-min locomotor activity test to determine whether or not the animals had become hyperactive in response to sugar. Results showed that amphetamine-sensitized animals were hyperactive following a taste of sugar, but not water. Experiment 2: All subjects were then given access to 10% sucrose for 1 h daily for five consecutive days. Results showed that the amphetamine-sensitized group consumed more sucrose across the 5-day measurement period. These results suggest that sugar may be acting on the same system as amphetamine to trigger hyperactivity, and that alterations in this system caused by repeated doses of amphetamine can instigate an appetite for sugar that persists for at least a week.     

Loss of locomotor sensitisation in response to morphine in D1 receptor deficient mice

Mice lacking D1 receptors were used to study the role of these receptors in morphine-induced antinociception and locomotor sensitisation. In the hot-plate test D1 receptor deficient (-/-) and wild-type (+/+) mice showed similar reaction times under basal conditions. A single injection of 1.25 mg/kg and 2.5 mg/kg morphine resulted in a stronger antinociceptive response in D1 receptor deficient mice than in wild-type animals. Tolerance to the analgesic effect did not develop in both groups of animals when 12.5 mg/kg morphine was chronically applied twice daily for 13 days. There was no change in basal locomotor activity between saline-injected wild-type and D1 receptor deficient mice. After chronic treatment wild-type mice showed a continuous increase in locomotor activity, indicating the development of sensitisation. In contrast, a subchronic administration of morphine did not change locomotor activity in mutant mice. The lack of the development of locomotor sensitisation in D1 deficient mice was associated with reduced levels of immunoreactive mu opioid receptors in dorsal striatal patches as compared to wild-type mice. In contrast, no change in the distribution of immunoreactive mu receptors could be detected in areas related to pain pathways such as the spinal cord. Taken together, these results suggest an involvement of D1 receptors in morphine-induced locomotor activity and analgesia.