Rationale and objectives: Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. Methods: The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and µ-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. Results: The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization. Conclusions: The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies.

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in major depression. The physiological alterations underlying reduced dopamine(DA)signalingcouldresultfromeitherdiminishedDAreleasefrompresynaptic neuronsorimpairedsignaltransduction,eitherduetochangesinreceptornumberor functionand/oralteredintracellularsignalprocessing.Therearedatasupportingeachofthesemechanisms,althoughinterpretationofpreviousresearchisconfoundedbyissuesaroundstudypopulation, medication status, and technological limitations. In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure. Animal models of major depression show considerable responsiveness to manipulations of DA neurotransmission. Several studies, including postmortem investigations, particularly of subjects with severe depression, have demonstrated reduced concentrations of DA metabolites both in the cerebrospinal fluid and in brain regions that mediate mood and motivation. Although the neuroimaging findings are not unequivocal, several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possiblyreflectedbyacompensatoryup-regulationofD2receptors.ThesealterationsinDAsignalingmay underlie the findings of increased “liking” or “high” feelings reported by severely depressed subjects treated with d-amphetamine compared with the response of less severely ill and normal control subjects. The efficacy of medications that directly act on DA neurons or receptors, such as monoamine oxidase inhibitors and pramipexole, suggests that subtypes of depression stemming from a primary DA dysfunction exist. Further research on the contribution of DA to the pathophysiology of depressionisjustifiedtoimproveoutcomesforpatientswithtreatment-resistantandnonremittingdepression.

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The role of dopamine in the pathophysiology of depression.

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.

Both HIV infection and methamphetamine dependence can be associated with brain dysfunction. Little is known, however, about the cognitive effects of concurrent HIV infection and methamphetamine dependence. The present study included 200 participants in 4 groups: HIV infected/methamphetamine dependent (HIV+/METH+), HIV negative/methamphetamine dependent (HIV−/METH+), HIV infected/methamphetamine nondependent (HIV+/METH−), and HIV negative/methamphetamine nondependent (HIV−/METH−). Study groups were comparable for age, education, and ethnicity, although the HIV−/METH− group had significantly more females. A comprehensive, demographically corrected neuropsychological battery was administered yielding a global performance score and scores for seven neurobehavioral domains. Rates of neuropsychological impairment were determined by cutoff scores derived from performances of a separate control group and validated with larger samples of HIV+ and HIV− participants from an independent cohort. Rates of global neuropsychological impairment were higher in the HIV+/METH+ (58%), HIV−/METH+ (40%) and HIV+/METH− (38%) groups compared to the HIV−/METH− (18%) group. Nonparametric analyses revealed a significant monotonic trend for global cognitive status across groups, with least impairment in the control group and highest prevalence of impairment in the group with concurrent HIV infection and methamphetamine dependence. The results indicate that HIV infection and methamphetamine dependence are each associated with neuropsychological deficits, and suggest that these factors in combination are associated with additive deleterious cognitive effects. This additivity may reflect common pathways to neural injury involving both cytotoxic and apoptotic mechanisms. (JINS, 2004, 10, 1–14.)Note: Dr. Erin D. Bigler served as action editor during the course of this review.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S1355617704101021

Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons.

The present study examined the effects of both competitive (D-CPP-ene) and noncompetitive (MK-801) NMDA antagonists on behavioral sensitization to methamphetamine (MA). Behavioral effects of repeated administration of NMDA antagonists were also examined. Rats treated with MA according to an escalating dose schedule (2.5, 5, 7.5, and 10.0 mg/kg, SC, twice a day on days 1, 3, 5, and 7, respectively) indicated behavioral supersensitivity. Pretreatment with either MK-801 (0.5 mg/kg, IP) or D-CPP-ene (20 mg/kg, IP) prior to MA administration prevented the development of the supersensitivity. Rats treated with MK-801 showed a decrease in the motor activity when subsequently challenged with MK-801 compared with saline-treated rats. Likewise, rats administered with D-CPP-ene showed decreased motor activity when challenged with D-CPP-ene. There was no cross-sensitization nor tolerance between MA and MK-801 or D-CPP-ene. These results suggest that both competitive and noncompetitive NMDA antagonists block sensitization to MA and that repeated administration with NMDA antagonists results in behavioral tolerance.

Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine

Open pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression.

The role of glutamate in behavioral and neurotoxic effects of methamphetamine

We examined effects of nitric oxide (NO·) synthesis inhibition on methamphetamine (MA)-induced dopaminergic and serotonergic neurotoxicity. The toxic dose of MA (5 mg/kg, sc, X4) significantly decreased contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum (ST), and significantly decreased contents of serotonin (5-HT) in the ST, nucleus accumbens (NA) and medial frontal contex (MFC). Coadministration with a NO· synthase inhibitor, Nω-nitro-L-arginine methyl ester (LNAME) (30 mg/kg, ip, X2), reduced the MA-induced decreases in contents of DA, DOPAC and HVA in the ST, but not reduced the MA-induced decreases in contents of 5-HT in the ST, NA and MFC. These findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO· formation caused by the activation of postsynaptic DA receptor.

T. Ohmori

Papers

Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine

Open pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression.

The role of glutamate in behavioral and neurotoxic effects of methamphetamine

Effects of nitric oxide synthesis inhibition on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in the rat brain.

Scopolamine prevents the development of sensitization to methamphetamine.