Patricia H. Janak

Comparison of Mesocorticolimbic Neuronal Responses During Cocaine and Heroin Self-Administration in Freely Moving Rats

To compare neuronal activity within the mesocorticolimbic circuit during the self-administration of cocaine and heroin, multiple-channel single-unit recordings of spike activity within the rat medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) were obtained during the consecutive self-administration of cocaine and heroin within the same session. The variety of neuronal responses observed before the lever press are termed anticipatory responses, and those observed after the lever press are called post-drug infusion responses. For the total of the 110 mPFC and 111 NAc neurons recorded, 30–50% of neurons, depending on the individual sessions, had no alteration in spike activity in relation to either cocaine or heroin self-administration. Among the neurons exhibiting significant neuronal responses during a self-administration session, only a small portion (16–25%) of neurons responded similarly under both reinforcement conditions; the majority of neurons (75–84%) responded differently to cocaine and heroin self-administration as revealed by variations in both anticipatory and/or post-drug infusion responses. A detailed video analysis of specific movements to obtain the self-administration of both drugs provided evidence against the possibility that locomotive differences contributed to the observed differences in anticipatory responses. The overall mean activity of neurons recorded in mPFC and NAc measured across the duration of the session segment for either cocaine or heroin self-administration also was different for some neurons under the two reinforcement conditions. This study provides direct evidence that, in mPFC and NAc, heterogeneous neuronal circuits mediate cocaine and heroin self-administration and that distinct, but overlapping, subpopulations of neurons in these areas become active during operant responding for different reinforcers.

In Vivo Extracellular Recording of Striatal Neurons in the Awake Rat Following Unilateral 6-Hydroxydopamine Lesions

The purpose of this study was to further understand the functional effects of dopaminergic input to the dorsal striatum and to compare the effects of dopaminergic lesions in awake and anesthetized animals. We examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic bundle on the firing properties of dorsal striatal neurons in the awake freely moving rat using chronically implanted microwire electrode arrays. We recorded extracellular activity of striatal neurons under baseline conditions and following the systemic injection of apomorphine in awake and anesthetized subjects. Firing rates were higher in the hemisphere ipsilateral to the 6-OHDA lesion compared to rates of neurons from the contralateral unlesioned hemisphere. Striatal firing rates from sham and no-surgery control rats were, in general, higher than those from the contralateral unlesioned striatum of experimental subjects. Apomorphine (0.05 mg/kg, sc) normalized the differences in firing rates in lesioned animals by increasing firing of neurons within the contralateral unlesioned side, while simultaneously decreasing firing of neurons within the ipsilateral lesioned side. Mean firing rates were substantially higher in awake animals than in subjects anesthetized with chloral hydrate, perhaps reflecting anesthesia-induced decreases in excitatory input to striatal neurons. Chloral hydrate anesthesia decreased firing rates of neurons in the lesioned, unlesioned, and control striata to a similar degree, although absolute firing rates of neurons from the 6-OHDA-lesioned striata remained elevated over all other groups. Unilateral 6-OHDA lesions also altered the pattern of spike output in the awake animal as indicated by an increase in the number of bursts per minute following dopaminergic deafferentation. This and other burst parameters were altered by apomorphine. Our findings show that effects of dopaminergic deafferentation can be measured in the awake behaving animal; this model should prove useful for testing the behavioral and functional effects of experimental manipulations designed to reduce or reverse the effects of dopaminergic cell loss. In addition, these results suggest that the contralateral changes in striatal function which occur in the unilateral dopaminergic lesion model should be considered when evaluating experimental results.

Neuronal responses in prefrontal cortex and nucleus accumbens during heroin self-administration in freely moving rats

Chronic multi-channel single unit recordings of neuronal responses in prefrontal cortex (PFC) and nucleus accumbens (NAc) were made in 9 male Sprague Dawley rats to determine patterns of neuronal activity during heroin self-administration. Up to 32 neurons were recorded simultaneously in these two brain regions while rats lever pressed on a continuous reinforcement schedule for intravenous infusion of heroin (30 microg/kg/infusion). The variety of neuronal responses observed before and after each self-administered heroin infusion can be classified according to the following categories: (1) neurons that increased or (2) decreased their activity immediately before the lever press; (3) neurons that increased or (4) decreased their activity after the heroin infusion; and, (5) neurons that did not alter their activity either before or after the lever press for heroin infusion. The majority (69% in the PFC and 65% in the NAc) of neurons sampled fell into this last category of no change, indicating that a selected fraction becomes active during this specific task. In general, NAc neurons displayed more post-heroin responses than PFC neurons while the proportion of neurons showing responses before the lever press was similar in the mPFC and the NAc. This initial description of the responses of PFC and NAc neurons during heroin self-administration suggests that the neuronal circuit of the mesocorticolimbic system is involved in heroin self-administration. This circuit appears to contribute both to the initiation of drug-seeking behavior (pre-lever press phasic neuronal responses), as well as the action of heroin infusion itself (post-infusion phasic neuronal responses) by activation of different subsets of neurons.

Neuronal spike activity in the nucleus accumbens of behaving rats during ethanol self-administration

Many lines of evidence support the importance of the nucleus accumbens (NAC) for ethanol-reinforced behavior. The nature of the neuronal activity that occurs in this region during ethanol self-administration is not known. We recorded from ensembles of single-units primarily located within the shell of the NAC during operant responding for oral ethanol solutions by well-trained rats. Of 90 units recorded from seven sessions from seven rats, 41 (46%) did not exhibit significant changes in relation to the experimental events. Of the 49 units (54%) that did exhibit significant phasic changes, alterations in firing rate occurred in relation to the following experimental events: operant response (63%), tone stimulus (20%), and ethanol delivery (63%). In addition, changes in spike activity during the intervals between the three experimental events were noted in 33% of the units. Most units (55% of responsive units) responded to multiple experimental events. Thus different but overlapping populations of neurons in the NAC represent each event that occurs along the temporal dimension of a single trial performed to obtain ethanol reward. The data suggest that the NAC plays a crucial role in linking together conditioned and unconditioned internal and external stimuli with motor plans to allow for ethanol-seeking behavior to occur.

Mesolimbic Neuronal Activity across Behavioral States

ABSTRACT: A goal of neurophysiology of the mesolimbic system is to determine the activity patterns within the regions in the prefrontal cortex, ventral neostriatum, and amygdala that regulate behavioral patterns to seek rewards. A new technology has been introduced in which arrays of microwires are implanted in different brain regions while activity patterns of ensembles of neurons are recorded for long periods of time during freely moving behaviors. Multichannel instrumentation and software is used for data acquisition and analysis. An initial hypothesis was that neural signals would be encountered in the nucleus accumbens and associated regions specifically related to reward. However, an initial study of neural activity and behavioral patterns during a simple lever press for intravenous cocaine (1 mg/kg) revealed that phasic excitatory or inhibitory neural activity patterns often appear prior to the reward phase. Individual neurons throughout the mesolimbic system appear to code information specific to sensory and motor events, tones, or lever presses in the chain of tasks leading to all rewards so far studied. Different spatial temporal patterns also appear within the same neural populations, as reward is changed from injected cocaine to heroin, from ingested pure water to ethanol in water or sucrose. Overall, patterns of activity for each neuron are found to shift dynamically during the operant task as changes are made in the target reward. Significant shifts in activity of mesolimbic neurons that are unrelated to specific sensory‐motor events also appear during complex sessions, such as during a bout of ethanol consumption to reach satiation or during progressive ratio tasks with increasing difficulty. An emerging hypothesis is that some candidate neural elements in the mesolimbic system code the anticipated reward, whereas others serve internal logic functions of motivation that mediate extinction or resumption of specific goal‐directed behaviors.

Activity patterns in mesolimbic regions in rats during operant tasks for reward

Publisher Summary This chapter describes the existence of a rich diversity of coding in prefrontal cortex related to reward. These include: (1) subsets of neurons that generate activity specific for the task sequence leading to reward, (2) selectivity for the reward modality, (3) cognitive signals corresponding to position, task segment, and outcome, with behavior governed by associative rules; and (4) embedded timing mechanisms. The ingredients of elemental operations ascribed to primate brain in the view appear in modified form in rat when appropriate behavioral paradigms are employed. The chapter discusses that some components of frontal cortical-striatal information flow may be used solely as learning signals functioning mainly to form associations in regions of cortex responsible for future behavior. One conjecture is that the neural machinery responsible for timing behavior may play a critical role in assigning a possible significance to the events, which have preceded a reward, such that a process of strengthening an association can begin. Investigation of these issues will constitute a major experimental task for the future.

Rapid decay of cocaine-induced behavioral sensitization of locomotor behavior

Sprague Dawley rats received three daily intraperitoneal (i.p.) injections of saline or 15 mg/kg cocaine. Following an interval of 2, 5 or 8 days, the behavioral response of separate groups of rats to a challenge injection of cocaine (15 mg/kg) was tested in an open field. After repeated cocaine (15 mg/kg) injection, movement in both the vertical and horizontal plane was increased in cocaine-treated rats 2, but not 5 or 8, days after treatment as compared to saline-treated subjects. In addition, behavioral ratings along an ordinal scale designed to reflect increases in behavioral activation were increased in cocaine-treated rats 2, but not 5 or 8, days after treatment. These results stand in contrast to other reports demonstrating long-lasting neural and behavioral changes after similar treatment regimens. Taken together, the results suggest that a treatment regimen of 15 mg/kg per day of cocaine for 3 days produces behavioral sensitization of locomotor behavior; however, this cocaine-induced behavioral sensitization does not persist beyond a few (< 5) days after repeated cocaine treatment, using the current experimental parameters.