Ontogeny of the behavioral response to dopamine agonists after chronic cocaine

 The behavioral response to separate and combined administration of dopamine D₁ and D₂ receptor agonists was assessed acutely and after chronic cocaine exposure (30 mg/kg SC b.i.d. for 5 days) in infant (PND₁₁) and weanling (PND₂₀) rats. In infants, quinpirole (quin) and SKF-38393 (SKF) elevated locomotion, mouthing and sniffing acutely. Rearing was increased and mouthing decreased by combined administration. In weanlings, quin increased locomotion, mouthing and sniffing in weanlings, while SKF increased only mouthing. SKF inhibited quin-induced rearing and locomotion. Infants treated chronically with cocaine showed sensitized quin- and quin/SKF-induced locomotion and quin/SKF stimulated rearing and sniffing. In weanlings, locomotion was sensitized with all drug combinations, and rearing with SKF alone. These results indicate a developmental progression in the psychopharmacological response to dopamine receptor stimulation. While both D₁ and D₂ receptors are active in infants, the full complement of acute responses and complete capacity for sensitization develop later. Received: 13 January 1996 / Final version: 4 September 1996     

Gradient of dopamine responsiveness to dopamine receptor agonists in subregions of the rat nucleus accumbens

The present study sought to investigate the possibility that the degree of selectivity of dopamine D3/D2 receptor agonists such as quinelorane, 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), quinpirole and apomorphine on dopamine D3 over D2 receptor subtypes can be assessed by measuring dopamine transmission in the shell vs. core compartments of the nucleus accumbens by using microdialysis in freely moving rats. Significant reductions in dialysate dopamine levels compared to vehicle-treated animals were observed in the shell of the nucleus accumbens with 3, 10 and 30 microg/kg quinelorane, 100 microg/kg 7-OH DPAT, 25 and 100 microg/kg quinpirole, and 100 microg/kg apomorphine. In the core subregion, significant reductions in dopamine were seen at 10 and 30 microg/kg quinelorane, 25 and 100 microg/kg 7-OH-DPAT, 100 microg/kg quinpirole and 100 microg/kg apomorphine. However, a significant shell/core dichotomy could only be observed in response to the lowest dose of quinelorane (3 microg/kg) with the shell being hyper-responsive compared with the core. The present findings suggest that quinelorane is one of the most selective dopamine D3 receptor agonists based on its ability to target the shell subregion of the nucleus accumbens.     

NMDA or AMPA/kainate receptor blockade prevents acquisition of conditioned place preference induced by D<Subscript>2/3</Subscript> dopamine receptor stimulation in rats

Rationale Recent experiments from this laboratory demonstrated synergistic effects of AMPA/kainate receptor blockade and D_2/3 dopamine (DA) receptor stimulation on brain stimulation reward and locomotor activity.Objectives Using place conditioning, this study explored further the interaction between DA and glutamate (Glu) using the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801, the AMPA/kainate receptor antagonist NBQX, and the D_2/3 DA receptor agonist 7-OH-DPAT.Methods Effects of these compounds, alone and combined, were measured in male Sprague–Dawley rats using an unbiased two-compartment place conditioning procedure.Results 7-OH-DPAT (0.03–5.0 mg kg^–1, s.c.) administered immediately prior to conditioning was ineffective; when administered 15 min prior to conditioning, only the highest dose (5.0 mg kg^–1, s.c.) induced conditioned place preference (CPP). Acquisition of 7-OH-DPAT-induced CPP was blocked by MK-801 (0.06 or 0.13 mg kg^–1, i.p.) or NBQX (0.5 g) microinjected into the nucleus accumbens (NAS) shell subregion. Intra-NAS shell administration of 7-OH-DPAT (5.0 g) or NBQX (0.5 g), alone or combined, failed to induce place conditioning, and this lack of effect was not due to state dependency. Administration of MK-801 or 7-OH-DPAT (5.0 mg kg^–1) during the conditioning phase acutely increased horizontal activity, but neither compound, alone or combined, induced conditioned locomotor effects.Conclusions Acquisition of place conditioning induced by systemic administration of 7-OH-DPAT is blocked by systemic NMDA receptor antagonism by MK-801 or by the AMPA/kainate receptor antagonist NBQX microinjected into the NAS shell subregion.Anna-Maria Biondo and Robert L.H. Clements contributed equally to this work.     

Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists andd-amphetamine

The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 µg/side of the dopamine receptor agonists SKF 38393 (D₁) and quinpirole (D₂) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonistd-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.     

Hyperlocomotion and increased dopamine efflux in the rat nucleus accumbens evoked by electrical stimulation of the ventral subiculum: role of ionotropic glutamate and dopamine D1 receptors

Rationale and objectives: The role of glutamatergic afferents from the hippocampus in the modulation of dopamine (DA) efflux in the nucleus accumbens (NAcc) and concomitant increases in locomotor activity was examined following brief high-frequency electrical stimulation of the ventral subiculum (vSub). Reverse dialysis of ionotropic glutamate receptor (iGluR) antagonists into the NAcc identified the relative contributions of N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors in the modulation of DA efflux, whereas microinjection of these compounds or selective DA D₁ or D₂ receptor antagonists were used to analyze the roles of glutamatergic and DA receptors in the stimulation-induced hyperlocomotion. Methods and results: Electrical stimulation of the vSub at 20 Hz (10 s, 300 μA) induced a significant increase in (1) DA levels in the NAcc (≈30% from pre-stimulation DA levels) and (2) locomotor activity (≈400%). The evoked DA release was completely blocked by reverse dialysis of a selective non-NMDA antagonist DNQX (10 μM and 100 μM), whereas only a high dose of the NMDA antagonist AP-V (100 μM) was effective. The increased motor activity, however, was only slightly attenuated by reverse dialysis of these drugs. Bilateral intra-NAcc injection of DNQX (1 μg/0.5 μl) blocked the increased motor activity induced by vSub stimulation relative to saline treatment. In contrast, bilateral intra-NAcc injection of AP-V (1 μg/ 0.5 μl) alone caused a significant increase in locomotor activity. The increased motor activity induced by vSub stimulation appears to be mediated through the DA D₁ receptor, as systemic administration of the D₁ antagonist SCH 23390 (0.25 mg/kg and 1 mg/kg), but not the D₂ antagonist sulpiride (2 mg/kg and 10 mg/kg) blocked these effects. Conclusions: These data indicate an important role for hippocampal glutamatergic afferents in modulating the release of DA through iGluR on DA-receptive neurons in the NAcc and possibly on output neurons to the ventral tegmental area, which subsequently elicits a prolonged increase in locomotor behavior. The role of this circuit in mediating context-dependent behavioral sensitization to repeated administration of psychostimulants is discussed. Received: 13 October 1999 / Accepted: 21 December 1999     

Preferential increase of extracellular dopamine in the rat nucleus accumbens shell as compared to that in the core during acquisition and maintenance of intravenous nicotine self-administration

Rationale It has been reported that passive administration of nicotine increases preferentially extracellular dopamine (DA) release in the shell as compared to that in the core of the nucleus accumbens (NAc). To date, no information is available if this also applies to active, response-contingent nicotine administration. Objective This study was aimed to monitor the changes of extracellular DA in the NAc shell and core during active intravenous nicotine self-administration (SA). Methods Rats were bilaterally implanted with chronic cannulae and were trained to self-administer nicotine (0.03 mg/kg, i.v.) in single daily 1-h session for 6 weeks, with an initial fixed ratio (FR) 1 schedule increased to FR 2. Dialysate DA from the NAc shell and core was monitored before and for 90 min after the start of SA. Results Significant increases of active nose-pokes over inactive ones were found starting from the 16th SA session. No differences were found in basal extracellular DA in the NAc subdivisions. Data analysis showed (1) significant increases over basal of dialysate DA in the NAc subdivisions during nicotine SA, starting from the first week in the shell and from the second week in the core, (2) preferential increase of extracellular DA during nicotine SA in the shell (24–43%) compared to that in the core (10–23%) and (3) no change in dialysate DA in NAc subdivisions during extinction. Conclusions Response-contingent nicotine SA preferentially increases the DA output in the NAc shell as compared to that in the core, independently from the duration of the nicotine exposure. Increase in NAc DA is strictly related to nicotine action since is not observed during extinction in spite of active responding.     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.     

Monitoring extracellular dopamine in the rat nucleus accumbens shell and core during acquisition and maintenance of intravenous WIN 55,212-2 self-administration

Rationale WIN 55,212-2, a potent cannabinoid receptor 1 agonist, is self-administered by animals to evaluate abuse liability of cannabinoids, but to date no information is yet available about its effects on dopaminergic transmission during active response-contingent administration.Objectives This study monitored the changes of extracellular dopamine (DA) in the nucleus accumbens (NAc) shell and core during active intravenous WIN 55,212-2 self-administration (SA).Methods Rats, implanted with a jugular catheter and bilateral intracerebral chronic cannulae, were trained for 3 weeks to self-administer WIN 55,212-2 (12.5 μg/kg) in single daily 1-h sessions under a fixed ratio 1 (FR 1) schedule, than switched to FR 2 for a further week. During SA sessions, microdialysis assays were performed every 3rd day, and then daily starting from the 13th session. Dialysate DA from the NAc shell and core was monitored before, during, and for 30 min after SA.Results Dialysate DA increased during WIN 55,212-2 SA starting from the 1st week in the NAc shell and on the 2nd week in the core. The increase of dialysate DA in the NAc shell was larger than that in the core on all weeks. Dialysate DA did not change during extinction sessions in spite of active nose poking.Conclusions Response-contingent WIN 55,212-2 SA preferentially increases the NAc shell DA output as compared to that of the core independently from the duration of the WIN 55,212-2 exposure. Increase in NAc DA is strictly related to WIN 55,212-2 actions because it is not observed during extinction despite active responding.     

Microinfusion of corticotropin-releasing factor into the nucleus accumbens shell results in increased behavioral arousal and oral motor activity

 Corticotropin-releasing factor (CRF) is a 41 amino acid peptide postulated to be involved in integrating the physiological and behavioral responses to stress. The purpose of this experiment was to determine the effects of CRF microinfused into the nucleus accumbens core (AcbC) and shell (AcbSh) subregions. Rats were tested for general motor activity, cage crossings, and rearing following CRF (0, 125, 250, or 500 ng). Behavioral observations were also made to determine the profile of activity caused by CRF infusion into the Acb. CRF in the AcbSh but not the AcbC regions elicited an increase in general motor activity that lasted approximately 2 h. When compared with ventricular injections, CRF in the AcbSh had greater activating effects. The CRF-induced behavioral profile consisted of increases in grooming, sniffing, and oral behavior. Results are discussed as they pertain to the involvement of the AcbSh in stress, motivated behavior, and drug sensitization. Received: 17 September 1996 / Final version: 2 November 1996     

Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens

The mu- and delta-opioid receptors located at the terminal level in nucleus accumbens are involved in the opiate modulation of dopamine release in this brain area. However, recent studies suggest that the effects of opioid drugs on the core subregion of nucleus accumbens may completely differ from those observed in the shell. We used in vivo microdialysis to simultaneously apply selective mu- and delta-opioid receptor agonists and to measure extracellular levels of dopamine in three subregions of the accumbens, namely shell, core, and the transition zone between them. The regional analysis of these subregions of the accumbens demonstrated that basal levels of dopamine and its metabolites were higher in the core, and decreased from this subregion to the shell. Retrodialysis application to the core of both the selective mu-receptor agonist ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) (1 micromol/L)) and of the selective delta-opioid receptor agonist ([D-Pen(2), D-Pen(5)]-enkephalin (DPDPE) (50 nmol/L)) increased the dialysate levels of dopamine. However, the application of these drugs to the shell significantly reduced the dopamine levels in this subregion. Local application of the same doses of these drugs in the transition zone between the shell and the core did not significantly affect the dopamine levels in dialysates. These results suggest that the opioid circuits modulating dopaminergic activity in the shell could differ from those in the core of the nucleus accumbens.     

Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat

 Studies indicate that nucleus accumbens (NAcc) dopamine neurotransmission is involved in the reinforcing and direct effects of cocaine. The present study was initiated to explore further the relationship of NAcc extracellular dopamine concentrations ([DA]_e) and cocaine self-administration using a yoked littermate design. In the first experiment, one rat from each litter was trained to self-administer cocaine IV (SA; 0.33 mg/inf) under a fixed ratio 2 schedule, while a second rat received simultaneous infusions of cocaine yoked to the infusions of the SA (YC). NAcc [DA]_e and cocaine concentrations ([COC]) were assessed during the test sessions using in vivo microdialysis combined with microbore HPLC procedures. [DA]_e and [COC] were significantly elevated in the SA and YC groups during the self-administration session; however, [DA]_e were greater in the SA group compared to the YC group in the first hour of the session, even though [COC] were not significantly different. On the following day, the rats previously allowed to self-administer cocaine were administered response-independent cocaine infusions yoked to the infusion pattern from the previous day. [DA]_e were significantly elevated above baseline levels during the session but were significantly less than concentrations obtained when cocaine was self-administered by these subjects. [COC] during the sessions were not significantly different between the two days. Baseline [DA]_e were not significantly different between the SA and YC groups or between Day 1 and Day 2. Furthermore, there was no significant difference in the in vitro probe recovery between one and two days following probe implantation. These results suggest that the context in which cocaine was administered significantly altered the neurochemical response to equivalent brain concentrations of cocaine. NAcc [DA]_e was significantly increased when the delivery of cocaine infusions was contingent on the behavior of the rat, indicative of a role in the neural processes underlying cocaine reinforcement. Received: 23 May 1996 / Final version: 11 April 1997     

Passive avoidance in rats: Disruption by dopamine applied to the nucleus accumbens

The acquisition of a one-trial step-through passive avoidance task was examined in rats following the administration of nialamide IP and dopamine (DA) or saline into the nucleus accumbens. DA-treated rats displayed impaired learning of the task as evidenced by their lower step-through latencies on a retest trial 7 days later. The specificity of this impairment was studied in a 2×2 design involving intracerebral injections prior to both training and testing trials. It was found that DA treatment prior to the training trial disrupted learning or memorization of the task but that DA did not affect performance or retrieval and did not induce state-dependent learning. These findings suggest that DA applied to the nucleus accumbens does not facilitate learning per se.     

Role of AMPA and NMDA receptors in the nucleus accumbens shell in turning behaviour of rats: interaction with dopamine receptors

The role of AMPA and NMDA receptors in the shell of the nucleus accumbens in turning behaviour of rats was investigated. Unilateral injection of the AMPA receptor agonist, AMPA (0.25, 0.4, 0.5 and 1 microg), into the shell of the nucleus accumbens dose-dependently produced contraversive pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping, while injection of AMPA (0.5 microg) into the core produced only a marginal effect. This shell-specific AMPA effect was dose-dependently inhibited by the AMPA receptor antagonist, NBQX (1 and 10 ng), which alone did not produce turning behaviour. The AMPA-induced pivoting was also dose-dependently inhibited by the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.5 microg). Neither MK-801 (0.1, 0.5 and 5 microg) nor the NMDA receptor agonist, NMDA (0.5 and 1 microg), injected unilaterally into the shell, produced turning behaviour. Unilateral injection of a mixture of dopamine D(1) (SKF 38393, 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the shell has been found to elicit contraversive pivoting. The dopamine D(1)/D(2) receptor antagonist, cis-(Z)-flupentixol (1 and 10 microg), injected into the shell, in doses known to block dopamine D(1)/D(2) receptor-mediated pivoting, also significantly inhibited AMPA (0.5 microg)-induced pivoting. Moreover, both NBQX (1 and 10 ng) and MK-801 (0.1 and 0.5 microg), injected into the shell, significantly inhibited dopamine D(1)/D(2) receptor-mediated pivoting. It is therefore concluded that unilateral stimulation of AMPA receptors in the shell of the nucleus accumbens can elicit contraversive pivoting, and that both AMPA and dopamine D(1)/D(2) receptors play a critical role in shell-specific pivoting in contrast to NMDA receptors that at best play only a modulatory role.     

Chronic morphine induces long-lasting changes in acetylcholine release in rat nucleus accumbens core and shell: an in vivo microdialysis study

 Previously, only in vitro studies have shown that chronic administration of morphine provokes long-lasting enhanced activity of accumbal cholinergic neurons, which may contribute to the behavioural sensitization, positive reinforcement and aversive effects associated with enhanced drug-seeking. The present study was aimed at clarifying whether these adaptive changes would also be supported by in vivo microdialysis measurements in freely moving rats, distinguishing between the accumbal substructures shell and core, and observing behavioural changes simultaneously. Acute administration of morphine dose-dependently decreased acetylcholine (ACh) release in the nucleus accumbens (NAc), with 10 mg/kg SC being most effective, 5 mg/kg ineffective. On day 5 of spontaneous abstinence from chronic morphine treatment (10–40 mg/kg morphine dose once daily for 5 days), when withdrawal symptoms were still present, even a lower morphine dose (5 mg/kg) was effective in decreasing ACh release in the NAc. During the later phase of abstinence, when no withdrawal symptoms were detectable, the opposite effect, i.e. an increase of ACh release was found. This later effect may represent a long-lasting neuroadaptive effect of morphine. These adaptive effects seemed to be more prominent in the NAc shell. Concurrent with these changes in ACh release, morphine challenges produced marked behavioural stereotypes, possibly indicating behavioural sensitization. Received: 7 April 1998 / Final version: 23 July 1998     

Locomotor hyperactivity caused by dopamine infusion into the nucleus accumbens of rat brain: specificity of action

Rats selected as high-activity and low-activity responders to the hyperactivity-inducing action of peripherally administered (-)N-n-propylnorapomorphine [(-)NPA] were subject to intra-accumbens infusion of dopamine, noradrenaline, serotonin, acetylcholine and GABA (0.48 l/h, 25 g/24 h, 13 days). Locomotor activity was measured during infusion and for a minimum of 35 days thereafter. After discontinuation of infusion the animals' responsiveness to (-)NPA was also assessed and, on the 2nd day of withdrawal, sensitivity to the hyperactivity-inducing action of acute intra-accumbens dopamine was determined. Dopamine caused a biphasic pattern of hyperactivity during infusion with peaks of responding between days 2–5 and 8–12: normal values returned after withdrawal of infusion. However, 2–3 weeks after withdrawal of intra-accumbens dopamine infusion animals showed reversed responding to (-)NPA challenge, the initial low-active animals giving a high-active response and high-active animals giving low-activity. Infusions of noradrenaline, serotonin, GABA and acetylcholine produced some increase in locomotor activity towards the termination of infusion, but no treatment could replicate the first hyperactivity peak and no treatment, after withdrawal, could reverse the responsiveness to (-)NPA of high- and low-active animals. Acute injections of dopamine into the nucleus accumbens showed that the infusion of the different neurotransmitter substances caused change within that nucleus. Nevertheless, changes in locomotor behaviour following the infusion of dopamine into the nucleus accumbens are specific for dopamine.     

Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor activity and dopamine release in the nucleus accumbens

The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may be related in part to the ability of 5-HT to modulate the function of the dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male Sprague-Dawley rats. Systemic administration of either fluoxetine or fluvoxamine enhanced cocaine-induced locomotor activity in a dose-dependent manner; fluoxetine (10 mg/kg, IP) also enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. To test the hypothesis that the NAc serves as the locus of action underlying these effects following systemic cocaine administration, fluoxetine (1 and 3 micro g/0.2 micro l/side) or fluvoxamine (1 and 3 micro g/0.2 micro l/side) was microinfused into the NAc shell prior to systemic administration of cocaine (10 mg/kg, IP). Intra-NAc shell infusion of 3 micro g of fluoxetine or fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux in the NAc is mediated in part by local actions of the SSRIs in the NAc.     

Effects of (–)-ephedrine on locomotion, feeding, and nucleus accumbens dopamine in rats

 The intent of the present study was to determine the effects of systemic injections of the sympathomimetic agent ephedrine (EPH) on extracellular dopamine (DA) levels within the rat nucleus accumbens (NAC) and to compare these effects with those of EPH on locomotion and on feeding. In experiment 1, adult male rats were prepared with an indwelling 3 mm microdialysis probe positioned within the NAC. The rats were injected (IP) with vehicle, 5, 10, or 20 mg/kg (–)-EPH with dialysates collected every 20 min for 100 min after drug injection. Systemic injections of 5, 10 or 20 mg/kg (–)-EPH significantly enhanced extracellular levels of NAC DA over baseline by 79%, 130%, and 400%. Systemic injection of 20 mg/kg EPH significantly reduced NAC levels of DOPAC and HVA by 37% and 31%. The effects of EPH on brain dopamine activity were stereospecific given that an additional group of rats injected with 20 mg/kg (+)-EPH exhibited smaller changes in NAC DA (<25%), DOPAC (<10%), and HVA levels (<20%) than did rats injected with 20 mg/kg (–)-EPH. In experiment 2, adult male rats were injected (IP) with 0, 5, 10, or 20 mg/kg (–)-EPH prior to placement in automated activity chambers. Total distance traveled was significantly increased by 10 and 20 mg/kg (–)-EPH, but not by 5 mg/kg (–)-EPH. In experiment 3, adult male rats were injected (IP) with 0, 2.5, 5, or 10 mg/kg (–)-EPH or with 0, 2.5, 5, or 10 mg/kg (+)-EPH prior to a 30-min feeding test. Although each EPH enantiomer decreased feeding, (–)-EPH was more potent in feeding suppression than was (+)-EPH. The present results suggest that EPH may alter locomotion and feeding via an indirect action on brain dopamine activity. Received: 23 January 1997 / Final version: 2 August 1997     

Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core

Rationale Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (d-amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% l-amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for d-amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between d-amphetamine and l-amphetamine have not been well characterized.Objectives To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes.Results The presence of l-amphetamine in the d,l-amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The d,l-amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When l-amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of d,l-amphetamine.Conclusions These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that l-amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals.     

Effects of dopamine receptor stimulants on locomotor activity of rats with electrolytic or 6-hydroxydopamine-induced lesions of the nucleus accumbens

Ergometrine (8 mg/kg) injected intraperitoneally into normal rats had little effect on locomotor activity. In contrast, rats with selective 6-hydroxydopamine-induced lesions of dopamine terminals in the nucleus accumbens showed a strong stimulation of locomotor activity following injection of this dose of ergometrine.The dopamine analogue 2-amino-6-7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) (150 g), caused strong and long lasting stimulation of locomotor activity when injected intracerebroventricularly into rats. The ADTN response was markedly reduced in rats with bilateral electrolytic lesions of the nucleus accumbens, but unchanged in rats with bilateral electrolytic lesions of the caudate nucleus. At a lower dose level (50 g) ADTN, injected intracerebroventricularly, had little effect on the locomotor activity of normal or sham-operated rats. This dose of ADTN was, however, effective in causing locomotor stimulation of rats with bilateral 6-hydroxydopamine-induced lesions of the nucleus accumbens.These results support the view that the dopamine receptors in the nucleus accumbens are involved in the actions of locomotor stimulant drugs.     

A functional effect of dopamine in the nucleus accumbens and in some other dopamine-rich parts of the rat brain

Dopamine (5 to 50 g) applied bilaterally to the nucleus accumbens of reserpine-nialamide pretreated rats produced a marked dose-dependent rise in coordinated locomotor activity, devoid of stereotypies such as gnawing, rearing and licking seen after dopamine application (50 g) to the neostriatum. The locomotor activity was completely blocked by pimozide, but not by phenoxybenzamine. The effects of apomorphine or d-noradrenaline were similar to those of dopamine. In contrast, l-noradrenaline produced a convulsive syndrome devoid of coordinated locomotor activity, and this convulsive syndrome could be completely blocked by phenoxybenzamine but not by pimozide. Release of endogenous dopamine by d- or l-amphetamine (10 and 50 g) in the nucleus accumbens produced a rise in coordinated activity, the d-isomer was about 4 times as potent as the l-isomer, and the effect of the d-isomer was blocked completely by -methyltyrosine. Bilateral application of trifluoperazine (2.5 g) to the nucleus accumbens completely blocked the effect of systemically administered d-amphetamine (1.5 and 3.0 mg/kg), but similar application to the area of the central nucleus of the amygdala or the neostriatum was much less effective. Partial protection of the endogenous dopamine stores against the depleting action of reserpine by local application of metatyramine to the nucleus accumbens resulted in a higher level of basal activity than in control animals. Application of dopamine or noradrenaline to the area of the central nucleus of the amygdala or to the olfactory tubercles did not lead to any consistent changes in locomotor activity.The nucleus accumbens and olfactory tubercles contained most of the dopamine in the limbic forebrain, with noradrenaline more evenly distributed.These data suggest that the nucleus accumbens plays an important role in the locomotor activity in rats.