Opiate versus psychostimulant addiction: the differences do matter

Abstract

The publication of the psychomotor stimulant theory of addiction in 1987 and the finding that addictive drugs increase dopamine concentrations in the rat mesolimbic system in 1988 have led to a predominance of psychobiological theories that consider addiction to opiates and addiction to psychostimulants as essentially identical phenomena. Indeed, current theories of addiction - hedonic allostasis, incentive sensitization, aberrant learning and frontostriatal dysfunction - all argue for a unitary account of drug addiction. This view is challenged by behavioural, cognitive and neurobiological findings in laboratory animals and humans. Here, we argue that opiate addiction and psychostimulant addiction are behaviourally and neurobiologically distinct and that the differences have important implications for addiction treatment, addiction theories and future research.

Figure 1. Dopamine receptor blockade or lesions of the mesolimbic dopamine system decrease cocaine reward but not heroin reward

a | The effect of dopamine receptor blockade: rats were trained to lever press for intravenous heroin (0.06 mg kg⁻¹ per infusion) or cocaine (0.75 mg kg¹ per infusion) on a fixed-ratio 1 (FR1) reinforcement schedule (each lever press was reinforced with drug infusion). After stable self-administration, the rats were injected on different days with different doses of the dopamine receptor antagonist a-flupenthixol (left part). Lower doses (0.1 or 0.2 mg kg⁻¹) of a-flupenthixol increased cocaine intake but not heroin intake (right part); this effect presumably reflects a compensatory response to offset a decrease in the rewarding effects of cocaine but not heroin. A higher dose of a-flupenthixol (0.4 mg kg⁻¹), which causes sedation, decreased both heroin and cocaine self-administration (right part). b | The effect of dopaminergic lesions: rats were trained to self-administer heroin or cocaine, as above. After stable self-administration, dopamine terminals in the nucleus accumbens (NAc) were lesioned with 6-hydroxydopamine (6-OHDA) (left part). Post-lesion responding for cocaine decreased over days, reflecting extinction of cocaine-reinforced responding. By contrast, post-lesion responding for heroin increased over days, reflecting recovery of the rewarding effects of heroin (right part). DA, dopamine; DAR, dopamine receptor; DAT, dopamine transporter; GABAR, GABA recptor; MOR, mu opioid receptor; VTA, ventral tegmental area. Part a is modified, with permission, from REF. 20 © (1982) Springer. Part b is modified, with permission, from REF 21 © (1984) Springer.

Figure 2. Morphine and cocaine have opposite effects on structural neuroplasticity in the NAc and mPFC

a | Groups of rats were trained to self-administer morphine or cocaine intravenously for several weeks. The control groups were given daily intravenous infusions of vehicle for the same period of time. After 1 month of withdrawal from the drugs, the rats’ brains were processed using the Golgi staining procedure. Rats that were exposed to cocaine showed increased dendritic branching and increased spine density in both nucleus accumbens (NAc) medium spiny neurons and medial prefrontal cortex (mPFC) pyramidal neurons. By contrast, rats that were exposed to morphine had both reduced dendritic branching and reduced spine density in these brain regions. b | A summary of changes in spine density and dendritic branching that occur after exposure to cocaine or morphine relative to controls. A dissociation between the effects of cocaine and morphine was also observed in the orbital prefrontal cortex (oPFC) and in the primary somatosensory cortex (S1). Data from REF. 71.

Figure 3. Initiation of drug use and transition to compulsive drug use

a | In a runway procedure, two groups of rats were trained to traverse a straight alley to obtain either five heroin injections (0.06 mg kg⁻¹ per infusion) or five cocaine injections (0.75 mg kg⁻¹ per infusion) in the goal box. In heroin-trained rats, the running times of rats to the goal box to obtain heroin infusions decreased over days, indicating that heroin serves as an operant reinforcer (reward). In cocaine-trained rats, the time to obtain cocaine infusions increased over days, owing to repeated cycles of forward locomotion and retreats before reaching the goal box (a behavioural pattern that mimics the behaviour of hungry rats that receive both food and shock in the goal box). b | In the unlimited drug self-administration procedure, two groups of rats were trained to lever press for intravenous heroin (0.01 mg kg⁻¹ per infusion) or cocaine (1.0 mg kg⁻¹ per infusion) on a fixed-ratio 1 (FR1) reinforcement schedule for 24 hours per day. Heroin-trained rats gradually increased their drug intake over days and then maintained stable drug intake, whereas cocaine-trained rats rapidly lost control over cocaine intake and died of drug overdose within 12 days. cTo test the effect of impulsivity on self-administration, groups of naive rats were first assessed for trait impulsivity in the five-choice serial-reaction time test. Animals that showed premature responses — reaction times (RTs) were shorter than the inter-trial interval (ITI) — were classified as high impul-sivity, and animals that responded only when a stimulus appeared — reaction times were equal to the inter-trial interval — were classified as low impulsivity (top panels). They were then trained to lever press for either intravenous heroin (0.04 mg kg⁻¹ per infusion) or cocaine (0.25 mg kg⁻¹ per infusion). After 5 days of short access (1 h per d) to heroin or cocaine, the rats were given extended (6 h per d) access to the drugs for 18 consecutive days. High impulsivity predicted escalation of cocaine self-administration but not heroin self-administration (bottom panels). Part a is modified, with permission, from REF. 103 © (1993) Elsevier. Part b, data from REF. 117. Part c, left graph is modified, with permission, from REF. 29 © (2010) Springer. Part c, right graph is modified, with permission, from REF. 133 © (2007) American Association for the Advancement of Science.

Figure 4. Similarities and differences in the brain sites controlling reinstatement of cocaine seeking and heroin seeking

a | Horizontal section showing the mesocorticolimbic dopamine pro-jections (shown by purple lines) from the ventral tegmental area (VTA) and nigrostriatal dopamine projections (shown by dashed purple lines) from the substantia nigra (SN) to various brains areas, and the glutamatergic projections (shown by blue lines) to the nucleus accumbens (NAc). b | Several brain sites are implicated in the reinstatement of both heroin seeking and cocaine seeking. The brain areas that are involved depend on the way in which reinstatement is induced — by exposing animals to non-contingent injections of a drug (‘drug priming’), to drug-associated discrete or contextual cues, or to stress. c | Some brain sites are differentially implicated in heroin reinstatement (shown in orange) and cocaine reinstatement (shown in purple), depending on how reinstatement was induced. The basolateral and central nuclei of the amygdala (BLA and CeA, respectively), the bed nucleus of the stria terminalis (BNST) and the ventromedial prefrontal cortex (vmPFC) are differentially implicated in the reinstatement of heroin seeking induced by heroin priming. The vmPFC is also differentially involved in the reinstatement of heroin seeking that is induced by exposure to heroin-paired discrete cues or contextual cues. By contrast, the dorsomedial PFC (dmPFC) and the NAc core are differentially implicated in the reinstatement of cocaine seeking induced by exposure to cocaine-associated contextual cues. DH, dorsal hippocampus; DLS, dorsolateral striatum; VH, ventral hippocampus; VP ventral pallidum. Brain sections are modified, with permission, from REF. 256 © (2005) Elsevier.

Figure 5. Setting differentially affects heroin and cocaine use in rats and humans

a | In a study that examined drug taking as a function of setting, standard two-lever self-administration chambers were used (one lever was paired with drug infusions and the other lever was inactive). Some rats were transferred to the chambers immediately before the start of the sessions (referred to as non-resident rats), whereas other rats were kept in these chambers at all times (referred to as resident rats). Heroin was more rewarding in the resident rats than in the nonresidents rats (indicated by an upward shift in the dose-response curve). By contrast, cocaine was more rewarding in the non-resident rats than in the residents rats (indicated by a left shift in the dose-response curve of non-resident rats). b | In a study that examined drug-induced neural activity in the caudate nucleus as a function of setting, drug-naive resident and non-resident rats with intravenous catheters received a single ‘self-administration dose’ of either heroin (25 µg kg⁻¹) or cocaine (400 µg kg⁻¹), and their brains were processed 30 min later for in situ hybridization of Fos mRNA expression. Cocaine exposure induced greater increases in Fos expression in the dorsal and ventral parts of the caudate nucleus of non-resident rats than in that of resident rats, whereas heroin exposure induced greater increases in Fos expression in resident rats than non-resident rats. c | In a study that examined drug preference as a function of setting, resident and non-resident rats with double-lumen catheters were first trained to self-administer heroin and cocaine on alternate days, and were then given the opportunity to choose between cocaine and heroin within the same session. Most resident rats preferred heroin over cocaine, whereas most non-resident rats preferred cocaine over heroin. d | In a study that examined setting preferences as a function of drug in humans, most addicts reported using heroin at home and cocaine outside the home, regardless of whether the two drugs were injected (top panel) or snorted (bottom panel). Only a minority of addicts (<10%) indicated no clear preference for the setting of drug taking. Part a, left graph is modified, with permission, from REF. 183 © (2007) Springer. Part a, right graph, data from REF. 182. Part b is modified, with permission, from REF. 188 © (2009) Springer. Part c is modified, with permission, from REF. 184. © (2009) Elsevier. Part d, data from REFS. 184, 207.