Psychostimulant Self-administration Research Articles

Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration

Individual vulnerability to the reinforcing effects of drugs appear to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with higher locomotor responses to novelty (High Responders, HR) tend to acquire amphetamine SA, while animals with the lower responses (Low Responders, LR) do not. In this study, we examined whether activity of dopaminergic (DA) and serotoninergic (5-HT) systems differed between HR and LR animals. These transmitter systems are thought to be involved in the reinforcing effects of psychostimulants. Animals from both groups were sacrificed under basal conditions and after exposure for 30 or 120 min to a novel environment, and the DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, and 5-hydroxyindolacetic acid (5-HIAA) contents were determined in the prefrontal cortex, nucleus accumbens and striatum. The HR rats displayed a specific neurochemical pattern: a higher DOPAC/DA ratio in the nucleus accumbens and striatum and a lower one in the prefrontal cortex. Furthermore, HR animals had lower overall 5-HT and 5-HIAA levels, corresponding to the mean of these compounds for the three structures studied over the three environmental conditions. Since similar DOPAC/DA ratios are found in animals in which the propensity to psychostimulants SA was induced by brain lesions of life events, an opposite pattern of dopaminergic activity in the prefrontal cortex (decrease) and in the ventral and dorsal striatum (increase) may be one of the neurobiological substrate of the predisposition to acquire amphetamine self-administration. The development of this difference may be influenced by interactions between dopaminergic and serotominergic systems. These results suggest that potential therapeutic strategies for the treatment of addiction will need to take into account the functional heterogeneity of projection systems rather than concentrate on a single neurotransmitter.

Relationships between mesolimbic dopamine function and eating behavior.

These experiments are the first to correlate a specific stimulus of eating--the orosensory stimulation by sucrose--to mesolimbic dopaminergic activity. The pharmacological results and the increase in hypothalamic DOPAC/DA are convergent evidence for this relationship. The meaning of the relationship is not clear. The possibility that the decreased intake after dopaminergic receptor antagonist treatment and the increase in hypothalamic DOPAC/DA is related to the ingestive movements necessary for sham feeding seems unlikely for the following reasons: first, at least one dose of the antagonist had a preferential inhibition on sucrose intake compared to water intake; second, the D1 and D2 selective receptor antagonists decreased the initial rate of sucrose intake, but did not affect the rate of decay of sucrose intake over a 30-min test; third, in the second neurochemical experiment (Table 1), the volume ingested during 9 min of sham feeding 10% sucrose was not significantly different from the volume ingested from sham feeding 40% sucrose, but there was a significantly larger increase in the hypothalamic DOPAC/DA after 40% sucrose. Of course, a finer measurement of movements, such as lick rate, may reveal a significant difference that would correlate with the metabolic change. Fourth, striatal DOPAC/DA did not change during sham feeding of sucrose. Fifth, Bailey et al. demonstrated that a response-frequency summation analysis of the inhibitory effect of pimozide on sucrose intake did not reveal a motoric deficit. Thus, we interpret the increase of hypothalamic DOPAC/DA during the sham feeding of sucrose as evidence that activation of mesolimbic dopaminergic terminals in the hypothalamus is necessary for the normal processing of the central sensory and/or positive-reinforcing information produced by oral sucrose stimulation. Experiments are in progress to test this hypothesis and to attempt to distinguish between the sensory and positive-reinforcing effects of sucrose during sham feeding. In addition to generating this specific hypothesis concerning sucrose and hypothalamic DA activity, the results of these experiments suggest that the sham feeding preparation will be useful for the analysis of the important problem of the natural reinforcing properties of sweet taste. And finally, since sham feeding of sucrose is a form of oral self-stimulation, it provides a new experimental tool for comparing the role of central DA mechanisms in the positive-reinforcing effects of food, psychostimulant self-administration, and intracranial electrical self-stimulation.

Psychostimulant self-administration by beagle dogs in a progressive-ratio paradigm.

The relative reinforcing efficacy of cocaine, amphetamine, mazindol, and fenfluramine was quantified using a progressive-ratio paradigm. Catheterized beagle dogs (N = 6) were given access to response-contingent drug infusions during three 1-h trials each day. According to a predetermined schedule, the response requirement to obtain one infusion trial was increased daily until the dogs failed to complete the necessary fixed-ratio (FR); i.e., until they reached a "break-point" in their ratio behavior. Fenfluramine (in doses ranging from 0.0625-4.0 mg/kg/infusion) did not maintain self-administration behavior at or above the minimum requirement (FR 30). In contrast, all doses of cocaine (0.2-1.6 mg/kg/infusion), d-amphetamine (0.035-0.28 mg/kg/infusion), and mazindol (0.0225-0.18 mg/kg/infusion) sustained responding at large FR values. The highest FR values were maintained by cocaine, followed by d-amphetamine, then mazindol. Generally the dogs completed higher FRs for higher doses of a drug.