Accumbens Cell Firing Research Articles

Behavioral responding and nucleus accumbens cell firing are unaltered following periods of abstinence from sucrose

A critical feature of cocaine addiction is the strong propensity to relapse following periods of abstinence. Here, we examined whether abstinence from sucrose self-administration in rats altered behavioral responding and nucleus accumbens (NAc) cell firing in a manner similar to that observed following cocaine abstinence. Rats (n = 22) were trained to self-administer sucrose on a short-access schedule, previously shown to increase motivated behavior following sucrose abstinence, and then underwent either a 0, 7, or 30 day period of abstinence. Next, electrophysiological recording procedures were used to examine NAc activity (n = 199 neurons) during resumption of sucrose self-administration. Results showed no increase in sucrose-seeking or changes in cell firing of NAc neurons following any abstinence period. Furthermore, in a separate group of animals (n = 17) trained under identical conditions, sucrose-seeking behaviors were assessed during extinction and cue-induced reinstatement to further examine if any changes in motivated responding are evident following abstinence. Again, no evidence was obtained for any alterations in sucrose-seeking across abstinence conditions. These results suggest that natural rewards, such as sucrose, when provided in short access, do not always elicit robust changes in motivated responding, or NAc cell firing following abstinence unlike that observed in prior studies with cocaine. These findings are discussed with respect to the role of the NAc in processing goal-directed behaviors for drug vs. natural rewards following periods of abstinence.

Prefrontal cortical cell firing during maintenance, extinction, and reinstatement of goal‐directed behavior for natural reward

The prefrontal cortex (PFC) is important for higher cognitive functioning and the processing of reward-related information. Here, electrophysiological recording procedures were used to examine cell firing in the PFC in rats (n = 12) during water reinforcement sessions consisting of three phases. In phase one (maintenance), animals pressed a lever (fixed ratio 1) for water reinforcement (0.05 ml/press) paired with an auditory stimulus. Of 62 neurons recorded during maintenance, 39 (63%) exhibited one of three types of patterned discharges relative to the reinforced response for water. Specifically, PFC neurons exhibited increases in firing rate within seconds preceding the response (type PR; n = 9 cells) or increases (type RFe; n = 16 cells) or decreases (type RFi; n = 14 cells) in firing rate immediately following response completion. The remaining neurons did not alter their firing profiles relative to the reinforced response (type nonphasic cells; n = 23 cells). In phase two (extinction), lever press responses had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, phase three (reinstatement) began, during which each lever press response was again associated with water reinforcement paired with the stimulus. Results indicate differential effects of extinction/reinstatement on cell firing rates and patterns dependent on cell type. These findings are discussed with respect to the adaptive nature of PFC activity during goal-directed behaviors for "natural" rewards, and are considered relative to prior studies that examined nucleus accumbens cell firing during a similar behavioral task.

Nucleus accumbens cell firing and rapid dopamine signaling during goal-directed behaviors in rats

The nucleus accumbens (Acb) is a key neural substrate underlying goal-directed behaviors for both drugs of abuse as well as ‘natural’ rewards. Here, I review electrophysiological and electrochemical studies completed in our laboratory that examined Acb cell firing and rapid dopamine signaling during behaviors directed toward reward procurement. Electrophysiological studies are reviewed showing that Acb neurons exhibit patterned discharges relative to operant responding for intravenous self-administration of cocaine versus ‘natural’ reinforcement in rodents. Importantly, subsequent studies showed that discrete subsets of Acb neurons are selectively activated during multiple schedules for a natural reward (water or food) versus cocaine self-administration. These later findings indicate that separate neural circuits selectively process information about goal-directed behaviors for cocaine versus natural reward. In addition, recent findings are reviewed showing that reinforcer selective firing of Acb neurons is not a direct consequence of chronic drug exposure. Next, electrochemical studies are summarized that used fast scan cyclic voltammetry to measure rapid (subsecond) changes in dopamine in the Acb during cocaine self-administration as well as ‘natural’ reinforcement in rodents. These findings are considered with respect to the role of dopamine in modulating the activity of Acb neurons that encode goal-directed behaviors, the functional organization of the Acb on a microcircuit level, and proposed directions for future studies.

Nucleus accumbens cell firing during goal-directed behaviors for cocaine vs. ‘natural’ reinforcement

Numerous investigations indicate that the nucleus accumbens (Acb) is an important neural substrate mediating the reinforcing properties of ‘natural’ rewards (food or water) as well as abused substances. Here, our electrophysiological studies that examined Acb cell firing within seconds of lever press responding for intravenous cocaine vs. water or food reinforcement in rats are reviewed. Initial investigations revealed that a subset of Acb neurons exhibits four types of firing patterns within seconds of the reinforced response for intravenous cocaine during self-administration sessions. Three of those four cell types were also observed during water reinforcement sessions. In a subsequent study, the activity of the same Acb neurons was examined in rats responding on multiple schedules for either two distinct ‘natural’ reinforcers (water and food), or one of those ‘natural’ reinforcers and the intravenous self-administration of cocaine. The results showed that the majority of neurons tested exhibited similar, overlapping neuronal firing patterns across the two ‘natural’ reinforcer conditions. In contrast, the majority of neurons examined displayed differential, nonoverlapping firing patterns relative to operant responding for water (or food) vs. cocaine reinforcement. Additional studies that examined the role of associative factors on Acb cell firing during cocaine self-administration sessions are reviewed. Collectively, these findings illustrate the dynamic nature of Acb cell firing in behaving animals, and provide insight into how Acb neurons process information about goal-directed behaviors for ‘natural’ reinforcers vs. abused substances.

An examination of nucleus accumbens cell firing during extinction and reinstatement of water reinforcement behavior in rats

Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats ( n=13) during water reinforcement sessions consisting of three phases. During phase one (maintenance), a lever press resulted in water reinforcement (fixed ratio 1; 0.05 ml/press) paired with an auditory stimulus (0.5 s). Of 128 Acb neurons recorded during maintenance, 40 cells (31%) exhibited one of three types of neuronal firing patterns described previously [ J. Neurosci. 14 (12) (1994) 7735–7746; J. Neurosci. 20 (11) (2000) 4255–4266]. Briefly, Acb neurons exhibited increases in firing rate within seconds preceding the reinforced response (type PR) or increases (type RFe) or decreases (type RFi) in activity seconds following response completion. In phase two (extinction), subsequent lever pressing had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, animals were given water reinforcement/auditory stimulus ‘primes’ to reestablish lever pressing behavior during the third phase (reinstatement). Results indicated that all types of phasic neurons (PR, RFe and RFi) exhibited an attenuated firing rate during extinction, and in some cases recovery of patterned discharges were observed during reinstatement. No significant changes in cell firing were observed for any cell type during presentation of the stimulus prime used to reestablish operant responding following extinction. These findings are discussed in terms of how Acb neurons process information related to ‘natural’ reinforcers versus drugs of abuse.

Nucleus accumbens cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats

Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats ( N=13) during cocaine self-administration sessions consisting of three phases. In phase one (maintenance), each lever press resulted in an intravenous cocaine infusion (0.33 mg, 6 s) paired with a tone-houselight stimulus (20 s). Of 144 Acb cells recorded during maintenance, 39 neurons (27%) exhibited phasic firing relative to the cocaine-reinforced response [4–8]. Briefly, Acb neurons showed increases in firing rate within seconds preceding the reinforced response and/or changes (increases or decreases) in activity within seconds following response completion. In phase two (extinction), saline was substituted for cocaine in the task. Results indicated that cells displaying exclusively anticipatory discharges during maintenance exhibited similar phasic activity during extinction. However, neurons that displayed post-response activity during the maintenance phase typically showed significant attenuation of phasic firing rates during extinction. After 30 min of no responding, animals were ‘primed’ with an intravenous infusion of cocaine, and self-administration was reestablished during phase three (reinstatement). Results showed that pre-response discharge patterns remained relatively intact while post-response cells typically exhibited a partial recovery of phasic activity. Similar findings were observed during other extinction experiments in which the stimulus only was removed (CS extinction). These findings support the notion that specific factors operating within the self-administration context differentially control pre- versus post-response discharge patterns of Acb neurons.

Activation of accumbens cell firing by stimuli associated with cocaine delivery during self-administration

Electrophysiological recording procedures were used in behaving rats (n = 11) to examine the responsiveness of nucleus accumbens (Acb) neurons to stimuli associated with intravenous cocaine delivery during self-administration sessions. Of 208 Acb neurons recorded during cocaine (0.33 mg/inf) self-administration sessions, 78 cells exhibited one of four types of patterned discharges (increases and/or decreases in firing rate) immediately before and/or following the cocaine-reinforced response. All phasically active Acb cells were examined in test sessions consisting of "probe" trials (18-20 per session) during which either the drug only was delivered (0.33 mg/inf cocaine, 6 sec) or the stimulus only (tone-houselight, 20 sec) was randomly presented by the computer, interspersed between reinforced lever press responses. Results show that Acb cells that exhibit postresponse changes in firing rate within seconds of the reinforced response appear to be controlled, at least in part, by the stimulus paired with cocaine delivery during the self-administration session and not via a direct pharmacological action of cocaine. In contrast, neurons displaying exclusively preresponse activity do not appear to be influenced by presentation of the drug-associated stimulus or by a direct pharmacological action of the cocaine, but may be related to initiation of the operant response. These findings are discussed with respect to the role of the Acb in mediating conditioned responses associated with drug reinforcement.

Examination of factors mediating the transition to behaviorally correlated nucleus accumbens cell firing during cocaine self-administration sessions in rats

We have previously reported that at the initiation of cocaine self-administration sessions, neurons in the nucleus accumbens (NA) exhibit a spontaneous transition in firing rate from activity unrelated to the reinforced response, to one of four types of patterned discharges (Carelli RM, King VC, Hampson RE, Deadwyler SA. Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Res 1993;626:14–22; Carelli RM, Deadwyler SA. Dose-dependent transitions in nucleus accumbens cell firing and behavioral responding during cocaine self-administration sessions in rats. J Pharm Exp Ther 1996;277(1):385–393; Carelli RM, Deadwyler SA. Cellular mechanisms underlying reinforcement-related processing in the nucleus accumbens: electrophysiological studies in behaving animals. Pharmacol Biochem Behav 1997;57:(2)1–10). This transition in NA cell firing is cocaine dose-dependent and is accompanied by a shift from high response rates at the start of the session (‘Load-up’ behavior) to a lower steady rate of responding thereafter (termed ‘Session’ phase responding). Two experiments were conducted to examine further factors that may mediate this process. Experiment 1 examined the effects of pre-session, response-independent delivery of cocaine on behavioral/neural transitions. Results revealed an absence of Load-up responding and the immediate onset of NA patterned activity at the start of the session. Experiment 2 examined the involvement of dopamine D 1 versus D 2 receptors in mediating the corresponding behavioral/neural transitions. Animals were pretreated with either saline, the dopamine D 1 receptor antagonist SCH23390 (2.5–20 μg/kg, SC), or the dopamine D 2 receptor antagonist eticlopride (2.5–20 μg/kg, SC) 30 min prior to the cocaine (0.33 mg/inf) self-administration session. SCH23390 significantly increased the number of Load-up responses at 10 and 20 μg/kg and the number of responses following the Load-up phase (i.e. during the Session phase) at 5, 10, and 20 μg/kg. Eticlopride increased the number of Session responses (5, 10, and 20 μg/kg), but did not alter the number of Load-up responses at any dose tested. The transition in NA cell firing corresponded with the shift in behavioral responding and was delayed within the session following SCH23390 but not eticlopride pretreatment. These findings support the notion that cocaine self-administration sessions in rats consists of two distinct behavioral phases that are mediated by different neurophysiological mechanisms operating in the NA.

Methylenedioxymethamphetamine-induced inhibition of neuronal firing in the nucleus accumbens is mediated by both serotonin and dopamine

Methylenedioxymethamphetamine (MDMA) is a mood-altering, legally-restricted drug that has been reported to inhibit glutamate-evoked firing of cells in the nucleus accumbens. This study used extracellular recording combined with microiontophoresis to examine whether the inhibitory effect of MDMA on neuronal firing in the nucleus accumbens is mediated by serotonin and/or dopamine. Serotonin and serotonin agonists with relative selectivity for the receptor subtypes 5-HT 1A, 5-HT 1B, 5-HT 2A/2C and 5-HT 3 all significantly ( P < 0.01) inhibited glutamate-evoked firing of cells in the nucleus accumbens compared to the effects of an acidic saline control solution (30–60 nA, 60 s ejection currents for all). The current (dose)-dependent inhibition produced by the serotonin agonists did not differ significantly from the inhibition produced by MDMA except for the 5-HT 1A agonist 8-hydroxy-(2-di-n-propylamino)tetralin, which inhibited glutamate-evoked firing significantly more than MDMA or any of the other serotonin agonists. At the highest ejection current tested (60 nA, 60 s), glutamate-evoked firing was inhibited by MDMA in 94% of tested cells, by serotonin in 80% of tested cells and by the serotonin receptor subtype agonists in 95–100% of the tested cells. In addition to being mimicked by serotonin and serotonin agonists, MDMA-induced inhibition of glutamate-evoked firing in the nucleus accumbens was partially blocked by the serotonin antagonists ketanserin (100% of tested cells), methysergide (80% of tested cells), methiothepin (100% of tested cells) and WAY100135 (100% of tested cells). Furthermore, application of the serotonin uptake blocker fluoxetine, which prevents MDMA-induced serotonin release, also significantly attenuated MDMA-induced inhibition of glutamate-evoked firing in all of the cells that were tested. These observations suggest that MDMA-induced inhibition of nucleus accumbens cell firing is at least partially mediated by serotonin. Depletion of dopamine by pretreatment with the neurotoxin 6-hydroxydopamine and the synthesis inhibitor α-methyl- p-tyrosine blocked the inhibition of glutamate-evoked firing produced by MDMA applied with low ejection currents (30–40 nA, 60 s). However, this dopamine depletion had no effect on inhibition of glutamate-evoked firing produced by serotonin ejected with low or high currents (20–60 nA, 60 s). These results suggest that both dopamine release and an intermediate step of MDMA-induced serotonin release are necessary for the inhibitory effects of MDMA on neuronal excitability in the nucleus accumbens. The dopamine- and serotonin-mediated inhibitory effects of MDMA on glutamate-evoked firing of nucleus accumbens cells may play a role in the mood-altering properties of this increasingly popular drug. Copyright © 1996 IBRO. Published by Elsevier Science Ltd.