Thomas J.R. Beveridge

Parallel studies of cocaine-related neural and cognitive impairment in humans and monkeys

Cocaine users display profound impairments in executive function. Of all the components of executive function, inhibition, or the ability to withhold responding, has been studied the most extensively and may be most impaired. Consistent with these deficits, evidence from imaging studies points to dysregulation in medial and ventromedial prefrontal cortices, areas activated during performance of inhibition tasks. Other aspects of executive function including updating, shifting and decision making are also deficient in cocaine users, and these deficits are paralleled by abnormalities in patterns of prefrontal cortical activation. The extent to which cocaine plays a role in these effects, however, is not certain, and cannot be determined solely on the basis of human studies. Investigations using a non-human primate model of increasing durations of cocaine exposure revealed that initially the effects of cocaine were restricted to ventromedial and orbital prefrontal cortices, but as exposure was extended the intensity and spatial extent of the effects on functional activity also expanded rostrally and laterally. Given the spatial overlap in prefrontal pathology between human and monkey studies, these longitudinal mapping studies in non-human primates provide a unique window of understanding into the dynamic neural changes that are occurring early in human cocaine abuse.

Distribution of norepinephrine transporters in the non-human primate brain

Noradrenergic terminals in the central nervous system are widespread; as such this system plays a role in varying functions such as stress responses, sympathetic regulation, attention, and memory processing, and its dysregulation has been linked to several pathologies. In particular, the norepinephrine transporter is a target in the brain of many therapeutic and abused drugs. We used the selective ligand [(3)H]nisoxetine, therefore, to describe autoradiographically the normal regional distribution of the norepinephrine transporter in the non-human primate central nervous system, thereby providing a baseline to which alterations due to pathological conditions can be compared. The norepinephrine transporter in the monkey brain was distributed heterogeneously, with highest levels occurring in the locus coeruleus complex and raphe nuclei, and moderate binding density in the hypothalamus, midline thalamic nuclei, bed nucleus of the stria terminalis, central nucleus of the amygdala, and brainstem nuclei such as the dorsal motor nucleus of the vagus and nucleus of the solitary tract. Low levels of binding to the norepinephrine transporter were measured in basolateral amygdala and cortical, hippocampal, and striatal regions. The distribution of the norepinephrine transporter in the non-human primate brain was comparable overall to that described in other species, however disparities exist between the rodent and the monkey in brain regions that play a role in such critical processes as memory and learning. The differences in such areas point to the possibility of important functional differences in noradrenergic information processing across species, and suggest the use of caution in applying findings made in the rodent to the human condition.

Chronic cocaine self-administration is associated with altered functional activity in the temporal lobes of non human primates

Previous studies utilizing a nonhuman primate model have shown that cocaine self‐administration in its initial stages is accompanied by alterations in functional activity largely within the prefrontal cortex and ventral striatum. Continued cocaine exposure may considerably change this response. The purpose of the present investigation was to characterize the effects of reinforcing doses of cocaine on cerebral metabolism in a nonhuman primate model of cocaine self‐administration, following an extended history of cocaine exposure, using the quantitative 2‐[14C]deoxyglucose (2‐DG) method. Rhesus monkeys were trained to self‐administer 0.03 mg/kg/injection (n = 4) or 0.3 mg/kg/injection (n = 4) cocaine and compared to monkeys trained to respond under an identical schedule of food reinforcement (n = 6). Monkeys received 30 reinforcers per session for a total of 100 sessions. Metabolic mapping was conducted at the end of the final session. After this extended history, cocaine self‐administration dose‐dependently reduced glucose utilization throughout the striatum and prefrontal cortex similarly to the initial stages of self‐administration. However, glucose utilization was also decreased in a dose‐independent manner in large portions of the temporal lobe including the amygdala, hippocampus and surrounding neocortex. The recruitment of temporal structures indicates that the pattern of changes in functional activity has undergone significant expansion beyond limbic regions into association areas that mediate higher order cognitive and emotional processing. These data strongly contribute to converging evidence from human studies demonstrating structural and functional abnormalities in temporal and prefrontal areas of cocaine abusers, and suggest that substance abusers may undergo progressive cognitive decline with continued exposure to cocaine.

Abstinence from Chronic Cocaine Self-Administration Alters Striatal Dopamine Systems in Rhesus Monkeys

Although dysregulation within the dopamine (DA) system is a hallmark feature of chronic cocaine exposure, the question of whether these alterations persist into abstinence remains largely unanswered. Nonhuman primates represent an ideal model in which to assess the effects of abstinence on the DA system following chronic cocaine exposure. In this study, male rhesus monkeys self-administered cocaine (0.3 mg/kg per injection, 30 reinforcers per session) under a fixed-interval 3-min schedule for 100 days followed by either 30 or 90 days abstinence. This duration of cocaine self-administration has been previously shown to decrease DA D2-like receptor densities and increase levels of D1-like receptors and DA transporters (DAT). Responding by control monkeys was maintained by food presentation under an identical protocol and the same abstinence periods. [3H]SCH 23390 binding to DA D1 receptors following 30 days of abstinence was significantly higher in all portions of the striatum, compared to control animals, whereas [3H]raclopride binding to DA D2 receptors was not different between groups. [3H]WIN 35 428 binding to DAT was also significantly higher throughout virtually all portions of the dorsal and ventral striatum following 30 days of abstinence. Following 90 days of abstinence, however, levels of DA D1 receptors and DAT were not different from control values. Although these results indicate that there is eventual recovery of the separate elements of the DA system, they also highlight the dynamic nature of these components during the initial phases of abstinence from chronic cocaine self-administration.

Effects of chronic cocaine self-administration on norepinephrine transporters in the nonhuman primate brain

RationaleWhile cocaine blocks dopamine and serotonin transporters, considerably less emphasis has been placed on its effects following blockade of the norepinephrine transporter (NET). To date, no studies have made a systematic investigation of the effects of chronic cocaine on primate NET density.ObjectiveWe previously reported increases in NET density in portions of the monkey bed nucleus of stria terminalis after 100 days of cocaine self-administration. In the present study we extend these findings and assess the changes in [3H]nisoxetine binding in additional brain regions of rhesus monkeys chronically self-administrating cocaine.Results[3H]Nisoxetine binding sites in the A1 noradrenergic cell group were significantly higher after 5 days of cocaine exposure. One hundred days of self-administration also induced a higher density of NET binding within the A1 cell group; however, in addition, the effects extended to the nucleus prepositus, as well as forebrain regions such as hypothalamic nuclei, basolateral amygdala, parasubiculum, and entorhinal cortex.ConclusionsThese data demonstrate that cocaine self-administration alters the noradrenergic system of nonhuman primates. Although cocaine affected NET binding sites in the forebrain projections of both the ventral (VNAB) and dorsal (DNAB) noradrenergic bundles, the alteration in the A1 cell group at the early time-point suggests that the VNAB appears to be more sensitive than the DNAB to the effects of cocaine. Given the role of norepinephrine in arousal and attention, as well as mediating responses to stress, long-term exposure to cocaine is likely to result in significant changes in the way in which information is perceived and processed by the central nervous system of long-term cocaine users.

Recovering from cocaine: Insights from clinical and preclinical investigations

Cocaine remains one of the most addictive substances of abuse and one of the most difficult to treat. Although increasingly sophisticated experimental and technologic advancements in the last several decades have yielded a large body of clinical and preclinical knowledge on the direct effects of cocaine on the brain, we still have a relatively incomplete understanding of the neurobiological processes that occur when drug use is discontinued. The goal of this manuscript is to review both clinical and preclinical data related to abstinence from cocaine and discuss the complementary conclusions that emerge from these different levels of inquiry. This commentary will address observed alterations in neural function, neural structure, and neurotransmitter system regulation that are present in both animal models of cocaine abstinence and data from recovering clinical populations. Although these different levels of inquiry are often challenging to integrate, emerging data discussed in this commentary suggest that from a structural and functional perspective, the preservation of cortical function that is perhaps the most important biomarker associated with extended abstinence from cocaine.

The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats

BACKGROUND Given the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats. METHODS Rats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6 h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule. RESULTS Animals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose. CONCLUSIONS LY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.

Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats

Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, has been used clinically to treat muscle spasticity, rigidity and pain. More recently, interest in the use of baclofen as an addiction medicine has grown, with promising preclinical cocaine and amphetamine data and demonstrated clinical benefit from alcohol and nicotine studies. Few preclinical investigations, however, have utilized chronic dosing of baclofen, which is important given that tolerance can occur to many of its effects. Thus the question of whether chronic treatment of baclofen maintains the efficacy of acute doses is imperative. The neural substrates that underlie the effects of baclofen, particularly those after chronic treatment, are also not known. In the present study, therefore, rats were treated with either a) vehicle, b) acute baclofen (5 mg/kg) or c) chronic baclofen (5 mg/kg, t.i.d. for 5 days). The effects of acute and chronic baclofen administration, compared to vehicle, were assessed using locomotor activity and changes in brain glucose metabolism (a measure of functional brain activity). Acute baclofen significantly reduced locomotor activity (horizontal and total distance traveled), while chronic baclofen failed to affect locomotor activity. Acute baclofen resulted in significantly lower rates of local cerebral glucose utilization throughout many areas of the brain, including the prefrontal cortex, caudate putamen, septum and hippocampus. The majority of these functional effects, with the exception of the caudate putamen and septum, were absent in animals chronically treated with baclofen. Despite the tolerance to the locomotor and functional effects of baclofen following repeated treatment, these persistent effects on functional activity in the caudate putamen and septum may provide insights into the way in which baclofen alters the reinforcing effects of abused substances such as cocaine, alcohol, and methamphetamine both in humans and animal models.

Withdrawal from extended‐access cocaine self‐administration results in dysregulated functional activity and altered locomotor activity in rats

Much work has focused on determining the consequences of cocaine self‐administration on specific neurotransmitter systems, thus neglecting the global changes that occur. Previous imaging studies have focused on the effects of cocaine self‐administration in the presence of high blood levels of cocaine, but have not determined the functional effects of cocaine self‐administration after cocaine has cleared. Extended‐access cocaine self‐administration, where animals administer cocaine for 6 h each day, results in escalation in the rate of cocaine intake and is believed to model the transition from recreational use to addiction in humans. We aimed to determine the functional changes following acute (48 h) withdrawal from an extended‐access, defined‐intake self‐administration paradigm (5 days, 40 injections/day, 6 h/day), a time point when behavioral changes are present. Using the 2‐[14C]deoxyglucose method to measure rates of local cerebral glucose metabolism, an indicator of functional activity, we found reductions in circuits related to learning and memory, attention, sleep, and reward processing, which have important clinical implications for cocaine addiction. Additionally, lower levels of functional activity were found in the dorsal raphe and locus coeruleus, suggesting that cocaine self‐administration may have broader effects on brain function than previously noted. These widespread neurochemical reductions were concomitant with substantial behavioral differences in these animals, highlighted by increased vertical activity and decreased stereotypy. These data demonstrate that behavioral and neurochemical impairments following cocaine self‐administration are present in the absence of drug and persist after cocaine has been cleared.

Functional effects of cocaine self-administration in primate brain regions regulating cardiovascular function

Cocaine abuse is associated with autonomic dysregulation, such as altered blood pressure and heart rate. Both central and peripheral mechanisms have been implicated in mediating these changes, however, to date, no study has examined functional changes in activity within central autonomic-associated brain regions in response to cocaine in non-human primates. The aim of the present study was to measure local cerebral glucose utilization, in selected autonomic brain regions, in rhesus monkeys that had self-administered cocaine (0.3 mg/kg/infusion) for 5 days (initial) or 100 days (chronic). Measurements were compared with control monkeys, in which responding was maintained by food reinforcement. In general, decreased rates of glucose utilization were observed in targeted areas following both 5 and 100 days of cocaine self-administration compared to control values. However, after initial stages of cocaine exposure, significant reductions in the forebrain were restricted to the bed nucleus of stria terminalis and in the brainstem to the nucleus tractus solitarius and dorsomotor nucleus of the vagus nerve. The pattern of significantly altered functional activity induced by chronic 100-day cocaine self-administration extended within the forebrain to include the paraventricular hypothalamic nucleus, and in the brainstem to include additional autonomic-related nuclei, the nucleus ambiguus and locus coeruleus. These results suggest that even at the initial stages of cocaine self-administration, functional changes in activity occur in autonomic and reward-related brain regions. These alterations progress with prolonged cocaine exposure, and therefore may be involved in mediating changes in central autonomic control and the neuroadaptations reported to result from chronic drug abuse.