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Compelling evidence suggests a primary role for the mesoaccumbens dopaminergic pathway in the behavioral effects of amphetamine and cocaine, but the roles of other projections to the accumbens, including those arising in the hippocampal formation, are less clear. The authors evaluated the effects of discrete excitotoxic lesions of either the dorsal or ventral subiculum on the locomotor activating, reinforcing, and sensorimotor gating-disruptive effects of psychomotor stimulant drugs. Whereas dorsal subiculum-lesioned rats were hyperactive in tests of exploratory locomotion and startle reactivity, ventral subiculum-lesioned rats exhibited an attenuated locomotor response to amphetamine, moderately impaired acquisition of cocaine self-administration, and reduced levels of prepulse inhibition of startle. These 2 behavioral profiles overlap considerably with those previously observed in rats with lesions of the rostrodorsal and caudomedial accumbens, respectively, and suggest that projections from dorsal subiculum to accumbens core and ventral subiculum to accumbens shell exert distinct influences on behavioral responses that are amplified by psychomotor stimulant drugs.
RATIONALE: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D(1-like )and D(2-like )receptor mechanisms may be involved, recent studies suggest that D(1-like )and D(2-like )agonists have differing profiles of cocaine-related actions. OBJECTIVE: To develop a procedure for rapid assessment of complete dose-effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D(1-like )and D(2-like )agonists on cocaine self-administration using this procedure. METHODS: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D(1-like )and D(2-like )agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. RESULTS: Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose- effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D(1-like) agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br-APB (0.1-1. 0 mg/kg) produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D(2-like) agonists quinelorane (0.001-0.01 mg/kg) and 7-OH-DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D(2-like) agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. CONCLUSIONS: The results suggest that D(1-like) and D(2-like) agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.
Effects of D1-like and D2-like agonists were compared in rats (Rattus norvegicus) with differing levels of experience (24 or 9 mo) in a cocaine discrimination procedure (5.6 mg/kg cocaine; fixed-ratio 20 schedule of food presentation). Cocaine, d-amphetamine, and D2-like agonists (quinelorane, 7-OH-DPAT) dose-dependently substituted for cocaine in both groups of rats. In contrast, D1-like agonists (SKF 82958, SKF 77434) substituted for cocaine only in rats with less discrimination experience. Pretreatment with D2-like agonists increased the stimulus effects of low cocaine-doses in both groups, whereas D1-like agonists produced these effects only in rats with less discrimination experience. The data suggest that the stimulus effects of cocaine overlap with those of D2-like agonists across a broader range of conditions than with those of D1-like agonists. Thus, D2-like receptors may play an especially important role in cocaine's behavioral effects.
Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D2 receptor antagonist, eticlopride, or to the selective dopamine D1 receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing.
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The reinforcing effects of D(1-like) and D(2-like) agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D(1-like) agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D(2-like) agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped dose-effect functions. Pretreatment with the D(1-like) agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the dose-effect function for cocaine self-administration downward, whereas pretreatment with the D(2-like) agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D(1-like) and D(2-like) agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D(1-like) agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D(2-like) agonists increased the intervals between self-administered cocaine injections. The results suggest that D(2-like) agonists, but not D(1-like) agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D(2) receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine.
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The three dopamine agonists with highest reported D3 receptor selectivity in vitro, pramipexole, quinelorane and PD128,907, decreased self-administration of a high dose of cocaine in rats as a result of a leftward shift in the cocaine dose-effect function. In contrast the D3 preferring antagonist nafadotride increased cocaine self-administration. Moreover the relative potencies of these and other D2-like dopamine agonists (lisuride, 7-OH-DPAT, quinpirole, apomorphine, bromocriptine) to modulate cocaine self-administration were highly correlated with their relative potencies for increasing mitogenesis in vitro in cell lines expressing D3 but not D2 receptors. These results support the hypothesis that the D3 receptor may be an important target for pharmacotherapies for cocaine abuse and dependence.
There are many sources of reinforcement in the spectrum of cocaine dependence that contribute to the compulsive cocaine self-administration or loss of control of cocaine intake that constitutes the core of modern definitions of dependence. The development of withdrawal has long been considered an integral part of drug addiction but has lost its impact in the theorization of drug dependence because of new emphasis on the neurobiological substrates for the positive-reinforcing properties of drugs. The present treatise reviews the neurobiological substrates for the acute positive reinforcing effects of cocaine and what is beginning to be known about the neurobiological substrates of cocaine withdrawal. The concept of motivational or affective withdrawal is reintroduced, which reemphasizes opponent process theory as a model for the motivational effects of cocaine dependence. The same neural substrates hypothesized to be involved in the acute reinforcing properties of drugs (basal forebrain regions of nucleus accumbens and amygdala) are hypothesized to be altered during chronic drug treatment to produce the negative motivational states characterizing drug withdrawal. Within these brain regions, both the neurochemical system(s) on which the drug has its primary actions and other neurochemical systems may undergo adaptations to chronic presence of the drug. An understanding of the adaptations of the motivational systems of the brain accompanying cocaine dependence leads to important predictions not only about the etiology, treatment, and prevention of cocaine addiction but also about the vulnerability of these motivational systems in non-drug-induced psychopathology.
Application of animal models of psychostimulant abuse for experimentation in mice is becoming increasingly important for studying the contribution of genetic differences, as well as the roles of selected (targeted) genes, in specific behaviors. The purpose of this study was to investigate strain differences in cocaine self-administration behavior between C57BL/6 x SJL hybrid mice and BALB/cByJ mice. These two strains were chosen because BALB/cByJ mice have a well-developed behavioral pharmacological profile, and hybrid strains on a C57BL/6 background are commonly used for generating transgenic expressing and knockout mutant mice. C57BL/6 x SJL mice dose-dependently acquired cocaine self-administration (1.0 mg/kg/injection but not 0.25 mg/kg/injection) by responding selectively in the active nose-poke hole and maintaining stable levels of daily drug intake; they also exhibited a characteristic inverted-U-shaped cocaine dose-effect function. BALB/cByJ mice failed to acquire cocaine self-administration at either dose under the same test conditions. The strain differences observed in self-administration did not seem to be attributed to other behavioral differences because the two strains exhibited similar amounts of spontaneous nose-poking in the absence of reinforcers, and BALB/cByJ mice responded more than C57BL/6 x SJL mice in a food-reinforced nose-poke operant task. Importantly, the dose-effect function for the motor stimulating effects of cocaine (3.8-30 mg/kg intraperitoneally) suggests enhanced sensitivity but reduced efficacy of cocaine in stimulating motor activity in BALB/cByJ mice relative to the C57BL/6 x SJL hybrid mice. These results indicate that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is not the result of differences in spontaneous activity or performance, but may reflect different sensitivities to the reinforcing, or rate-disrupting, properties of cocaine. The data support an influence of genetic background in the liability to self-administer cocaine. Thus, a hypothesis is proposed that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is related to differences in brain monoamine systems linked to the high "emotionality" profile of BALB/c mice in novel or fearful situations, including perhaps cocaine administration.
Prepulse inhibition of the acoustic startle reflex is an operational measure of sensorimotor gating. The neural substrates of prepulse inhibition may be relevant to the pathophysiology of neuropsychiatric disorders that are characterized by sensorimotor gating deficits, including schizophrenia. Studies have demonstrated abnormalities within the hippocampal formation of schizophrenia patients, and animal studies have revealed that the hippocampus, and specifically the ventral subiculum, regulates prepulse inhibition. The ventral subiculum sends a dense glutamatergic projection to the nucleus accumbens, and the nucleus accumbens is known to potently regulate prepulse inhibition via dopaminergic and non-N-methyl-D-aspartate (non-NMDA) glutamatergic mechanisms. In the present study, we examined whether the hippocampal regulation of prepulse inhibition is mediated through subiculo-accumbens glutamatergic efferents. Intra-ventral subiculum infusion of NMDA dose dependently reduced prepulse inhibition, and this effect of NMDA was reversed by co-infusion of the NMDA receptor antagonist D,L-amino-5-phosphonovaleric acid (AP5). The prepulse inhibition-disruptive effect of intra-ventral subiculum NMDA infusion was not prevented by infusion of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into the nucleus accumbens core or shell subregions. Pretreatment with the D2 receptor antagonist haloperidol also failed to block the prepulse inhibition-disruptive effects of intra-ventral subiculum NMDA infusion. Thus, the present findings suggest that while prepulse inhibition is regulated by NMDA activity in the ventral subiculum, this effect does not appear to be mediated via nucleus accumbens dopamine D2 receptors or via nucleus accumbens non-NMDA glutamatergic substrates.
The mechanism by which two D3 receptor-preferring agonists, 7-hydroxydipropylaminotetralin (7-OH-DPAT) and quinelorane, modulate cocaine reinforcement was examined by monitoring nucleus accumbens dopamine levels with in vivo microdialysis while rats intravenously self-administered the following four different drug solutions consecutively: (1) cocaine; (2) a combination of cocaine plus a low dose of either agonist; (3) either agonist alone; and finally, (4) a physiological saline solution. Both 7-OH-DPAT (4 micrograms/infusion) and quinelorane (0.25 microgram/infusion) decreased cocaine (0.25 mg/infusion) intake in a manner indicating an enhancement of cocaine reinforcement and simultaneously decreased the cocaine-induced elevations in nucleus accumbens dopamine levels by > 50%. Subsequent self-administration of either 7-OH-DPAT (4 micrograms/infusion) or quinelorane (0.25 microgram/infusion) alone resulted in significant, but stable, increases in drug intake, with a concurrent decrease in nucleus accumbens dopamine levels to approximately 50% below nondrug baseline levels. These findings indicate that postsynaptic D3 receptor stimulation in the nucleus accumbens enhances the reinforcing properties of cocaine. In a second experiment, local application of 7-OH-DPAT via reverse dialysis (30 and 100 nM perfusate concentrations) dose-dependently decreased nucleus accumbens dopamine efflux to 76 +/- 3.9 and 61 +/- 6.3% of baseline, respectively, whereas there was no effect of this agonist on dopamine efflux in the ipsilateral striatum of these same animals. Coperfusion with the D3 receptor-preferring antagonist nafadotride dose-dependently blocked the effect of 7-OH-DPAT on nucleus accumbens dopamine efflux. These results suggest that, at low concentrations, 7-OH-DPAT selectively activates D3 receptors in vivo.
This study tested the hypothesis that blockade of D-1 dopamine receptors in the nucleus accumbens shell, central nucleus of the amygdala or dorsal striatum by intracerebral microinjection of the dopamine antagonist SCH 23390 produces an attenuation of the effects of self-administered cocaine. Microinjection of SCH 23390 (0-4.0 micrograms total dose) into any of the three brain regions dose-dependently increased the rate of cocaine self-administration, consistent with a partial attenuation of the effects of cocaine under these conditions (0.25 mg cocaine i.v.; fixed-ratio 5 timeout 20 s). The regional rank order potency of SCH 23390 was accumbens > amygdala > striatum, striatal injections being equipotent with subcutaneous administration. Moreover, SCH 23390 produced rapid effects on cocaine self-administration only when injected into the accumbens or amygdala. The time course of this regional selectivity was consistent with the rate of diffusion of SCH 23390 from the site of injection as measured by quantitative autoradiography, demonstrating that the regional selectivity of intracerebral injections of SCH 23390 is time-dependent. These results support a role for D-1 dopamine receptors in the nucleus accumbens and amygdala in the effects of self-administered cocaine, and suggest that D-1 receptors in certain portions of the 'extended amygdala' may be an important substrate for the reinforcing actions of cocaine.
The present study investigated the effects of systemic administration of the putative dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on the acquisition and expression of morphine-induced place preference in male Wistar rats. Using a a 3-day schedule of conditioning it was found that 7-OH-DPAT in a broad dose range (0.01, 0.25 and 5.0 mg/kg) did not produce significant place preference. However, the administration of either 0.25 or 5.0 mg/kg of 7-OH-DPAT 15 min prior to the exposure to morphine (1 mg/kg) prevented the acquisition of a morphine place preference, whereas the 0.01 mg/kg dose of the dopamine receptor agonist was uneffective. In addition, when 7-OH-DPAT was acutely administered 15 min prior to the testing session of an already established morphine place preference, the 0.01 mg/kg dose prevented the expression of this conditioned response. This effect was not observed with either 0.25 and 5.0 mg/kg doses of this dopamine D3 receptor agonist. It was suggested that the different dose related effects of 7-OH-DPAT on the acquisition and expression of morphine place preference might be related to the intrinsic ability of this agonist for interacting with pre- and postsynaptic dopamine D3 receptors located in limbic projecting areas of the mesencephalic dopamine system, although involvement of dopamine D2 receptors cannot be excluded. The pattern of effects seen with 7-OH-DPAT suggests that it may be useful for treating opiate dependence and craving.
Prepulse inhibition (PPI) is the normal reduction in a startle response that occurs when a weak stimulus ("prepulse") precedes the startling stimulus by 30 to 500 msec. Schizophrenic patients are deficient in this operational measure of sensorimotor gating; therefore, animal models of deficient PPI may provide information useful in the understanding and treatment of schizophrenia. Prepulse inhibition is disrupted in rats by systemic administration of direct dopamine agonists having affinity for the D2 subtype family (D2, D3, and D4) of dopamine receptors. This study tested the hypothesis that dopamine agonists and antagonists with different affinities for D3 and D2 receptors differ in their relative potencies to modulate PPI. The dopamine agonists quinpirole, 7-hydroxy-N,-N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and apomorphine were approximately equipotent in decreasing PPI. Pretreatment with haloperidol (13 to 130 nmol/kg sc), but not equimolar doses of UH 232, prevented the disruption of PPI produced by the highest dose (0.6 mumol/kg sc) of each agonist. Given the 100-fold higher affinity of haloperidol relative to UH 232 for D2 receptors, and equal relative affinities of these antagonists for D3 receptors, these data are consistent with previous studies suggesting that dopamine agonists may modulate PPI in the rat through the D2 subtype of dopamine receptors.
The hypothesis that mesolimbic dopamine is selectively involved in cocaine reinforcement was investigated in the rat. Animals were trained under a multiple schedule in which responding was reinforced by intravenous cocaine (0.75 mg/kg/injection) or food (45-mg pellets) under fixed-ratio 15 schedule requirements in alternate 30-min components of a 2-hr daily session. Infusion of the catecholaminergic neurotoxin 6-hydroxydopamine, but not the vehicle solution, into the region of the nucleus accumbens and olfactory tubercle produced selective reductions in cocaine self-administration without significantly altering responding maintained by food within the same sessions. This effect was reproduced in intact animals by substituting saline for cocaine in the self-administration component. These results support the hypothesis that the reinforcing effects of cocaine are dependent upon mesolimbic dopamine and demonstrate that cocaine self-administration can be disrupted in animals without altering behavior maintained by a nondrug reinforcer.