Rat Nucleus Accumbens Neurons Research Articles

Influences of calcitonin gene-related peptide on mu opioid receptors in nucleus accumbens neurons of rats

The Mu opioid receptor (MOR) has been shown to participate in the analgesic effect of the calcitonin gene-related peptide (CGRP) in the nucleus accumbens (NAc) of adult rats. However, it is not clear whether and how CGRP regulates the MOR at the molecular levels. In the present study, it is found that the level of MORs on the cell membrane of NAc neurons was increased twice more than the control level following CGRP treatment (1μM, 30min), which is a phenomenon that was blocked by the peptidergic antagonist CGRP8–37. No direct physical interaction was observed between MORs and CGRP receptors, and neither brefeldin A nor dynosore preincubation affected such effects of CGRP. However, addition of 20μM monensin 1h before CGRP treatment significantly blocked the action of CGRP on surface MORs. In living animals, microinjection of CGRP (1nmol in 1μl) into the NAc partially restored morphine antinociception in morphine-tolerant rats, and the effect of CGRP on surface MORs extended beyond normal NAc neurons to chronic morphine-treated NAc neurons. To conclude, these results demonstrate that CGRP can act on MORs and increase the number of surface MORs in NAc neurons, partially explaining the involvement of opioid receptors in CGRP-induced antinociception in the rat NAc.

Repeated cocaine exposure decreases dopamine D2‐like receptor modulation of Ca2+ homeostasis in rat nucleus accumbens neurons

The nucleus accumbens (NAc) is a limbic structure in the forebrain that plays a critical role in cognitive function and addiction. Dopamine modulates activity of medium spiny neurons (MSNs) in the NAc. Both dopamine D₁-like and D₂-like receptors (including D1R or D(1,5)R and D2R or D(2,3,4)R, respectively) are thought to play critical roles in cocaine addiction. Our previous studies demonstrated that repeated cocaine exposure (which alters dopamine transmission) decreases excitability of NAc MSNs in cocaine-sensitized, withdrawn rats. This decrease is characterized by a reduction in voltage-sensitive Na(+) currents and high voltage-activated Ca(2+) currents, along with increased voltage-gated K(+) currents. These changes are associated with enhanced activity in the D1R/cAMP/PKA/protein phosphatase 1 pathway and diminished calcineurin function. Although D1R-mediated signaling is enhanced by repeated cocaine exposure, little is known whether and how the D2R is implicated in the cocaine-induced NAc dysfunction. Here, we performed a combined electrophysiological, biochemical, and neuroimaging study that reveals the cocaine-induced dysregulation of Ca(2+) homeostasis with involvement of D2R. Our novel findings reveal that D2R stimulation reduced Ca(2+) influx preferentially via the L-type Ca(2+) channels and evoked intracellular Ca(2+) release, likely via inhibiting the cAMP/PKA cascade, in the NAc MSNs of drug-free rats. However, repeated cocaine exposure abolished the D₂R effects on modulating Ca(2+) homeostasis with enhanced PKA activity and led to a decrease in whole-cell Ca(2+) influx. These adaptations, which persisted for 21 days during cocaine abstinence, may contribute to the mechanism of cocaine withdrawal.

Cue‐evoked encoding of movement planning and execution in the rat nucleus accumbens

The nucleus accumbens is involved in the modulation of motivated behaviour by reward-associated sensory information. However, little is known about the specific nature of the nucleus accumbens' contribution to generating movement. We investigated motor encoding by nucleus accumbens neurons in rats performing a delayed response task that allowed us to dissociate the effects of sensory and motor events on firing. In a subset of neurons, firing in the delay period preceding movement was highly selective; this selectivity was tightly correlated with the direction of the subsequent movement, but not with the sensory properties of the instructive cue. Direction selectivity in this population of neurons developed over the course of the delay period, with the strongest selectivity apparent just prior to movement onset. Selectivity was also apparent in nucleus accumbens neurons during movement, such that firing showed a tight correlation with movement direction, but not the instructive cue presented nor the spatial destination of the movement. These results are consistent with the hypothesis that a subpopulation of nucleus accumbens neurons contributes to the selection and execution of specific motivated behaviours.

Rat Nucleus Accumbens Neurons Persistently Encode Locations Associated With Morphine Reward

When rats and mice are free to explore a familiar environment they spend more time in a previously rewarded location. This conditioned place preference (CPP) results from an increased probability of initiating transitions from an unrewarded location to one previously paired with reward. We recorded nucleus accumbens (NAc) neurons while rats explored a three-room in-line apparatus. Before place conditioning, approximately equal proportions of NAc neurons show excitations or inhibitions when the rat is in each of the rooms (morphine paired, center or saline paired). Conditioning increased the proportion of neurons inhibited while the rat was in the morphine room and neurons excited in the saline room. Many of the neurons in these two groups responded during room transitions. Furthermore, the postconditioning increase in the population of neurons with room-selective responding persisted for several weeks after the last morphine treatment. This long-lasting change in population responses of NAc neurons to initially neutral locations is a neural correlate of the change in location preference manifest as CPP.

Rat Nucleus Accumbens Neurons Predominantly Respond to the Outcome-Related Properties of Conditioned Stimuli Rather Than Their Behavioral-Switching Properties

It has been proposed that nucleus accumbens neurons respond to outcome (reward and punishment) and outcome-predictive information. Alternatively, it has been suggested that these neurons respond to salient stimuli, regardless of their outcome-predictive properties, to facilitate a switch in ongoing behavior. We recorded the activity of 82 single-nucleus accumbens neurons in thirsty rats responding within a modified go/no-go task. The task design allowed us to analyze whether neurons responded to conditioned stimuli that predicted rewarding (saccharin) or aversive (quinine) outcomes, and whether the neural responses correlated with behavioral switching. Approximately one third (28/82) of nucleus accumbens neurons exhibited 35 responses to conditioned stimuli. Over 2/3 of these responses encoded the nature of the upcoming rewarding (19/35) or aversive (5/35) outcome. No response was selective solely for the switching of the rat's behavior, although the activity of approximately one third of responses (11/35) predicted the upcoming outcome and was correlated with the presence or absence of a subsequent behavioral switch. Our data suggest a primary functional role for the nucleus accumbens in encoding outcome-predicting information and a more limited role in behavioral switching.

Repeated Cocaine Administration Decreases Calcineurin (PP2B) but Enhances DARPP-32 Modulation of Sodium Currents in Rat Nucleus Accumbens Neurons

Our previous studies have demonstrated that repeated cocaine (COC) administration reduces voltage-sensitive sodium and calcium currents (I(Na) or VSSCs and I(Ca) or VSCCs, respectively) in medium spiny nucleus accumbens (NAc) neurons of rats. The present findings further indicate that chronic COC-induced I(Na) reduction in NAc neurons is regulated by decreased dephosphorylation and enhanced phosphorylation of Na(+) channels. Whole-cell voltage-clamp recordings revealed that dephosphorylation of Na(+) channels by calcineurin (CaN) enhanced I(Na), while inhibition of protein phosphatase 1 (PP1) by phosphorylated dopamine- and cAMP-regulated phosphoprotein (M(r)=32 kDa) (DARPP-32) at the site of threonine 34 (p-Thr.34-DARPP-32) suppressed I(Na), in freshly dissociated NAc neurons of saline-pretreated rats. However, the effects of CaN on enhancing I(Na) were significantly attenuated, and the action of p-Thr.34-DARPP-32 to decrease I(Na) was mimicked, although not potentiated, by repeated COC pretreatment. Dephosphorylation of Na(+) channels by PP1 also enhanced I(Na), but this effect of PP1 on I(Na) was not apparently affected by repeated COC administration. Western blot analysis indicates that the protein levels of CaN and DARPP-32 were significantly decreased and increased, respectively, while the PP1 levels were unchanged, in the COC-withdrawn NAc as compared to saline-pretreated controls. Combined with previous findings, our results indicate that both CaN and PP1 modulate the increase in I(Na) via enhancing dephosphorylation, while p-Thr.34-DARPP-32 reduces I(Na) by inhibiting PP1-induced dephosphorylation, thereby stabilizing the phosphorylation state, of Na(+) channels in NAc neurons. They also suggest that chronic COC-induced I(Na) reduction may be attributed to a reduction in Ca(2+) signaling, which disrupts the physiological balance of phosphorylation and dephosphorylation of Na(+) channels.

Encoding of palatability and appetitive behaviors by distinct neuronal populations in the nucleus accumbens.

Obesity is a major public health problem. Palatability (i.e., the reinforcing value of food, derived from orosensory cues) is a significant factor in determining food intake and contributes to increased consumption leading to obesity. The nucleus accumbens is a ventral striatal region that is important for both appetitive and consummatory behaviors and has been implicated in modulating palatability. In this study, we investigated palatability encoding in the firing of nucleus accumbens neurons in rats. Nucleus accumbens neurons with significant changes in firing rate during consummatory behavior displayed one of two principal firing patterns. Firing in one class of nucleus accumbens neurons was correlated with the palatability of sucrose reinforcers; changes in neural activity in this class consisted primarily of excitations. Within this group of neurons, a subset was sensitive to the relative value of sucrose reinforcers, as assessed by a behavioral contrast paradigm. A second and distinct population of nucleus accumbens neurons, with changes in firing that were pre-dominantly inhibitions, was not sensitive to reinforcer palatability; rather, these inhibitions were present even during unreinforced bouts of licking. In addition, the onset of these inhibitions typically occurred before the initiation of the licking behavior itself. We propose that two primary classes of nucleus accumbens neurons contribute to neural processing immediately before and during reinforcer consumption: inhibitions related to initiation and maintenance of consummatory behaviors and excitations that encode reinforcer palatability.

Alterations in dendritic morphology of prefrontal cortical and nucleus accumbens neurons in post-pubertal rats after neonatal excitotoxic lesions of the ventral hippocampus

Neonatal ventral hippocampal (nVH) lesions in rats result in adult onset of a number of behavioral and cognitive abnormalities analogous to those seen in schizophrenia, including hyperresponsiveness to stress and psychostimulants and deficits in working memory, sensorimotor gating and social interaction. Molecular and neurochemical alterations in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of nVH-lesioned animals suggest developmental reorganization of these structures following neonatal lesions. To determine whether nVH lesions lead to neuronal morphological changes, we investigated the effect of nVH lesion on dendritic structure and spine density of pyramidal neurons of the PFC and medium spiny neurons of the NAcc. Bilateral ibotenic acid-induced lesion of the VH was made in Sprague-Dawley pups at postnatal day 7 (P7); and at P70, neuronal morphology was quantified by modified Golgi-Cox staining. The results show that length of basilar dendrites and branching and the density of dendritic spines on layer 3 pyramidal neurons were significantly decreased in rats with nVH lesions. Medium spiny neurons from the NAcc showed a decrease in the density of dendritic spines without significant changes in dendritic length or arborization. The data, comparable to those observed in the PFC of schizophrenic patients, suggest that developmental loss of excitatory projections from the VH may lead to altered neuronal plasticity in the PFC and the NAcc that may contribute to the behavioral changes in these animals.

Dopamine receptor subtypes selectively modulate excitatory afferents from the hippocampus and amygdala to rat nucleus accumbens neurons.

The nucleus accumbens (NAc) receives excitatory afferents from several cortical and limbic regions and dense dopaminergic inputs from the ventral tegmental area. We examined the effects of dopamine (DA) D1 and D2 selective drugs on the responses evoked in the NAc shell neurons recorded in vitro by stimulation of hippocampal and amygdaloid afferents. Activation of hippocampal and amygdaloid afferents induced excitatory postsynaptic responses that were depressed by bath application of DA in most of the cells recorded. The DA effect was substantially blocked by the D1 receptor antagonist SCH 23390, but not by the D2 receptor antagonist eticlopride. Moreover, the D1 receptor agonist SKF 38393, but not the D2 receptor agonist quinpirole, mimicked the effects of DA, although a small population of neurons exhibited a D1-mediated facilitation of the EPSP amplitude following fornix stimulation. These data demonstrate a DA receptor subtype-specific modulation of glutamatergic inputs to the NAc, with D1 agonists attenuating amygdaloid inputs, whereas hippocampal-evoked responses were either depressed or potentiated by D1 stimulation. Such facilitation or attenuation of hippocampal afferents against a background of suppression of other afferents would permit the hippocampus to have a dominant influence over behavior during periods of exploration.

Postsynaptic modulation of AMPA- and NMDA-receptor currents by Group III metabotropic glutamate receptors in rat nucleus accumbens

Whole cell patch clamp recordings from rat nucleus accumbens neurons were made in order to study the effect of metabotropic glutamate receptors and dopamine on postsynaptic glutamate receptor mediated currents. AMPA- and NMDA-R currents were evoked by flash photolysis of caged glutamate, while spike-dependent release of neurotransmitters was prevented by adding tetrodotoxin and bicuculline to the bath solution. Spontaneous potentiation of NMDA- but not AMPA-R current was observed in the early phase of stimulation, followed by depotentiation and subsequent stabilization. The Group III metabotropic glutamate receptor antagonist MAP4 induced a transient potentiation of both AMPA- and NMDA-R current amplitudes, without affecting rise times and decay time constants. In contrast, the Group I–II metabotropic glutamate receptor antagonist MCPG and the neurotransmitter dopamine did not exert significant effects on either AMPA- or NMDA-R currents. These data suggest that at least one of the Group III subtypes is located postsynaptically in the nucleus accumbens and is able to dampen the activity of ionotropic glutamatergic receptors. In contrast, our results do not support a modulation of postsynaptic AMPA- and NMDA-R currents by Group I/II metabotropic glutamate receptors or dopamine. Modulation of both AMPA- and NMDA-R currents in the nucleus accumbens is likely to play a major role in setting the cellular excitability in response to behaviourally relevant limbic inputs, and in regulating the plasticity of these responses.

D1 dopamine receptor stimulation increases GluR1 surface expression in nucleus accumbens neurons.

The goal of this study was to understand how dopamine receptors, which are activated during psychostimulant administration, might influence glutamate-dependent forms of synaptic plasticity that are increasingly recognized as important to drug addiction. Regulation of the surface expression of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR1 plays a critical role in long-term potentiation, a well-characterized form of synaptic plasticity. Primary cultures of rat nucleus accumbens neurons were used to examine whether dopamine receptor stimulation influences cell surface expression of GluR1, detected using antibody to the extracellular portion of GluR1 and fluorescence microscopy. Surface GluR1 labeling on processes of medium spiny neurons and interneurons was increased by brief (5-15 min) incubation with a D1 agonist (1 microm SKF 81297). This effect was attenuated by the D1 receptor antagonist SCH 23390 (10 microm) and reproduced by the adenylyl cyclase activator forskolin (10 microm). Labeling was decreased by glutamate (10-50 microm, 15 min). These results are the first to demonstrate modulation of AMPA receptor surface expression by a non-glutamatergic G protein-coupled receptor. Normally, this may enable ongoing regulation of AMPA receptor transmission in response to changes in the activity of dopamine projections to the nucleus accumbens. When dopamine receptors are over-stimulated during chronic drug administration, this regulation may be disrupted, leading to inappropriate plasticity in neuronal circuits governing motivation and reward.

Repeated cocaine treatment decreases whole-cell calcium current in rat nucleus accumbens neurons.

Dopamine D1 receptors within the nucleus accumbens (NAc) are intricately involved in the rewarding effects of cocaine and in withdrawal symptoms after cessation of repeated cocaine administration. These receptors couple to a variety of ion channels to modulate neuronal excitability. Using whole-cell recordings from dissociated adult rat NAc medium spiny neurons (MSNs), we show that, as in dorsal striatal MSNs, D1 receptor stimulation suppresses N- and P/Q-type Ca(2+) currents (I(Ca)) by activating a cAMP/protein kinase A/protein phosphatase (PP) signaling system, presumably leading to channel dephosphorylation. We also report that during withdrawal from repeated cocaine administration, basal I(Ca) density is decreased by 30%. Pharmacological isolation of specific I(Ca) components indicates that N- and R-type, but not P/Q- or L-type, currents are significantly reduced by repeated cocaine treatment. Inhibiting PP activity with okadaic acid enhances I(Ca) in cocaine withdrawn, but not control, NAc neurons, suggesting an increase in constitutive PP activity. This suggestion was supported by a significant decrease in the ability of D1 receptor stimulation and direct activation of cAMP signaling to suppress I(Ca) in cocaine-withdrawn NAc neurons. Chronic cocaine-induced reduction of I(Ca) in NAc MSNs will globally impact Ca(2+)-dependent processes, including synaptic plasticity, transmitter release, and intracellular signaling cascades that regulate membrane excitability. Along with our previously reported reduction in whole-cell Na(+) currents during cocaine withdrawal, these findings further emphasize the important role of whole-cell plasticity in reducing information processing during cocaine withdrawal.

Position sensitivity in phasically discharging nucleus accumbens neurons of rats alternating between tasks requiring complementary types of spatial cues

To determine how hippocampal location-selective discharges might influence downstream structures for navigation, nucleus accumbens neurons were recorded in rats alternating between two tasks guided respectively by lit cues in the maze or by extramaze room cues. Of 144 phasically active neurons, 80 showed significant behavioral correlates including displacements, immobility prior to, or after reward delivery, as well as turning, similar to previous reports. Nine neurons were position-selective, 22 were sensitive to task and platform changes and 40 others were both.Although the accumbens neurons showed the same behavioral correlate in two or four functionally equivalent locations, these responses were stronger at some of these places, evidence for position sensitivity. To test whether position responses were selective for room versus platform cues, the experimental platform was rotated while the rat performed each of the two tasks. This revealed responses to changes in position relative to both platform and room cues, despite the fact that previous studies had shown that place responses of hippocampal neurons recorded in the same task are anchored to room cues only. After these manipulations and shifts between the two tasks, the responses varied among simultaneously recorded neurons, and even in single neurons in alternating visits to reward sites. Again this contrasts with the uniformity of place responses of hippocampal neurons recorded in this same task. Thus accumbens position responses may derive from hippocampal inputs, while responses to context changes are more likely to derive from other signals or intrinsic processing.Considering the accumbens as a limbic-motor interface, we conclude that position-modulated behavioral responses in the accumbens may be intermediate between the allocentric reference frame of position-selective discharges in the hippocampus and the egocentric coding required to organize movement control. The conflicting responses among simultaneously recorded neurons could reflect competition processes serving as substrates for action selection and learning.

Morphine acutely and persistently attenuates nonvesicular GABA release in rat nucleus accumbens.

Withdrawal from repeated exposure to morphine causes a long-lasting increase in the reactivity of nucleus accumbens nerve terminals towards excitation. The resulting increase in action potential-induced exocytotic release of neurotransmitters, associated with behavioral sensitization, is thought to contribute to its addictive properties. We recently showed that activation of N-methyl-D-aspartate (NMDA) as well as dopamine (DA) D1 receptors in rat striatum causes tetrodotoxin-insensitive transporter-dependent GABA release. Since sustained changes in extracellular GABA levels may play a role in drug-induced neuronal hyperresponsiveness, we examined the acute and long-lasting effect of morphine on this nonvesicular GABA release in rat nucleus accumbens slices. The present study shows that morphine, through activation of mu-opioid receptors, reduces nonvesicular NMDA-induced [(3)H]GABA release in superfused nucleus accumbens slices. Moreover, prior repeated morphine treatment of rats (10 mg/kg, sc, 14 days) caused a reduction in NMDA-stimulated [(3)H]GABA release in vitro until at least 3 weeks after morphine withdrawal. This persistent neuroadaptive effect was not observed studying dopamine D1 receptor-mediated [(3)H]GABA release in nucleus accumbens slices. Moreover, this phenomenon appeared to be absent in slices of the caudate putamen. Interestingly, even a single exposure of rats to morphine (>2 mg/kg) caused a long-lasting inhibition of NMDA-induced release of GABA in nucleus accumbens slices. These data suggest that a reduction in nonvesicular GABA release within the nucleus accumbens, by enhancing the excitability of input and output neurons of this brain region, may contribute to the acute and persistently enhanced exocytotic release of neurotransmitters from nucleus accumbens neurons in morphine-exposed rats.

Amphetamine Withdrawal Alters Bistable States and Cellular Coupling in Rat Prefrontal Cortex and Nucleus Accumbens Neurons RecordedIn Vivo

Repeated amphetamine administration is known to produce changes in corticoaccumbens function that persist beyond termination of drug administration. We have found previously that long-term alteration in dopamine systems leads to changes in gap junction communication, expressed as dye coupling, between striatal neurons. In this study, the cellular bases of amphetamine-induced changes were examined using in vivo intracellular recordings and dye injection in ventral prefrontal-accumbens system neurons of control and amphetamine-treated rats. Rats that had been withdrawn from repeated amphetamine displayed a significant increase in the incidence of dye coupling in the prefrontal cortex and nucleus accumbens, which persisted for up to 28 d after withdrawal. The increased coupling was limited to projection neurons in both prefrontal cortical and accumbens brain regions, as identified by their axonal trajectory or the absence of interneuron-selective immunocytochemical markers. These changes occurred with no substantial loss of tyrosine hydroxylase-immunoreactive terminals in these cortical and accumbens regions, ruling out dopamine degeneration as a precipitating factor. Previous studies showed that nitric oxide plays a role in the regulation of coupling; however, amphetamine-withdrawn rats had fewer numbers of neurons and processes that stained for nitric oxide synthase immunoreactivity. In amphetamine-treated rats, a higher proportion of cortical cells fired in bursts, and a larger proportion of accumbens and prefrontal cortical neurons exhibited bistable membrane oscillations. By increasing corticoaccumbens transmission, amphetamine withdrawal may lead to neuronal synchronization via gap junctions. Furthermore, this adaptation to amphetamine treatment persists long after the drug is withdrawn.

Tonic firing of rat nucleus accumbens neurons: changes during the first 2 weeks of daily cocaine self-administration sessions

Activity of single neurons in the nucleus accumbens (NAcc) of rats was recorded extracellularly on the 2nd and 15th days of intravenous cocaine self-administration. Each of the two electrophysiological recording sessions consisted of three successive phases: a pre-drug baseline recording period, a cocaine self-administration session, and a post-drug recording period. Firing of individual neurons was typically inhibited during the self-administration session, relative to the pre-drug period. The inhibition was greater on the 15th day relative to the 2nd day. Additionally, firing rates during the pre-drug period and the self-administration session were typically lower on the 15th day as compared to the 2nd day. The present data are consistent with previous acute electrophysiological findings and are in line with the hypothesis that repeated drug self-administration engenders changes in the mesoaccumbens pathway that contribute to drug addiction.

Phasic Firing Time Locked to Cocaine Self-Infusion and Locomotion: Dissociable Firing Patterns of Single Nucleus Accumbens Neurons in the Rat

The activity of single nucleus accumbens (NAcc) neurons of rats was extracellularly recorded during intravenous cocaine self-administration sessions (0.7 mg/kg per infusion, fixed ratio 1). We reported previously that NAcc neurons showed a change, usually a decrease, in firing rate during the first 1 min after the cocaine-reinforced lever press. This postpress change was followed by a progressive reversal of that change, which began within the first 2 min after the press and was not complete until the last 1 min before the next lever press (termed the change + progressive reversal firing pattern). In the present study we documented a regular pattern of locomotion that occurred in parallel with the change + progressive reversal firing pattern. This observation suggested that discharges time locked to locomotion may determine the change + progressive reversal firing pattern. However, 55% of the neurons failed to show firing time locked to locomotion that could have contributed to the change + progressive reversal firing pattern. Moreover, for all neurons, the change + progressive reversal firing pattern was apparent even if the calculation of firing rate excluded all periods of locomotion. The present data showed that the change + progressive reversal firing pattern is not solely attributable to phasic changes in firing time locked to the execution of locomotion. The change + progressive reversal firing pattern closely mirrors changes in drug level and dopamine overflow observed by previous researchers and may thus be a component of the neurophysiological mechanism by which drug level regulates drug-taking behavior during an ongoing self-administration session.

Voltage- and use-dependent inhibition by amphetamine of field potentials and Na + current in rat nucleus accumbens neurons

The psychostimulant amphetamine (AMPH) is known to act as an indirect dopamine agonist by promoting dopamine release. Here we demonstrate direct AMPH inhibition of field potentials and Na + currents in rat nucleus accumbens (NAc) neurons. The experiments were done with field potential recordings from NAc slices and whole-cell recordings from isolated NAc neurons. In NAc slices, AMPH inhibited the field potentials. The inhibition increased when the NAc neurons were depolarized with higher extracellular K + or when the field potentials were evoked at a higher rate. In isolated NAc neurons, AMPH inhibited the Na + currents. The inhibition increased when Na + currents were activated from more depolarized holding potentials or were activated more frequently. The voltage- and use-dependent inhibition of field potentials and Na + currents by AMPH suggests a similar mechanism of AMPH action with local anesthetics and antiarrhythmic drugs.

Tonic inhibition of single nucleus accumbens neurons in the rat: a predominant but not exclusive firing pattern induced by cocaine self-administration sessions

Inhibition of nucleus accumbens neurons is hypothesized to be a mechanism that contributes to the reinforcing (addictive) effects of cocaine and other drugs. To test this hypothesis, the activity of single nucleus accumbens neurons of rats was recorded extracellularly during cocaine self-administration sessions. Fifty-eight percent of neurons were tonically inhibited during cocaine self-administration relative to predrug baseline; thirty-one percent were tonically excited. A majority of both excited and inhibited neurons showed phasic increases in firing time-locked to self-infusion. The high percentage of tonically inhibited neurons is in line with the strong inhibitory effects of cocaine and amphetamine observed in previous anesthetized and slice recording studies; however, the prevalence of inhibition, relative to excitation, was less than might have been expected on the basis of the earlier recording studies. The present results support the hypothesis that accumbal (tonic) inhibition contributes to drug taking. However, they also suggest that changes in firing that are distinct from the tonic inhibition may additionally contribute to accumbal mediation of drug taking and drug addiction. The uniform observation of predominant inhibition among the various electrophysiology studies is consistent with the heuristic value of anesthetized and slice recording methods in identifying potential neurophysiological correlates of drug taking; however, the existence of firing patterns (e.g., phasic increases) uniquely associated with self-administration behavior (and thus absent in anesthetized and slice studies), as well as the unique presence of the primary behavior of interest in studies such as the present one, underscores the importance of conducting electrophysiological investigations of drug taking and drug addiction in the self-administering animal in parallel with anesthetized and slice studies whenever possible.

Glutamate receptor regulation of rat nucleus accumbens neurons in vivo.

Extracellular single cell recording and microiontophoretic techniques were used to characterize the roles of ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs) in glutamate-induced excitation of rat nucleus accumbens (NAc) neurons in vivo. Pulse-ejected glutamate (16-128 nA) induced a current-dependent increase in the firing of quiescent NAc neurons. A stronger excitatory response to alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) was observed at much lower ejection currents (0.1-6.4 nA). Compared to AMPA and glutamate, N-methyl-D-aspartate (NMDA) induced a much less potent excitation in a narrow current range (1-4 nA) and only when neurons were previously "primed" with other excitatory amino acids (EAAs). Higher ejection currents of all three EAA agonists drove NAc neurons into a state of apparent depolarization block. AMPA-evoked firing was selectively blocked by the AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) whereas NMDA-induced activity was selectively prevented by the NMDA receptor antagonist 2-amino-5-phosphonovalerate (D-AP5). DNQX, but not D-AP5, significantly attenuated glutamate-evoked activity. The mGluR receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-t-ACPD) failed to evoke activity of NAc neurons, but significantly reduced the excitatory effects of other EAAs. This modulatory effect of 1S,3R-t-ACPD was consistently blocked by the selective mGluR antagonist L(+)-2-amino-3-phopsonopropionic acid (L-AP3) whereas another mGluR antagonist (RS)-4-carboxy-3-hydroxy phenylglycine (4C3HPG) was inconsistent in this regard. These results indicate that the excitatory effects of glutamate on rat NAc neurons in vivo are primarily mediated by non-NMDA iGluRs and that mGluRs function to dampen excessive glutamate transmission through iGluRs.