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Cocaine and the Changing Brain

The Brain Is Not The Same After Chronic Cocaine: Network-Level Changes In Basal Ganglia Circuits


Ann Graybiel, Ph.D.
Massachusetts Institute of Technology
Cambridge, MA

The ventral striatum, the ventral pallidum, and the dopaminergic and serotonergic inputs to these regions are thought to be critical to the expression of the behavioral and rewarding effects of cocaine. Such expression occurs under the modulating influence of complex mechanisms that involve cue stimuli and stimuli related to reward. One can think of such a modulating neurocircuit as consisting of the dorsally lying basal ganglia, the thalamus, and the frontal cortex. This circuit seems to act as a cognitive pattern generator (analogous to the motor pattern generators of the brainstem) that can evaluate the cognitive aspects of stimulation and eventually activate other brain circuits wired in with the ventral striatum and pallidum to produce behavioral activation. We know that the neurocircuitry of the dorsal striatum, with its dopamine inputs, falls into two broad categories connected with the striosome and the matrix compartments. We also know that this neurocircuitry is strongly linked to both the limbic system via the striosomes and the sensory-motor circuitry of the striatum via the matrix. An emphasis on the circuitry is instructive because chronic treatment with cocaine or amphetamine, in contrast to acute administration of these drugs, presents a compelling model of neuroplasticity: We believe different neural circuits become activated in response to cocaine as a result of chronic exposure to the drug. This presentation emphasizes data supporting this view for circuits involving the dorsal striatum.

The acute administration of cocaine or amphetamine induces striking increases in the expression of immediate early genes (IEGs) that serve as markers of neural activation. We assessed the activation of c-Fos, JunB, and ARC (a cytoplasmic gene related to the cytoskeleton). Acutely, cocaine activated many regions, particularly the matrix component of both the ventral and dorsal striatum. The degree of activation was not dose dependent, and we obtained similar results for a variety of genes. When we conducted precisely the same experiments using amphetamine instead of cocaine, we found that the pattern of activation was very different. We observed that, in the entire front end of the caudate-putamen, the predominant activation was in the striosomes, instead of in both compartments as had been seen after cocaine.

When cocaine is administered repeatedly, its effects are remarkably long-lasting. For example, in the rat, behavioral sensitization persists for as long as 87 days after a short period of repeated cocaine administration; it is thought that the central effects of repeated psychostimulant administration can essentially last a lifetime in an animal. Therefore, we asked what the effects of chronic cocaine treatment would be on gene induction in the striatum. We varied the number of days that rats were given cocaine and then probed for the expression of the IEGs. As others have found, after acute treatment with cocaine followed by a survival time of 2 or 18 hours, we could see the induction both of IEGs such as Fos and JunB and of chronic FRAs (Fos-related antigens). With 7 days of treatment (with 2-hour survival time withdrawal), we observed a downregulation of c-Fos and JunB and an upregulation of chronic FRAs, monitored by Western blot analysis.

When we analyzed the anatomic compartments in the caudate-putamen showing the gene activation, we were surprised to find that, after only 4 days of chronic cocaine treatment, a shift had begun to occur in the anatomic localization of the activation relative to that seen after acute cocaine or amphetamine treatment. We found that the IEG expression shifted toward a striosomal pattern, which is what we had seen with acute amphetamine treatment but not with acute cocaine treatment. We traced changes in levels of expression in these gene products over the course of 7 days, when Fos and JunB were clearly downregulated. But what happened during withdrawal of cocaine? We plotted the recovery of gene expression to a challenge by giving an injection of cocaine after different lengths of withdrawal and measuring how much IEG induction occurred. After a week of withdrawal that followed a week of repeated cocaine treatment, the previously suppressed c-FOS had recovered by at least half. There was a striking lateral and anterior pattern of patchiness of JunB and of FRAs in the striatum. Even more important, when the Fos response reappeared, it appeared heightened in the striosomes, with much less expressed in the matrix. These results suggested that we were seeing a change in the inducibility of genes and the expression of their gene products that had some real circuit pattern to it-possibly a very important aspect of the effects of chronic exposure to cocaine. Our results suggest that the brain circuits responding to the drug after chronic use are different from the circuits responding to the first acute dose.

Double-staining Fos-expressing cells for dynorphin showed that most responding (Fos-positive) cells were dynorphin-positive. These findings show an interesting correlation with those of Yasmin Hurd and Miles Herkenham, who published a single-case report of striatal prodynorphin mRNA in situ hybridization in a sudden-death cocaine user. They found a marked increase of prodynorphin in striosomes, relative to control levels. Thus, both in this (single) human case and in our animal studies, the results suggest that cocaine tends to activate the striosomal system after chronic use.

In primates, the only regions known to project selectively to striosomes are the anterior part of the anterior cingulate gyrus (or caudal medial prefrontal cortex) and the caudal orbital frontal cortex. These areas are strongly implicated in psychiatric disorders such as obsessive-compulsive disorder. These regions of the cortex are tightly linked to the amygdala, the hippocampus, and the mediodorsal thalamus by circuits involved in learning and memory and to limbic circuits that relate, for example, to the locomotor behavior mediated by the nucleus accumbens.

This neural circuit, linked to the striosomal subsystem within the striatum, in certain ways resembles the ventral tegmental area in that nondopaminergic cells appear to enjoy a special relationship with dopamine-containing neurons of the midbrain. These special striatal compartments may instruct the reward-related neurons of the nigral/ventral tegmental area complex. One of the things that may occur at the systems level by virtue of repeated exposure (of an animal or person) to cocaine is some shift in the normal balance between the context and evaluation of stimuli, heavily influenced by reward signals.

Dopamine and glutamate are key coplayers in many neuroplastic systems within the basal ganglia. Glutamatergic cortical afferents project to the striatum, perhaps bearing presynaptic dopamine receptors. They synapse on the spines of the medium spiny neurons. Many dopamine-containing afferents terminate on the very same spines that receive cortical inputs, suggesting that dopamine can fine-tune the inputs to the spiny neurons. Both dopamine and glutamate strongly affect plasticity in the corticostriatal system, perhaps by LTP and LTD. Therefore, we wanted to be able to look at the effects of dopamine on glutamate transmission in the striatum.

We stimulated the somatomotor cortex in monkeys and rats, looked for striatal activation of IEGs as a measurable population response, and found that activation of c-Fos and JunB occurred in the matrix, in projection neurons that express enkephalin. To look at the effects of dopamine on this corticostriatal system, we concentrated on studying cortical activation in the rat. We first developed a method for stimulating the cortex in awake rats. We implanted chronic wells over the somatomotor cortex and removed local GABAergic inhibition in the cortex by applying picrotoxin (or CSF, for the control studies) epidurally over the somatomotor cortex via the chronically implanted wells. We were able to activate striatal IEGs using this methodology.

To study the effects of dopamine transmission on this activation, we first systemically injected the broad-spectrum dopamine D2 antagonist haloperidol and then applied the local picrotoxin activation to the cortex. This combination produced a strong synergistic IEG activation, as if there were enhanced input signaling from the cortex when D2 receptors were blocked. Intrastriatal injections of the dopamine D2 receptor antagonist sulpiride also enhanced corticostriatal transmission as measured by gene induction. Thus, dopamine receptors inside the striatum (which are targets of cocaine) can have a dramatic effect on corticostriatal transmission. We further found that this activation of striatal IEGs was dependent on NMDA receptor activation, as it was inhibited by application of the antagonist MK801.

How would chronic cocaine exposure affect corticostriatal transmission? To study this issue, we administered cocaine or saline i.p. to rats for 1 week to downregulate Fos and then locally stimulated the cortex by epidural application of picrotoxin to see whether the cocaine exposure would influence cortically evoked gene expression in the striatum. In control experiments we found, as expected, that Fos remained downregulated after the combination of repeated cocaine plus systemic saline or after repeated cocaine plus acute cocaine. Repeated saline plus picrotoxin also produced the expected robust corticostriatal induction of Fos, but repeated cocaine led to a dramatic decrease in the ability of the corticostriatal stimulation to activate IEGs in the striatum in the repeated cocaine plus picrotoxin group. This experiment shows that it is possible to look at circuit-level changes that go beyond inducing genes merely by giving drug. We can use the cortical stimulation to probe the effects of cocaine on corticostriatal circuit function.

It is clear that cocaine is a major activator of basal ganglia loops and that cocaine can lead to massive neural activation at the circuit level. If we look at the full circuit diagram of outflow of the basal ganglia, including pathways leading to the neocortex, it is striking that the basal ganglia outflow leads not only to the somatomotor cortex or premotor cortex but also to the prefrontal cortex. This pattern of connectivity suggests that some of the circuit-level changes found after even a week of cocaine treatment could influence not only downstream circuits that involve locomotion and the development of stereotypy but also upstream circuits leading to what we have called cognitive pattern generators in the cortex. This may be one way in which cocaine can influence cognitive activity after chronic exposure to this drug.


Acknowledgment

This research was supported by National Institute on Drug Abuse Grant No. DA-08037.

Selected References

Berretta, S.; Parthasarathy, H.B.; and Graybiel, A.M. Local release of GABAergic inhibition in the motor cortex induces immediate-early gene expression in indirect pathway neurons of the striatum. J Neurosci 17:4752-4763, 1997.

Graybiel, A.M. Building action repertoires: Memory and learning functions of the basal ganglia. Curr Opin Neurobiol 5:733-741, 1995.

Graybiel, A.M. The basal ganglia and cognitive pattern generators. Schizophr Bull 23:459-469, 1997.

Hillegaart, V.; Berretta, S.; and Graybiel, A.M. Effects of chronic cocaine exposure on corticostriatal transmission in the rat. Soc Neurosci Abstr 22:410, 1996.

Hurd, Y.L., and Herkenham, M. Molecular alterations in the neostriatum of human cocaine addicts. Synapse 13:357-369, 1993.

Moratalla, R.; Elibol, B.; Vallejo, M.; and Graybiel, A.M. Network-level changes in expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal. Neuron 17:147-156, 1996.


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