External incentives and internal states guide goal-directed behavior via the differential recruitment of the nucleus accumbens and the medial prefrontal cortex.

Goal-directed behavior is governed by internal physiological states and external incentives present in the environment (e.g. hunger and food). While the role of the mesocorticolimbic dopamine (DA) system in behavior guided by environmental incentives has been well studied, the effect of relevant physiological states on the function of this system is less understood. The current study examined the role of the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAcc) in the kind of food-reinforced behaviors known to be sensitive to the internal state produced by food deprivation conditions. Operant lever-press reinforced on fixed ratio 1 (FR1) and progressive ratio (PR) schedules was tested after temporary inactivation of, or DA receptor blockade in, the prelimbic mPFC or NAcc core of rats with differing levels of food deprivation (0, 12 and 36-h). Food deprivation increased PR breakpoints, as well as the number of lever-presses emitted on the FR1 schedule. Both temporary inactivation and DA blockade of NAcc reduced breakpoints across deprivation conditions, while temporary inactivation and DA blockade of mPFC reduced breakpoints only in food-deprived rats. Neither manipulation of mPFC and NAcc had any effect on behavior reinforced on the FR1 schedule. Thus, mPFC and NAcc were differentially relevant to the behaviors tested-NAcc was recruited when the behavioral cost per reinforcer was rising or high regardless of food deprivation conditions, while mPFC was recruited when food-deprived animals behaved through periods of sparse reinforcement density in order to maximize available gain.

Effects of food deprivation on goal-directed behavior, spontaneous locomotion, and c-Fos immunoreactivity in the amygdala.

Previous work in our laboratory has shown that food deprivation and food presentation produce different patterns of neuronal activity (as measured by c-Fos immunoreactivity) in the medial prefrontal cortex and nucleus accumbens of rats. Since the amygdala has been implicated in both motivational and reinforcement processes and has neuronal connections to both the prefrontal cortex and nucleus accumbens, it was of interest to assess amygdaloid c-Fos immunoreactivity during similar manipulations of food deprivation and presentation. In the current study, c-Fos counts in both basolateral and central amygdalar nuclei were observed to increase in rats 12- and 36-h food deprived (relative to 0-h controls)-an effect reversed by the presentation of either a small or large meal (2.5 or 20g of food). In another experiment, rats working on a progressive ratio schedule of reinforcement exhibited elevated break-points as a function of food deprivation, a result consistent with the view that the feeding manipulations increased the subjects' level of motivation. In contrast, food deprivation reduced the spontaneous locomotor activity of rats, presumably as a result of an inherent energy-conservation strategy when no food is readily available. These data suggest that the state of food deprivation is associated with: (a) enhanced behavioral output only when food is attainable (increased goal-directed behavior, but decreased spontaneous activity), and (b) increased synaptic engagement in neuronal circuits involved in affective valuation and related decision-making (increased c-Fos counts in the amygdala).

Alcohol consumption is preferred to water in rats pretreated with intravenous cocaine.

Clinical and anecdotal reports suggest a high incidence of alcohol administration during cocaine use, potentially as a means to diminish the aversive effects of cocaine that follow the initial positive drug effects. We have previously shown that in the operant runway, oral ethanol significantly reduces the approach-avoidance retreats that develop in response to IV cocaine. The current study was intended to test whether rats given the same dose of IV cocaine administered in our previous study would choose to consume ethanol rather than water in a two bottle choice paradigm. We also examined whether significant serum levels of the psychoactive cocaine metabolite, cocaethylene, were found in our animals that may account for the preference for ethanol. Animals pretreated with cocaine drank significantly more ethanol than did animals pretreated with saline. There were no measurable levels of cocaethylene at 10 or 40 min post-cocaine and extremely low values at the 20-min time point, indicating that cocaethylene formation does not reinforce the co-administration of cocaine and alcohol in rats. These data demonstrate that the presence of cocaine serves as a primary factor in the preference for alcohol in thirsty rats, potentially to reduce the well-documented negative/anxiogenic properties of cocaine.

Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues.

The conditioning of cocaine's pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocaine-related stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous cocaine (S(+)) vs. the availability of non-rewarding (S(-)) saline solution, and then placed on extinction conditions during which intravenous solutions and S(D) were withheld. The rats were then presented with the S(+) or S(-) alone in 60-min reinstatement sessions conducted at 3-day intervals. To examine the long-term persistence of the motivating effects of the cocaine S(+), a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S(+) selectively elicited robust responding at the previously active lever. The efficacy and selectivity of this stimulus to elicit responding remained unaltered throughout a 34-day phase of repeated testing as well as following the additional extended abstinence period. In pharmacological tests, conducted in a separate group of rats, the dopamine (DA) D(1) antagonist SCH 39166 (10 microg/kg), the D(2/3) antagonist nafadotride (1 mg/kg), and the D(2/3) agonist PD 128907 (0.3 mg/kg) suppressed the cue-induced response reinstatement while the D(1) agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenuating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-related stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S(+) to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior.

Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors.

The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse. These changes lead to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. Considerable evidence exists implicating perturbations in DA and 5-HT transmission in the nucleus accumbens--neurochemical systems that are activated by cocaine and ethanol self-administration and deficient during withdrawal--as potential substrates for these affective changes. In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress-like consequences of withdrawal that are common to all drugs of abuse. A growing body of evidence also implicates dysregulation of the non-neuroendocrine CRF stress system within the central nucleus of the amygdala as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse. Moreover, a possible link may exist between long-lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence. Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug-related stimuli. The long-lasting efficacy of drug- and alcohol-associated contextual stimuli in eliciting drug-seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine. With cocaine, D1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala may be important substrates for the motivating effects of drug-related environmental stimuli. With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug-seeking behavior. Finally, conditioning factors (i.e., exposure to drug-associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies.

Non reciprocal cross-sensitization between cocaine and BTCP on locomotor activity in the rat.

Measurement of locomotor sensitization was employed to characterize the effect of intermittent treatment with N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) and cocaine in the rat. Like cocaine, BTCP possesses high affinity for the dopamine transporter and inhibits dopamine reuptake. Although both drugs exhibit similar behavioral and neurochemical profiles with acute administration, there is tentative evidence to suggest that following chronic treatment BTCP does not induce neurochemical sensitization, and can attenuate cocaine-induced neurochemical sensitization in the striatum. Male Wistar rats were randomly divided into five groups after determining baseline locomotor activity. Three groups were treated with either saline (saline/saline), cocaine (20 mg/kg; cocaine/cocaine), or BTCP (10 mg/kg; BTCP/BTCP) for 10 days. The remaining two groups were treated with cocaine (20 mg/kg) or BTCP (10 mg/kg) for 3 days, followed by administration of BTCP (10 mg/kg; cocaine/BTCP) or cocaine (20 mg/kg; BTCP/cocaine) for 7 days. Locomotor sensitization was observed in all groups. However, although cross-sensitization on the day of substitution (day 4) was found in the BTCP/cocaine group, cross-sensitization was not observed in the cocaine/BTCP group. These results suggest that although the locomotor-activating effects of BTCP and cocaine are similar, the two drugs do not act identically, and different neural mechanisms may underlie BTCP and cocaineinduced sensitization.

Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens.

The conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to be a critical factor in the long-term addictive potential of this drug. Cocaine-related stimuli may increase the likelihood of relapse by evoking drug craving, and brain-imaging studies have identified the amygdala and nucleus accumbens (NAcc) as putative neuroanatomical substrates for these effects of cocaine cues. To study the significance of environmental stimuli in the recovery of extinguished cocaine-seeking behavior, male Wistar rats were trained to associate discriminative stimuli (SDeltas) with response-contingent availability of intravenous cocaine vs. saline. The rats then were subjected to repeated extinction sessions during which cocaine, saline, and the respective SDeltas were withheld until the animals reached an extinction criterion of

Amphetamine infusions into the prefrontal cortex attenuate the sensitization to amphetamine.

1. Adult male rats were implanted with chronic medial prefrontal cortex cannulae. 2. On each of 5 consecutive days, rats received bilateral 0.5 ml intra-prefrontal cortex injections of either 5 mg d-amphetamine or saline, followed by a subcutaneous injection of either 1 mg/kg d-amphetamine or saline. 3. Immediately after the drug treatments each rat was placed into a photocell equipped locomotor activity chamber for 60 min. 4. Administration of d-amphetamine into the prefrontal cortex did not block the acute locomotor response to subcutaneous d-amphetamine nor did it in itself produce an increase in locomotor activity. However, prefrontal cortex amphetamine treatments did attenuate the sensitized locomotor effects of subcutaneous amphetamine that developed over trials/days. 5. Dopamine in the prefrontal cortex may be involved in the development of amphetamine-induced behavioral sensitization.

To push or not to push: on the rearrangement of movable objects by a mobile robot.

We formulate and address the problem of planning a pushing manipulation by a mobile robot which tries to rearrange several movable objects in its work space. We present an algorithm which, when given a set of goal configurations, plans a pushing path to the "cheapest" goal or announces that no such path exists. Our method provides detailed manipulation plans, including any intermediate motion of the pusher while changing contact configuration with the pushed movables. Given a pushing problem, a pushing path is found using a two-phase procedure: a context sensitive back propagation of a cost function which maps the configuration space, and a gradient descent phase which builds the pushing path. Both phases are based on a dynamic neighborhood filter which constrains each step to consider only admissible neighboring configurations. This admissibility mechanism provides a primary tool for expressing the special characteristics of the pushing manipulation. It also allows for a full integration of any geometrical constraints imposed by the pushing robot, the pushed movables and the environment. We prove optimality and completeness of our algorithm and give some experimental results in different scenarios.

Repeated stimulation of the ventral tegmental area sensitizes the hyperlocomotor response to amphetamine.

The locomotor-activating effects of amphetamine have been reported to increase with repeated drug administration. Although the precise underlying mechanisms for this behavioral sensitization effect remain unknown, many investigators have suggested a role for the mesolimbic dopaminergic system that emanates from cell bodies in the ventral tegmental area (VTA) of the midbrain. To test this hypothesis, the present study examined the effects of repeated electrical stimulation of the VTA (in place of repeated amphetamine administration) on the hyperlocomotor actions of d-amphetamine. Locomotor activity induced by 0.75 mg/kg SC amphetamine was assessed during two 90-min tests, one before and one after a 14-day treatment regimen during which animals experienced daily 15-min sessions of intracranial VTA stimulation. Each session involved the delivery of 600 trains of 0.5 s 60-Hz sine-wave stimulation applied at one of four intensities: 0, 15, 30, or 45 microA. An additional comparison group of rats self-administered 30 microA of VTA stimulation. Data analysis revealed that both the self-stimulation and the high current groups were reliably more active posttreatment compared to pretreatment. No such sensitization-like effects were observed in any of the other treatment groups. These results are consistent with the hypothesis that repeated activation of VTA neurons can produce a sensitization to the behavioral effects of d-amphetamine.

Simultaneous brightness discrimination and reversal: the effects of amphetamine administration in the two stages.

Rats were trained in a Y-maze on a two-choice simultaneous brightness discrimination with light as S+ and dark as S- (Stage 1), and were then switched to reversal, where the reinforcement contingencies of the original training were reversed (Stage 2). d-Amphetamine, 1 mg/kg, was administered in a 2 X 2 design, i.e., drug-no drug in Stage 1 and drug-no drug in Stage 2. The administration of the drug in Stage 1 improved the acquisition of the initial brightness discrimination and facilitated reversal learning independently of the drug administered in Stage 2. In addition, the administration of the drug in Stage 2 only improved performance towards the end of reversal training. The results indicate that amphetamine enhances the attention to, or the associability of, the discriminative stimuli, leading to a rapid learning to these stimuli under changed contingencies of reinforcement.