Mark O. West

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.

Changes in activity of the striatum during formation of a motor habit

To examine experience‐dependent plasticity of striatal neurons during habit learning in awake, freely moving animals, single neurons in the dorsolateral striatum (54 neurons related specifically to vertical head movement and 14 unresponsive neurons, i.e. not related to any body movement) were recorded and tracked off‐line to assess changes in firing rate over sessions as performance of instrumental head movement became automatic and habitual. Rats were trained to emit operant vertical head movements that triggered water delivery for 14 sessions (2 h per session, one session per day). Rats significantly increased the number and efficiency of head movements over sessions until reaching asymptotic behaviour. Habit formation was indicated by significantly higher levels of instrumental responding exhibited by rats during a late, relative to an early, session in which the reward was devalued. As head movements became habitual across sessions, most head movement‐related neurons (89%) exhibited decreased firing rate, while a small population (11%) exhibited increased or maintained firing rate. The rate of decrease in firing by the majority correlated with the rate of improvement in movement efficiency over sessions. All unresponsive neurons, though not apparently related to movement, exhibited decreased firing rate over sessions. Our findings suggest that, during habit learning, the striatum may shift from facilitating acquisition of efficient movement with a large population of neurons to modulating or maintaining habitual movement with stronger firing of fewer movement‐related neurons.

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.

Anesthetics Eliminate Somatosensory-Evoked Discharges of Neurons in the Somatotopically Organized Sensorimotor Striatum of the Rat

The somatotopic organization of the lateral striatum has been demonstrated by anatomical studies of corticostriatal projections from somatosensory and motor cortices and by single-cell recordings in awake animals. The functional organization in the rat, characterized thus far in the freely moving rat preparation, could be mapped more precisely if a stereotaxic, and possibly an anesthetized, preparation could be used. Because striatal discharges evoked by innocuous somatosensory stimulation are used in mapping, this study tested whether such discharges can be observed during anesthesia, encouraged by responsiveness during anesthesia in somatosensory cortical layers projecting to the striatum. Electrode tracks through lateral striatum of anesthetized rats (pentobarbital or ketamine) revealed spontaneously discharging neurons but no discharges evoked by somatosensory examination (passive manipulation and cutaneous stimulation of 14 body parts). Similar tracks in chronically implanted rats showed evoked firing at numerous sites during wakefulness but not during anesthesia (pentobarbital or urethane). Comparisons of the activity of individual neurons between wakefulness and anesthesia showed that pentobarbital, ketamine, chloral hydrate, urethane, or metofane eliminated evoked firing and suppressed spontaneous firing. Recovery time was greater for neural than for behavioral measures. Thus, mapping as proposed is ruled out, and more importantly, the data show that somatotopically organized lateral striatal neurons stop discharging in response to natural stimulation during anesthesia. Available data indicate they do not reach threshold in response to depolarizations produced by glutamatergic corticostriatal synaptic transmission projected from the somatosensory cortex. These data and demonstrations of anesthetic-induced imbalances in most striatal neurotransmitters emphasize that many results regarding striatal physiology and pharmacology during anesthesia cannot be extrapolated to behavioral conditions, thus indicating the need for more empirical testing in conscious animals.

Distributions of single neurons related to body parts in the lateral striatum of the rat

Single unit recordings in awake, unrestrained rats confirmed and extended previous findings regarding the functional organization of the lateral striatum. In individual electrode tracks, clusters of neurons related functionally to an individual body part were interspersed with clusters related to other body parts. The overlapping distributions of these neurons were arranged somatotopically in the dorsal-ventral dimension. The distribution of hind limb neurons was most dorsal and showed no overlap with the distribution of neurons related to oral sensorimotor activity. Oral representation was most ventral of all body parts and extended to the ventral boundary of the lateral striatum. Representations of other body parts overlapped with that of the hind limb dorsally but differed primarily in the degree to which they extended ventrally. Forelimb representation extended farther ventrally than that of the hind limb, but did not extend as far ventrally as that of the neck. Despite substantial overlap in the dorsal-to-ventral order of hind limb-forelimb-neck-face representations, single neurons showed no evidence of overlap, or convergence, of body parts. These data provide a more complete description of the dorsal-ventral somatotopy in the lateral striatum of the rat, which as shown previously, extends throughout the medial-lateral, and much of the anterior-posterior dimensions of the lateral striatum.

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.

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.

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.