Laura L. Peoples

Phasic Firing of Single Neurons in the Rat Nucleus Accumbens Correlated with the Timing of Intravenous Cocaine Self-Administration

To examine potential neural mechanisms involved in cocaine self-administration, the activity of single neurons in the nucleus accumbens of rats was recorded during intravenous cocaine self-administration. Lever pressing was reinforced according to a fixed-ratio 1 schedule. On a time base comparable to the interinfusion interval, half the neurons exhibited phasic firing patterns time locked to the cocaine reinforced lever press. For almost all neurons, this pattern consisted of a change in firing rate postpress, typically a decrease, followed by a reversal of that change. The postpress change was closely related to the lever press. Typically, it began within the first 0.2 min postpress and culminated within the first 1.0 min postpress. For a small portion of responsive neurons, the reversal of the postpress change was punctate and occurred within 1–3 min of either the last lever press or the next lever press so that firing was stable during much of the interinfusion interval. For the majority of neurons, the reversal was progressive; it began within 2 min after the previous lever press, and it was not complete until the last 0.1–2.0 min before the next lever press. The duration of this progressive reversal, but not of the postpress change, was positively correlated with the interinfusion interval. Thus, in addition to exhibiting changes in firing related to the occurrence of self-infusion, the majority of neurons also exhibited progressive changes in firing related to the spacing of infusions. In a structure that has been shown to be necessary for cocaine self-administration, such a firing pattern is a likely neurophysiological component of the mechanism that transduces declining drug levels into increased drug-related appetitive behavior. It is, thus, a neural mechanism that may contribute to compulsive drug-maintained drug taking.

Operant behavior during sessions of intravenous cocaine infusion is necessary and sufficient for phasic firing of single nucleus accumbens neurons

The activity of individual accumbens neurons in rats was recorded in relation to intravenous cocaine infusions that were either response (i.e., lever press) contingent or response non-contingent. Neural firing was additionally recorded in relation to non-reinforced lever presses. Comparisons of firing under the three conditions showed that operant behavior was necessary and sufficient for preinfusion firing to occur. Surprisingly, the same was true, in many cases, for firing that occurred during the infusion. For other neurons, firing during the infusion was unrelated to operant behavior and possibly related to infusion stimuli. The relationship to operant behavior exhibited by the majority of NAcc neurons is consistent with previous studies that demonstrated a necessary relationship between NAcc neurons and cocaine reinforced operant behavior.

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.

Neurons in accumbens subterritories of the rat: Phasic firing time-locked within seconds of intravenous cocaine self-infusion

Individual neurons were recorded extracellularly in the nucleus accumbens (NAcc) of rats during cocaine self-administration sessions. NAcc neurons exhibited a variety of phasic changes in firing rate within the few seconds before and/or after cocaine self-infusion. Analysis of the topographical distribution of the phasic firing patterns showed that there were no differences between NAcc subterritories in the nature of phasic changes in firing exhibited by neurons in relation to cocaine self-infusion. However, the prevalence of phasic firing was lower in the border regions of the caudal shell and within the caudal shell itself relative to the remainder of the NAcc.

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.

Low-dose amphetamine elevates movement-related firing of rat striatal neurons.

To study the striatal role in amphetamines stimulant effects on motor behavior, single neurons were recorded in the dorsolateral striatum of unrestrained rats before and after amphetamine injection (0.5 or 1.0 mg/kg, i.p.). Comparisons of firing were made between similar motor behaviors before and after injection. Mean locomotor firing rates increased 5% to 276% within 30 min after injection and reversed within 2 h. Firing related to specific head- or forelimb-movements, which were similar in all measured parameters before and after injection, was elevated several hundred percent after injection and then reversed, the time course paralleling that of the stimulant effect on these movements. Elevation of movement-related striatal firing rates by low doses of the psychomotor stimulant is in line with established increases in firing rate normally observed for striatal neurons related to motor behavior.

Phasic Accumbal Firing May Contribute to the Regulation of Drug Taking during Intravenous Cocaine Self-administration Sessions

Recent studies have applied chronic extracellular recording techniques to the intravenous cocaine self-administration paradigm to investigate the neurophysiological mechanisms that contribute to drug taking (e.g., Refs. 1–4). Data of one study suggest that a large percentage of nucleus accumbens (NAcc) neurons exhibit a change in firing during limited-access (fixed-ratio 1) self-administration sessions that is both synchronized to the self-infusion behavior and has a time course comparable to the interval that elapses between successive self-infusions. A firing pattern with such a time course may be involved in the regulation of the self-infusion behavior (cf. Ref. 4). The focus of the present study was to further characterize neurons that exhibit this firing pattern.

Firing rate dependent effect of cocaine on single neurons of the rat lateral striatum

Cocaines effects on striatal neurons related to vertical head movement were studied during a task requiring vertical head movement. The proportion of long-distance head movements was increased by low doses but decreased by the high dose, which produced stereotypic head bobbing. At all doses, normally low firing rates related to movement were elevated to a greater degree than were normally high firing rates. At the high dose, normally high firing rates were strongly suppressed, a restriction which may contribute to the decreased behavioral diversity characteristic of stereotypy.

Amphetamine Exposure Enhances Accumbal Responses to Reward-Predictive Stimuli in a Pavlovian Conditioned Approach Task

Acute and repeated exposure to psychostimulants such as amphetamine enhances the effects of pavlovian conditioned stimuli on conditioned behavior. It is hypothesized that amphetamine facilitates conditioned stimulus (CS) effects by selectively enhancing accumbal neuronal responses to stimuli. To test this hypothesis, rats were trained to discriminate between two pavlovian stimuli. One stimulus (i.e., CS+) was paired with sucrose delivery [i.e., unconditioned stimulus (US)], and the other stimulus (i.e., CS−) was paired with the absence of sucrose. Animals developed a conditioned approach response that occurred during the CS+ but not during the CS−. We tested the effect of different doses of amphetamine (0, 0.25, 0.5, or 1.0 mg/kg) on this conditioned approach behavior as well as on accumbal neuronal responses time locked to the CS+, the CS−, and the US. Acute amphetamine exposure increased conditioned approach behavior during the CS+, but not during the CS−. This change in behavior was associated with a selective increase in the magnitude of accumbal responses during the CS+. Repeated amphetamine administration followed by a drug-free period and reexposure did not affect the conditioned behavior, but increased accumbal responses to the CS+. These findings support the hypothesis that amphetamine exposure enhances behavioral responses to pavlovian conditioned stimuli by amplifying accumbal responses to those stimuli.

Abstinence from Cocaine and Sucrose Self-Administration Reveals Altered Mesocorticolimbic Circuit Connectivity by Resting State MRI

Previous preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of natural rewards. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period. These procedures are known to induce behavioral changes and neuroadaptations. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic (PrL) cortex and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, indicating potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross-sectional human studies may reflect the consequence of rather a predispositional predecessor to their dependence.