Chronic phencyclidine administration remains the single best model for human psychosis. The crucial paper by Jentsch and colleagues (Jentsch et al., 1997), identifies every element needed for a satisfactory representation of the schizophrenia syndrome.
Though acute NMDA receptor antagonists induce hypermetabolism, prolonged phencyclidine induces a hypometabolic state (Wu et al., 1991; Tamminga et al., 1995) accompanied by severe dopaminergic disturbances (Aalto et al., 2005; Narendran et al., 2005).
Moghaddam's comments emphasize that there are multiple routes to psychosis, and these may converge on cortical glutamatergic/dopaminergic interactions (
Moghaddam's comments emphasize that there are multiple routes to psychosis, and these may converge on cortical glutamatergic/dopaminergic interactions (Narendran et al., 2005). But the numerous studies by her own group and those of Farber, Krystal, Vollenweider, Newcomer, Rowland, Tamminga, and Lahti suggest that there is much to be learned from additional work on the NMDA receptor antagonist preparation.
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Excellent overview. My daughter has been addicted to meth for over twenty years and I AM seeing her inability to make constructive, long-term decisions, even when "clean." Our oldest son has schizophrenia, and although he is highly functioning, shows some of the impairment(s) my daughter exhibits.View all comments by Elizabeth Ryan
Moghaddam is correct in arguing that long-term intake of, or exposure to, amphetamine-like drugs produces a spectrum of changes in cortical and subcortical function that underlie cognitive and affective abnormalities that relate to the abuse potential of the drugs, as well as the associated drug-induced psychotic symptoms. This may be particularly true for methamphetamine (Yui et al., 1999). Indeed, Jane Taylor and I proposed 7 years ago now (Jentsch and Taylor, 1999) that dysregulation of frontal cortical function is a common feature of long-term exposure to drugs of abuse; today, this is a phenomenon that is generally accepted as contributing directly to the addictive process (London et al., 2000; Everitt et al., 2001;
Moghaddam is correct in arguing that long-term intake of, or exposure to, amphetamine-like drugs produces a spectrum of changes in cortical and subcortical function that underlie cognitive and affective abnormalities that relate to the abuse potential of the drugs, as well as the associated drug-induced psychotic symptoms. This may be particularly true for methamphetamine (Yui et al., 1999). Indeed, Jane Taylor and I proposed 7 years ago now (Jentsch and Taylor, 1999) that dysregulation of frontal cortical function is a common feature of long-term exposure to drugs of abuse; today, this is a phenomenon that is generally accepted as contributing directly to the addictive process (London et al., 2000; Everitt et al., 2001; Robinson and Berridge, 2003; Goldstein and Volkow, 2002; Lubman et al., 2004). In that sense, the concept that amphetamine alters frontal lobe function in important ways relevant to both addictive and psychotic disorders is hardly new.
A separate question touched upon in the article and subsequent discussion is whether either amphetamine or phencyclidine represents a more informative or valid model for schizophrenia and/or its symptoms than the other.
For nearly 60 years, investigators have used amphetamine-like and phencyclidine-like drugs to simulate psychopathological states in human beings and animals that correspond (to varying degrees) with sequelae of schizophrenia. One clear issue that has emerged from the 6 decades of research is that these two drugs produce some similar and some different effects on behavior, which is not surprising, owing to their distinctive pharmacologic and neurochemical mechanisms of action. What is unfortunate is that the apparent differences have led to a history of conflict over which represents the better model for psychotic disorders. In opposition to the overly dogmatic arguments of those in favor of one approach or the other, I argue that we should focus on the commonalities of the action of these two classes of agents to find the mechanisms that will ultimately have the broadest implications for understanding schizophrenia.
What is clear is that, under the right conditions (dose, route of administration, frequency and duration of exposure, etc.), people who are passively exposed to these drugs or who voluntarily consume them can show psychopathological states that include behavioral dimensions of psychotic disorders; this is markedly different from a drug like nicotine which virtually never does. Although these agents very specifically produce psychopathology of interest to schizophrenia researchers, the “right conditions” required for each to achieve temporary or persistent psychotomimetic effects are not known. For example, it is simply not clear what determines which methamphetamine abusers will develop psychotic symptoms and which will not (is it ethnicity, age of onset, total lifetime dose, underlying genetic risk?).
If we knew what the right conditions were for both drugs and could mimic those in animals, I believe that we would find a common set of neuroadaptations in the prefrontal cortex and its striato-pallido-thalamic targets that represent the final common pathway by which these two otherwise distinct agents dysregulate the normal mental and emotional function of animals and people who are exposed to them. I further propose that, if we knew the right conditions under which cannabis induced psychotic symptoms, it would point to the same pathway. At this nexus, we will additionally discover mechanisms that help to explain the comorbidity between substance abuse and psychotic disorders, as the common features for all of these agents is their abuse liability and psychotomimetic properties.
Without the information about the right conditions, the conflict over the validity of amphetamine versus phencyclidine models is unresolvable. Clearly, there are many studies in which one or the other drug was given to animals with little behavioral, physiological, or anatomical feature of schizophrenia being induced. But this is not because there is no general validity for either model; it is because we haven’t learned quite yet what the conditions are under which these drugs affect people in a manner relevant to the field and should be expected to affect animals.
At the current time, concluding that one or the other model is better (whatever that means, in scientific terms) or is more accurate in its ability to induce a model for the disorder is premature.
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The acknowledgment that amphetamine psychosis (like schizophrenia) can have inverse effects (both hypo- and hyperfunction) on different regions of the prefrontal cortex (PFC) is an important one, and worth emphasizing. There is regional specificity of effects within the PFC, not just a global increase or decrease in function. In addition to the distinction between the orbital and medial PFC mentioned in the article, there is converging evidence from the working memory imaging literature that schizophrenia may have inverse effects on ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, with increased VLPFC and decreased DLPFC activation in schizophrenia (Glahn et al., 2005). This has potentially important implications for understanding compensatory performance strategies, and for devising cognitive remediation interventions.
Glahn, D.C., Ragland, J.D., Abramoff, A., Barrett, J., Laird, A.R., Bearden, C.E., Velligan, D.I.: Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp. 2005 May;25(1):60-9. Abstract
View all comments by J. Daniel Ragland
PRIMARY NEWSModeling Psychosis in Prefrontal Cortex—The Effects of Amphetamine