The role of accumbal hypoactivity in cocaine addiction.

Cocaine-induced hypoactivity of the nucleus accumbens (NAC) is hypothesized to contribute to cocaine addiction. There are two important questions related to this hypothesis. First, cocaine addiction is characterized by an increase in drug-directed behavior and a simultaneous weakening of other motivated behaviors. However, the NAC contributes to both drug- and nondrug-directed behavior. Moreover, the nature of the contributions is similar and associated predominantly with excitatory phasic firing patterns. Given these observations, it is not clear how hypoactivity of NAC neurons might contribute to the behaviors that characterize cocaine addiction. Second, various types of investigations have documented neurochemical and molecular adaptations that could underlie NAC hypoactivity. However, there is also evidence of other adaptations in the NAC and in NAC afferents, which are expected to have an excitatory influence on NAC neural activity. In the present review, we will briefly overview these issues. We will also describe a hypothesis and related empirical evidence that may contribute to answering these questions. Further investigation of the issues and the hypothesis may contribute to a better understanding of the neuroadaptations that contribute to cocaine addiction.

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.

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.

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

Cocaine's 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.

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.

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

To study the striatal role in amphetamine's 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 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 level 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 level 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.

Drug discrimination training with low doses: maintenance of discriminative control.

Procedures are reported that maintain control by the drug cue during and after drug discrimination training with lower doses that yield predominantly vehicle-appropriate choices. Twelve pigeons were trained to discriminate chlordiazepoxide (CDP) from saline using two-key (drug vs. vehicle) drug discrimination procedures. Intermixed within each block of 30 sessions were nine sessions of training with 8.0 mg/kg CDP, nine with one of seven lower training doses (4.0, 2.8, 2.0, 1.4, 1.0, 0.7, or 0.5 mg/kg CDP), and 12 with saline. The lower training dose was decreased across blocks. The three lowest training doses (1.0, 0.7, and 0.5 mg/kg CDP) yielded predominantly saline-appropriate choices but had no effect on discrimination of 8.0 mg/kg CDP or saline. Three doses (2.0, 1.4, and 1.0 mg/kg CDP) were retrained, and each yielded percentages of drug-appropriate choices nearly identical to those obtained during previous training. This drug discrimination procedure maintains control by the drug cue during and after training with vehicle-like doses of the training drug and may allow for repeated assessment of effects of low training doses.

Representation of the body in the lateral striatum of the freely moving rat: single neurons related to licking.

This study examined the relationship of single-neuron activity (n = 739), recorded from the lateral striatum of freely moving rats, to oral movements involved in licking single drops of liquid. Certain neurons (n = 74) fired specifically in relation to licking. Their firing rates increased during licking, but remained near zero in the absence of licking, throughout a full sensorimotor examination of the remainder of the orofacial area and all other body parts. Another category of neurons (n = 17) fired during licking but also fired in the absence of licking, during one or more other orofacial sensorimotor function(s). Lick-related neurons were located in the lateral striatum, throughout the entire anterior-posterior range studied (from +1.5 to -1.5 mm anterior-posterior, A-P, bregma = 0). Summed over the full A-P range, they were located significantly ventral to representations of the trunk and limbs. These findings extend the characterization of the somatotopic organization exhibited by lateral striatal neurons in the rat, to include representation of oral functions, consistent with converging evidence regarding the functional organization of the striatum.