Methamphetamine (Meth) is an incredibly addictive psychostimulant with devastating effects on the central nervous system (Mori et al., 2006; Melo et al., 2012; Miladi-Gorji et al., 2015). The prevalence of Meth abuse, as an escalating public health issue (Melo et al., 2012), has increased dramatically, reaching epidemic proportions worldwide (Camarasa et al., 2010) over the last 20 years (Moenk and Matuszewich, 2012). The universality of this drug can be due to its low price and simple production in comparison with cocaine or heroin (Macúchová et al., 2013). Long-term Meth abuse is linked to ventricular hypertrophy, cardiomyopathies, premature atherosclerosis, and kidney failure (Melo et al., 2012). Due to the effects of Meth on neuronal excitability, short-term Meth can cause euphoria and increased alertness and also improve motor activity and awareness (Chen et al., 2012). Meth abuse is associated with significant health problems, including psychosis, psychomotor dysfunction, anxiety, and depression. Clinical investigations have identified impaired functions of the striatal and cortical systems (Krasnova et al., 2010), and several cognitive deficiencies after Meth abuse, even years of drug abstinence (Reichel et al., 2014), leading to deficits in attention, learning, episodic memory, information processing, working memory, decision-making, and impulse control. Meth also causes memory deficits concomitant with reducing hippocampal volume and deleterious structural changes within the hippocampus (Krasnova et al., 2010; Moenk and Matuszewich, 2012; Braren et al., 2014). It diminishes cognition (Melo et al., 2012) and causes significant impairment in the performance of hippocampus-dependent spatial tasks, such as the Morris water maze (MWM) (Vorhees et al., 2000; Ghazvini et al., 2016). Investigations on human fetuses exposed to Meth also have demonstrated cognitive deficits and malformations in different structures of the brain involved in learning (Moenk and Matuszewich, 2012). Some studies have shown that high doses of Meth impaired spatial learning and memory, while lower doses did not (Chen et al., 2012).

Opioids can change the activity of dopaminergic neurons and consequently, alter the pharmacodynamic effect of Meth on the dopaminergic system. It has been reported that the opioid system may be affected by the conditioned cues following Meth administration (Lelong-Boulouard et al., 2006).

Buprenorphine (Bup) is a semi-synthetic partial agonist of the μ-opioid receptor, which has antagonistic effects on the κ- and δ- opioid receptors. It also has poor euphoric impacts and a weak negative effect on respiration (Pournaghash and Riley, 1993; Lelong-Boulouard et al., 2006). Bup causes a limited degree of physical dependency; therefore, it produces better clinical outcomes than morphine and other related agonists (Glover and Davis, 2008). It has been reported that Bup attenuates Meth-induced self-injurious behavior (Mori et al., 2006). Moreover, μ-opioid receptor-mediated pathways may influence the genetic risk for Meth consumption and Bup interferes with the acquisition of Meth intake in mice, potentially due to Bup’s partial agonist activity (Eastwood and Phillips, 2014). Adding Bup to the matrix method resulted in a significant reduction in Meth cravings (Salehi et al., 2015).

Little is known on the effects of Bup on memory function and the reports in this regard are often controversial. The effect of Bup on the improvement or impairment of learning and memory has been evaluated using various tests, experimental species, and doses (Lelong-Boulouard et al., 2006). This investigation was done to examine the efficiency of Bup in inhibiting the learning and memory deficits caused by the administration of Meth in rats.

The results of the current study indicated that Meth, Bup, and Meth + Bup increased the escape latency and traveled distance compared to the sham group, indicating deterioration in the spatial memory. Moreover, Bup decreased the escape latency on the third and fourth days compared to the first day of training. Thus, during training Bup administration alone had only a moderate effect on spatial impairment.

Also, STL and TDC were found to be decreased in the Bup and Meth + Bup groups, indicating an enhancement in the aversive memory. This observation suggests that Bup alone and in combination with Meth exert its positive effects on aversive memory. Therefore, the most interesting finding of the passive avoidance task was the effectiveness of Bup in the potentiation of aversive memory.

The role of Meth abuse in cognitive-related deterioration is not well known. Nevertheless, previous investigations have recommended that while the acute use of Meth may enhance memory and attention, chronic use results in reduced memory function (Seminerio et al., 2013). It has been reported that exposure to Meth during preadolescence improves spatial learning in male rats (Macúchová et al., 2013). Surprisingly, clinical studies have also declared that Meth can result in improved learning and memory function, including visuospatial perception and response speed following limited stimulant usage (Braren et al., 2014). Conversely, repeated Meth injection showed learning and mnemonic impairments (Jia et al., 2008). Some studies have shown that single-day regimens produce cognitive deficits (Braren et al., 2014). Furthermore, repeated Meth-provoked behavioral sensitization caused cognitive impairment. In addition, long-term memory deficiencies have been recognized in chronic Meth abusers (Kamei et al., 2006). Acute administration of a high dose of Meth (>2–10 mg/kg) caused impairments in spatial and non-spatial memory functions, caused by the degeneration of serotonergic and dopaminergic nerve terminals in the brain (Lee et al., 2011). Accordingly, animals previously exposed to a 1-day Meth regimen had dysfunctions in an appetitive maze sequential learning task and motor performance tasks and demonstrated mild spatial memory dysfunctions (Marshall et al., 2007). In contrast, low-dose Meth (2 mg/kg) injection caused hyperlocomotion but did not alter memory (Lee et al., 2011). The importance of morphine and other opioids in memory processes has been well described (Lelong-Boulouard et al., 2006).

Our data demonstrated that the co-administration of Meth + Bup increased the escape latency in comparison with the Meth group on the fourth day of training. It means that Bup partially potentiated Meth-induced memory impairment. In agreement with our results, it has been shown that opioid receptor agonists may diminish short- and/or long-term memory processes (Lelong-Boulouard et al., 2006). In this regard, the endogenous opioid system may play a crucial role in stress-induced memory impairment (Cao et al., 2015). In addition, Bup induced deficits in long-term memory in the passive avoidance test and short-term memory deficits in the Y-maze test (Lelong-Boulouard et al., 2006). Stimulation of κ-opioid receptors enhanced memory dysfunction arising from the blockade of muscarinic M1 receptors (Ukai et al., 1997). In contrast, acute administration of Bup improved short-term memory for social reward cues (Syal et al., 2015).

After repeated administration, Meth adheres to the dopamine transporter (DAT) on dopaminergic nerve terminals through a pseudo-transmitter function, which increases dopamine release but represses dopamine reuptake, leading to an increase in the level of dopamine in the synaptic cleft (Chen et al., 2012; Seminerio et al., 2013). As a result, Meth triggers dopamine release from the cytosol within the extracellular space using reverse transport by the DAT (Melo et al., 2012). Consistently, acute treatment with a low dose of Meth (2 mg/kg) enhanced striatal extracellular concentrations of dopamine. Furthermore, Meth reduced the intraneuronal oxidative metabolism of dopamine by the repression of monoamine oxidase (Pereira et al., 2011). Also, acute administration of Meth caused an increase in the dopamine level in the nucleus accumbens (Macúchová et al., 2013).

Meth is neurotoxic and directly damages neurons and memory function (Chen et al., 2012). Dopamine pathways are involved in cognition (Macúchová et al., 2013). Dopamine has been exhibited to change various cognitive functions, including attention, memory, response inhibition, and task switching (Seminerio et al., 2013). Long-term use of Meth damages dopaminergic systems and reduces various indices of dopamine terminal integrity, particularly in the striatum (Camarasa et al., 2010; Braren et al., 2014). Meth affects both the prefrontal cortex and striatum via the dopaminergic system. Dopamine deficiencies in the striatum decrease simple task performance and reaction time while dopamine deficits in the prefrontal cortex contribute to cognitive dysfunction (Seminerio et al., 2013). Changes caused by chronic exposure to Meth in rats include selective damage to dopaminergic terminals within the dorsal striatum and hippocampus, long-lasting decreases in dopamine content, loss of dopamine transporters, and a reduction in the activity of tyrosine hydroxylase and DAT (Camarasa et al., 2010; Braren et al., 2014). Vesicular monoamine transporter 2 has an essential role in Meth-induced toxicity (Melo et al., 2012). Meth reduces long-term potentiation (LTP) and produces synaptic maladaptation through changing excitatory synaptic transmission by the activation of the serotonin and dopamine receptor systems (Chen et al., 2012).

Furthermore, Meth use leads to nerve terminal degeneration by the production of nitrogen and reactive oxygen species. Nerve terminal and axonal degeneration can occur in the nigrostriatal dopaminergic projections, potentially resulting in cognitive impairment (Seminerio et al., 2013). Meth also induces cortical cell degeneration. Specifically, the Meth-induced degeneration of cortical neurons may only express the most apparent consequences of the powerful and enduring effects of Meth on the cerebral cortex (Marshall et al., 2007). This evidence is furthermore confirmed by the reports of the positive association between Meth intake and cell death in the prefrontal cortex and negative association between Meth intake and hippocampal volume in rodents (Krasnova et al., 2010).

Bup causes a progressive increase in extracellular dopamine and enhances basal levels of dopamine in the NAc (Sorge and Stewart, 2006). Also, Bup, like other partial μ-receptor agonists, stimulates the release of dopamine in the mesolimbic system (Nantwi et al., 1998). Moreover, opioid receptor agonists can change the activity of dopamine neurons and alter the pharmacodynamic impacts of Meth on the dopaminergic system (Sorge and Stewart, 2006).

Meth increases glutamate release in various brain regions, such as the cerebral cortex, hippocampus, and striatum (Lee et al., 2011). Conversely, prolonged administration of Bup can decrease glutamate function. Continuous exposure to Bup also results in reduced glutamatergic activity in the NAc and striatum (Sorge and Stewart, 2006). In contrast, Bup treatment increased basal levels of glutamate in the NAc of rats (Placenza et al., 2008). The glutamatergic system is perturbed by Meth exposure, leading to increased glutamate signaling. GluA2 (GluR2) incorporation into AMPA receptors in multiple brain regions is associated with Meth treatment and subsequent reduction in glutamate overflow and associated excitotoxicity (Olsen et al., 2013). In addition, Meth-induced impaired memory function due to alterations of N-Methyl-D-aspartate (NMDA) receptor binding sites in the hippocampus and prefrontal cortex may also underlie the memory and learning deficits correlated with the administration of it (Lee et al., 2011). NMDA receptors are needed for synaptic plasticity associated with learning and memory (Lee et al., 2011; Barzegar et al., 2015).

Other neurotransmitter systems, in addition to the dopaminergic and glutamatergic systems, may be involved in the effects of Meth and Bup on learning and memory. The increased, unchanged, or decreased serotonin (5HT) content after Meth administration has been reported (Melo et al., 2012). Meth may cause a decrease in the concentration of 5HT and its particular metabolites, a reduction in the number of 5HT transporter binding sites, a decline in the activity of tryptophan hydroxylase, and the loss of 5HT transporters in the striatum and hippocampus (Marshall et al., 2007). Conversely, opioids can increase the 5HT release and their analgesic effect depends partly on the consequent activation of postsynaptic 5HT1_A receptors (Tao et al., 2003). Gamma-aminobutyric acid (GABA) receptors play a role in Meth-associated rewarding memories (Jiao et al., 2016). Intra-NAc infusion of muscimol (a GABA receptor agonist) reduced Meth-induced enhancement of LTP in the dentate gyrus-, while the infusion of AP5 (an NMDA receptor antagonist) inhibited Meth-induced improvement of LTP (Heysieattalab et al., 2016). The existence of interactions between GABAergic and opiate systems in the brain has been declared. The extensive concentration of opioid receptors in the limbic system (thalamus, amygdala, and NAc), hippocampus, and cerebral cortex suggests that GABA neurons are involved in emotional responses and many other cognitive processes (Lelong-Boulouard et al., 2006). In addition, the opioid-induced release of dopamine is likely a secondary response, owing to the inhibition of GABA interneurons, which results in the disinhibition of dopaminergic neurons (Johnson and North, 1992).

In summary, this study demonstrated that Bup administration accentuates the learning and memory impairment induced by Meth administration in rats. While Bup impairs spatial learning and memory, it potentiates aversive memory. Since Bup exhibits lower side effects compared to other opioids, it may be desirable for the treatment of avoidance memory discrepancies in patients with Meth addiction.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Rats used in this investigation were treated under the Guide for the Care and Use of Laboratory Animals, and the investigation protocols were proved by the Institutional Animal Care and Use Committee at Hamadan University of Medical Sciences (IR.UMSHA.REC.1400.346).

MT, AK, and FE wrote the manuscript and revised it. AR-K, NF, and SK supervised the study and performed the experiment. MA and SR analyzed the data. All authors approved the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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