29 September 2006. Amphetamine “psychosis,” typically brought on by repeated exposure to the drug, mimics many aspects of the psychosis of untreated schizophrenia. Much of the research into the biological substrates of this psychosis has focused on subcortical nuclei, but there is also evidence for amphetamine-induced changes in cortical areas, particularly prefrontal cortex (PFC).
Two recent papers explore the cortical changes brought on by repeated amphetamine administration in animal models: in a paper published online August 16, 2006, in Neuropsychopharmacology, Lynn Selemon and colleagues at Yale University report that several years after a series of exposures to amphetamine, pyramidal cells in the PFC of monkeys have altered dendritic morphologies, specifically changes that suggest atrophy of the dendritic arbors, indicating that these are permanent brain changes wrought by the drug.
Houman Homayoun and Bita Moghaddam of the University of Pittsburgh, writing in the August 2 issue of the Journal of Neuroscience, report that the electrophysiological characteristics of PFC neurons begin to change after just a few doses of the drug, and that the amphetamine exposure has opposite effects in two subregions of prefrontal cortex—a progressive hyperactivation of orbitofrontal cortex and hypoactivation of medial prefrontal cortex.
Amphetamine psychosis has been proposed as a model for some features of schizophrenia, particularly the positive symptoms such as hallucinations (Snyder, 1973). It has generally been argued that initial physiologic changes in subcortical midbrain dopaminergic neurons and their targets in the striatum sensitize the neural networks involved so that later exposures can induce psychosis. This model of amphetamine sensitization has also been adopted as a paradigm for researchers interested in the addictive powers of drugs of abuse.
The Yale group founded by the late Patricia Goldman-Rakic, whose work has been carried on by Selemon and others, has argued for an important role of prefrontal cortex in mediating the changes in behavior that occur following repeated amphetamine exposure, whether in humans or animals. Working in monkeys, they found that amphetamine generates both psychotic-like behaviors and deficits in working memory, the latter a function in which prefrontal cortex plays a critical role.
In their current paper, Selemon and colleagues revisited brain tissue from monkeys that had been part of the earlier behavioral experiments. The animals had received low doses of the drug for 6 or 12 weeks, followed by challenge doses during experiments. Three years after these exposures, the authors report, Golgi impregnation revealed reductions in overall dendritic branching in PFC, in peak spine density in layers II and superficial III, as well as in the distance from the cell body to the region of peak spine density.
This evidence parallels findings in schizophrenia of reductions in the complexity of dendritic arbors in prefrontal cortex in schizophrenia patients. However, they differ from findings in rodents, in which Terry Robinson and colleagues at the University of Michigan have reported that repeated amphetamine exposure leads to increases in measures of dendritic “health,” such as length, branching, or spine density. In addition to possible methodologic differences, Selemon and colleagues point out that the rat morphologic studies were done several months, rather than years, after the amphetamine exposure. “[I]t is possible that the rodent findings represent the early changes in morphology that occur in response to a sensitizing regimen of AMPH exposure while those reported here represent the long-term consequences to a prolonged and seemingly permanent state of dopamine dysregulation in the prefrontal cortex,” they write.
The chicken or the egg?
Which comes first as a result of amphetamine administration— restructuring in subcortical nuclei or in cortical areas? Does one necessarily precede or influence the other? In their recent paper, Homayoun and Moghaddam report that cortical changes occur very early in a paradigm of amphetamine sensitization, suggesting that these are not necessarily sequelae of subcortical changes. The authors report that the amphetamine model produces hypofunction of the medial prefrontal cortex (mPFC), and hyperfunction of orbitofrontal cortex (OFC), findings which, they point out, parallel imaging data from patients with schizophrenia (Ragland et al., 2004).
The authors recorded single-cell activity from mPFC and OFC in conscious, behaving rats. In the first set of experiments, the animals were moving about their home cages, with no particular tasks to attend to. Using an array of implanted electrodes, the authors recorded from a number of neurons at a time, presumed to be pyramidal cells based on their firing patterns. In both mPFC and OFC, the researchers found neurons that are excited by or inhibited by amphetamine, as indicated by changes in firing rate. Neurons in both areas became more responsive to amphetamine during the course of the 5-day (2 mg/kg i.p.) sensitization protocol, and remained more responsive for at least a month after amphetamine exposure. However, there were region-specific differences. Firing rates and clusters of action potentials, or “bursting,” generally decreased in mPFC, but increased in OFC. “This is significant because both the rate and pattern of single-unit firing in the PFC are critical for the maintenance of cognitive functions and reinforcement assessment that are served by these regions,” the authors write.
Of course, idling in their home cage may not particularly tax the rats’ PFC neurons, so Homayoun and Moghaddam recorded from animals that were engaged in an operant responding task where they had to do some thinking and keep track of which hole to nose poke in order to receive a food reward. With increasing amphetamine exposure, the rats perform more poorly, and the researchers report electrophysiological findings consistent with the first experiment—growing mPFC inhibition mirrored by OFC excitation paralleling the impairment in the learning task.
“Given the evidence establishing that mPFC neurons sustain cognitive functions, such as reasoning and decision making, and OFC neurons encode the salient value of rewards, the present data may suggest that even limited exposure to amphetamine delivers a ‘double whammy’ that may be critical for development of addiction or psychosis: it reduces the influence of mPFC on behavior at the same [time] that it exaggerates the salient value of a rewarding experience,” conclude the authors.—Hakon Heimer.
Homayoun H, Moghaddam B. Progression of cellular adaptations in medial prefrontal and orbitofrontal cortex in response to repeated amphetamine. J Neurosci. 2006 Aug 2;26(31):8025-39. Abstract
Selemon LD, Begovic A, Goldman-Rakic PS, Castner SA. Amphetamine Sensitization Alters Dendritic Morphology in Prefrontal Cortical Pyramidal Neurons in the Non-Human Primate. Neuropsychopharmacology. 2006 Aug 16; [Epub ahead of print] Abstract
Q&A with Bita Moghaddam. SRF questions by Hakon Heimer.
Q: Leaving schizophrenia aside for the moment, what are the most important findings and take-home messages of your paper in terms of the amphetamine sensitization model.
A: It suggests that the influence of medial prefrontal cortex on behavior has diminished at the same time as the influence of the orbitofrontal cortex on behavior has been increased. So what are the implications of that? Well, we know that medial prefrontal cortex controls executive functions like decision-making and planning, so if those functions have been disrupted, then the ability to make decisions, or perform other cognitive functions that are regulated by prefrontal cortex like working memory are compromised. On the other hand, the orbitofrontal cortex is responsible for putting salient values on stimuli, so by becoming overactive, or by possibly having more of a control over behavior, it may be exaggerating the value of what’s immediately apparent.
Q: How do these results bear on the chicken-and-egg question: are amphetamine-induced changes likely to be subcortical or cortical first, or simultaneous? Is that a useful way to think about this question?
A: That is a good question, but I think, frankly, it doesn’t matter in terms of function. What amphetamine is essentially doing is releasing monoamines all over the brain, and although a lot of dopamine is being released in the striatum, serotonin, norepinephrine, as well as dopamine are also being released in the prefrontal cortex. But let’s, for the sake of argument, assume that initially it is the striatum that’s being disrupted. The bottom line is that it’s resulting in cortical dysfunction. So for schizophrenia, you could argue: okay, regardless of whether the cortical dysfunction is primary or secondary to the striatal dysfunction, this is a model that is producing prefrontal cortical hypofunction.
Our data suggest that, actually, prefrontal cortex changes may precede striatal changes, only because we see plasticity after a single injection, whereas most of the published work on subcortical systems report plasticity after several days of treatment.
Q: Getting to schizophrenia, you jokingly said in an e-mail that the repeated amphetamine model had been hijacked by the drug abuse crowd as the model of drug-induced plasticity that leads to addiction. Could you just say a little bit about the value of the amphetamine model for psychosis research?
A: Its relevance to addiction is highly theoretical, whereas its relevance to schizophrenia is backed up by well-documented clinical findings. It is a well-characterized model of psychosis and has excellent predictive validity for antipsychotic drugs. Also, recent work, including our paper, shows that it has construct validity in terms of prefrontal cortical deficits. It is a model that, I would argue, has advantages over the PCP model and other pharmacological models, the first being its predictive validity because the amphetamine psychosis is treated with antipsychotic drugs. A PCP-induced psychosis is not typically treated with antipsychotic drugs. I think the field has been dismissing the amphetamine model because people assume that it’s only a model of psychosis …it’s not really modeling affective and cognitive deficits in schizophrenia. But the work that Pat Goldman-Rakic’s lab and Lynn Selemon did shows that actually, no, there are indeed cognitive deficits. We have also seen sustained working memory deficits in rats after amphetamine, so this model is clearly associated with cognitive deficits. Addiction literature also shows that stimulant abusers have working memory and cognitive deficits. In short, I think the assumption that the amphetamine model does not model cognitive or “cortical” deficits related to schizophrenia is unfounded.
In terms of negative symptoms, our data showing changes in orbitofrontal cortex after amphetamine is interesting. Orbitofrontal cortex has a great deal of influence on emotional processing, suggesting that the circuits that control affective regulation and possibly negative symptoms are also profoundly disrupted by chronic amphetamine.
Q: The operant conditioning paradigm that you use—can you draw any link from that very simple task to schizophrenia, or is that too much of a stretch.
A: It’s too much of a stretch.
Q: So the value of this part of the study is demonstrating changes in different states.
A: Yes. To quote a colleague, “How do you know that it is the drug and not behavior that is affecting cortical neurons?” Amphetamine makes animals hyperactive so the concern was that locomotion or the “behavioral state” may lead to secondary changes in cortical neurons. To address this, we tested animals in two different behavioral states, while they were doing nothing in their home cage and while they were in a Skinner box doing an instrumental responding task.
Q: How do you think this is relevant to schizophrenia?
A: I am excited about the coexistence of prefrontal cortex hypoactivity and orbitotemporal area hyperactivity! It’s consistent with the few imaging studies in patients with schizophrenia that have actually looked at both regions and see a similar diverging pattern of prefrontal cortex hyperactivation and orbitoprefrontal overactivation: an example is an American Journal of Psychiatry paper from Raquel Gur’s group (Ragland et al., 2004). I also think our findings provide a cellular basis for why there are these sustained cognitive disruptions in the amphetamine models that are, again, relevant to schizophrenia. With something like the PCP or ketamine models, you don’t see a prefrontal cortex hypofunction. You see just an exaggerated discharge of all activity, which is clearly impairing prefrontal function, but you don’t see hypoactivity at the neuronal level. It is important that in animals that were doing a task, the change in the pattern of activation—medial prefrontal neurons becoming less active, orbitofrontal neurons becoming more active—was selective to those neurons that were encoding goal-directed behavior. And again, I think in that sense, this does have relevance to both cognitive and negative symptoms of schizophrenia. You have a model that’s selectively disrupting the pattern of activity of those neurons that may play a role in planning for goal-directed and reward-related behavior.
Q: In what way is the drug abuse research of potential interest to people studying schizophrenia psychosis? How do you see the links between these two literatures?
A: For basic science people, they are highly linked. We read each other’s papers, because we’re very much studying the same pathways. Clinically speaking, comorbidity is a huge issue. Nearly 80 percent of patients with schizophrenia smoke. Incidence of abuse of other drugs is 60-80 percent, depending on whose stats you look at. I know the schizophrenia field is becoming very interested in comorbidity. I think we can learn a lot about addiction and schizophrenia by studying mechanisms that are common in both disorders. It is great that in the past few years the addiction literature has been paying a lot of attention to cognition, mostly because the rates of abstinence, or failure to remain abstinent, are very much dependent on cognitive functioning. Many in the drug abuse field are thinking that addiction is a cortical disease, so they are finding themselves reading the schizophrenia/affective disorder literature. I think the literatures are highly related. I know at the basic level, a lot of us go to each other’s meetings and read each other’s papers.