PubMed · 5429463
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F O Wells. 1970-05-09. Action on amphetamines.. https://doi.org/10.1136/bmj.2.5705.361
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Animal studies have shown that nicotine and psychostimulant drugs (amphetamine and cocaine) share the property of inducing long-lasting behavioral and neurochemical sensitization, which is thought to contribute to their addictive properties. Neuroplasticity subserving learning and memory mechanisms is considered to be involved in psychostimulant-induced sensitization and addiction behavior. Because nicotinic receptors in the brain play a role in the storage of drug-related information underlying reinforcement learning, we evaluated the possibility that activation of central nicotinic receptors may underlie psychostimulant-induced sensitization. Repeated exposure of rats to nicotine profoundly enhanced the psychomotor effects of nicotine and amphetamine 3 weeks after nicotine pretreatment. Moreover, the nicotinic receptor antagonist mecamylamine completely blocked the induction, but not the long-term expression, of behavioral sensitization to amphetamine in amphetamine-pretreated rats. Mecamylamine also prevented the development of cocaine-induced behavioral sensitization. Behavioral sensitization induced by nicotine, amphetamine, or cocaine was associated with an increase in the electrically evoked release of [(3)H]dopamine from nucleus accumbens slices. Coadministration of mecamylamine during pretreatment with nicotine, amphetamine, or cocaine prevented the development of this long-term hyperreactivity of nucleus accumbens dopamine neurons. Similarly, the high-affinity non-alpha7 subtype nicotinic receptor antagonist dihydro-beta-erythroidine prevented the development of amphetamine-induced behavioral and neurochemical sensitization. These data indicate that nicotinic receptor activation (by endogenously released acetylcholine) is a common denominator initiating neuroplasticity involved in the development of amphetamine, as well as cocaine-induced sensitization.
Changes in activity of basal ganglia neurons, especially those in the striatum, are thought to underlie the characteristic behavioral patterns produced by d-amphetamine (AMPH). To study the role of the substantia nigra pars reticulata (SNr), a major basal ganglia output nucleus, we recorded from SNr neurons before and after a behaviorally activating dose of AMPH (0.5 mg/kg) in rats trained to nosepoke for sucrose reinforcement. Before AMPH, task-related behaviors were associated primarily with increases or both increases and decreases in SNr firing. Although these same behavior-related patterns persisted after AMPH, their relative magnitude was significantly attenuated. Units unresponsive during task events were unaffected by AMPH. Thus, rather than change the overall level of SNr firing, a behaviorally active dose of AMPH exerts context-dependent effects on the activity of SNr neurons.
There is growing evidence that the neurotrophic environment of the denervated striatum may change with time following a lesion of the nigrostriatal pathway in young adult rats. To test this hypothesis, we implanted fetal dopamine grafts into the striatum at several different time points relative to the nigrostriatal pathway lesion and allowed the grafts to integrate with the host for a period of 1 month; subsequently, we observed the function and morphology of the dopamine grafts. Fetal grafts were implanted at the following time points relative to the lesion: 1 week before (-1 Week), at the same time (Week 0), 1 week after (1 Week), 4 weeks after (4 Weeks), or 12 weeks after (12 Weeks). Amphetamine-induced rotational behavior was assessed 4 weeks after grafting for all groups. Rotational scores indicate that grafts for the 1 Week group showed the greatest reversal of amphetamine-induced rotational behavior that was also significantly greater than the scores for the -1 Week group. Morphological analysis revealed that grafts in the Week 0, 1 Week and 4 Weeks groups showed a significantly larger area of tyrosine hydroxylase-positive (TH+) fiber outgrowth than in the -1 Week group, while fiber outgrowth for the 12 Weeks group was significantly lower than for the 1 Week group. Cell count analysis for TH+ neurons within the graft indicate a significantly greater number of TH+ neurons in grafts for the 1 Week group than in grafts for the -1 Week. The results of this study suggest that neurotoxic lesions may induce a compensatory increase in neurotrophic activity within the denervated striatum of young rats that is conducive to the survival and outgrowth of fetal dopamine grafts. These data also correlate well with reports that the expression of several specific dopaminergic neurotrophic factors within the striatum increase following a neurotoxic lesion of the nigrostriatal pathway in young adult rats.