PubMed · 14422666
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D H MILMAN. 1960. Multiple tics.. https://doi.org/10.1176/ajp.116.10.935
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Neuroadaptations in the cAMP signal transduction system have been proposed to play a critical role in psychostimulant-induced behavioral sensitization. Studies relevant to this hypothesis have provided conflicting evidence, however, because repeated cocaine and amphetamine treatment has been alternately reported to either increase or decrease protein kinase A (PKA) activity in the nucleus accumbens and dorsal striatum. In an attempt to reconcile these disparate findings, PKA activity and the stimulatory G-protein subunits, G(salpha) and G(olfalpha), were measured after rats had received a sensitization-inducing regimen of amphetamine or cocaine. Results showed that seven consecutive daily injections of amphetamine or cocaine produced locomotor sensitization and caused a reduction in accumbal PKA activity. A challenge injection of amphetamine on the test day also reduced dorsal striatal PKA activity. G(salpha) levels were unaffected by psychostimulant exposure, while G(olfalpha) levels in the nucleus accumbens declined significantly after amphetamine or cocaine pretreatment. Because repeated amphetamine and cocaine treatment both induced behavioral sensitization and decreased accumbal PKA activity, it appears that psychostimulant-induced increases in PKA activity are not necessary for the ultimate expression of behavioral sensitization.
Competition between endogenous neurotransmitters and radiolabelled tracers, as measured by positron emission tomography (PET), may provide a measure of endogenous neurotransmitter flux in vivo. For example, carbon-11 labelled raclopride has been effectively used to monitor dopamine release following pharmacological and behavioural manipulations. The current study describes a rodent model of amphetamine-induced [11C]raclopride reduction, which allowed the characterisation of the dose-response and temporal dynamics of this reduction over a 24-h time course. Over the range studied, a monotonic dose-response relationship between amphetamine dose and [11C]raclopride reduction was observed. When compared with previously published microdialysis data, an approximate 16% reduction in [11C]raclopride binding potential was associated with a approximately 25-fold increase in extracellular dopamine. A reduction of 20-30% in raclopride binding was observed 30 min after amphetamine injection (4 mg/kg i.p.). This reduction in [11C]raclopride binding persisted for 4 h but returned to baseline by 8 h. The data suggest a persistent amphetamine-induced raclopride displacement in rodents and reinforce findings from nonhuman primates that a simple competitive occupancy model may not adequately explain the temporal characteristics of the amphetamine-induced decrease in radiotracer binding.
This study was aimed at determining the role of prefrontal cortex neurons in the development of the potentiation of amphetamine-induced locomotor activity by repeated central injections of D-Tyr[11]neurotensin. Excitotoxic lesions of the prefrontal cortex were made by injecting bilaterally at three anterior-posterior placements 2 microg/microl of ibotenic acid. Ten days after surgery, locomotor responses to an intracerebroventricular injection of 0.18 or 18 nmol/10 microl of D-Tyr[11]neurotensin, or vehicle-saline, were measured in different groups of lesioned and sham rats. Ambulatory, non-ambulatory and vertical movements were measured for 2 h in activity cages starting immediately after the injection. This training phase was repeated on four occasions, every second day. One week after the last day of the training phase (day 14), locomotor responses to a single injection of amphetamine (0.75 mg/kg, IP) were measured in all rats. Results show that D-Tyr[11]neurotensin produced in sham animals a dose-dependent initial suppression of locomotor activity followed by an augmentation. The latter behavioral effect tended to be smaller in the lesioned rats, but not statistically different than in sham, suggesting that prefrontal cortex neurons do not play a major role in the stimulant effect of neurotensin on locomotor activity. However, sham rats pre-exposed to the high dose of D-Tyr[11]neurotensin showed stronger non-ambulatory and vertical movements than saline pre-exposed rats when tested with amphetamine; this sensitization effect was not observed in lesioned rats. The present results show that prefrontal cortex neurons are part of the neural circuitry involved in the development of amphetamine sensitization by repeated activation of central neurotensin receptors.