Non-pharmacological factors that determine drug use and addiction

Abstract

Based on their pharmacological properties, psychoactive drugs are supposed to take control of the natural reward system to finally drive compulsory drug seeking and consumption. However, psychoactive drugs are not used in an arbitrary way as pure pharmacological reinforcement would suggest, but rather in a highly specific manner depending on non-pharmacological factors. While pharmacological effects of psychoactive drugs are well studied, neurobiological mechanisms of non-pharmacological factors are less well understood. Here we review the emerging neurobiological mechanisms beyond pharmacological reinforcement which determine drug effects and use frequency. Important progress was made on the understanding of how the character of an environment and social stress determine drug self-administration. This is expanded by new evidence on how behavioral alternatives and opportunities for drug instrumentalization generate different patterns of drug choice. Emerging evidence suggests that the neurobiology of non-pharmacological factors strongly determines pharmacological and behavioral drug action and may, thus, give rise for an expanded system's approach of psychoactive drug use and addiction.

Keywords: Drug abuse; Drug addiction; Drug instrumentalization; Environment; Social stress.

Figure 1.

Drug preferences in rats that were trained to self-administer heroin and cocaine either at home or outside the home on alternate days and were then given the opportunity to choose between the two drugs within the same session, for several daily sessions (see text for details). At home, most rats exhibited a preference for heroin over cocaine. Outside the home, most rats tended to prefer cocaine to heroin. Some rats did not exhibit significant drug preferences; data from: Caprioli et al. (2009). Both the Mann-Whitney test and the Fisher exact probability test indicated significant differences in preference (p≤0.05).

Figure 2.

Setting preferences for heroin versus cocaine use in individuals with substance use disorder in studies using a within-subject design. Most of these individuals reported using heroin exclusively or prevalently at home. In contrast, the same individuals reported using cocaine exclusively or prevalently outside the home. Similar results were obtained in addicts using the intravenous route or the intranasal route for both drugs. Some addicts did not report clear setting preferences. Data from: Caprioli et al. (2009) and Badiani and Spagnolo, (2013). The McNemar's test indicated a significant within-subject shift in the setting for cocaine vs. heroin taking (p < 0.0001).

Figure 3.

The setting of drug taking affects in opposite directions the intake of drugs that depress the central nervous system (CNS), such as opioid agonists and alcohol, versus drug that have a stimulant effects on the CNS, such as cocaine, amphetamine, and ketamine (data from: Caprioli et al. (2007, 2008), Testa et al. (2011), and De Luca and Badiani (2011)).

Figure 4.

Peri-infusion 50-kHz USVs in the 10 s before and 40 s after each of the ten consecutive self-administered infusions for rats trained to self-administer heroin and cocaine on alternate days, either at home or outside the home. Data were collected on sessions 13 and 14 and were expressed as delta score relative to saline self-administration sessions (sessions 15 and 16); for details see: Avvisati et al. (2016).

Figure 5.

Increase in lever pressing (means ± SEM) during a reinstatement session in rats that were trained to self-administer heroin and cocaine on alternate days, either at home or outside the home, and then underwent an extinction procedure. At the beginning of the reinstatement session, independent groups of rats received non-contingent intravenous infusions of one of three doses of cocaine or heroin. At home, rats relapsed into heroin seeking but not into cocaine seeking. Outside the home, the rats relapsed into cocaine seeking but not into heroin seeking. Data were expressed as change in lever pressing relative to the last extinction session. * and *** indicate a main effect of priming (p≤0.01 and p≤0.0001, respectively); for details see: Montanari et al. (2016)

Figure 6.

Total number of intravenous cocaine infusions self-administered during a 24 h unrestricted-access binge by rats exposed to 10 d of episodic stress (n = 14; light gray bars) and corresponding controls (n = 14; open bars) or exposed to 36 d of continuous social stress (n = 9; dark gray bars) and corresponding controls (n = 8; open bars). All values are means ± SEM; #p < 0.05, ##p < 0.01, compared with the relevant control group (data from: Miczek et al. (2011)).

Figure 7.

Effects of episodic social defeat stress on total IV infusions self-administered in an unlimited access cocaine “binge” (0.3 mg/kg/infusion, FR1) in male (control n=8, stressed n=8) and female (control n=12, stressed n=10) rats. Self-administration terminated after 120 minutes without a cocaine infusion. Values are means ± SEM; #p<0.05, ##p<0.01 vs same-sex control (data from: Holly et al. (2012)).

Figure 8.

20% ethanol intake (g/kg/day) during continuous access 2-bottle choice over the course of 20 days, starting 10 days after moderate (n=39) or mild (n=19) social defeat stress (control, n=29). Data points are 5-day averages ± SEM beginning on the day indicated (i.e. 25 signifies days 25– 29); **p<0.001 vs. controls (adapted from: Norman et al. (2015)).

Figure 9.

Dopamine levels (pmol/15 μl) in the nucleus accumbens. White circles are mice with continuous ethanol (EtOH) access (CA; n = 7), gray triangles are mice with intermittent EtOH access (IA; n = 7), and black squares are socially defeated mice with intermittent EtOH access (Str+IA; n = 7). Arrows denote intra-VTA microinjections of aCSF and 0.6 μg CP376395. Values are means ± SEM, *p < 0.05 vs. CA, #p < 0.05 vs. baseline. The bars show area under the curve (AUC) after the CP376395 microinjection (data from: Hwa et al. (2016)).

Figure 10.

Role of VTA CRF during stress on later cocaine self-administration. Top: Stressed rats pretreated with aCSF before each social defeat (dark gray, n = 11) self-administered significantly more cocaine during a 24 h “binge” compared with aCSF-pretreated nonstressed controls (white, n = 13). This was prevented with intra-pVTA antagonism of CRF-R1 (light gray, CP, n = 4), but not intra-aVTA CRF-R1 antagonism (medium gray, CP, n = 4). Cumulative infusions in 2 h bins are shown on the left, with total infusions shown on the right. Bottom: Conversely, intra-aVTA CRF-R2 antagonism (medium gray, A2B, n = 4), but not intra-pVTA CRF-R2 antagonism (light gray, A2B, n = 5), prevented stress escalation of cocaine self-administration during the 24 h binge. **p < 0.01 vs. aCSF-nonstressed, ###p < 0.001 vs. aCSF-stressed (data from: Holly et al. (2016)).

Figure 11.

Choice between heroin and a nondrug alternative. (a) Top view of an operant chamber showing a rat choosing between a heroin-paired lever and a sweet water-paired lever. (b) Mean preference scores (± SEM) as a function of testing sessions. The horizontal dashed line at 0 represents the indifference level. Values above 0 indicate a preference for water sweetened with saccharin while values below 0 indicate a preference for intravenous heroin. (c) Mean preference scores as a function of i.v. heroin doses. *, different from the indifference level (p< 0.05, t-test) (adapted from: Lenoir et al. (2013)).