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Role of 5-HT2A and 5-HT2C/B receptors in the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on striatal single-unit activity and locomotion in freely moving rats
Abstract
Like amphetamine, a locomotor-activating dose of 3,4-methylenedioxymethamphetamine (MDMA) predominantly excites striatal single-unit activity in freely moving rats. Although both D1- and D2-like dopamine (DA) receptors play important roles in this effect, MDMA, unlike amphetamine, strongly increases both DA and serotonin (5-HT) transmission.
This study was conducted to investigate the 5-HT receptor mechanisms underlying the striatal effects of MDMA.
We recorded the activity of >200 single units in the striatum of awake, unrestrained rats in response to acute MDMA administration (5 mg/kg) combined with the selective blockade of either 5-HT2A or 5-HT2C/B receptors.
Prior administration of SR-46349B (a 5-HT2A antagonist 0.5 mg/kg) blocked nearly all MDMA-induced striatal excitations, which paralleled its significant attenuation of MDMA-induced locomotor activation. Conversely, prior administration of SB-206553 (a 5-HT2C/B antagonist 2.0 mg/kg) had no effect on the amount of MDMA-induced locomotor activation or the distribution of single-unit responses to MDMA. However, a coefficient-of-variation analysis indicated significantly less variability in the magnitude of both MDMA-induced neuronal excitations and inhibitions in rats that were pretreated with SB-206553 compared to vehicle. Analysis of concurrent single-unit activity and behavior confirmed that MDMA-induced striatal activation was not merely due to behavioral feedback, indicating a primary action of MDMA.
These results support and extend our previous findings by showing that 5-HT2A and 5-HT2C/B receptors differentially regulate the expression of MDMA-induced behavioral and striatal neuronal responses, either directly or through the modulation of DA transmission.
... The widely used amphetamine (AMPH) derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) increases synaptic levels of dopamine (DA) and serotonin (5-HT) in striatum and prefrontal cortex (Gudelsky and Yamamoto, 2008), causing acute changes in the functioning of neurons in these regions. For example, we reported that acute MDMA (5.0 mg/kg) administration caused DA-and 5-HT-dependent changes in the activity of dorsal striatal neurons in freely moving rats (Ball et al., 2003;Ball and Rebec, 2005). Moreover, we found that repeated administration of MDMA resulted in relatively longlasting changes in both the electrophysiology of dorsal striatal neurons (Ball et al., 2006) and the morphology of neurons within ventral striatum (nucleus accumbens; NAc) and medial prefrontal cortex (Ball et al., 2009). ...
... The dose of 5.0 mg/kg (weight of salt; dissolved in 0.9% saline) was used for all injections. We have used this dose in previous studies (Ball et al., 2003;Ball and Rebec, 2005;Ball et al., 2006) because it is a relatively low dose, yet induces robust behavioral activation. ...
... At the beginning of each experimental session, rats were placed into the recording chamber and unit activity was discriminated as described above. Recording sessions were 120 min in length and divided into three successive periods as in our previous studies (Ball et al., 2003;Ball and Rebec, 2005;Ball et al., 2006). Period 1 (10 min) served as pre-baseline, during which no treatment was administered, but single-unit activity was recorded to ensure a stable signal. ...
We examined whether repeated exposure to the increasingly abused amphetamine (AMPH) derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) results in long-lasting neurobehavioral changes, and further, the ability of contextual cues to modulate these changes. We focused on dorsal striatum, a brain region implicated in the formation of persistent drug-related habits. Rats were transported to a novel recording chamber and treated with once-daily injections (s.c.) of (±)-MDMA (5.0 mg/kg) or saline for 5 days, followed by a challenge injection 14 days later either in the same (Experiment 1) or different context (Experiment 2). Chronically implanted micro-wire bundles were used to record from populations of striatal neurons on days 1, 5, and challenge. Twenty-four hours after the last injection, brains were removed and processed using a modified Golgi method to assess changes in neuronal morphology. A sensitized locomotor response was observed following MDMA challenge in 11 of 12 rats in Experiment 1 (same context), whereas only 58% of rats (7 of 12) displayed sensitization in Experiment 2 (different context). Furthermore, several alterations in striatal electrophysiology were apparent on challenge day, but only in rats that displayed sensitization. Conversely, structural changes in striatal medium spiny neurons, such as increases in spine density, were observed in MDMA-treated rats regardless of whether they displayed behavioral sensitization. Thus, it appears that reorganization of synaptic connectivity in dorsal striatum may contribute to long-lasting drug-induced behavioral alterations, but that these behavioral alterations are subject to modification depending on individual differences and the context surrounding drug administration.
... In freely moving rats, MDMA has a predominantly excitatory effect on striatal neuronal activity that is reversed by DA D 1 -and D 2 -like receptor antagonists (Ball et al., 2003). The 5-HT 2A receptor antagonist SR-46349B also reverses the behavioural and striatal effects of MDMA, either directly or via the modulation of DA efflux (Ball & Rebec, 2005). ...
... To test the hypothesis that contextual drug associations are important to the expression of behavioural sensitization to chronic MDMA, a separate group of rats, in Experiment 2, received repeated injections of MDMA alternately in the recording chamber or home cage, according to the timeline in Experiment 1. These studies extend our previous investigations into the acute effects of MDMA on dorsal striatal activity and behaviour (Ball et al., 2003;Ball & Rebec, 2005). ...
... A mean baseline firing rate was obtained for each unit by averaging unit activity during Period 2. Changes in firing rate for individual units were calculated as a percentage of the baseline for each 5-min bin in Period 3. As established previously (Ball et al., 2003;Haracz et al., 1993;Ball & Rebec, 2005), changes in firing rate of > 50% were considered a departure from baseline, and units showing increases or decreases of this magnitude for at least three consecutive bins (15 min) were classified as excited or inhibited, respectively. If changes in activity did not reach 50% in either direction, a unit was classified as unresponsive. ...
To investigate the neuronal mechanisms underlying the behavioural alterations that accompany repeated exposure to MDMA (ecstasy), we recorded the activity of > 200 striatal units in response to multiple, intermittent, locomotor-activating doses (5.0 mg/kg) of MDMA. Rats were treated with once-daily injections of either saline or MDMA for 5 days when housed in their home cage, followed by a challenge injection 3-5 days later when housed in a recording chamber. Because contextual drug associations might be particularly important to the expression of behavioural sensitization to chronic MDMA, a separate group of rats received repeated injections of MDMA alternately in the recording chamber or home cage, according to the above timeline. A sensitized locomotor response was observed only in rats that had previously experienced MDMA in the context of the recording chamber, and only on the challenge day. These sensitized animals also showed a decreased basal firing rate in neurons that were subsequently excited by MDMA when compared with the same category of neurons earlier in the treatment regimen. This resulted in a greater percentage increase from the baseline firing rate on the challenge day compared with the first and fifth days of treatment, even though this trend was not evident with an analysis of absolute firing rate. These results strongly support a role for context in the expression of MDMA-induced locomotor sensitization, and implicate striatal involvement in the neurobehavioural changes associated with the repeated use of MDMA.
... The restriction of neurobiological changes in SERT-KO rats to the serotonergic system provides a unique research tool to examine the effect of constitutive SERT dysfunction in MDMA toxicity, furthering our understanding of this protein in the mechanism of action of MDMA. Acute monoamine release and subsequent activation of postsynatic monoamine receptors following MDMA treatment is accompanied by significant increases in body temperature (Shioda et al., 2008) and hyperactivity (Ball et al., 2003;Ball and Rebec, 2005) in rats. Evidence suggests that body temperature elevation in response to MDMA requires the concomitant activation of sympathetic nervous system pathways and the hypothalamic-pituitary-adrenal axis, reflective of a thermogenic response (Mills et al., 2004). ...
... The role of 5-HT release in MDMA-induced locomotion is thought to occur via indirect modulation of the striatal DA system. Pharmacological blockade of 5-HT 2A receptors decreases MDMA-mediated striatal excitation in parallel with a suppression in locomotor activity (Ball and Rebec, 2005). Our results reveal a significant delay, and attenuation, in MDMA-induced horizontal velocity in SERT-deficient rats compared with WT counterparts (Fig. 4A). ...
3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a ring-substituted amphetamine derivative with potent psychostimulant properties. The neuropharmacological effects of MDMA are biphasic in nature, initially causing synaptic monoamine release, primarily of serotonin (5-HT), inducing thermogenesis and hyperactivity (5-HT syndrome). The long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to 5-HT nerve terminals. The effects of MDMA are in part mediated by an ability to inhibit the presynaptic 5-HT reuptake transporter (SERT). Using a SERT-knockout (SERT-KO) rat model, we determined the effects of SERT deficiency on thermoregulation, locomotor activity, and neurotoxicity in SERT-KO or Wistar-based wild-type (WT) rats exposed to MDMA. WT and SERT-KO animals exhibited the highest thermogenic responses to MDMA (4x 10mg/kg, sc at 12 h intervals) during the diurnal (first and third) doses according to peak body temperature and area under the curve (∑ºC*h) analysis. Although no differences in peak body temperature were observed between MDMA-treated WT and SERT-KO animals, ∑ºC*h following the first MDMA dose was reduced in SERT-KO rats. Exposure to a single dose of MDMA stimulated horizontal velocity in both WT and SERT-KO rats, however, this effect was delayed and attenuated in the KO animals. Finally, SERT-KO animals were insensitive to MDMA-induced long-term (7 days) depletions in 5-HT and its metabolite, 5-hydroxyindole acetic acid (5-HIAA), in both cortex and striatum. In conclusion, SERT deficiency modulated MDMA-mediated thermogenesis, hyperactivity and neurotoxicity in KO rats. The data confirm that the SERT is essential for the manifestation of the acute and long-term effects of MDMA.
... Las RSAs también tienen actividad intrínseca relativamente débil en los receptores de varios neurotransmisores, actuando como agonistas directos de los receptores 5-HT1A/D y 5-HT2, α1/2 (28), β, D1/2, M1/2 Y H1/2 (2). Más recientemente se han implicado los receptores 5-HT2A Y 5-HT2C/B en la regulación de las respuestas neuronal estriatal y conductual inducida por MDMA, tanto de forma directa como a través de la modulación de la transmisión de dopamina (29,30). ...
... En consumidores humanos de "éxtasis", hay evidencias de déficits en marcadores bioquímicos serotonérgicos, que correlacionan con disfunciones a largo plazo en memoria y aprendizaje (34)(35)(36). Hay varios mecanismos interrelacionados, que contribuyen a la neurotoxicidad inducida por MDMA, como la formación de metabolitos neurotóxicos, la recaptación del MDMA y sus metabolitos por los transportadores de 5-HT, la activación de los receptores 5-HT2A (30,37), disfunción mitocondrial (38,39), fosforilación de las proteínas de choque térmico y la consecuente disminución de la actividad de las chaperonas (40)(41)(42), excitotoxicidad del glutamato (43), la hipertermia, la formación de especies reactivas de oxígeno y nitrógeno, evidencias de toxicidad cardiacas (44)(45)(46) y neuroinflamación (38,47,48). ...
... On the last self-administration day, we compared time-out responding following the first MDMA infusion to time-out responding following the last MDMA infusion and found no significant difference [t(6) = 0.00, p = 1.00], arguing against non-specific behavioral activation as a cause of lever pressing. In addition, we injected a subset of rats (n = 6) with 5.0 mg/kg MDMA, a dose known to elicit behavioral activation (Ball et al., 2003(Ball et al., , 2006Ball and Rebec, 2005), two days after CS-induced reinstatement and monitored lever pressing (lever presses had no programmed consequences during these sessions). This procedure did not induce lever-pressing behavior [no significant difference from the level of responding during extinction; t(5) = 0.67, p = 0.27], further supporting our conclusion. ...
... In contrast to CS presentations, passive MDMA injections (5 mg/kg) did not significantly increase lever pressing during extinction. This result provides strong evidence that the lever pressing during CS-induced reinstatement sessions does not reflect non-specific behavioral activation (as opposed to goaldirected behavior), because this dose of MDMA induces robust locomotor activation (present results; Ball et al., 2003Ball et al., , 2006Ball and Rebec, 2005). Interestingly, this finding also suggests that, in contrast to other drugs of abuse (Lê ̣ and Shaham, 2002;Shalev et al., 2002), drug exposure may not reinstate MDMA seeking following extinction. ...
The widely used recreational drug MDMA (ecstasy) supports self-administration in animals, but it is not known whether MDMA-associated cues are able to reinstate drug seeking in a relapse model of drug addiction. To assess this possibility, drug-naïve rats were trained to press a lever for MDMA infusions (0.30 mg/kg/infusion, i.v.) paired with a compound cue (light and tone) in daily 2 h sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. Conditioned cue-induced reinstatement tests were conducted after lever pressing was extinguished in the absence of MDMA and the conditioned cues. Conditioned cues reinstated lever pressing after extinction, and the magnitude of reinstatement was positively correlated with the level of responding during MDMA self-administration. These results show for the first time that conditioned cues can trigger reinstatement of MDMA-seeking behavior in rats, and that individual differences in the pattern of MDMA self-administration can predict the magnitude of reinstatement responding.
... In addition, MDMA also binds to monoamine transporters and to VMAT 2 and inhibits their function directly (Battaglia et al., 1988;Partilla et al., 2006;Rudnick and Wall, 1992;Simmler et al., 2013). Besides modulating synaptic monoamine concentrations, MDMA also displays affinity as an agonist at serotonin 5-HT 1A , 5-HT 2A , 5-HT 2B and 5-HT 2C , α 2A adrenergic, dopamine D 1 and D 2 (Ball and Rebec, 2005;Eshleman et al., 2013;Rickli et al., 2015;Simmler et al., 2013), as well as adrenergic α 1 and β, muscarinic M 1 and M 2 , histamine H 1 (Battaglia et al., 1988) and acetylcholine nicotinic receptors (Garcia-Ratés et al., 2010). While MDMA has some agonist properties at the human trace amine-associated receptor 1 (TAAR1), which has been associated with the regulation of monoamine transporters and dopaminergic activity (Miller, 2011), its activity is significantly lower at human TAAR1 than at rodent TAAR1 (Simmler et al., 2016). ...
The last two decades have seen a revival of interest in the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA) as an adjunct to psychotherapy, particularly for the treatment of post-traumatic stress disorder. While clinical results are highly promising, and MDMA is expected to be approved as a treatment in the near future, it is currently the only compound in its class of action that is being actively investigated as a medicine. This lack of alternatives to MDMA may prove detrimental to patients who do not respond well to the particular mechanism of action of MDMA or whose treatment calls for a modification of MDMA's effects. For instance, patients with existing cardiovascular conditions or with a prolonged history of stimulant drug use may not fit into the current model of MDMA-assisted psychotherapy, and could benefit from alternative drugs. This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives in the future, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action and entactogenic commonalities with MDMA. The substances examined derive from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole and amphetamine classes. Several compounds from these classes are identified as potential alternatives to MDMA.
... Its 5-HT 2A versus 5-HT 2B/C receptor selectivity ratio is less than 10:1, compared to greater than 300:1 for MDL100,907 (Palfreyman et al., 1993). However, in both control animals (Ball and Rebec, 2005) and in dopamine supersensitive animals outside of the context of antipsychotics (Bishop et al., 2005;Filip et al., 2004), blockade of either 5-HT 2B or 5-HT 2C receptors generally does not affect the locomotor response to dopamine agonists [c.f., (Zayara et al., 2011)]. Blockade of 5-HT 2 receptors with ritanserin had no effect on spontaneous locomotion, in either experimental group. ...
Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025-0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate-putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.
... To confirm 5-HT actions of MDMA in STN, we first focused on the role of 5-HT 2A-and 5-HT 1A-receptors, and receptor subtypes with well-established roles with regard to diverse behavioural effects of MDMA: 5-HT 2A receptors are involved in locomotor impairment as shown in singleunit recordings and animal behavioural studies ( Kehne et al. 1996;Bankson and Cunningham 2001;Fletcher et al. 2002;Ball and Rebec 2005;Orejarena et al. 2011) as well as human antagonist studies ( Liechti et al. 2000b). 5-HT 1A-R is responsible for MDMA's anxiogenic effect ( Bhattacharya et al. 1998;Müller et al. 2007). ...
3,4-Methylene-dioxy-N-methylamphetamine (MDMA, 'ecstasy') has a broad spectrum of molecular targets in the brain, among them receptors and transporters of the serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic systems. Its action on the serotonergic system modulates motor systems in rodents and humans. Although parts of the basal ganglia could be identified as mediators of the motor effects of MDMA, very little is known about the role of the subthalamic nucleus (STN). Therefore, this study investigated the modulation of spontaneous action potential activity of the STN by MDMA (2.5-20 µM) in vitro. MDMA had very heterogeneous effects, ranging from a complete but reversible inhibition to a more than twofold increase in firing at 5 µM. On average, MDMA excited STN neurons moderately, but lost its excitatory effect in the presence of the 5-HT2A antagonist MDL 11,939. 5-HT1A receptors did not appear to play a major role. Effects of MDMA on transporters for serotonin (SERT) and norepinephrine (NET) were investigated by coapplication of the reuptake inhibitors citalopram and desipramine, respectively. Similar to the effects of 5-HT2A receptor blockade, antagonism of SERT and NET bestowed an inhibitory effect on MDMA. From these results, we conclude that both the 5-HT and the noradrenergic system mediate MDMA-induced effects on STN neurons.
... Similar to other amphetamine-like drugs, MDMA causes increases in extracellular catecholamine levels (Green et al. 1995), but MDMA is unique in that it potently increases serotonin (5-HT) levels as well (Gough et al. 1991;Kankaanpaa et al. 1998). Accordingly, both dopamine and 5HT receptor mechanisms are involved in the acute neurobehavioral effects of MDMA (Ball et al. 2003;Ball and Rebec 2005;Bankson and Cunningham 2001;Bubar et al. 2004). Although it has been shown that MDMA-associated cues reinstate extinguished MDMA seeking in rats (Ball et al. 2007) and mice (Orejarena et al. 2010), there is very little information regarding the neural mechanisms underlying this behavior. ...
Rationale
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a widely abused drug, particularly in adolescent and young adult populations. Although it was shown that MDMA-associated cues reinstate extinguished MDMA seeking in an animal relapse model, there is little information regarding the neural mechanisms underlying this behavior.
Objectives
Because the medial prefrontal cortex (mPFC) plays an important role in relapse to cocaine and methamphetamine seeking, we tested the effects of lidocaine inactivation of prelimbic (PL) and infralimbic (IL) subregions of mPFC on cue-induced relapse to MDMA seeking.
Methods
Rats were trained to respond for MDMA infusions (0.50 mg/kg/infusion, i.v.) paired with a discrete cue in daily 2-h sessions. Responding was reinforced contingent on a modified fixed ratio 5 schedule of reinforcement. Cue-induced reinstatement tests were conducted after responding was extinguished in the absence of MDMA and the conditioned cues. Prior to reinstatement tests, rats received bilateral microinjections of either lidocaine (100 μg/0.5 μl/side) or physiological saline (0.5 μl/side) delivered to either PL or IL mPFC.
Results
Microinjections of lidocaine into PL completely blocked reinstatement of MDMA-seeking behavior compared with saline microinjections into the same region. Lidocaine microinjections did not, however, have an effect on food-maintained responding, ruling out a nonspecific disruption of motor performance. Conversely, lidocaine inactivation of IL had no effect on reinstatement of MDMA seeking or food-maintained responding.
Conclusions
Our results provide direct support for PL activation in reinstatement of MDMA-seeking behavior. Moreover, akin to cocaine seeking, there appears to be differential involvement of PL and IL subregions in this behavior.
... These behavioural findings diverge from our microdialysis results, and suggest that in the absence of 5-HT 2A Rs, a complex monoaminergic dysregulation could take place eliciting singular basal and MDMA-evoked locomotor responses. Most pharmacological studies using acute administration of 5-HT 2A R antagonists have shown a reduction in MDMA-induced locomotor activation in several animal species, although contradictory results have also been reported (Ball & Rebec, 2005 ;Bankson & Cunningham, 2002 ;Fantegrossi et al. 2003 ;Herin et al. 2005 ;Kehne et al. 1996). Thus, compensatory mechanisms in KO mice leading to opposite changes with respect to acute blockade of these receptors cannot be completely ruled out. ...
The serotonergic system appears crucial for (±)-3,4-methylenedioxymethamphetamine (MDMA) reinforcing properties. Current evidence indicates that serotonin 5-HT2A receptors (5-HT2ARs) modulate mesolimbic dopamine (DA) activity and several behavioural responses related to the addictive properties of psychostimulants. This study evaluated the role of 5-HT2ARs in MDMA-induced reinforcement and hyperlocomotion, and the reinstatement of MDMA-seeking behaviour. Basal and MDMA-stimulated extracellular levels of DA in the nucleus accumbens (NAc) and serotonin and noradrenaline in the prefrontal cortex were also assessed. Self-administration of MDMA was blunted in 5-HT2AR knockout (KO) mice compared to wild-type (WT) littermates at both doses tested (0.125 and 0.25 mg/kg per infusion). Horizontal locomotion was increased by MDMA (10 and 20 mg/kg i.p.) to a higher extent in KO than in WT mice. DA outflow in the NAc was lower in KO compared to WT mice under basal conditions and after MDMA (20 mg/kg) challenge. In WT mice, MDMA (5 and 10 mg/kg i.p.) priming did not reinstate MDMA-seeking behaviour, while cue-induced reinstatement was prominent. This cue-induced reinstatement was blocked by administration of the selective 5-HT2AR antagonist, SR46349B (eplivanserin) at a dose of 0.5 mg/kg, but not at 0.25 mg/kg. Our results indicate that 5-HT2ARs are crucial for MDMA-induced reinforcement and cue-induced reinstatement of MDMA-seeking behaviour. These effects are probably due to the modulation of mesolimbic dopaminergic activity.
... Serotonergic neurons from the dorsal raphé nucleus project to the VTA and the NAcc and impact dopaminergic neurotransmission [2,3]. Thus, regulation of mesolimbic DA activity by 5-HT and its receptors plays an important role in the reinforcing effects of drugs of abuse [4], including the 'club drug' MDMA5678. MDMA binds to and reverses the dopamine transporter (DAT) and the serotonin transporter (SERT) to produce carrier-mediated efflux of DA and 5-HT, respectively [9]. However, when access to SERT is blocked by selective serotonin reuptake inhibitors (SSRI), MDMA-evoked DA efflux in the NAcc is reduced101112. ...
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT2B receptors to the reinforcing properties of MDMA.
We show here that 5-HT2B−/− mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT2B receptor-independent behavioral effects.
These results underpin the importance of 5-HT2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.
... Behavioral effects of MDMA have been studied in rodents for many years (Gold & Koob 1989;Green et al. 2003;Ball & Rebec 2005;Daza-Losada et al. 2007), but the mechanisms underlying these effects are still poorly understood. Few studies have focused on the possible interaction between the delta opioid system and the effects of this substituted amphetamine (Reid et al. 1996;Compan et al. 2003). ...
The delta opioid system is involved in the behavioral effects of various drugs of abuse. However, only a few studies have focused on the possible interactions between the opioid system and the effects of 3,4-methylenedioxymethamphetamine (MDMA). In order to examine the possible role of the delta opioid system in MDMA-induced behaviors in mice, locomotor activity and conditioned place preference (CPP) were investigated in the presence of naltrindole (NTI), a selective delta opioid antagonist. Moreover, the consequences of acute and chronic MDMA administration on pro-enkephalin (Penk) and pro-opiomelanocortin (Pomc) gene expression were assessed by real-time quantitative polymerase chain reaction (QPCR). The results showed that, after acute MDMA administration (9 mg/kg; i.p.), NTI (5 mg/kg, s.c.) was able to totally block MDMA-induced hyperlocomotion. Penk gene expression was not modulated by acute MDMA, but a decrease of Pomc gene expression was observed, which was not antagonized by NTI. Administration of the antagonist prevented the acquisition of MDMA-induced CPP, suggesting an implication of the delta opioid receptors in this behavior. Following chronic MDMA treatment, only the level of Pomc was modulated. The observed increase was totally blocked by NTI pre-treatment. All these results confirm the interactions between the delta opioid system (receptors and peptides) and the effects of MDMA.
... The dose of 5.0 mg/kg (weight of salt; dissolved in 0.9% saline) was used for all injections during the pretreatment period. This is a dose we have used in previous studies (Ball et al., 2003(Ball et al., , 2006Ball and Rebec, 2005) because it is a relatively low dose, yet induces robust behavioral activation. ...
Repeated, intermittent exposure to the psychomotor stimulants amphetamine and cocaine induces a progressive and enduring augmentation of their locomotor-activating effects, known as behavioral sensitization, which is accompanied by similarly stable adaptations in the dendritic structure of cortico-striatal neurons. We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also results in long-lasting behavioral and morphological changes in mesocortical (medial prefrontal cortex) and ventral striatal (nucleus accumbens) neurons. Rats received two daily injections of either 5.0 mg/kg (+/-)-MDMA or saline vehicle, approximately 6 h apart, for 3 consecutive days, followed by 4 drug-free days for a total of 3 weeks. Following a 4-week drug-free period, MDMA-pretreated rats displayed behavioral sensitization, as well as large increases in spine density and the number of multiple-headed spines on medium spiny neurons in core and shell subregions of nucleus accumbens. In medial prefrontal cortex, the prelimbic subregion showed increased spine density on distal dendrites of layer V pyramidal neurons, while the anterior cingulate subregion showed a change in the distribution of dendritic material instead. Collectively, our results show that long-lasting locomotor sensitization to MDMA is accompanied by reorganization of synaptic connectivity in limbic-cortico-striatal circuitry. The differential plasticity in cortical subregions, moreover, suggests that drug-induced structural changes are not homogeneous and may be specific to the circuitry underlying long-term changes in drug-seeking and drug-taking behavior.
... Serotonin, a crucial neurotransmitter involved in a variety of brain functions (Aghajanian & Sanders-Bush, 2000) and neuropsychiatric disorders, is released in the striatum by dense projections from the raphe (Steinbusch, 1981;Imai et al. 1986;Pickel & Chan, 1999). Serotonin receptors are abundant in the striatum (Ward & Dorsa, 1996;Hoyer et al. 2002), where they affect single-unit responses to drugs of abuse (Ball & Rebec, 2005). To cast light on the cellular action of serotonin in the striatum we therefore investigated its effects on cholinergic interneurones with non-invasive, perforated-patch techniques. ...
We investigated the effects of 5-hydroxytryptamine (5-HT, serotonin) in striatal cholinergic interneurones with gramicidin-perforated whole-cell patch recordings. Bath-application of serotonin (30 microm) significantly and reversibly increased the spontaneous firing rate of 37/45 cholinergic interneurones tested. On average, in the presence of serotonin, firing rate was 273 +/- 193% of control. Selective agonists of 5-HT(1A), 5-HT3, 5-HT4 and 5-HT7 receptors did not affect cholinergic interneurone firing, while the 5-HT2 receptor agonist alpha-methyl-5-HT (30 microm) mimicked the excitatory effects of serotonin. Consistently, the 5-HT2 receptor antagonist ketanserin (10 microm) fully blocked the excitatory effects of serotonin. Two prominent after-hyperpolarizations (AHPs), one of medium duration that was apamin-sensitive and followed individual spikes, and one that was slower and followed trains of spikes, were both strongly and reversibly reduced by serotonin; these effects were fully blocked by ketanserin. Conversely, the depolarizing sags observed during negative current injections and mediated by hyperpolarization-activated cationic currents were not affected. In the presence of apamin and tetrodotoxin, the slow AHP was strongly reduced by 5-HT, and fully abolished by the calcium channel blocker nickel. These results show that 5-HT exerts a powerful excitatory control on cholinergic interneurones via 5-HT2 receptors, by suppressing the AHPs associated with two distinct calcium-activated potassium currents.
... Because cocaine also disrupts serotonin (5-HT) transport, at least some of the striatal action of this drug may involve an increase in striatal 5-HT. In fact, systemic injection of 3,4-methylenedioxy-methamphetamine (MDMA or ecstasy), an amphetamine derivative with a potent 5-HT-releasing action, increases both behavioral activity and striatal firing rate in rats, and these effects are blocked by 5-HT antagonists (Ball and Rebec, 2005). ...
The motor-activating effects of amphetamine and other psychostimulants such as cocaine depend on an increase in dopamine (DA) transmission in the striatum, a key component of the basal ganglia and the forebrain motive circuit. This review focuses on research aimed at using electrophysiological techniques--including extracellular unit recording and iontophoresis--in alert, fully functioning animals to understand how these drugs alter striatal neuronal processing under behaviorally relevant conditions. The data indicate that DA works in conjunction with glutamate (GLU), an excitatory amino acid, to enhance the signal-to-noise ratio of afferent information. This DA-GLU interaction appears to play a critical role in the amphetamine-induced activation of striatal neurons. The pattern of striatal activation, moreover, changes as the behavioral response changes from unfocused locomotion to highly focused, stereotyped behavior, but interestingly, the striatal response pattern is not reflected in substantia nigra reticulata, a primary target of striatal efferents. Although cocaine also activates striatal neurons during behavior, the underlying mechanisms appear to be complicated by factors unique to this drug and deserve further evaluation. Collectively, these findings provide unique insight into the neuronal processes by which the striatum participates in psychostimulant-induced motor behavior.
... These data indicate a role for striatal and nigral 5-HT2 receptors in MDMA-evoked nigrostriatal DA release and further suggest potential mediation by GABAergic input to the nigra. Recent electrophysiological work in the freely moving rat demonstrates that systemic administration of SR46349B, but not the 5-HT2C receptor inverse agonist SB 206553, blocked MDMAinduced excitation of striatal neurons (Ball and Rebec, 2005). An imaging study in humans demonstrated that administration of psilocybin, a 5-HT2A and 5-HT1A receptor agonist, displaced binding of the D2 receptor antagonist [ 11 C]raclopride in the striatum (Vollenweider et al., 1999). ...
The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.
... These investigators demonstrated that systemic MDMA injections excite most striatal output cells, and the degree of cell excitation is positively correlated with ambulation (Ball et al., 2003 ). Prior treatment with antagonists selective for 5- HT 2A or D 2 receptors reduces MDMA-induced striatal excitations and ambulation in a parallel fashion (Ball and Rebec, 2005). The single unit data, coupled with our correlation data, provide compelling evidence that striatal 5-HT and DA are involved in motor effects of MDMA. ...
(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, or Ecstasy) is an illicit drug that evokes transporter-mediated release of monoamines, including serotonin (5-HT) and dopamine (DA). Here we monitored the effects of MDMA on neurochemistry and motor activity in rats, as a means to evaluate relationships between 5-HT, DA, and behavior. Male rats undergoing in vivo microdialysis were housed in chambers equipped with photobeams for measurement of ambulation (i.e., forward locomotion) and stereotypy (i.e., head weaving and forepaw treading). Microdialysis probes were placed into the n. accumbens, striatum or prefrontal cortex in separate groups of rats. Dialysate samples were assayed for 5-HT and DA by microbore HPLC-ECD. Rats received two i.v. injections of MDMA, 1 mg/kg followed by 3 mg/kg 60 min later; neurochemical and locomotor parameters were measured concurrently. MDMA produced dose-related elevations in extracellular 5-HT and DA in all regions, with the magnitude of 5-HT release always exceeding that of DA release. MDMA-induced ambulation was positively correlated with dialysate DA levels in all regions (P<0.05-0.0001) and with dialysate 5-HT in striatum and cortex (P<0.001-0.0001). Stereotypy was strongly correlated with dialysate 5-HT in all areas (P<0.001-0.0001) and with dialysate DA in accumbens and striatum (P<0.001-0.0001). These data support previous work and suggest the complex spectrum of behaviors produced by MDMA involves 5-HT and DA in a region- and modality-specific manner.
In this chapter, we will review the current literature underlying the essential role played by the 5-HT2B receptor in the regulation of serotonin and dopamine neurotransmission, by first focusing on its involvement in the psychostimulant effects of the club-drug Ecstasy, then by further describing its contribution to the psychostimulant effects of amphetamine, and finally, by presenting its role in the psychostimulant effects of cocaine. Throughout this review, we will compare the current findings in mice and rats with an emphasis on interspecies discrepancies. to conclude, we will discuss the potential pharmacotherapeutic strategies for the treatment of psychostimulant addiction.
Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there is an increased propensity to engage in risk-taking and impulsive behaviors like drug use. This review examines the human and preclinical literature on adolescent drug use and its consequences, with a focus on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA. It is the case for all the substances reviewed here that very little is known about their effects in adolescent populations. An emerging aspect of the literature is that dissociatives and MDMA produce mixed reinforcing and aversive effects and that the balance between reinforcement and aversion may differ between adolescents and adults, with consequences for drug use and addiction. However, many studies have failed to directly compare adults and adolescents, which precludes definitive conclusions about these consequences. Other important areas that are largely unexplored are sex differences during adolescence and the long-term consequences of adolescent use of these substances. We provide suggestions for future work to address the gaps we identified in the literature. Given the widespread use of these drugs among adolescent users, and the potential for therapeutic use, this work will be crucial to understanding abuse potential and consequences of use in this developmental stage.
Acute exposure to ± 3,4-methylenedioxymethamphetamine (MDMA) preferentially increases release of serotonin (5-HT), and a role of 5-HT in many of the behavioral effects of acute exposure to MDMA has been demonstrated. A role of 5-HT in MDMA self-administration in rats has not, however, been adequately determined. Therefore, the present study measured the effect of pharmacological manipulation of some 5-HT receptor subtypes on self-administration of MDMA. Rats received extensive experience with self-administered MDMA prior to tests with 5-HT ligands. Doses of the 5-HT1A antagonist, WAY 100635 (0.1–1.0 mg/kg), 5-HT1B antagonist, GR 127935 (1.0–3.0 mg/kg), and the 5-HT2A antagonist, ketanserin (1.0–3.0 mg/kg) that have previously been shown to decrease self-administration of other psychostimulants and that decreased MDMA-produced hyperactivity in the present study did not alter MDMA self-administration. Experimenter-administered injections of MDMA (10.0 mg/kg, ip) reinstated extinguished drug-taking behaviour, but this also was not decreased by any of the antagonists. In contrast, both WAY 100635 and ketanserin, but not GR 127935, decreased cocaine-produced drug seeking in rats that had been trained to self-administered cocaine. The 5-HT1A agonist, 8-OH-DPAT (0.1–1.0 mg/kg), but not the 5-HT1B/1A agonist, RU 24969 (0.3–3.0 mg/kg), decreased drug-seeking produced by the reintroduction of a light stimulus that had been paired with self-administered MDMA infusions. These findings suggest a limited role of activation of 5-HT1A, 5-HT1B or 5-HT2 receptor mechanisms in MDMA self-administration or in MDMA-produced drug-seeking following extinction. The data suggest, however, that 5-HT1A agonists inhibit cue-induced drug-seeking following extinction of MDMA self-administration and might, therefore, be useful adjuncts to therapies to limit relapse to MDMA use.
The use of psychoactive drugs is a wide spread behaviour in human societies. The systematic use of a drug requires the establishment of different drug use-associated behaviours which need to be learned and controlled. However, controlled drug use may develop into compulsive drug use and addiction, a major psychiatric disorder with severe consequences for the individual and society. Here we review the role of the serotonergic (5-HT) system in the establishment of drug use-associated behaviours on the one hand and the transition and maintenance of addiction on the other hand for the drugs: cocaine, amphetamine, methamphetamine, MDMA (ecstasy), morphine/heroin, cannabis, alcohol, and nicotine. Results show a crucial, but distinct involvement of the 5-HT system in both processes with considerable overlap between psychostimulant and opioidergic drugs and alcohol. A new functional model suggests specific adaptations in the 5-HT system, which coincide with the establishment of controlled drug use-associated behaviours. These serotonergic adaptations render the nervous system susceptible to the transition to compulsive drug use behaviours and often overlap with genetic risk factors for addiction. Altogether we suggest a new trajectory by which serotonergic neuroadaptations induced by first drug exposure pave the way for the establishment of addiction.
Drug addiction is a major psychiatric disease with, currently, no truly effective treatment available. Drug addiction involves many different behaviors. Given the involvement of serotonin (5-HT) in virtually all behaviors and brain plasticity at cellular, molecular and systems levels, one can readily assume a 5-HT contribution to the establishment and maintenance of addiction-related behaviors and their neuronal mechanisms. In this chapter we review the role of the 5-HT system in addiction-related behaviors for major addictive drugs, such as cocaine, amphetamine, methamphetamine, MDMA (ecstasy), morphine, heroin and nicotine. We discuss the impact of these drugs on 5-HT activity, and how this activity might translate into behavior by activating 5-HT receptors. The effects of serotonergic manipulations on addiction-related behaviors in animal models and in human therapy of addiction are reviewed. Intensive research has shown that drug-induced 5-HT activation does not have a uniform ‘proactive effect’ (i.e., neurochemical activity that triggers behavioral activation) on addiction-related behavior, but might often serve a 'counteractive function', thus limiting the expression of behavior which is driven by other neurochemical effects of the drug. 5-HT receptors can have very different effects on addiction-related behaviors depending on their localization in the brain, the cell type, and the synapse. Some receptor populations do appear to have proactive effects – i.e., translate the drug-induced 5-HT increase into addiction-related behaviors – while others counteract them, or are not involved. While acknowledging this complexity will be important for an understanding of the 5-HT role in drug addiction, it also provides a challenge to the use of 5-HT system components for therapy in humans.
Hallucinogens are a class of substances that induce profound changes in perception and cognition. A closely related drug, 3,4-methylenedioxymethamphetamine (MDMA), produces euphoria and a feeling of empathy, with minimal sensory distortion. Both of these classes of substances produce their effects by interacting with the serotonergic system. This chapter will review the receptor interactions that contribute to the behavioral effects of serotonergic hallucinogens and MDMA. In rodents, the behavioral effects of hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and mescaline are primarily mediated by activation of 5-HT2A receptors. There is evidence, however, that 5-HT1A receptors, 5-HT2C receptors and dopamine receptors may play a secondary role. The molecular requirements for interaction of hallucinogens with the 5-HT2A receptor are well-defined on the basis of structure-activity relationships. By contrast with the hallucinogens, MDMA is a potent releaser of monoamines that has complex effects on serotonergic, dopaminergic and noradrenergic systems. In recent years, psilocybin and MDMA have been administered to human volunteers in controlled clinical trials. Human studies confirm that the 5-HT2A receptor plays a primary role in mediating the subjective effects of psilocybin, whereas the effects of MDMA are largely attributable to carrier-mediated release of serotonin. These findings emphasize the importance of clinical investigation of hallucinogenic drugs. Additionally, there is a growing consensus that these drugs are likely to show therapeutic efficacy in the treatment of certain psychiatric disorders.
The physical and functional interactions between serotonin-glutamate and serotonin-dopamine signaling have been suggested to be involved in psychosis pathophysiology and are supposed to be relevant for antipsychotic treatment. Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT(2A) receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT(2A) homomers. Additionally, direct evidence has been provided that D(2) and 5-HT(2A) receptors form physical heterocomplexes which exert a functional cross-talk, as demonstrated by studies on hallucinogen-induced signaling. Moving from receptors to postsynaptic density (PSD) scenario, the scaffolding protein PSD-95 is known to interact with N-methyl-D-aspartate (NMDA), D(2) and 5-HT(2) receptors, regulating their activation state. Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile. Signaling molecules, such as Akt and glycogen-synthase-kinase-3 (GSK-3), could be involved in the mechanism of action of antipsychotics, targeting dopamine, serotonin, and glutamate neurotransmission. Altogether, these proteins stand at the crossroad of glutamate-dopamine-serotonin signaling pathways and may be considered as valuable molecular targets for current and new antipsychotics. The aim of this review is to provide a critical appraisal on serotonin-glutamate and serotonin-dopamine interplay to support the idea that next generation schizophrenia pharmacotherapy should not exclusively rely on receptor targeting strategies.
The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT(2C) receptors on the effects of different classes of addictive drugs, illustrated by reference to data using pharmacological and genetic tools. The neurochemical mechanism of the interaction between 5-HT(2C) receptors, with focus on the mesocorticolimbic dopaminergic system, and drugs of abuse (using cocaine as an example) is discussed. Finally, we integrate recent nonclinical and clinical research and information with marketed products possessing 5-HT(2C) receptor binding affinities. Accordingly, available nonclinical data and some clinical observations targeting 5-HT(2C) receptors may offer innovative translational strategies for combating drug dependence.This article is part of a Special Issue entitled: Brain Integration.
The indirect serotonin (5-HT) agonist 3,4-methylenedioxymethamphetamine (MDMA) produces a distinct behavioral profile in rats consisting of locomotor hyperactivity, thigmotaxis, and decreased exploration. The indirect 5-HT agonist α-ethyltryptamine (AET) produces a similar behavioral profile. Using the Behavioral Pattern Monitor (BPM), the present investigation examined whether the effects of MDMA and AET are dependent on the novelty of the testing environment. These experiments were conducted in Sprague-Dawley rats housed on a reversed light cycle and tested during the dark phase of the light/dark cycle. We found that racemic MDMA (RS-MDMA; 3 mg/kg, SC) increased locomotor activity in rats tested in novel BPM chambers, but had no effect on locomotor activity in rats habituated to the BPM chambers immediately prior to testing. Likewise, AET (5 mg/kg, SC) increased locomotor activity in non-habituated animals but not in animals habituated to the test chambers. These results were unexpected because previous reports indicate that MDMA has robust locomotor-activating effects in habituated animals. To further examine the influence of habituation on MDMA-induced locomotor activity, we conducted parametric studies with S-(+)-MDMA (the more active enantiomer) in habituated and non-habituated rats housed on a standard or reversed light cycle. Light cycle was included as a variable due to reported differences in sensitivity to serotonergic ligands during the dark and light phases. In confirmation of our initial studies, rats tested during the dark phase and habituated to the BPM did not show an S-(+)-MDMA (3 mg/kg, SC)-induced increase in locomotor activity, whereas non-habituated rats did. By contrast, in rats tested during the light phase, S-(+)-MDMA increased locomotor activity in both non-habituated and habituated rats, although the response in habituated animals was attenuated. The finding that habituation and light cycle interact to influence MDMA- and AET-induced hyperactivity demonstrates that there are previously unrecognized complexities associated with the behavioral effects of these drugs.
Methylenedioxymethamphetamine (MDMA; "Ecstasy") is commonly abused by humans in environments such as nightclubs and rave parties where other drugs of abuse are readily available. Despite the popularity of polysubstance abuse among recreational MDMA users, relatively few controlled experimental studies have documented the neurobehavioral effects of MDMA in combination with other abused substances. This study employed conditioned place preference procedures (CPP) to assess the locomotor activating and place conditioning effects of acute concurrent administration of MDMA (1.5 or 3.0 mg/kg) and cocaine (10 or 20 mg/kg) in rats. Results indicate that low dose MDMA can enhance the locomotor and conditioned rewarding effects of cocaine. These findings may have important implications for understanding the contribution of serotonergic-dopaminergic interactions in the abuse liability of MDMA when used in combination with cocaine or other psychostimulant drugs.
We verified the hypothesis that serotonin (5-HT)(2) receptors control the locomotor effects of nicotine (0.4 mg kg(-1)) in rats by using the 5-HT(2A) receptor antagonist M100907, the preferential 5-HT(2A) receptor agonist DOI, the 5-HT(2C) receptor antagonist SB 242084, and the 5-HT(2C) receptor agonists Ro 60-0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5-HT(2) receptor ligands, M100907 (2 mg kg(-1)) or DOI (1 mg kg(-1)) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg(-1)), Ro 60-0175 (1 mg kg(-1)), and WAY 163909 (1.5 mg kg(-1)) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1-5, 10) with nicotine, none of 5-HT(2) receptor ligands administered during the second withdrawal period (Days: 11-14) to nicotine-treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5-HT(2A) receptors (but not 5-HT(2C) receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5-HT(2A) receptors enhances the development of nicotine sensitization and activation of 5-HT(2C) receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5-HT(2) receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization.
Male Wistar rats were used to verify the hypothesis that serotonin (5-HT)(2A) or 5-HT(2C) receptors may control the locomotor effects evoked by nicotine (0.4 mg/kg). The 5-HT(2A) receptor antagonist (M100,907), the 5-HT(2A) receptor agonist (DOI), the 5-HT(2C) receptor antagonist (SB 242,084), and the 5-HT(2C) receptor agonists (Ro 60-0175 and WAY 163,909) were used. M100,907 (0.5-2mg/kg) did not alter, while DOI (1 mg/kg) enhanced the nicotine-induced hyperlocomotion. The effect of DOI was antagonized by M100,907 (1 mg/kg). SB 242,084 (0.25-1 mg/kg) augmented, while Ro 60-0175 (1 and 3 mg/kg) and WAY 163,909 (1.5 mg/kg) decreased the overall effect of acute nicotine; effects of Ro 60-0175 and WAY 163,909 were attenuated by SB 242,084 (0.125 mg/kg). In another set of experiments, M100,907 (2 mg/kg) on Day 10 attenuated, while DOI (0.1-1 mg/kg) enhanced the nicotine-evoked conditioned hyperlocomotion in rats repeatedly (Days 1-5) treated with nicotine in experimental chambers. SB 242,084 (0.125 or 1 mg/kg) did not change, while Ro 60-0175 (1 mg/kg) or WAY 163,909 (1.5 mg/kg) decreased the expression of nicotine-induced conditioned hyperactivity. Only DOI (0.3 and 1 mg/kg) and SB 242,084 (1 mg/kg) enhanced the basal locomotion. The present data indicate that 5-HT(2A) receptors are significant for the expression of nicotine-evoked conditioned hyperactivity. Conversely, 5-HT(2C) receptors play a pivotal role in the acute effects of nicotine. Pharmacological stimulation of 5-HT(2A) receptors enhances the conditioned hyperlocomotion, while activation of 5-HT(2C) receptors decreases both the response to acute nicotine and conditioned hyperactivity.
We have recently demonstrated that co-administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") with the reversible monoamine oxidase type A (MAO-A) inhibitor moclobemide at an ambient temperature of 22 degrees C significantly increases striatal 5-HT outflow and 5-HT-mediated behaviors. In the present study, using microdialysis, we examined the effects of co-administration of MDMA or para-methoxyamphetamine (PMA) with moclobemide on striatal 5-HT outflow at the elevated ambient temperatures of 30 degrees C. Samples were collected every 30 min for 4 h and analyzed by high-performance liquid chromatography assay with electrochemical detection (HPLC-ED). 5-HT-mediated effects on body temperature and behavior were also recorded. Rats were treated with either saline or 20 mg/kg (i.p.) moclobemide, followed by 10 mg/kg (i.p.) MDMA, 10 mg/kg (i.p.) PMA or saline 60 min later. Both MDMA and PMA produced significant increases in 5-HT outflow (370% peak and 309% peak, respectively, P<0.05). MDMA and PMA significantly increased body temperature (+2.0 degrees C and +2.1 degrees C, respectively, P<0.01) and drug-related behaviors (P<0.05). When MDMA or PMA was co-administered with moclobemide, additional significant increases were seen in 5-HT outflow (850% peak, P<0.01 and 1450% peak, P<0.001, respectively) and only MDMA showed additional significant increase in body temperature (+5.0 degrees C, P<0.001). No additional increases were seen in behavioral activity. When moclobemide was co-administered with MDMA, sustained increases in body temperature were recorded that were significantly higher than with MDMA alone and such increases were not observed in our previous study at normal room temperature. Our results suggest greater risk of MDMA-induced adverse effects on body temperature regulation, compared with PMA, when used in combination with moclobemide at elevated ambient temperatures.
Single-unit recordings from 50 striatal neurons in freely moving rats revealed generally low activity (<3 spikes/sec) during resting behavior and movement-related excitations in most (n = 36) neurons. While activating behavior, d-amphetamine (1.0 mg/kg, sc) usually excited and inhibited motor- and nonmotor-related neurons, respectively, relative to resting baseline firing rates. A behavioral clamping analysis, which controlled for neuronal effects secondary to behavior, yielded results suggesting a primary, amphetamine-induced excitation of striatal motor-related neurons. Haloperidol (0.1–1.0 mg/kg) strongly inhibited behavior and neuronal activity when injected 30 min after amphetamine. Clozapine (5.0–30.0 mg/kg) inhibited only selected behaviors, but reliably produced haloperidol-like reversals of amphetamine-induced neuronal excitations. A literature review revealed that the neuronal results in behaving animals differ markedly from the inhibitory striatal responses to amphetamine and the excitatory responses to dopamine antagonists often found in immobilized or anesthetized rat preparations. These contrasting, preparation-dependent results support a model based on drug interactions with a proposed neuromodulatory function of striatal dopamine, which is to facilitate or attenuate the activity of neurons receiving, respectively, substantial, or little excitatory afferent input.
HARACZ, J. L., J. T. TSCHANZ, Z. WANG, K. E. GRIFFITH AND G. V. REBEC. Amphetamine effects on striatal neurons: Implications for models of dopamine function. NEUROSCI BIOBEHAV REV 22(5) 613–622.—Models of dopamine function based on the bidirectional neuromodulation of afferents and were tested by determining whether cortical ablation would affect the excitatory and inhibitory effects of amphetamine (AMPH) on striatal neurons in freely moving rats. By minimizing pre- and post-AMPH behavioral differences, behavioral clamping revealed that cortical ablation blocked the capacity of AMPH to produce a net excitation of striatal neurons that had shown AMPH-induced excitations under non-clamping conditions. Cortical ablation did not affect AMPH-induced neuronal inhibitions under behavioral clamping conditions. These results suggest that AMPH, possibly by enhancing dopaminergic neuromodulation, facilitates or inhibits the activity of neurons that respectively receive substantial or little cortical input. Thus, the findings support models that assign dopamine the capacity to increase the gain of neuronal information processing. Basic research relevant to these models is reviewed and potential clinical implications are discussed.
MDMA ("ecstasy") has been widely reported as a drug of abuse and as a neurotoxin. This report describes the mechanism of MDMA action at serotonin transporters from plasma membranes and secretory vesicles. MDMA stimulates serotonin efflux from both types of membrane vesicle. In plasma membrane vesicles isolated from human platelets, MDMA inhibits serotonin transport and [3H]imipramine binding by direct interaction with the Na(+)-dependent serotonin transporter. MDMA stimulates radiolabel efflux from plasma membrane vesicles preloaded with [3H]serotonin in a stereo-specific, Na(+)-dependent, and imipramine-sensitive manner characteristic of transporter-mediated exchange. In membrane vesicles isolated from bovine adrenal chromaffin granules, which contain the vesicular biogenic amine transporter, MDMA inhibits ATP-dependent [3H]serotonin accumulation and stimulates efflux of previously accumulated [3H]serotonin. Stimulation of vesicular [3H]serotonin efflux is due to dissipation of the transmembrane pH difference generated by ATP hydrolysis and to direct interaction with the vesicular amine transporter.
The ventral tegmental area (VTA) is a central element in a system that mediates the reinforcing properties of natural stimuli (such as food), brain stimulation, and drugs of abuse. Although considerable effort has been applied to understanding how drugs of abuse influence this system, relatively little work has examined its function during conditioned reinforcement tasks in awake, behaving animals. In the present studies, bundles of four to eight microwire electrodes were chronically implanted in the VTA or prefrontal cortex (PFC) of male Wistar rats. Following recovery from surgery, simultaneous recordings from multiple single neurons and unit clusters were obtained in rats pressing a lever for a sucrose solution on a fixed-ratio schedule of reinforcement. Consistent with the hypothesis that these neurons encode information related to motivation, most of the neurons in both VTA and PFC showed significant modulation of firing rate associated with one or more events occurring within the response/reinforcement cycle. These events included lever presses, onset and end of a tone signaling sucrose delivery, and onset and end of sucrose consumption. Significant decreases in firing rate were observed, coincident with onset of the tone and sucrose delivery, or with consumption. These decreases were sustained through the end of sucrose consumption. A number of neurons also discharged bursts of activity associated with individual lever presses. These findings provide a clear demonstration that VTA neuronal activity is modulated during motivated behavior. Similar information about events within the ongoing response/reinforcement cycle appears to be distributed through many neurons within the VTA, and may be mirrored in target structures such as PFC.
Cocaine is the principal alkaloid of Erythoxylon coca, a shrub that grows in the Andean Highlands and the northwestern portions of the Amazon River in South America. The coca plant has been cultivated by the Indians in these areas for several thousand years, and the dried leaves are still used today. Those living in the Highland areas mix the leaves with lime or ash and chew or suck this combination. Addition of the alkaline ash promotes release of the cocaine by changing the pH of saliva. Amazonian Indians first pulverize the alkaline and coca leaf combination. They place this combination into their mouths, where it is mixed with saliva and then swallowed. Coca ingested in these ways has been used for religious, medicinal, and energizing purposes for centuries (see JOHANSON arid FISCHMAN 1989 for a more complete discussion of this history). Since significant cocaine plasma levels can be attained when coca leaves are chewed and sucked as described (PALY et al. 1980), the effects achieved by coca chewing are undoubtedly due to the actions of this principal constituent.
Originally sold as a bronchodilator in the early 1930s, amphetamine soon became known for its stimulant effects on behavior (Angrist, 1983). The drug has been used to overcome fatigue and to improve performance on certain types of motor or cognitive tasks (Koelega, 1993; Laties & Weiss, 1981). These stimulant effects often occur in conjunction with feelings of euphoria, a combination that has led to the widespread abuse of amphetamine and its analogs, including a pure form of methamphetamine known as “ice,” which emerged on the recreational drug scene in the late 1980s (Cho, 1990). Invariably, abuse of these drugs induces a psychosis that is clinically similar to paranoid schizophrenia (Akiyama, Hamamura, Ujike, Kanzaki, & Otsuki, 1991; Snyder, 1973).
3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy"), a synthetic analogue of 3,4-methylenedioxyamphetamine, has been the center of recent debate over its potential for abuse vs its use as a psychotherapeutic agent. Following its emergency classification in Schedule 1 by the Drug Enforcement Administration in 1985, 3,4-methylenedioxyethamphetamine (MDEA,”Eve") has appeared as MDMA’s legal replacement. MDMA is thought to be safe by recreational users and by psychotherapists who support its use. The details of five deaths associated with the use of MDMA and MDEA are reported. In three patients, MDMA or MDEA may have contributed to death by the induction of arrhythmias in individuals with underlying natural disease. In another patient, use of MDMA preceded an episode of bizarre and risky behavior that resulted in accidental death. In another patient, MDMA was thought to be the immediate cause of death. Death as a consequence of the use of these drugs appears to be rare, but it does occur; this outcome may be more common in individuals with underlying cardiac disease.
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), a synthetic analogue of 3,4-methylenedioxyamphetamine, has been the center of recent debate over its potential for abuse vs its use as a psychotherapeutic agent. Following its emergency classification in Schedule 1 by the Drug Enforcement Administration in 1985, 3,4-methylenedioxyethamphetamine (MDEA,"Eve") has appeared as MDMA's legal replacement. MDMA is thought to be safe by recreational users and by psychotherapists who support its use. The details of five deaths associated with the use of MDMA and MDEA are reported. In three patients, MDMA or MDEA may have contributed to death by the induction of arrhythmias in individuals with underlying natural disease. In another patient, use of MDMA preceded an episode of bizarre and risky behavior that resulted in accidental death. In another patient, MDMA was thought to be the immediate cause of death. Death as a consequence of the use of these drugs appears to be rare, but it does occur; this outcome may be more common in individuals with underlying cardiac disease.
(JAMA 1987;257:1615-1617)
1The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters.2Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCAMDMA(+)-Fen>>(+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph>>pCA=MDMA>>(+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine).3[3H]-5-HT and/or [3H]-dopamine release induced by all these compounds was partially (31–80%), but significantly Ca2+-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by ω-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca2+-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release.4Methiothepin inhibited the Ca2+-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70 nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor.5These results indicate that the release induced by these compounds is both ‘carrier-mediated’ and Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependent release is mediated by Ca2+-influx (mainly through P-type Ca2+-channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5-HT and dopamine synaptosomes.British Journal of Pharmacology (1997) 121, 1735–1743; doi:10.1038/sj.bjp.0701325
Neostriatal single-unit activity was recorded in freely moving rats. A majority (62%) of the 24 recorded neurons were activated during motor behavior such as locomotion (n = 11) or head movements (n = 4). The behavioral response to amphetamine (1.0 mg/kg) was associated with increases (n = 17) or decreases (n = 7) in firing rate. A significantly greater proportion of motor-related neurons were excited by the drug compared to nonmotor-related cells. These results, which confirm the heterogeneity of amphetamine-induced effects in the neostriatum, indicate that the baseline motor-response characteristics of neostriatal neurons may determine their response to amphetamine.
Single-unit recordings from neostriatal neurons showing movement-related excitations were obtained in freely moving, cortically ablated rats and sham-lesioned controls. d-Amphetamine (AMPH, 1.0 mg/kg s.c.) increased neuronal activity relative to resting baseline firing rates in both groups of animals, but cortical ablation significantly attenuated this effect. A behavioral clamping analysis, which compared neuronal activity during identically rated pre- and post-AMPH behaviors, revealed that: (a) AMPH enhanced movement-related neuronal activity in sham-lesioned controls, but not in cortically ablated rats; and (b) the drug-induced neuronal activation in control rats was not simply secondary to the behavioral activation produced by AMPH. In contrast to its neuronal effects, cortical ablation did not affect ratings of AMPH-induced locomotion, rearing, or head movements, though sniffing scores showed a postive correlation with lesion size. Thus, corticostriatal projections are critically involved in AMPH-induced excitations of neostriatal motor-related neurons.
Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and (±)-3,4-methylenedioxymethamphetamine (MDMA; 3–300 μg/kg per infusion) during daily 1-h sessions. From four to over nine times more cocaine infusions were obtained than saline infusions during baseline sessions. When MDMA was substituted for cocaine, at least one dose was self-administered in 3 of the 4 monkeys at rates that exceeded the range of saline infusions. In fact, two of the monkeys self-administered a dose of MDMA at a greater rate than cocaine. These results demonstrate that MDMA can serve as a positive reinforcer for rhesus monkeys and, taken together with other preclinical behavioral studies, suggest a potential for recreational use of MDMA by humans.
Selective D1 (SCH-23390) and D2 (eticlopride and sulpiride) dopamine receptor antagonists were assessed for their ability to reverse the effects of 1.0 mg/kgd-amphetamine on excitatory motor-related neurons in the striatum of freely moving rats. SCH-23390 (0.125, 0.25, 0.5 and 1.0 mg/kg) rapidly and consistently blocked amphetamine-induced neuronal excitations as did eticlopride (0.25 and 1.0 mg/kg). In contrast, (−)-sulpiride (10, 20 and 40 mg/kg) failed to alter the neuronal response to amphetamine. Similarly, SCH-23390 and eticlopride also blocked the behavioral effects of amphetamine, but sulpiride did not. Collectively, these results support the involvement of D1 and D2 dopamine receptors in the excitatory effects of amphetamine on striatal neurons, but suggest caution in assessing the neuronal and behavioral effects of sulpiride.
Rats were treated with repeated injections of saline or one of two doses of (+/-)3,4-methylenedioxymethamphetamine (MDMA; 5 or 20 mg/kg, s.c.). Rats pretreated with either of the two repeated MDMA treatment regimens demonstrated an augmented increase in motor activity to an injection of MDMA made 12 days after the last repeated injection compared with either the first MDMA injection or MDMA given to animals pretreated with repeated saline. Furthermore, animals pretreated with the highest dose of repeated MDMA revealed a greater behavioral response to cocaine (15 mg/kg, i.p.). Microdialysis was conducted in the nucleus accumbens and the capacity of MDMA (5 mg/kg, s.c.) to elevate extracellular dopamine content was augmented in rats pretreated with repeated MDMA compared with the animals pretreated with repeated saline. These data reveal repeated MDMA administration produces behavioral sensitization and enhanced dopamine transmission in the nucleus accumbens of rats.
The purpose of this experiment was to investigate the effects of repeated exposure to methylenedioxymethamphetamine (MDMA) on responses of neurons in the nucleus accumbens of anesthetized rats to microiontophoretically-applied dopamine and serotonin. In tests conducted 1-4 days or 9-15 days following the last injection of MDMA (20 mg/kg, s.c., twice daily for 4 days), the inhibitory effects of both dopamine and serotonin on glutamate-evoked firing of nucleus accumbens cells were significantly attenuated compared to effects in control rats that were pretreated with saline injections. The inhibitory effect of the D1 receptor agonist SKF38393 was also significantly attenuated in the MDMA-pretreated rats. In contrast, the amount of inhibition of glutamate-evoked firing produced by application of GABA did not significantly differ between the MDMA-pretreated and the saline-pretreated rats. The neurotoxicity of the MDMA treatment regimen was confirmed by demonstrating that 3H-paroxetine binding was significantly decreased in the medial prefrontal cortex and the nucleus accumbens of the MDMA-pretreated rats. The mechanisms that produce the attenuated inhibitory responses to dopamine and serotonin following repeated injections of MDMA are not known. However, the results of these experiments indicate that repeated MDMA administration induces long-lasting changes in dopaminergic as well as serotonergic neurotransmission in the nucleus accumbens.
The neostriatum has been implicated in the behavioral response to amphetamine and in the ability of neuroleptic drugs to attenuate this response (e.g., Rebec and Bashore, 1984). Recent efforts to identify the mechanisms underlying amphetamine-induced behavioral effects have focused on single-unit recordings of neostriatal activity in freely moving animals. When such recordings are obtained exclusively from neurons that are active in rats performing a locomotor task, amphetamine causes a further increase in firing rate (West et al., 1987). In contrast, neurons sampled when animals are resting quietly show a heterogeneous response to amphetamine that includes both excitations and inhibitions (Gardiner et al., 1988; Ryan et al., 1989). These divergent results may reflect a differential action of amphetamine on motor- and nonmotor-related neurons. In an initial test of this hypothesis, we found that cells activated during movement were significantly more likely to increase their firing rate to amphetamine than neurons showing activity unrelated to movement (Haracz et al., 1989). In this report, we extend this research and also compare the ability of haloperidol, a classical neuroleptic that blocks virtually all components of the amphetamine behavioral response, and clozapine, an atypical drug that reverses relatively few amphetamine-induced behaviors (Tschanz and Rebec, 1989), to block the neuronal response to amphetamine.
Thesis (Ph. D.) [Pharmacy]--University of Pittsburgh, 1970.
The risk of adverse reactions to 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as "ecstasy", is now widely known in both the USA and UK, but the patterns of illness remain varied. We report our experience during 1990 and 1991. There has been a recent increase in cases of severe toxicity following recreational misuse of small amounts of MDMA. Among 7 fatalities, the pattern of toxicity included fulminant hyperthermia, convulsions, disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Until now, there have been few reports of this type of toxicity from MDMA, which may be related both to the potential of the drug to alter thermoregulation and to the circumstances of misuse. In addition, we have monitored 7 cases of hepatotoxicity and suspect that the frequency of this complication is increasing; a history of MDMA misuse should be sought in young people presenting with unexplained jaundice or hepatomegaly. We also describe 5 subjects involved in road traffic accidents in whom MDMA was identified. Misuse of MDMA can have severe acute toxic effects; few data are available concerning long-term morbidity, and this deserves close monitoring in future.
The highly selective 5-HT2 receptor antagonist, MDL 100,907, was used to explore the role of serotonin in the stimulation of dopaminergic function produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). MDL 100,907 blocked MDMA-stimulated dopamine synthesis in vivo without affecting basal synthesis. The long-term deficits in 5-HT concentrations believed to be a consequence of MDMA-induced dopamine release were also blocked by MDL 100,907 over the same dose range. In vivo microdialysis confirmed that 5-HT2 receptor blockade with MDL 100,907 attenuated MDMA-induced increases in extracellular concentrations of striatal dopamine. In contrast to its effect on MDMA-induced synthesis, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine. In vivo dopamine release produced by haloperidol was also unaffected by MDL 100,907. The results suggest a permissive role for 5-HT2 receptors in the activation of the dopamine system which occurs during states of high serotonergic activity or during conditions of elevated dopamine efflux with high D2 receptor occupancy.
The effect of dopamine (DA) and serotonin (5-HT) uptake inhibitors on 3,4-methylenedioxymethamphetamine (MDMA)-induced increase in DA efflux was studied using in vivo microdialysis. MDMA was infused directly into the anterolateral striatum via the dialysis probe. The local administration of MDMA produced a dose- and time-dependent increase in the extracellular concentration of DA in the striatum. Peripheral administration of the DA uptake blockers, mazindol (5 mg/kg, i.p.) or GBR 12909 (10 mg/kg, i.p.), produced a slight but significant increase in the extracellular concentration of DA. Moreover, pretreatment with either mazindol or GBR 12909 30 min before the infusion of MDMA (10 microM) significantly attenuated the MDMA-induced increase in the extracellular concentration of DA. Pretreatment with fluoxetine (10 mg/kg, i.p.), a 5-HT uptake blocker, 30 min before the infusion of MDMA produced a slight but significant inhibition of MDMA-induced increase in DA concentration. In contrast, pretreatment with the 5-HT2/1C antagonist, ketanserin (3 mg/kg, i.p.), had no significant effect on the increase in DA concentration produced by the local administration of MDMA. These data are suggestive that MDMA increases the concentration of DA in the striatum, in part, via a carrier-mediated mechanism which is largely independent of its effects on 5-HT release.
Extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) were assayed in the caudate of freely moving rats using microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-EC) to detect changes in their release. Dialysates were assayed at 20-minute intervals for four hours after an intraperitoneal (IP) injection of MDMA (10 mg/kg). In a separate study to determine MDMA effects on total caudate levels of the above neurochemicals, animals were injected IP with MDMA (10 mg/kg) and then sacrificed at 20, 60, 120 and 180 minutes after treatment. Brains were quickly removed, and caudate nuclei were dissected for neurochemical analysis using HPLC-EC. MDMA elicited an amphetamine-like increase in DA release, followed by an increase in DA content. DOPAC and HVA were both reduced in homogenate. 5-HT release was also increased, followed by a drop in caudate homogenate levels by three hours. DA extracellular content was 686% of control at 80 minutes; caudate homogenate levels were 122% at 120 minutes. 5-HT extracellular release was 123% at 20 minutes, then decreased thereafter. It is concluded that the acute effect of MDMA on caudate is at least as great on the DA as it is on the 5-HT system.
The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of 3H-5-HT than of 3H-DA. The amphetamine derivatives (+/-)fenfluramine, (+/-)norfenfluramine, (+/-)MDE, (+/-)PCA, and d-methamphetamine are all potent releasers of 3H-5-HT and show varying degrees of activity as 3H-DA releasers. The hallucinogen DOM does not cause significant release of either 3H-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting 3H-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.
This study examined the [3H]5-HT-releasing properties of 3,4-methylenedioxymethamphetamine (MDMA) and related agents, all of which cause significant release of [3H]5-HT from rat brain synaptosomes. 5-HT uptake blockers dose dependently block MDMA-induced [3H]5-HT release. The EC50s of the uptake drugs in blocking MDMA-induced release correlate with their affinity for the 5-HT uptake site labeled by [3H]paroxetine (r = 0.98; P less than 0.01). These data demonstrate that the 5-HT uptake carrier plays a significant role in the release of 5-HT induced by MDMA and related agents.
Methylenedioxymethamphetamine (MDMA) is a phenylethylamine with novel mood-altering properties in humans. MDMA shares the dopamine-releasing properties of amphetamine but has been found to be a more potent releaser of serotonin (5-HT). The present study undertook to determine the relative roles of dopamine and 5-HT release in MDMA-induced locomotor hyperactivity. S-(+)MDMA produced dose-dependent increases of rat locomotion. Investigatory behaviors such as holepokes and rearings were suppressed by (+)MDMA. Pretreatment with the selective 5-HT uptake inhibitors fluoxetine, sertraline and zimelidine inhibited (+)MDMA-induced locomotor hyperactivity but failed to antagonize the reduction of holepokes and rearings. Because 5-HT uptake inhibitors have been found previously to block the MDMA-induced release of 5-HT in vitro, and because fluoxetine was found to have no effect on (+)amphetamine-induced hyperactivity, the present results suggest that (+) MDMA-induced locomotor hyperactivity is dependent on release of endogenous 5-HT. Additionally, prior depletion of central 5-HT with p-chlorophenylalanine partially antagonized the (+)MDMA-induced hyperactivity, although catecholamine synthesis inhibition with alpha-methyl-p-tyrosine did not block the effects of (+)MDMA. Taken together, these studies suggest that (+)MDMA increases locomotor activity via mechanisms that are dependent on the release of central 5-HT and that are qualitatively different from the mechanism of action of (+)amphetamine.
The efferent projections of the core and shell areas of the nucleus accumbens were studied with a combination of anterograde and retrograde tract-tracing methods, including Phaseolus vulgaris-leucoagglutinin, horseradish peroxidase and fluorescent tracers. Both the core and shell regions project to pallidal areas, i.e. ventral pallidum and entopeduncular nucleus, with a distinct topography in the sense that the core projection is located in the dorsolateral part of ventral pallidum, whereas the shell projects to the medial part of the subcommissural ventral pallidum. Both regions of the accumbens also project to mesencephalon with a bias for the core projection to innervate the substantia nigra-lateral mesencephalic tegmentum, and for the shell projection to reach primarily the ventral tegmental-paramedian tegmentum area. The most pronounced differences between core and shell projections exist in regard to the hypothalamus and extended amygdala. Whereas the core projects primarily to the entopeduncular nucleus including a part that invades the lateral hypothalamus, the shell, in addition, projects diffusely throughout the rostrocaudal extent of the lateral hypothalamus as well as to the extended amygdala, especially its sublenticular part. Both the core and shell of the accumbens have unmistakable striatal characteristics both histologically and in their connectional patterns. The shell, however, has additional features that are reminiscent of the recently described extended amygdala [Alheid G.F. and Heimer L. (1988) Neuroscience 27, 1-39; de Olmos J.S. et al. (1985) In The Rat Nervous System, pp. 223-334]; in fact, the possibility exists that the shell represents a transitional zone that seems to characterize most of the fringes of the striatal complex, where it adjoins the extended amygdala.
Methylenedioxymethamphetamine (MDMA) is a phenylethylamine with a chemical structure that resembles both the amphetamines and mescaline and has both stimulant and perception altering properties. The stimulant properties of MDMA were assessed in photocell cages designed to measure locomotor activity in rats. MDMA, over a range of doses (2.5-10.0 mg/kg, SC) produced locomotor hyperactivity which lasted up to 4 h. Further studies examined the role of the mesolimbic dopamine system in the hyperactivity induced by MDMA. 6-Hydroxydopamine lesions of the Nucleus accumbens attenuated the locomotor response produced by MDMA. The well characterized attenuation of the locomotor response produced by amphetamine was also demonstrated in the same rats. The present study demonstrates similarities in the stimulant properties of MDMA and amphetamine, and also suggests that as with amphetamine, the locomotor activation associated with MDMA may involve the presynaptic release of dopamine in the region of the Nucleus accumbens. However, MDMA may have a more unusual pharmacological profile because of its longer duration of action, neurotoxic potential, and differences in the qualitative aspects of its psychoactive effects.
Specific behaviors comprising the serotonin syndrome (low body posture, forepaw treading, headweaving) and the autonomic signs of piloerection and salivation were determined and analyzed with locomotor activity in response to MDMA at three doses (2.5, 5.0, and 7.5 mg/kg). All behaviors were dose-responsive. Serotonin syndrome behaviors increased in both intensity and duration of response with increasing doses. In contrast, locomotion varied only in intensity. Subchronic injections, in the same group of animals, permitted an analysis of acute vs. subchronic effects on these same behaviors. Both the serotonin syndrome and locomotor behaviors were augmented on subsequent testing, indicating that, (+/-)MDMA, like amphetamine, is capable of producing behavioral sensitization.
MDMA (methylenedioxymethamphetamine) is a recreational drug of abuse known as "Ecstasy" which markedly decreases regional brain serotonin (5-HT) content and produces 5-HT nerve terminal degeneration in forebrain areas of the rat. In order to determine the acute and chronic behavioral effects of MDMA, adult rats were given MDMA at 0, 5 or 10 mg/kg, po for 4 consecutive days. Alternatively, parachloroamphetamine (PCA) at 5 mg/kg was administered under the same regimen. Within 30 min after the first dose, the MDMA-treated rats exhibited the serotonin motor syndrome consisting of straub tail and splayed hindlimbs comparable to that seen in the PCA-treated rats. This serotonin motor syndrome, with a duration of about 2 hr, was less pronounced after subsequent doses. At 2-4 wk after the last dose, no significant differences between control and treated rats were seen in emergence, hot plate response, auditory startle response or complex maze behavior even though a significant dose-related decrease (50%) in 5-HT concentration was observed in the frontal cortex and hippocampus of these rats 4 wks after the last dose. Adult female monkeys dosed po with 5 or 10 mg/kg of MDMA twice/day for 4 consecutive days demonstrated no spontaneous behavioral changes or weight loss compared to controls, but forebrain 5-HT concentration was reduced by 80% 1 mon after dosing. These data indicate that at doses only 2-3 times the human dose, MDMA produces significant forebrain 5-HT decreases but does not produce detectable residual behavioral alterations as assessed by these behavioral paradigms.
Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidol's effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), a synthetic analogue of 3,4-methylenedioxyamphetamine, has been the center of recent debate over its potential for abuse vs its use as a psychotherapeutic agent. Following its emergency classification in Schedule 1 by the Drug Enforcement Administration in 1985, 3,4-methylenedioxyethamphetamine (MDEA, "Eve") has appeared as MDMA's legal replacement. MDMA is thought to be safe by recreational users and by psychotherapists who support its use. The details of five deaths associated with the use of MDMA and MDEA are reported. In three patients, MDMA or MDEA may have contributed to death by the induction of arrhythmias in individuals with underlying natural disease. In another patient, use of MDMA preceded an episode of bizarre and risky behavior that resulted in accidental death. In another patient, MDMA was thought to be the immediate cause of death. Death as a consequence of the use of these drugs appears to be rare, but it does occur; this outcome may be more common in individuals with underlying cardiac disease.
MDMA (d,1-3,4-Methylenedioxymethamphetamine HCl; "ecstasy") self-injection (0.1-3.2 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time out allowing a maximum of eight injections per day. MDMA or MDMA vehicle (saline) was substituted for cocaine for a period of 14 or more days followed by a return to the cocaine baseline. MDMA (0.32-3.2 mg/kg/inj) maintained more injections and higher responses rates than were maintained by saline. The maximal number of injections maintained by MDMA and the maximal response rate maintained by MDMA were less than those maintained under baseline conditions with cocaine. The highest dose of MDMA tested maintained a cyclic pattern of self-injection, i.e., days of high numbers of injections intermixed with days of low numbers of injections. At the highest dose of MDMA tested, concurrent food maintained behavior was suppressed to an extent that food intake was also decreased.
The effects of the recently classified Schedule I amphetamine analog, 3,4-methylenedioxymethamphetamine [+/-)-MDMA) on caudate and nucleus accumbens dopamine release and metabolism were studied by in vivo voltammetry and HPLC with electrochemical detection. Monitored over a 3 h period, the magnitude of increase in dopamine release and the onset of effect were dose-dependent and similar for both brain areas following the 2.5 and 5 mg/kg dose of the drug. However, responses were different for these brain regions using 10 mg/kg of MDMA; the magnitude of increase was greater and the onset of effect more immediate in caudate. Analysis of dopamine and DOPAC tissue content in both caudate and nucleus accumbens verified the voltammetry results. This study provides the first evidence that MDMA induces dopamine release in vivo and that this effect is region, time- and dose-dependent.
We report here an in vitro pharmacologic profile for MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. The rank order of affinities of MDMA at various brain receptors and uptake sites are as follows: 5-HT uptake greater than alpha 2-adrenoceptors = 5-HT2 serotonin = M-1 muscarinic = H-1 histamine greater than norepinephrine uptake = M-2 muscarinic = alpha 1-adrenoceptors = beta-adrenoceptors greater than or equal to dopamine uptake = 5-HT1 serotonin much greater than D-2 dopamine greater than D-1 dopamine. MDMA exhibited negligible affinities (greater than 500 microM) at opioid (mu, delta and kappa), central-type benzodiazepine, and corticotropin-releasing factor receptors, and at choline uptake sites and calcium channels.
The effects of methylenedioxymethamphetamine (0.63-10.0 mg/kg) and N-ethyl-methylenedioxyamphetamine (1.0-10.0 mg/kg) on locomotor and investigatory responses of rats were measured in the Behavioral Pattern Monitor system, a system designed to measure both the quantity and quality of behavioral activity. Horizontal locomotion was increased considerably by these compounds in a dose-related manner. This hyperactivity was accompanied by an initial decrease in investigatory holepokes and rearings followed by a subsequent increase at the highest doses tested. Rats injected with these phenylethylamine derivatives also exhibited thigmotaxis and a tendency to avoid the center of the experimental chamber, a behavioral profile similar to hallucinogen-like drugs. Consequently, a disruption of the spatial patterns of locomotion was also observed. Analyses of these patterns revealed an increasing tendency toward more stereotyped, predictable locomotor paths with increasing dose. Rats circled around the perimeter of the chamber with individual animals demonstrating a predominant though not completely consistent direction of rotation. The methylenedioxymethamphetamine-induced increase in locomotion remained significantly elevated up to 4 hr after injection at a 10 mg/kg dose, whereas other aspects of motor activity returned to base-line levels more rapidly. Thus, methylenedioxymethamphetamine and N-ethyl-methylenedioxyamphetamine seem to possess both psychomotor stimulant properties and elements of a hallucinogen-like behavioral profile.
Administration of fenfluramine to rats produced decreases in 1-h food intake and locomotor activity. Short-term (2-6 days) or long-term (21-25 days) treatment with the monoamine oxidase (MAO) type A inhibiting antidepressant clorgyline potentiated fenfluramine-induced suppression of food intake but did not affect fenfluramine-induced suppression of locomotor activity. Although daily (4 h) food intake was not significantly less in clorgyline-treated animals relative to saline-treated controls, body weight gain was significantly less in clorgyline-treated animals relative to controls. These findings demonstrate a differential effect of clorgyline treatment on fenfluramine-induced suppression of food intake and locomotor activity.
The effect of dexamphetamine (DEX) on striatal multi-unit activity was examined in freely moving rats and again 24 or 48 hr later during immobilization. Animals which in the freely moving state responded with striatal activation following DEX, 1 mg/kg IP, did not respond to this dose of DEX after immobilization. Similarly with DEX 2.5 mg/kg IP, the incidence of excitatory responses seen in freely moving animals decreased to 18% after immobilization, and the incidence of inhibition and biphasic responses increased from 0% in freely moving animals to 52% in immobilized preparations. The results suggest that the response of striatal neurons to DEX is dependent upon the behavioural state of the animal. Furthermore, these findings indicate that the central actions of DEX are more complex than previously believed, and raises the speculation that the excitatory effects of DEX on striatal neurons may be mediated through excitatory striatal afferents.
Rats were allowed to self-administer cocaine during a 3-h session for 15 days. One to 11 days after the last cocaine exposure, rats were anesthetized with urethane and effects of microiontophoretically-applied dopamine on glutamate-evoked firing of neurons in the nucleus accumbens and in the caudate/putamen were tested. Dopamine produced a dose-dependent inhibition of glutamate-evoked firing in both the nucleus accumbens and the caudate/putamen of rats that had been repeatedly exposed to self-administered cocaine and in control rats. However, the DA-induced inhibition was significantly greater in the group that had self-administered cocaine. The cocaine self-administration group was significantly sensitized to the inhibitory effects of dopamine in both early (1-3 day) and later (9-11 days) periods of cocaine abstinence. Following cessation of repeated cocaine self-administration sessions, nucleus accumbens cells were also sensitized to the inhibitory effects of methylenedioxymethamphetamine (MDMA), a drug that increases extracellular levels of DA and serotonin in the nucleus accumbens. This sensitization to DA- and MDMA-induced inhibition in the nucleus accumbens and in the striatum indicates that long-term neuroadaptations occur in these regions of the nervous system following repeated exposure to self-administered cocaine.
In this study, the involvement of serotonergic and dopaminergic receptors in the modulation of the head-twitch (HTW) response to the 5-hydroxytryptamine (5-HT)2A/5-HT2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, was characterized in rats using novel and selective ligands at 5-HT2A, 5-HT2C, D1, D2 and 5-HT1A receptors. HTW were dose-dependently inhibited by the 5-HT2A/2C antagonists, ritanserin, metergoline, mesulergine, mianserin, ICI 169,369 and LY 58,537, by the preferential 5-HT2A antagonist, ketanserin and by the novel, selective 5-HT2A antagonist, SR 46349B. A further selective 5-HT2A antagonist, MDL 100,907, very potently abolished HTW (ED50 = 0.005 mg/kg). The order of relative potency correlated highly with their affinity at 5-HT2A (r = 0.83) but not 5-HT2C receptors (r = 0.06). In addition, the novel, selective 5-HT2C antagonist, SB 200,646A, failed to abolish HTW and the 5-HT2C agonists/5-HT2A antagonists, 1-(3-chlorophenyl)piperazine and 1-(3-trifluoromethylphenyl)piperazine, blocked, rather than elicited, HTW. The D1 antagonists, SCH 23390, NNC 112, NNC 756, SCH 39166 and A 69024, in this order of relative potency that correlated with their affinity at D1 receptors (r = 0.98), blocked HTW. The D2 antagonists, raclopride, eticlopride and haloperidol also blocked HTW. The 5-HT1A agonists, S 14671, S 14506, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, ipsapirone and (+)-flesinoxan, abolished HTW. The action of 8-hydroxy-2-(di-n-propylamino)tetralin was blocked by (-)-tertatolol (ID50 = 4.5 mg/kg), a novel 5-HT1A receptor antagonist. Similarly, (-)-tertatolol attenuated the action of S 14506 and abolished that of S 14671, buspirone and ipsapirone. A role of postsynaptic 5-HT1A receptors in the action of 5-HT1A agonists was suggested by the finding that parachlorophenylalanine (3 x 300 mg/kg, i.p.), which depleted cerebral pools of 5-HT, did not modify the activity of ipsapirone. The present data demonstrate that 5-HT2A receptors mediate HTW in rats and that both D1 and D2 receptors as well as (postsynaptic) 5-HT1A receptors play a role in their expression.
The effects of the amphetamine analog, 3,4-methylenedioxymethamphetamine (MDMA) were compared to the effects of d-amphetamine on the in vivo release of dopamine and gamma-aminobutyric acid (GABA) in the striatum and substantia nigra. The brain region-dependent role of the 5-HT2 receptors in the striatum and substantia nigra in regulating MDMA-induced dopamine and GABA release also was studied. Changes in the extracellular concentration of dopamine, 5-HT and GABA were measured simultaneously in the awake rat by in vivo microdialysis. The increase in striatal dopamine produced by systemic administration of MDMA was attenuated by infusion of TTX into the striatum. Infusion of the 5-HT2A/2C antagonist ritanserin into the striatum or the ipsilateral substantia nigra also significantly attenuated MDMA-induced dopamine release in the striatum. At the doses used in this study, MDMA but not d-amphetamine increased the extracellular concentrations of 5-HT and decreased GABA efflux in the substantia nigra. The ability of MDMA to decrease nigral GABA efflux also was blocked by the local infusion of ritanserin into either the substantia nigra or the striatum. Overall, these data provide evidence that MDMA increases dopamine release partly through an impulse-mediated mechanism. Furthermore, this increase in striatal dopamine efflux produced by MDMA is regulated, in part, by 5-HT2A/2C receptors in the striatum and the substantia nigra and ultimately by GABAergic input into the substantia nigra.
The nucleus accumbens has been implicated as an important site for the actions of many drugs that are used recreationally. This study examined the effects of methylenedioxymethamphetamine (MDMA), a euphoric and hallucinogenic drug, on glutamate-evoked neuronal firing and on extracellular levels of dopamine and serotonin in the nucleus accumbens of the rat. Microiontophoretic application of MDMA inhibited glutamate-evoked firing of most of the nucleus accumbens cells that were tested (83 of 86), as did microiontophoretic application of dopamine and serotonin. MDMA-induced inhibition of glutamate-evoked firing was partially blocked by the dopamine antagonist SCH39166 and was attenuated by combined pretreatment with inhibitors of both serotonin and catecholamine synthesis, p-chlorophenylalanine and alpha-methyl-p-tyrosine. MDMA applied directly into the nucleus accumbens and adjacent regions of the ventral striatum through a dialysis probe increased extracellular levels of both dopamine and serotonin. These results indicate that MDMA has inhibitory effects on glutamate-evoked neuronal firing in the nucleus accumbens and suggest that the inhibition is mediated by increased extracellular dopamine and serotonin. Furthermore, these results permit MDMA to be added to the extensive list of abused drugs that have been demonstrated to elevate extracellular levels of dopamine and serotonin in the nucleus accumbens.
Neuronal activity was recorded from the neostriatum of freely moving rats at least 1 week following either sham or bilateral ablations of frontal and somatosensory cortex. In both groups of animals, the majority of neurons increased firing rate in close temporal association with spontaneous movement. No group differences emerged either with respect to baseline firing rates or open-field behavior. Following amphetamine administration, however, the excitatory response of motor-related neurons was suppressed in cortical-lesioned rats. A behavioral clamping procedure, which assessed neuronal activity during matched pre- and post-amphetamine behaviors, confirmed these results, suggesting that the amphetamine-induced changes in neuronal activity reflect a direct drug effect independent of behavioral feedback. In animals that received a subsequent injection of 1.0 mg/kg haloperidol, cortical lesions attenuated the ability of this neuroleptic to block both the behavioral and neuronal effects of amphetamine. Collectively, these results support mounting evidence for an important modulatory influence of cortical afferents on the amphetamine-induced excitation of neostriatal neurons and the reversal of this effect by haloperidol.
When injected systemically in rats, amphetamine routinely activates striatal neurons that increase firing rate in close temporal association with movement but suppresses nonmotor-related neurons. To assess the role of striatal mechanisms in these opposing effects, D-amphetamine (20 micrograms/microliters) was infused (10 microliters/h) directly into the striatum of awake, behaving rats and single-unit activity was recorded simultaneously at the infusion site. Intrastriatal amphetamine reliably activated motor-related, but suppressed nonmotor-related neuronal activity shortly after infusion onset. These changes in firing rate preceded overt behavioral changes, in most cases by several minutes. When they did emerge, behavioral responses were characterized mainly by focused sniffing and head bobbing. Interestingly, the strongest behavioral responses, as measured by onset latency and response magnitude, were likely to result from infusions into motor-related rather than nonmotor-related recording sites. Systemic injection of haloperidol (1.0 mg/kg) shortly after infusion offset suppressed both behavior and striatal neuronal activity. Control infusions of intrastriatal saline had no consistent effect on either striatal neuronal activity or behavior. Collectively, these results indicate that the divergence in firing rate between motor- and nonmotor-related striatal neurons reflects an intrinsic action of amphetamine in the striatum rather than a secondary effect of behavioral feedback. Moreover, the linkage of motor-related striatal areas with the strongest behavioral responses to amphetamine suggests important functional differences between motor- and nonmotor-related striatal neurons.
The efferent connections of the rostral pole of the rat accumbens, where distinct core and shell subterritories can not be identified, were examined with the aid of the anterogradely transported plant lectin, Phaseolus vulgaris-leucoagglutinin (PHA-L), for comparison with the previously reported projection patterns of the accumbal core and shell. Injection sites and transported PHA-L were evaluated with the aid of reference to adjacent sections processed to display substance P or calbindin 28 kD immunoreactivities, i.e., markers that demonstrate the core and shell. Lateral parts of the rostral pole gave rise to a "core-like" projection system that involved the rostroventral globus pallidus, subcommissural ventral pallidum, entopeduncular nucleus and an adjacent part of the lateral hypothalamus, lateral ventral tegmental area, dorsal pars compacta, and structures in the lateral mesencephalic tegmentum and central grey. The medial part of the rostral pole gave rise to a "shell-like" innervation of the subcommissural ventral pallidum, lateral preoptic region, lateral hypothalamus, ventral tegmental area, dorsalmost pars compacta, retrorubral field, lateral midbrain tegmentum, and central grey. In contrast to the large numbers of axon varicosities observed through the entire length of lateral hypothalamus following shell injections, dense accumulations of axon collaterals and varicosities in hypothalamus were limited to the levels of origin of the stria medullaris bundle and entopeduncular nucleus and to the posterlateral region following medial injections. The medial part of the rostral pole contributed some projections to preoptic and sublenticular regions, but not to the bed nucleus of the stria terminalis. Noteworthy concentrations of calbindin immunoreactive cells observed in the lateral rostral pole correlate with the origin of the "basal ganglia-like" projection system, provoking the speculation that ventral striatal calbindin immunoreactive cells contribute principally to basal ganglia-like projections while cells lacking calbindin immunoreactivity contribute to the innervation of hypothalamus and midbrain tegmentum.