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. 2023 Mar 18;7:100148. doi: 10.1016/j.dadr.2023.100148

Prolonged exposure to cocaine self-administration results in a continued progression of alterations in functional activity in a nonhuman primate model

Linda J Porrino 1,⁎, Hilary R Smith 1, Thomas JR Beveridge 1, Mack D Miller 1, Susan H Nader 1, Michael A Nader 1
PMCID: PMC10074498  PMID: 37033159

Highlights

  • •

    Studies of cocaine's effects often use short drug exposures.

  • •

    More prolonged use results in expanded neurometabolic effects in an animal model.

  • •

    Beyond the striatum these effects extend to include broad cortical and limbic areas.

  • •

    These effects more closely mimic those seen in humans with long cocaine use histories.

Keywords: Cocaine, Self-administration, Rhesus monkeys, Glucose utilization

Abstract

Background

Studies of nonhuman primates with exposures of up to 100 days of cocaine self-administration (SA) have provided evidence that the central effects of cocaine progress over time. These durations of cocaine exposure, however, may be insufficient to capture the extent of the neurobiological alterations observed in cocaine users, many of whom use the drug for years. The goal of the present study was to determine whether 1.5 years of cocaine SA would result in further progression of alterations in functional brain activity.

Methods

Adult male rhesus monkeys were exposed to 300 sessions of high-dose cocaine SA over 1.5 years. Following the final session rates of local cerebral glucose utilization (LCGU) were assessed with the 2-[14C]-deoxyglucose method and compared to rates of LCGU in control monkeys who responded for food reinforcement. In addition, LCGU in these animals was compared to a previously published group of monkeys that had self-administered cocaine or food for 100 sessions over a 4–5 month period.

Results

Compared to 100 days of exposure, 300 days of cocaine SA further reduced LCGU in the post-commissural striatum and produced reductions in areas unaffected by the shorter duration of exposure, such as the hypothalamus, all of the amygdala, and large expanses of cortex.

Conclusions

These findings demonstrate a clear progression of the impact of cocaine on functional activity with increasing durations of drug experience and have important implications for the development of potential strategies for the treatment of cocaine use disorder.

1. Introduction

Cocaine use and abuse continue to be intractable public health concerns in the United States as well as worldwide. Neither treatment nor prevention strategies have had a significant impact on this problem. Despite advances in our knowledge of cocaine's cellular and molecular mechanisms, as well as our growing understanding of the effects of cocaine from a systems perspective, the search for effective pharmacotherapeutic agents to treat cocaine use disorder (CUD) has, to date, been largely unsuccessful. Much research has been focused on the development and testing of medications in preclinical settings, but when tested in clinical trials in cocaine users, many of these agents have failed or shown only mixed effects. Recently, there has been considerable attention paid to the difficulties in translating research in preclinical models to effective treatment strategies for substance abuse disorders. The National Institute on Drug Abuse issued a Request for Information detailing some of the issues and considerations for increasing the predictive value of animal models and the development of alternative strategies for predicting potential efficacy of pharmacotherapies in clinical settings. Several recent reviews (Czoty et al., 2016; Smith, 2019; Venniro et al., 2020) have described the features of current models and pointed to a number of the limitations of these models and ways to improve their predictive power. Models that better approximate the central features of human substance use disorders, including choice procedures, behavioral economics, escalated drug intake, and punished drug seeking have been increasingly incorporated into preclinical research approaches. In addition, factors such as social context, early life experience, polysubstance use and individual differences have been introduced in an effort of to develop better platforms for testing candidate medications.

One characteristic of many individuals suffering from CUD is the duration of their use. Most CUD patients who present for treatment have long histories of substance use. In our human-subjects laboratory, the majority of people tested had been using cocaine for an average of 17.9 years, with some subjects using cocaine for as long as 29 years. In contrast, most rodent studies utilize self-administration paradigms in which rodents generally self-administer for shorter durations (5–21 days). Even given the differences in lifespan, cocaine exposure in rodents is still much briefer than the experiences in human cocaine users. Thus, the shorter timeframe in rodents may be insufficient to adequately represent the behavioral and neurobiological effects of long-term cocaine exposure in humans.

Nonhuman primate models offer many advantages over rodent models of CUD, including a better model of the human neuroanatomy (Berger et al., 1991; Joel and Weiner, 2000) and the ability to study long-term (> 1 year) of cocaine self-administration. In our previous work, we have shown that the effects of cocaine exposure on functional brain activity progress with continued cocaine self-administration experience. While initially cocaine alters activity mainly in the ventral striatum, with continued exposure the effects of cocaine spread to involve greater expanses of the dorsal striatum and larger portions of the cortex and limbic system (Porrino et al., 2002, 2004, 2007). The longest exposure time in these studies was 100 sessions (∼ 3.3 months) of high- (0.3 mg/kg per injection) doses of cocaine self-administration experience (referred to in this paper as “chronic” exposure), resulting in intakes of ∼900 mg/kg, which is substantially greater than many preclinical studies of brain function. These observations are consistent with those of others (Henry et al., 2010; Kohut et al., 2020; Jedema et al., 2021) who, using different imaging approaches, have shown similar expansions of effects of cocaine with increasing durations of use and higher total intakes. For example, Henry et al., using positron emission tomography in nonhuman primate models of cocaine use, noted that with increasing access (60 limited access and 60 extended access conditions; total intakes averaging 250 mg/kg), the effects of cocaine expanded throughout the cortex and striatum. Similarly, Jedema et al. found increasing broad structural changes after approximately 140 sessions (total intakes, 600 mg/kg) using magnetic resonance imaging technology. However, when considering human use patterns, these durations and total intakes, too, are still relatively short and low and may not capture the full extent of the neurobiological alterations observed in cocaine users seeking treatment.

The goal of the present study was to determine, in a nonhuman primate model of long-term cocaine self-administration, whether even longer durations of exposure and higher total intakes would result in a continued progression of the distribution of alterations in functional brain activity. Rates of glucose utilization (LCGU) of monkeys who self-administered cocaine for 300 sessions over a 1.5 year period of time (referred to as “prolonged” exposure) were measured with the 2-[14C]-deoxyglucose (2-DG) method and compared to rates of LCGU in monkeys who responded for food reinforcement for a similar duration under the identical schedule of reinforcement. In addition, in order to provide a more complete depiction of the temporal course, rates of glucose utilization in these animals were compared to a previously published group of monkeys (re-analyzed for the current study; Beveridge et al., 2006; Porrino et al., 2004) that had self-administered 0.3 mg/kg per injection cocaine for 100 sessions over a 4–5 month period and their respective food-reinforced controls.

2. Material and methods

2.1. Subjects

A total of 8 male rhesus monkeys (Macaca mulatta) served as subjects (ages 7–13 yrs). All procedures were performed in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and were reviewed and approved by the Animal Care and Use Committee of Wake Forest University. In addition, data from 9 animals (5 food-reinforced controls and 4 cocaine self-administering monkeys; ages 7–13 yrs) from a previous study (Beveridge et al., 2006; Porrino et al., 2004) were included in the analyses. These animals had identical experimental histories except for the duration of reinforcement exposure (100 sessions vs. 300 sessions in the current study).

2.2. Cocaine self-administration

Details of the surgical and self-administration procedures have been described previously (Beveridge et al., 2006, 2009; Nader et al., 2002), with the exception of the cumulative duration of exposure. Briefly, monkeys were taken from their home cage, placed in primate chairs, and trained to respond under a fixed-interval 3-minute (FI-3-min) schedule of food reinforcement in operant chambers (previously described) until stable performance was obtained. Animals were then randomly assigned to food-reinforced (N = 4) or prolonged cocaine-reinforced (N = 4) groups and continued to respond under an FI-3-min schedule for either food or cocaine (0.3 mg/kg per injection) presentation. Experimental sessions continued for a total of 300 sessions (2750 mg/kg total cocaine intake); sessions ended after 30 reinforcers were delivered. Approximately 2 days before the end of the study, each monkey was surgically implanted with an indwelling catheter in the femoral artery. At the end of the 300th cocaine self-administration or food-reinforcement session, the terminal 2DG experiment was conducted (see below). In addition, for the purposes of the analysis, data from 9 animals (5 food-reinforced controls and 4 animals that had self-administered for 100 sessions, all under the identical conditions used in the current study, with total cocaine intakes of 900 mg/kg; “chronic” exposure) were included. Data from these animals have been previously reported (Beveridge et al., 2006; Porrino et al., 2004).

2.3. Measurement of local cerebral glucose utilization

The 2DG procedure was initiated at the end of the final behavioral session via infusion of an intravenous pulse of 2.76 MBq/kg [14C]2DG (PerkinElmer, Waltham, MA; specific activity 1850–2035 MBq/mmol), followed by a flush of heparinized saline, through catheters that exited through the back of the chamber. Timed arterial blood samples were collected from outside the operant chamber, to measure plasma [14C] concentrations, determined by liquid scintillation spectrophotometry (Beckman Instruments, Fullerton, CA), and plasma glucose concentrations, assessed using a glucose analyzer (Analox Instruments, London, UK). Approximately 45 min after tracer injection, animals were euthanized by an intravenous overdose of sodium pentobarbital (100 mg/kg). Monkeys were taken from the operant chambers to the necropsy suite and brains were removed rapidly, blocked, frozen in isopentane (−45 °C), and stored at −80 °C. Processing for autoradiography and quantitative densitometry of autoradiograms were carried out according to procedures previously reported (Beveridge et al., 2006; Porrino et al., 2004).

2.4. Statistical analyses

To make meaningful comparisons of temporal differences in cocaine-induced alterations in LCGU, the current data with prolonged cocaine exposure were combined with data from previously published studies (Beveridge et al., 2006; Porrino et al., 2004) in which animals self-administered cocaine for 100 sessions (chronic cocaine exposure). In total, data from 9 control (food-reinforced) and 8 cocaine self-administering animals were included in the current analysis (controls, N = 9; 100 cocaine self-administration sessions, N = 4; 300 cocaine self-administration sessions, N = 4). Controls were combined as no differences between study groups were observed. Autoradiograms from both studies were analyzed by the same experimenters to ensure the validity of comparisons between the two studies across brain regions and included re-analyses of autoradiograms from previous studies. Rates of glucose utilization were measured in 42 discrete brain regions. Values of rates of LCGU were analyzed in seven neuroanatomical groups (striatum, basal ganglia, frontal cortex, posterior cortex, thalamus, hypothalamus and limbic regions) by means of a two-way analysis of variance (treatment group X brain region, with brain region considered a repeated measure). In those neuroanatomical groups in which significant treatment effects and significant interactions (region x treatment) were observed, individual brain regions were further assessed with the Least Significant Difference tests for multiple comparisons. All statistical analyses were carried out using SPSS Statistical Software (version 26; IBM SPSS Software, Armonk, NY).

3. Results

3.1. Overview

Monkeys in the cocaine self-administration group earned 30 reinforcers per session (0.3 mg/kg/injection, 9.0 mg/kg/session) and, as previously reported (Beveridge et al., 2006; Porrino et al., 2004) responded at lower rates than food controls. Plasma glucose levels measured just prior to the initiation of the 2DG procedure did not differ significantly between or within groups: food controls, 0.74 ± 0.06 mg⁄ml (mean ± SEM); chronic cocaine (100 sessions self-administration), 0.77 ± 0.03 mg⁄ml; prolonged cocaine (300 sessions self-administration), 0.74 ± 0.09 mg⁄ml. Rates of local cerebral glucose metabolism were measured in 42 brain regions and the data are shown in Table 1, Table 2, Table 3. Global rates of cerebral metabolism were significantly lower in animals that self-administered cocaine for 100 sessions (3.3 months) and 300 sessions (1.5 years); 42.5 ± 2.1 µmol/100 g/min and 40.7 ± 1.9; mean ± S.E.M., respectively, when compared to those of food controls (49.0 ± 0.7 µmol/100 g/min; one way ANOVA, Least Significant Difference post-hoc test, p < .001). There were, however, no significant differences in global rates of cerebral metabolism between the two cocaine self-administration groups. Data from specific brain regions are described in detail below.

Table 1.

Striatum/ Basal Ganglia.

Brain Region Food-reinforced controls (N = 9) Chronic Cocaine Self-Administration (100 sessions) (N = 4) Prolonged Cocaine Self-Administration (300 sessions) (N = 4)
Rostral Pre-commissural Striatum
 Caudate 58 ± 1.6 44 ± 1.6** 46 ± 2.9**
 Putamen 59 ± 2.2 44 ± 2.1** 48 ± 3.6**
Caudal Pre-commissural Striatum
 Caudate 61 ± 1.7 48 ± 0.8** 50 ± 2.9**
 Putamen 62 ± 2.2 47 ± 1.1** 55 ± 2.1**
 Nucleus accumbens-core 46 ± 1.0 35 ± 1.2** 35 ± 1.3**
 Nucleus accumbens-shell 45 ± 1.4 32 ± 1.9** 33 ± 1.8**
Post-commissural Striatum
 Caudate 51 ± 1.0 47 ± 2.1 43 ± 1.7*t
 Putamen 55 ± 1.4 48 ± 1.1 46 ± 1.2*t
Basal ganglia
 Globus pallidus 36 ± 2.0 36 ± 3.4 38 ± 2.6
 Subthalamus 35 ± 2.0 35 ± 3.3 38 ± 2.6
 Ventral tegmental area 26 ± 2.1 22 ± 3.9 18 ± 2.2t
 Substantia nigra compacta 45 ± 1.6 44 ± 4.2 34 ± 2.8** t
 Substantia nigra reticulata 38 ± 1.5 33 ± 3.6 36 ± 2.6
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†Data represent rates of local cerebral glucose utilization (μmol/100 g/min) expressed as means ± S.E.M.

* P < .05, ** P < .01, different from Food Controls, Least Significant Test for multiple comparisons following two-way analysis of variance (treatment group X brain region, with brain region considered a repeated measure).

tP < 0.05, different from chronic CSA group, Least Significant Test for multiple comparisons following two-way analysis of variance (treatment group X brain region, with brain region considered a repeated measure).

Table 2.

Cortico-thalamic Areas.

Brain Region Food-reinforced controls (N = 9) Chronic Cocaine Self-Administration (100 sessions) (N = 4) Prolonged Cocaine Self-Administration (300 sessions) (N = 4)
Frontal Cortex
 Frontal pole 56 ± 1.7 48 ± 3.9 42 ± 4.0**
 Medial prefrontal 49 ± 1.7 38 ± 1.2** 38 ± 2.1**
 Orbital prefrontal 60 ± 3.0 49 ± 2.3* 47 ± 2.4**
 Dorsolateral prefrontal 59 ± 1.6 53 ± 2.0 54 ± 2.7
 Anterior cingulate 53 ± 1.6 41 ± 2.8* 46 ± 1.8*
 Motor (area 4) 51 ± 1.7 55 ± 3.6 49 ± 2.5
Temporal and Parietal Cortex
 Temporal pole 45 ± 2.5 32 ± 2.2** 28 ± 2.2**
 Insula 48 ± 1.4 43 ± 2.0 41 ± 2.6**
 Temporal gyrus 57 ± 1.8 52 ± 2.5 44 ± 2.1**t
 Entorhinal 41 ± 1.8 38 ± 2.7 31 ± 3.7**t
 Posterior cingulate 57 ± 3.4 41 ± 4.7* 42 ± 4.0*
 Inferior parietal cortex 54 ± 3.4 42 ± 2.9 41 ± 4.3*
Thalamus
 Midline 53 ± 1.5 43 ± 3.1** 42 ± 1.8**
 Ventral anterior 43 ± 1.8 40 ± 2.7 38 ± 0.9
 Mediodorsal 53 ± 2.0 43 ± 1.2** 43 ± 1.2**
 Ventrolateral 41 ± 1.8 38 ± 2.9 40 ± 1.7
 Habenula 39 ± 3.1 27 ± 1.2* 27 ± 2.0*
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†Data represent rates of local cerebral glucose utilization (μmol/100 g/min) expressed as means ± S.E.M.

* P < .05, ** P < .01, different from Food Controls, Least Significant Test for multiple comparisons following two-way analysis of variance (treatment group X brain region, with brain region considered a repeated measure).

tP < 0.05, different from chronic CSA group, Least Significant Test for multiple comparisons following two-way analysis of variance (treatment group X brain region, with brain region considered a repeated measure).

Table 3.

Limbic and related subcortical areas.

Brain Region Food-reinforced controls (N = 9) Chronic Cocaine Self-Administration (100 sessions) (N = 4) Prolonged Cocaine Self-Administration (300 sessions) (N = 4)
Amygdala
 Medial 28 ± 1.2 26 ± 1.6 20 ± 0.9**t
 Central 26 ± 1.8 24 ± 1.3 18 ± 1.0**t
 Basolateral 35 ± 1.2 30 ± 1.8* 23 ± 1.3**t
 Anterior 27 ± 1.6 26 ± 1.3 20 ± 0.6**t
Hypothalamus
 Preoptic area 30 ± 1.8 28 ± 1.9 20 ± 0.7**t
 Paraventricular 33 ± 1.4 26 ± 2.2 21 ± 1.7*
 Medial 31 ± 1.2 28 ± 1.9 24 ± 1.3**
 Lateral 30 ± 0.9 27 ± 2.8 23 ± 1.6**
 Posterior 38 ± 1.9 32 ± 2.8 24 ± 4.2**t
Limbic-Associated
 Bed nucleus of stria terminalis 35 ± 1.2 31 ± 1.7 26 ± 1.4**t
 Lateral septum 29 ± 1.4 24 ± 2.8 25 ± 1.5
 Hippocampus 36 ± 1.5 30 ± 1.7* 26 ± 2.1**
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†Data represent rates of local cerebral glucose utilization (μmol/100 g/min) expressed as means ± S.E.M.

* P < .05, ** P < .01, different from Food Controls, Least Significant Test for multiple comparisons following two-way analysis of variance (treatment group X brain region, with brain region considered a repeated measure).

tP < 0.05, different from chronic CSA group, Least Significant Test for multiple comparisons following two-way analysis of variance (treatment group X brain region, with brain region considered a repeated measure).

3.2. Striatum

In the striatum (Table 1), there were main effects of brain region (F7,14 = 44.024, p = .000) and group (F2,14 = 22.156, p < .001), as well as a significant region x group interaction (F14,14 = 1.866, p = .046). Rates of glucose utilization across the striatum were significantly lower in both the chronic (100 sessions; p < .002) and the prolonged (300 sessions; p < .002) groups compared to food controls, but not different from one another. Within individual striatal regions, post-hoc analyses revealed that rates of glucose utilization in all portions of the anterior and posterior pre-commissural striatum including the ventral striatum, caudate nucleus and putamen of animals in the chronic group were significantly lower than rates of food controls. There were no significant differences in any portion of the post-commissural striatum of the chronic animals as compared to controls. Similarly, rates of glucose utilization of animals in the prolonged cocaine self-administration group were lower in all portions of the ventral striatum, pre-commissural caudate and putamen as compared to rates of glucose utilization of the food controls. Rates of glucose utilization within the prolonged group were also reduced in both the post-commissural caudate and putamen, effects not seen in the chronic group. Significant differences between the chronic and prolonged groups were observed in the post-commissural striatum (Fig. 1).

Fig. 1.

Fig. 1

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Mean percent difference of rates of local cerebral glucose utilization (µmol/100 g/min) of selected brain regions in the striatum and cortex of animals measured after 100 (chronic; N = 4) and 300 (prolonged; N = 4) sessions of cocaine self-administration as compared to rates of food controls (N = 9) assessed immediately after their final session. Percentages were calculated by comparing individual rates in the chronic and prolonged groups to the mean of food controls. Data shown are the mean ± SEM. *p < .05, Student's t-test comparing chronic and prolonged groups. Areas in which differences are significant are labeled in bold. Abbreviations: MPFC, medial prefrontal cortex; NAc, nucleus accumbens core; PostCCaud, post-commissural caudate; PostCPut, post-commissural putamen; PreCCaud, precommissural caudate; PreCPut, precommissural putamen; Temporal, temporal gyrus.

3.3. Basal ganglia

Within the basal ganglia (Table 1), there was a significant main effect of brain region (F4,14 = 18.054, p<.001). However, there was no significant effect of group (F2,14 = 1.756, NS) or interaction (F8,14 = 1.808, NS). Within individual brain regions significant differences were noted in the ventral tegmental area and substantia nigra compacta of the prolonged groups as compared to both controls and to the chronic group.

3.4. Frontal cortex

Within frontal cortical regions (Table 2), statistical analyses revealed a significant main effect of brain region (F5,14 = 17.344, p<.001) and group (F2,14 = 10.116, p = .003), as well as a significant region x group interaction (F10,14 = 3.647, p = .001). Within individual divisions of frontal cortex, rates of glucose utilization in the chronic group were significantly lower than those of control animals in the medial and orbital prefrontal and anterior cingulate cortex. In contrast, rates of metabolism in the prolonged group were significantly lower than food controls in the frontal pole, medial, orbital, and anterior cingulate cortex. Rates of glucose utilization in the frontal pole of animals in the prolonged group were significantly lower than those of animals in the chronic group.

3.5. Temporal and parietal cortex

In the temporal and parietal cortex (Table 2), statistical analyses revealed a significant main effect of brain region (F5,14 = 17.221, p = .001) and of group (F2,14 = 11.469, p = .001), as well as a significant region x group interaction (F10,14 = 2.608, p = .045). Within individual cortical regions, rates of glucose utilization of the chronic group were significantly lower in the temporal pole and posterior cingulate cortex compared with food controls. Compared to food controls, LCGU of animals in the prolonged group that self-administered cocaine for 300 sessions were lower in the temporal pole, insula, temporal and entorhinal cortex, as well as in the posterior cingulate and inferior parietal cortex. Significant differences between chronic and prolonged groups were noted in the entorhinal and temporal cortex (Fig. 1).

3.6. Thalamus

Within the thalamus (Table 2), there was a significant main effect of brain region (F4,14 = 42.371, p = 0.000) and of group (F2,14 = 6.211, p = .012), as well as a significant region x group interaction (F8,14 = 2.815, p = 0.011) . Within individual thalamic nuclei, rates of glucose utilization of animals in the chronic group were significantly lower than those of the food controls in midline and mediodorsal nuclei, while rates in animals in the prolonged group were significantly lower in midline, mediodorsal and habenula nuclei. There were no differences between the chronic and prolonged groups within the nuclei of the thalamus.

3.7. Limbic system

Within the limbic regions (Table 3), there was a significant main effect of brain region (F6,14 = 18.346, p = .001) and of group (F2,14 = 13.073, p = .001), as well as a significant region x group interaction (F12,14 = 2.561, p = .048). Within specific portions, rates of glucose utilization of animals in the chronic group were significantly lower than those of the food controls in the hippocampus and basolateral amygdala. In contrast, rates of glucose utilization in animals in the prolonged group were significantly lower than those of food controls and the chronic group, throughout the amygdala, specifically in the medial, central, anterior, and basolateral nuclei, as well as in the hippocampus and bed nucleus of the stria terminalis. Significant differences between the chronic and prolonged groups were noted in all portions of the amygdala as well as the bed nucleus of the stria terminalis (Fig. 2) with rates within the prolonged group lower than those of the chronic group.

Fig. 2.

Fig. 2

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Mean percent difference of rates of local cerebral glucose utilization (µmol/100 g/min) of selected brain regions in the limbic system including amygdala and hypothalamus animals measured after 100 (chronic; N = 4) and 300 (prolonged; N = 4) sessions of cocaine self-administration as compared to rates of food controls (N = 9) assessed immediately after their final session. Percentages were calculated by comparing individual rates in the chronic and prolonged groups to the mean of food controls. Data shown are the mean ± SEM. *p < .05, Student's t-test between chronic and prolonged groups. Areas in which differences are significant are labeled in bold. Abbreviations: AAA, anterior amygdala area; BLA, basolateral amygdala nucleus; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; HPC, hippocampal formation; MH, medial hypothalamus; POA, Preoptic area of the hypothalamus.

3.8. Hypothalamus

Within the hypothalamus (Table 3), there was a significant main effect of brain region (F4,14 = 6.265, p = .001 and of group (F2,14 = 12.124, p = .001), as well as a significant region x group interaction (F8,14 = 2.237, p = .038). LCGU in animals in the prolonged group, but not the chronic group, were significantly lower than those of food controls in the preoptic area, paraventricular, medial, lateral and posterior nuclei of the hypothalamus. Significantly lower rates of glucose utilization were observed in the prolonged groups as compared to the chronic group in the preoptic area and the posterior hypothalamus (Fig. 2).

4. Discussion

The results of the current study demonstrate that prolonged cocaine self-administration alters rates of functional activity, as reflected by rates of local cerebral glucose utilization, throughout wide expanses of the brain including the striatum, prefrontal, temporal and parietal cortices, thalamus, basal ganglia and limbic system. These effects were more extensive and more intense following prolonged exposure to cocaine self-administration than following shorter exposure times, demonstrating a clear progression of the impact of cocaine on functional activity with continued experience with the drug. Following more prolonged exposure (300 sessions over ∼ 1.5 years with total intakes of 2750 mg/kg), continued cocaine self-administration further reduced glucose utilization rates in the post-commissural striatum and produced significant reductions in functional activity throughout all portions of the amygdala, hypothalamus, and large expanses of cortex, areas unaffected with shorter cocaine exposure histories (Figs. 1 and 2; Beveridge et al., 2006; Porrino et al., 2004). Thus, the effects of cocaine use progress from its effects in the earliest phases of cocaine experience studied after 5 days of self-administration (Porrino et al., 2002) when only the ventral striatum, rostromedial caudate and medial portions of the prefrontal cortex were altered, to encompass cognitive, autonomic, motor and sensory brain networks as cocaine use becomes more chronic (100 sessions) (Beveridge et al., 2006; Porrino et al., 2004) and prolonged (300 sessions) as seen here. Although the 300 sessions of cocaine self-administration along with the 2750 mg/kg total intakes used in the current study, already longer and greater than previous studies (Henry et al., 2010; Jedema et al., 2021; Kohut et al., 2020) of extended cocaine use, are not nearly as numerous or intakes as high as many cocaine users experience over the course of their drug histories, these data do indicate that the consequences of cocaine continue to expand and accumulate with continued use. This expansion of effects has important implications for treatment and recovery in that our focus on reversing the effects in a single system like the reward system are likely not to be sufficient to counteract its consequences throughout the many brain networks that long-term cocaine use impacts.

In considering the progression of the disruptions in functional activity that are the result of cocaine self-administration over time, it appears that many of the effects, especially those in striatum, prefrontal and temporal cortex, and thalamus occur relatively early in the trajectory of cocaine exposure, certainly within the first 100 sessions in our monkey models (Beveridge et al., 2006; Porrino et al., 2002, 2004). However, one of the more striking findings of the current study was the growing disruption of functional activity in the amygdala and hypothalamus that accompanied prolonged cocaine self-administration. Previous studies had shown only limited post-self-administration effects in portions of the amygdala (e.g. basolateral amygdala) and hypothalamus (e.g. paraventricular nucleus) following 100 sessions of cocaine experience, whereas in the current study widespread decreases in glucose utilization were seen throughout both regions. Numerous studies have implicated both the hypothalamus and amygdala in the regulation of stress, social behaviors, cue reactivity, homeostatic regulation, and autonomic function, among others (see, for example Heimer and Van Hoesen, 2005; Janak and Tye, 2015; McEwen, 2007). As has been shown, persistent disruptions in neural processing in these brain regions can then have wide influence on the control of these processes and behaviors, potentially resulting in increased drug taking, disrupted patterns of social interactions, increased anxiety, and interruptions in learning (Everitt et al., 1999; Jasinska et al., 2014; Koob and Kreek, 2007; Marchant, 2019; See et al., 2003).

The gap in research we are attempting to address “if or how the effects of cocaine on functional brain activity change with continued use” is a very difficult one to answer in human research. Most cocaine users who present for studies have long histories of cocaine use, often use many other substances including tobacco, alcohol, opiates and other stimulants, and have varied patterns of use and routes of administration. There are also differences in environmental circumstances (e.g., education, employment, housing, etc.) that could affect cocaine-related brain measures. The use of preclinical models of cocaine use provides significant advantages to address such questions, in this case, focusing exclusively on the pharmacological effects of cocaine. Close control of dose, frequency of use, and importantly duration of use, along with the elimination of potential pre-existing conditions and the confounds of other substance use are among the factors that permit direct inferences about causality not obtainable in studies of human cocaine users. Furthermore, nonhuman primates, as were employed in the current studies, have close homology to humans in terms of neuroanatomy, transmitter distribution, cognitive repertoires, and social interactions, increasing the ability to translate findings about the consequences of cocaine directly to aspects of human drug use. Similarities in the cytoarchitecture, connectivity patterns and neurochemistry of the cortex and striatum, in particular, of humans and nonhuman primates provide the basis for delineating the detailed trajectory of the regional distribution of alterations in functional activity resulting from continued cocaine use as seen in the current studies.

This study has several limitations that should be noted. The study was conducted only in males, although another study using PET imaging approaches that has shown expansion of cocaine effects with increasing exposure has included both sexes (Henry et al., 2010). Comparisons of males and females should be considered in future research. In addition, this investigation was cross-sectional by design. Ideally, repeated testing at multiple time points in the same animals would provide a more detailed picture of the trajectory of the progression of neurobiological alterations in function that occur as a result of cocaine use over time.

In summary, the current study adds to our understanding of the time course and anatomical trajectory of the effects of continued cocaine self-administration on functional brain activity as measured with the 2-deoxyglucose method. With continued use, the effects of cocaine spread from mainly ventral striatum and its direct connections in the initial phases of use (Porrino et al., 2002), to encompass more dorsal aspects of the striatum and larger expanses of the cortex and thalamus with more chronic exposure (Beveridge et al., 2006; Porrino et al., 2004, 2007), to even greater expanses of the striatum and cortex, as well as the amygdala and hypothalamus with even more prolonged use.

5. Conclusion

These findings have important implications for the development of potential strategies for the treatment of CUD. Many preclinical studies of the effects of candidate pharmacotherapies employ experimental paradigms that use relatively short durations of cocaine self-administration experience to test their potential therapeutic effects and may fail to consider wider influences of cocaine that develop with continued use. Testing with longer durations of exposure may provide stronger translational evidence before undertaking expensive clinical trials in individuals with CUD.

Contributors

All authors have reviewed and approved the final manuscript.

CRediT authorship contribution statement

Linda J. Porrino: Conceptualization, Methodology, Formal analysis, Resources, Writing – original draft, Visualization, Supervision, Funding acquisition. Hilary R. Smith: Methodology, Validation, Formal analysis, Investigation, Writing – review & editing, Visualization, Supervision. Thomas J.R. Beveridge: Conceptualization, Methodology, Formal analysis, Writing – review & editing, Investigation, Visualization, Supervision. Mack D. Miller: Methodology, Software, Investigation. Susan H. Nader: Formal analysis, Investigation, Visualization, Supervision. Michael A. Nader: Conceptualization, Methodology, Formal analysis, Resources, Writing – review & editing, Supervision, Funding acquisition.

Declaration of Competing Interest

None to declare.

Acknowledgements

This work was supported by the National Institute on Drug Abuse grants DA009085 and DA006634.

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