PubMed · 14626173
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Takashi Hara, Michiya Sugawara. 2003. [Flashback].. https://pubmed.ncbi.nlm.nih.gov/14626173/
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Studies have shown that intermittent sugar availability (12 h/day) produces signs of dependence in rats, including escalation of intake, mu-opioid and dopamine receptor changes, behavioral and neurochemical indices of withdrawal, and cross-sensitization with amphetamine. "Deprivation-effect" paradigms, whereby abstinence from a substance results in enhanced intake, are often used to measure "craving" for drugs of abuse, such as alcohol. The present study used operant conditioning to investigate consumption of sugar after abstinence in rats selected for glucose avidity. The experimental group was trained on a fixed ratio (FR-1) schedule for 25% glucose for 30 min/day for 28 days and also had glucose access in the home cages for an additional 11.5 h daily. The control group had only the 30-min/day access to glucose in the operant chambers. Then, both groups were deprived of glucose for 2 weeks. After this period of abstinence, animals were put back in the operant chambers. The experimental group responded significantly more than ever before, and significantly more than the control group. In conclusion, daily 12-h access to sugar, in the paradigm used, can result in an altered neural state that lasts throughout 2 weeks of abstinence, leading to enhanced intake. Together with previous results, this deprivation effect supports the theory that animals may become dependent on sugar under selected dietary circumstances.
Acute high dose methamphetamine (METH) dosing regimens are frequently used in animal studies, however, these regimens can lead to considerable toxicity and even death in experimental animals. Acute high dosing regimens are quite distinct from the chronic usage patterns found in many human METH abusers. Furthermore, such doses, especially in nonhuman primates, can result in unexpected death, which is unacceptable, especially when such deaths fail to accurately model effects of human usage. As a model of chronic human METH abuse we have developed a nonlethal chronic METH administration procedure for the rhesus macaque that utilizes an escalating dose protocol. This protocol slowly increases the METH dosage from 0.1 to 0.7 mg/kg b.i.d. over a period of 4 weeks, followed by a period of chronic METH administration at 0.75 mg/kg b.i.d. (= total daily METH administration of 1.5 mg/kg). In parallel to human usage patterns, METH injections were given 20-23 times a month. This regimen produced a number of behavioral and physiological effects including decreased food intake and a significant increase in urinary cortisol excretion.
In the central nervous system, tissue plasminogen activator (tPA) plays a role in synaptic plasticity and remodeling. Our recent study has suggested that tPA participates in the rewarding effects of morphine by regulating dopamine release. In this study, we investigated the role of tPA in methamphetamine (METH)-related reward and sensitization. Repeated METH treatment dose-dependently induced tPA mRNA expression in the frontal cortex, nucleus accumbens, striatum and hippocampus, whereas single METH treatment did not affect tPA mRNA expression in these brain areas. The METH-induced increase in tPA mRNA expression in the nucleus accumbens was completely inhibited by pre-treatment with R(+)-SCH23390 and raclopride, dopamine D1 and D2 receptor antagonists, respectively. In addition, repeated METH treatment increased tPA activity in the nucleus accumbens. There was no difference in METH-induced hyperlocomotion between wild-type and tPA-deficient (tPA-/-) mice. On the other hand, METH-induced conditioned place preference and behavioral sensitization after repeated METH treatment were significantly reduced in tPA-/- mice compared with wild-type mice. The defect of behavioral sensitization in tPA-/- mice was reversed by microinjections of exogenous tPA into the nucleus accumbens. Our findings suggest that tPA is involved in the rewarding effects as well as the sensitization of the locomotor-stimulating effect of METH.