Abnormal cerebral perfusion in chronic methamphetamine abusers: A study using 99mTC-HMPAO and spect

doi:10.1016/S0278-5846(97)00079-1

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 21, Issue 5, July 1997, Pages 789-796

https://doi.org/10.1016/S0278-5846(97)00079-1 Get rights and content

Abstract

1.
1. Cerebral blood flow of nine methamphetamine abusers with technetium-99m-hexamethyl-propyleneamine oxime (HMPAO) and single photon emission computed tomography (SPECT) as well as morphological examination with magnetic resonance imaging (MRI) were investigated.
2.
2. Six of these subjects exhibited multiple focal perfusion deficits in cerebral cortices without abnormalities in MRI including cerebral atrophy and/or infarctions.
3.
3. Cerebral perfusion deficits were detected in methamphetamine abusers even after a long abstinence period, suggesting that vascular changes were irreversible to some degree.
4.
4. HMPAO SPECT study appeared to be sensitive to the detection of cerebral perfusion abnormalities in drug abusers.

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SUDs are associated with neural adaptations that occur in response to and withdrawal from substances. In both animal and human models, acute and chronic responses to substances lead to a reduction in brain dopamine and alterations to a number of brain regions (e.g., ventral cingulate gyrus, involved in mood regulation; prefrontal cortex, involved in executive functioning; ventral striatum, involved in reward processing; thalamus, involved in arousal; Gouzoulis-Mayfrank et al., 1999; Iyo et al., 1997; Sapolsky, 2003; Volkow et al., 2001a, 2001b). In addition to the neuronal changes in response to substance administration, changes in the brain's reward circuitry and in the amygdala have been implicated in inducing the negative emotional symptoms that often occur during early phases of withdrawal (Philibin et al., 2011).
A common criticism of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013) is that its criteria are based more on behavioral descriptions than on underlying biological mechanisms. Increasingly, calls have intensified for a more biologically-based approach to conceptualizing, studying, and treating psychological disorders, as exemplified by the Research Domain Criteria Project (RDoC). Among the most well-studied neurobiological mechanisms is reward processing. Moreover, individual differences in reward sensitivity are related to risk for substance abuse and depression. The current review synthesizes the available preclinical, electrophysiological, and neuroimaging literature on reward processing from a transdiagnostic, multidimensional perspective. Findings are organized with respect to key reward constructs within the Positive Valence Systems domain of the RDoC matrix, including initial responsiveness to reward (physiological ‘liking’), approach motivation (physiological ‘wanting’), and reward learning/habit formation. In the current review, we (a) describe the neural basis of reward, (b) elucidate differences in reward activity in substance abuse and depression, and (c) suggest a framework for integrating these disparate literatures and discuss the utility of shifting focus from diagnosis to process for understanding liability and co-morbidity. Ultimately, we believe that an integrative focus on abnormal reward functioning across the full continuum of clinically heterogeneous samples, rather than within circumscribed diagnostic categories, might actually help to refine the phenotypes and improve the prediction of onset and recovery of these disorders.
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Binge users may exhibit highly focused and repetitive behaviors, known as “punding” (Fasano et al., 2008), such as the stereotyped handling and sorting of objects. Particular attention has been paid to the capacity of high and sustained doses of MA to cause psychological changes that resemble the symptoms of psychosis (Barr et al., 2006), although it is important to note that relatively few studies have observed this effect in people using only MA, and with no prior history of mental illness (Iwanami et al., 1994; Iyo et al., 1997, 2004). Binge-like use of MA has been reported to induce sleeplessness, hallucinations and paranoia (Leamon et al., 2010), which may be associated with irritability and unprovoked aggression (Payer et al., 2011).
Methamphetamine (MA) is a highly addictive psychostimulant drug that principally affects the monoamine neurotransmitter systems of the brain and results in feelings of alertness, increased energy and euphoria. The drug is particularly popular with young adults, due to its wide availability, relatively low cost, and long duration of psychoactive effects. Extended use of MA is associated with many health problems that are not limited to the central nervous system, and contribute to increased morbidity and mortality in drug users. Numerous studies, using complementary techniques, have provided evidence that chronic MA use is associated with substantial neurotoxicity and cognitive impairment. These pathological effects of the drug, combined with the addictive properties of MA, contribute to a spectrum of psychosocial issues that include medical and legal problems, at-risk behaviors and high societal costs, such as public health consequences, loss of family support and housing instability. Treatment options include pharmacological, psychological or combination therapies. The present review summarizes the key findings in the literature spanning from molecular through to clinical effects.
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The use of amphetamines, such as MA, is associated with cerebrovascular complications such as cerebrovascular accidents (CVA) (Perez et al., 1999; Westover et al., 2007; Yen et al., 1994), hemorrhage (Delaney and Estes, 1980; Westover et al., 2007), hypoxic damage (Kaye et al., 2008) and vasculitis (Salanova and Taubner, 1984). Interestingly, while changes to cerebral blood flow (CBF) in response to acute amphetamine exposure have been reported (Devous et al., 2001; Rose et al., 2006), there is evidence of long-term effects on CBF from MA use even in abstinent users (Chang et al., 2002; Hwang et al., 2006; Iyo et al., 1997), suggesting that the effect of MA on CBF is at least partially irreversible. Reports on the effect of MA on global or focal CBF are controversial and incomplete as seen by the variation in published data.
The use prevalence of the highly addictive psychostimulant methamphetamine (MA) has been steadily increasing over the past decade. MA abuse has been associated with both transient and permanent alterations in cerebral blood flow (CBF), hemorrhage, cerebrovascular accidents and death. To understand MA-induced changes in CBF, we exposed C56BL/6 mice to an acute bolus of MA (5 mg/kg MA, delivered IP). This elicited a biphasic CBF response, characterized by an initial transient increase (~ 5 minutes) followed by a prolonged decrease (~ 30 minutes) of approximately 25% relative to baseline CBF—as measured by laser Doppler flowmetry over the somatosensory cortex. To assess if this was due to catecholamine derived vasoconstriction, phentolamine, an α-adrenergic antagonist was administered prior to MA treatment. This reduced the initial increase in CBF but failed to prevent the subsequent, sustained decrease in CBF. Consistent with prior reports, MA caused a transient increase in mean arterial blood pressure, body temperature and respiratory rate. Elevated respiratory rate resulted in hypocapnia. When respiratory rate was controlled by artificially ventilating mice, blood PaCO₂ levels after MA exposure remained unchanged from physiologic levels, and the MA-induced decrease in CBF was abolished. In vivo two-photon imaging of cerebral blood vessels revealed sustained MA-induced vasoconstriction of pial arterioles, consistent with laser Doppler flowmetry data. These findings show that even a single, acute exposure to MA can result in profound changes in CBF, with potentially deleterious consequences for brain function.
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The aim of this study was to examine disturbances in regional cerebral blood flow (rCBF) associated with methamphetamine abuse.
Using Single Photon Emission Computed Tomography (SPECT), rCBF was measured in 20 men who had previously injected methamphetamine intravenously for over 30 months and who were now abstinent for a minimum of 9 months and for an average of 2 years. Values were compared with those in 12 healthy men who had never injected methamphetamine.
While rCBF was significantly and disproportionately reduced in subcortical and dorsal cortical brain regions, including the striatum, thalamus, cingulum, mesiodorsal prefrontal cortex, and pons (all t's > 8.3 after global normalization, corrected p's < 0.001), whole brain CBF was also significantly reduced in the former methamphetamine users. Binge use of methamphetamine is associated with long-term changes in both global and regional blood flows, likely representing severe and enduring neural toxicity of monoaminergic neurotransmitter systems in the brain, producing a pattern of hypoperfusion that resembles patterns reported previously for persons with atypical Parkinson's disease.
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²: Present address: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu-shi, Japan.

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Full length original paper clinical studyAbnormal cerebral perfusion in chronic methamphetamine abusers: A study using 99mTC-HMPAO and spect

Abstract

Psych Res

Necrotizing angitis associated with drug abuse

N Engl J Med

Epidemiology and amphetamine abuse in Japan and its social implication

Brain perfusion is abnormal in cocaine-dependent polydrug users: A study using Technetium-99m-HMPAO and ASPECT

J Nucl Med

Drug addiction and drug abuse

A study of CT scan in amphetamine psychosis

Ann Rep Pharmacopsychiat Res Found

Use and abuse of amphetamines in Japan

Treatment of methamphetamine-related mental disorders and follow-up study on its outcome

Full length original paper clinical study
Abnormal cerebral perfusion in chronic methamphetamine abusers: A study using ^99mTC-HMPAO and spect